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					                                      Appendix A
                              FDA REGULATIONS

                   CFR, Title 21, Part 50: Protection of Human Subjects

                     CFR, Title 21, Part 56: Institutional Review Boards

           CFR, Title 2 1, Part 3 12: Investigational New Drug Applcation
            (Subpart D - Responsibilities of Sponsors and Investigators)

                   CFR, Title 45, Part 46: Protection of Human Subjects
                                    (Subparts B, C, D)




© 2002 by CRC Press LLC
                                                                                Appendix A: FDA Regulations                203




                   Food and Drug Administration, HHS
                   50.24 Exception froni infornied consent re-                (2) A food adclitive petition, described
                       q u i r e m e n t s for emergency research.         in parts 171 and 571.
                   50.25 E l e m e n t s of informed consent.                 (3) Data and information about a sub-
                   50.27 D o c n m e n t a t i o n of informed consent.
                                                                           stance subniittecl a s p a r t of the proce-
                     AUTHORITY: U.S.C. 321, 346. 346a, 348. 352,
                                   21                                      dures for establishing t h a t t h e sub-
                   353. 355, 360. 360c-360f, 360h-3605, 371, 379e. 381:    stance i s generally recognized a s safe
                   42 U.S.C. 216, 241, 262, 2631s-26311.
                                                                           for use t h a t results or may reasonably
                     SOURCE: F R 36390. Mag 30. 1980. unless
                              45                                           be expected to result. directly or incli-
                   otherwise noted.                                        rectly, in i t s becoming a component or
                                                                           otherwise affecting the characteristics
                      Subpart A-General              Provisions            of a n y food, clescribed i n §§170.30 and
                                                                           570.30.
                   4 50.1 Scope.                                              (4)Data and information about a foocl
                     ( a ) This p a r t applies t o all cliiiical iii-     additive subinittecl a s part of t h e proce-
                   vestigations 'egulated by the Food and                  dures for foocl additives permitted t o be
                                                            r
                   Drug Adniinistratioii ~ ~ i i c l e sections            used on a n interim basis peiicliiig adcli-
                   505(ij and 520(gj of the Federal Food,                  tional study, described i n § 180.1.
                   Drug, and Cosmetic Act, a s well a s                       (5) Data and information about a sub-
                   clinical investigations t h a t support ap-             stance subinittecl a s p a r t of the proce-
                   plications for research or marketing                    dures for establishing a tolerance for
                   permits for products regulated by the                   unavoidable contaminants i n foocl and
                   Foocl and Drug Aclministration, includ-                 foocl-packaging niaterials. described i n
                   ing food and color additives. drugs for                 section 406 of the a c t .
                   human use. medical devices for human                       (6) An investigatioiial new drug appli-
                   use. biological products for hunian use.                cation, clescribecl i n part 312 of this
                   and electroiiic products. Additional                    chapter.
                   specific obligatioiis and coniinitnieiits                  (7) A new drug application, clescribed
                                             ls
                   of. and s t a n ~ l a ~ c of conduct for. per-          in part 314.
                   sons who sponsor or monitor clinical                       (8) Data and information about the
                   investigations involving particular t e s t             bioavailability or bioequivaleiice of
                   articles m a y also be found i n other                  drugs for human use subinittecl a s p a r t
                   parts (e.g., parts 312 and 812). Coinpli-               of the procedures for issuing. anieiid-
                   aiice with these parts is iiiteiidecl t o               ing, or repealing a bioequivalence re-
                   protect the rights and safety of sub-                   quirement. clescribed i n p a r t 320.
                   jects iiivolvecl in iiivestigations filed                  (9) Data and information about a n
                   with t h e Foocl and Drug Adininistra-                  over-the-counter drug for human use
                   tioii pursuant t o sections 406. 409. 502.              submitted a s part of t h e proceclures for
                   503, 505, 510, 513-516, 518-520, 721, and 801           classifyiiig these drugs a s generally
                   of t h e Federal Food. Drug. aiicl Cos-                 recognizecl a s safe and effective and n o t
                   metic Act and sections 351 and 354-360F                 misbranded. described i n part 330.
                   of the Public Health Service Act.                          (10) Data and information about a
                     (b) References i n this part to regu-                 prescription drug for human use sub-
                   latory sectioiis of the Code of Federal                 m i t t e d a s part of t h e proceclures for
                   Regulations are to chapter I of t i t l e 21,           classifyiiig these drugs a s generally
                   unless otherwise noted.                                 recognizecl a s safe and effective and n o t
                   r45 F R 36390. Mav 30. 1980: 46 F R 8979. J a n . 27.   misbranded. described i n this chapter.
                   i981. a s alnenclei a t 63 FR 26697. May 13. 1998.         (11) [Reserved]
                   64 FR 399. J a n . 5. 19991                                (12) An application for a biologics li-
                                                                           cense, clescribecl i n p a r t 601 of this
                   4 50.3 Definitions.                                     chapter.
                     As used in this part:                                    (13) Data and information about a bi-
                     ( a ) Act ineaiis the Federal Food.                   ological product submitted a s part of
                   Drug, and Cosinetlc Act, a s amended                    t h e proceclures for determining t h a t li-
                   (sees. 201-902. 52 S t a t . 1040 et seg. a s           ceiisecl biological products are safe and
                   amended (21 U.S.C. 321-3921).                           effective and n o t misbranded, clescribed
                     (b) Applzcutzo?~ for researclz or mar-                in part 601.
                   ketzny pei nut includes:                                   (14) Data and information about a n in
                     (1) A color additive petition. de-                    vitro diagnostic product subniittecl a s
                   scribed In part 71.                                     part of the proceclures for establishing,




© 2002 by CRC Press LLC
        204      Clinical Research Coordinator Handbook




                                                                                    21 CFR Ch. 1 (4-1-01 Edition)
                   amending, or repealing a standarcl for               direction t h e t e s t article i s aclminis-
                   these products. described i n part 809.              tered or dispensed to. or used iiivolv-
                      (15) An Application for a n Investiga-            ing, a subject, or, i n t h e event of a n in-
                   tional Device Erenzption, described i n              vestigation conducted by a t e a m of iii-
                   part 812.                                            clividuals, is t h e responsible leader of
                      (16) Data and information about a                 t h a t teani.
                   medical clevice submitted a s part of the                (el Sponsor ineans a person who initi-
                   procedures for classifying these de-                 a t e s a clinical investigation. but who
                   vices, clescribecl i n section 513.                  cloes not actually conduct t h e inves-
                      (17) Data and information about a                 tigation. i.e.. the t e s t article is acliniii-
                   medical clevice submitted a s part of the            istered or dispensed to or used involv-
                   procedures for establishiiig. anieiiding.                                        the
                                                                        ing. a subject ~ u ? d e ~ inimecliate cli-
                   or repealing a standard for these de-                rection of another individual. A person
                   vices. clescribecl i n section 514.                  other t h a n a n iiidiviclual (e.g.. corpora-
                      (18) An application for preinarket ap-            tion or agency) t h a t uses one or more
                   proval of a niedical clevice. clescribecl i n        of i t s own einployees t o conduct a cliii-
                   section 515.                                         ical investigation i t has initiated i s
                      (19) A product development protocol               coiisiderecl to be a sponsor (iiot a spoii-
                   for a medical device, clescribed i n sec-            sor-investigator), and the einployees
                   tion 515.                                            are considered to be investigators.
                      (20) Data and information about a n                   ( f ) Spoi~sor-i?zvestigc~tor
                                                                                                        ineans a n incli-
                   electronic product subniittecl a s part of           vidual who both initiates aiicl actually
                   t h e proceclures for establishing, amend-           conducts, alone or with others, a clin-
                   ing. or                 a standard for these         ical investigation. i.e.. under whose ini-
                   products, clescribecl in section 358 of the          mediate direction the t e s t article i s acl-
                   Public Health Service Act.                           niinisterecl or dispensed to. or used iii-
                      (21) Data and information about a n               volving, a subject. The t e r m cloes n o t
                   electronic product subniittecl a s part of           include aiiy person other t h a n a n indi-
                   t h e procedures for obtaining a variance            vidual, e.g., corporation or agency.
                   froin aiiy electronic product perforn-                   (g) Hiinzc~n subject means a n incli-
                   ance standard, a s clescribed i n § 1010.4.          vidual who is or becomes a participant
                      (22) Data and iiiforination about a n             in research. either a s a recipient of the
                   electronic product submitted a s part of             t e s t article or a s a control. A subject
                   t h e procedures for granting. anieiidiiig.          niay be either a healthy human or a pa-
                   or extending a n exemption from a radi-              tient.
                   ation safety perforinaiice staiidarcl. a s               (h) Institution meaiis aiiy public or
                   clescribecl i n § 1010.5.                            private e n t i t y or agency (including
                      (c) Cliniccll investigation nieans aiiy           Federal. S t a t e . and other agencies).
                   experiment t h a t involves a t e s t article        The word facility a s used i n section
                   and one or more human subjects and                   520(g) of the a c t i s cleenied t o be syii-
                   t h a t either i s subject to requirements           onyinous with t h e t e r m institzition for
                   for prior submission t o the Foocl and               purposes of t h i s part.
                   Drug Administration uncler section                       ( i ) Institutional reviezu board (IRB)
                   505(i) or 520(g) of t h e a c t . or i s iiot sub-   nieans aiiy board. coininittee. or other
                   ject t o requirements for prior submis-              group forlnally designated by a n insti-
                   sion t o the Foocl and Drug Adniinistra-             t u t i o n t o review bioniedical research
                   tion uncler these sections of the a c t ,            involving humans a s subjects, t o ap-
                   but the results of which are inteiiclecl t o         prove the initiation of and coiicluct
                   be submitted l a t e r t o , or held for in-         periodic review of such research. The
                   spection by. the Foocl and Drug Aclmiii-             tern? has t h e same nieaniiig a s the
                   istration a s part of a n application for a          phrase institzitional reviezu conmittee a s
                   research or niarketing permit. The                   used i n section 520(g) of t h e act.
                   t e r m cloes n o t include experiments t h a t          ( j ) Test article means a n y drug (in-
                   are subject to t h e provisioiis of part 58          cluding a biological product for hunian
                   of this chapter, regarding nonclinical               use), medical clevice for human use,
                   laboratory studies.                                  human food additive. color additive.
                      (d) Investigator means a n individual             electronic product, or a n y other article
                   who actually conducts a clinical iiives-             subject to regulation under t h e a c t or
                   tigation, i.e., uncler whose immediate               under sections 351 and 354-360B of the




© 2002 by CRC Press LLC
                                                                                     Appendix A: FDA Regulations                          205




                   Food and Drug Administration, HHS
                   Public Health Service Act (42 U.S.C. 262                    ten, may include any exculpatory lan-
                   and 263b-26311).                                            guage through which the subject or the
                      ( k ) lWininzal risk means t h a t the prob-             representative is made t o waive or ap-
                   ability and magnitude of harm or dis-                       pear t o waive any of the subject's legal
                   comfort anticipatecl i n t h e research are                 rights, or releases or appears t o release
                   not greater i n and of themselves t h a n                   t h e investigator. the sponsor. t h e insti-
                   those ordinarily encountered i n daily                      tution, or i t s agents from liability for
                   life or during the perforniance of rou-                     negligence.
                   tine physical or psychological exanii-
                   nations or tests.                                           [46 F R 8951. J a n . 27. 1981. a s a m e n d e d n t 64
                                                                               F R 10942. M a r . 8. 19991
                      (1) Legally azithol-ized l-epreseiztative
                   nieans a n iiiclividual or judicial or                      $50.23 Exception from general re-
                   other body authorized under applicable                              quirements.
                   law t o coiiseiit on behalf of a prospec-
                   tive       subject      to  the        subject's               ( a ) The obtaining of inforinecl coiisent
                   particpation i n the procedure(s) iii-                      shall be cleeined feasible unless, before
                   volved in the research.                                     use of t h e test article (except a s pro-
                      (in) Family member nieaiis any one of                    vided in paragraph (b) of this section),
                   t h e followiiig legally competent per-                     both the investigator and a physician
                   sons: Spouse: parents: children (includ-                    who is not otherwise participating i n
                   ing adopted children): brothers. sisters.                   t h e clinical investigation certify i n
                   and spouses of brothers and sisters: and                    writing all of t h e following:
                   any individual related by blood or af-                         ( I ) The human subject is confronted
                   finity whose close association with the                     by a life-threatening situation necessi-
                   subject is the equivalent of a family re-                   t a t i n g the use of t h e test article.
                   lationship.                                                    (2) Informed consent cannot be ob-
                   [45 F R 36390. M n y 30. 1980. a s nmencled a t 46
                                                                               tained from the subject because of a n
                   F R 8950. J a n . 27. 1981: 54 F R 9038. M a r . 3. 1989:   inability to connnunicate with, or ob-
                   56 F R 28028, J u n e 18, 1991: 61 F R 51528. O c t . 2,    t a i n legally effective coiiseiit from. the
                   1996: 62 F R 39440. J u l y 23. 1997: 64 F R 399. J n n .   subject.
                   5. 1999: 64 F R 56448, O c t . 20. 19991                       (3) Time is not sufficient t o obtain
                                                                               coiisent froin t h e subject's legal rep-
                    Subpart B-Informed Consent of                              resentative.
                           Human Subjects                                         (4) There is available no alternative
                                                                               niethocl of approved or generally recog-
                     SOURCE: F R 8951. J n n . 27. 1981. u n l e s s
                              46                                               nized therapy t h a t provides a n equal or
                   otherwise noted.                                            greater likelihood of saving the life of
                                                                               t h e subject.
                   4 50.20 General requirements for in-                           (b) If immediate use of the test a r t i -
                         formed consent.                                       cle is. i n t h e investigator's opinion. re-
                      Except a s provided i n ss50.23 and                      quired to preserve the life of t h e sub-
                   50.24. no iiivestigator may involve a                       ject. and tinie is not sufficient to ob-
                   human being a s a subject i n research                      t a i n t h e independent determination re-
                   covered by these r e g ~ ~ l a t i o i~ s i i l ethe
                                                         i~         ss         quired i n paragraph ( a ) of t h i s section
                   investigator has obtained the legally                       in advance of using t h e test article, t h e
                   effective informed coiiseiit of the sub-                    cleterininatioiis of the clinical investi-
                   ject or t h e subject's legally authorized                  gator shall be made and, within 5 work-
                   representative. An investigator shall                       ing clays after the use of the article. be
                   seek such consent only under cir-                           reviewed and evaluated i n writing by a
                   cunistaiices t h a t provide the prospec-                   physician who is not participating i n
                   tive subject or the representative suffi-                   t h e clinical investigation.
                   cient opportunity t o coiisider whether                        ( c j The documentation required i n
                   or not t o participate and t h a t minimize                 paragraph ( a ) or (b) of this section
                   t h e possibility of coercion or ~ m d u e        iii-      shall be submitted t o the IRB within 5
                   fluence. The information t h a t is given                   working days after the use of the test
                   t o the subject or t h e representative                     article.
                   shall be i n language understandable t o                       ( d ) ( l ) Under 10 U.S.C. 1107(fj the
                   t h e subject or t h e representative. No                   President niay waive t h e prior coiiseiit
                   inforinecl consent, whether oral or writ-                   requirement for the aclministration of




© 2002 by CRC Press LLC
        206      Clinical Research Coordinator Handbook




                                                                                    21 CFR Ch. 1 (4-1-01 Edition)
                   a n investigational new drug to a mein-                 (iii) There is no available satisfac-
                   ber of the arniecl forces i n coiiiiection          t o r y alternative therapeutic or preven-
                   with the member's participation i n a               tive t r e a t m e n t in relation to t h e in-
                   particular military operation. The                  tended use of the investigational new
                   s t a t u t e specifies t h a t only t h e Presi-   clrug.
                   dent m a y waive informed consent i n                   (iv) Conclitioiiiiig use of t h e inves-
                   this connection and t h e President m a y           tigational new drug on t h e voluntary
                   grant such a waiver only if t h e Presi-            participation of each nieinber could
                   dent determines i n writing t h a t obtain-         sigiiificaiitly risk t h e safety aiicl health
                   ing consent: Is not feasible: i s contrary          of a n y individual nieinber who would
                   t o the best interests of the inilitary             decline i t s use, the safety of other inili-
                   member: or i s n o t in t h e interests of          t a r y personnel, and the accomplish-
                   national security. The s t a t u t e further        ment of t h e military mission.
                   provides t h a t i n niaking a cleterniina-             (v) A duly constituted institutional
                   tion t o waive prior informed consent               review board (IRB) established and op-
                   on the ground t h a t i t is not feasible or        erated i n accordance with the require-
                   t h e ground t h a t i t i s contrary t o the       nieiits of paragraphs (dj(2)and (dj(3) of
                   best interests of the military members              this section. responsible for review of
                   involvecl, the Presiclent shall apply t h e         t h e study. has reviewed and approved
                   stanclards and criteria t h a t a r e s e t         t h e iiivestigational new drug protocol
                   forth in the                   FDA regulations                                             n
                                                                       and the a ~ l i n i i i i s t ~ a t i oof the iiives-
                   for a waiver of the prior iiifornied coii-          tigational new clrug without informed
                   sent requirements of section 505(i)(4)of            coiisent. DOD's request i s to iiiclucle
                   t h e Federal Food, Drug, and Cosmetic              the        documentation              requirecl   by
                   Act (21 U.S.C. 355(i)(4)).Before such a             §56.115(a)(2)of this chapter.
                   determination may be made t h a t ob-                   (vi) DOD has explained:
                   taining inforined consent from mili-                    ( A ) The context i n which the inves-
                   t a r y personnel prior t o t h e use of a n in-    tigational drug will be adniiiiistered.
                   vestigational drug (including a n a n t i -         e.g., t h e setting or whether i t will be
                   biotic or biological product) in a spe-             self-adniinisterecl or i t will be adniiiiis-
                                                l e investigational
                   cific protocol ~ ~ i i c a n ~                      terecl by a health professional:
                   new drug application (IND) spoiisored                   (Bj The n a t u r e of t h e disease or con-
                   by the Departnieiit of Defense (DOD)                dition for which the preventive or
                   and limited t o specific military per-              therapeutic t r e a t m e n t i s intended: and
                   sonnel involved i n a particular mili-                  (C) To the extent there a r e existing
                   t a r y operation is not feasible or is con-        d a t a or information available, informa-
                   t r a r y t o t h e best interests of the mili-     tion on conditioiis t h a t could a l t e r the
                   t a r y members involvecl t h e Secretary           effects of the investigational clrug.
                   of Defense must first request such a cle-               (vii j DOD's recorclkeeping system i s
                   termination from the President, and                 capable of tracking and will be used t o
                   certify and document t o t h e President            t r a c k the proposecl t r e a t m e n t from
                   t h a t the following staiiclards and cri-          supplier t o t h e individual recipient.
                   t e r i a contained i n paragraphs (dj(1)               (viii) Each meniber iiivolvecl i n t h e
                   through (c1)(4)of this section have been            military operation will be given, prior
                   met.                                                t o the aclmiiiistration of the investiga-
                       ( i j The extent and strength of evi-           tional new drug, a specific written in-
                   dence of t h e safety and effectiveness of          formation sheet (including iiiforination
                   t h e investigational new drug in rela-             requirecl by 10 U.S.C. 1107(d)) con-
                   tion t o t h e medical risk t h a t could be        cerning the investigatioiial new drug.
                   encountered during the military oper-               t h e risks and benefits of i t s use, poten-
                   ation supports the drug's adininistra-              t i a l side effects. and other pertinent in-
                   tion under a n IND.                                 formation about t h e appropriate use of
                       (ii) The military operation presents a          t h e product.
                   substantial risk t h a t inilitary per-                 (ix) Medical records of inembers in-
                   sonnel niay be subject to a chemical.               volved i n t h e military operation will
                   biological. nuclear. or other exposure              accurately document t h e receipt by
                   likely t o produce death or serious or              nieinbers of the notification required
                   life-threatening injury or illness.                 by paragraph (d)(l)(viiijof t h i s section.




© 2002 by CRC Press LLC
                                                                             Appendix A: FDA Regulations                        207




                   Food and Drug Administration, HHS
                      (x) Medical records of members in-               necessary security clearances. This
                   volved i n t h e military operation will            IRB shall 'eview t h e proposed IND pro-
                   accurately document t h e receipt by                tocol a t a convened meeting a t which a
                   nieinbers of a n y investigational iiew             niajority of t h e members are present
                   drugs i n accordance with FDA regula-               including a t least one inember whose
                   tions iiiclucliiig part 312 of this chapter.        primary concerns are in nonscientific
                      (xi) DOD will provicle adequate fol-             areas and, if feasible, including a ma-
                   lowup to assess whether there are bene-             jority of the iionaffiliatecl menibers.
                   ficial or adverse health consequences               The         information       required       by
                   that             froni the use of t h e iiives-     §56.115(a)(2)of this chapter i s t o be pro-
                   tigational product.                                 vided t o t h e Secretary of Defense for
                      (xii) DOD i s pursuing drug develop-                         he~
                                                                       f ~ ~ r t review.
                   m e n t , including a time line, and mar-               (3) The duly constituted institutional
                   keting approval with due cliligeiice.               review boarcl. described i n paragraph
                      (xiii) FDA has concluded t h a t the in-         (clj(l)(vj of this section, must review
                   vestigational new drug protocol niay                and approve:
                   proceed subject t o a decision by the                   (i) The            iiiforniation sheet:
                   President on t h e informed coiiseiit                   (ii) The adequacy of the plan t o dis-
                   waiver request.                                     seminate information, including dis-
                      (xiv) DOD will provide training t o t h e        tribution of t h e iiiforination sheet t o
                   appropriate medical personnel and po-               potential recipients, on t h e investiga-
                   tential recipients on the specific inves-           tioiial product (e.g.. i n fornis other
                   tigational new drug t o be administered             t h a n written):
                   prior to i t s use.                                     (iii) The adequacy of the information
                      ( X V ) DOD has s t a t e d and justified the    and plans for i t s disseiniiiation t o
                   tinie period for which the waiver i s               health care proviclers, inclucling poten-
                   needed, n o t t o exceed one year, unless           t i a l side effects. coiitrainclicatioiis. po-
                   separately renewed ~ ~ i i c these staiid-
                                                      le~              tential interactions, and other perti-
                   arcls and criteria.                                 nent considerations: aiicl
                      (xvi) DOD shall have a coiitiiiuing ob-              (iv) An iiifornied coiisent forni a s re-
                   ligation to report t o the FDA and t o              quired by part 50 of this chapter, i n
                   the        President a n y chaiigecl         cir-   those circunistaiices i n which DOD de-
                   cumstances relating t o these standards             termines t h a t informed consent inay be
                   and criteria (iiicludiiig the tinie period          obtained from sonie or all personnel iii-
                   referred t o i n paragraph (clj(lj(xvj of           volved.
                   this section) or t h a t otherwise might                (4) DOD i s t o submit to FDA sum-
                   affect t h e determination t o use a n in-          maries of institutional review board
                   vestigational iiew drug without iii-                meetings a t which t h e proposed pro-
                   formecl consent.                                    tocol has been reviewed.
                      (xvii) DOD i s t o provide public notice             (5) Nothing in these criteria or stand-
                   a s soon a s practicable and consistent             ards i s intended t o preempt or l i m i t
                   with         classification       requirenieiits    FDA's and DOD's a u t h o r i t y or obliga-
                   through notice in the FEDERAL               REG-    tions under applicable s t a t u t e s and
                   ISTER describing each waiver of iii-                regulations.
                   formecl consent determination, a sum-               [46 FR 8951. J a n . 27. 1981. a s a m e n d e d nt 55
                   mary of the niost updated scientific iii-           F R 52817, Dec. 21. 1990: 64 F R 399. J a n . 5, 1999:
                   formation on t h e products used, and               64 F R 54188. Oct. 5. 19991
                   other pertinent information.
                      (xviii) Use of the investigational drug          4 50.24 Exception from informed con-
                   without informed coiiseiit otherwise                     sent requirements for emergency
                   conforms with applicable law.                            research.
                      (2) The duly constituted institutional             ( a ) The IRB 'esponsible for t h e re-
                   review boarcl, described i n paragraph              view, approval, and continuing review
                                of
                   (cl)(l)(v) this section. must include a t           of the clinical investigation described
                   least 3 nonaffiliatecl members who                  in this section inay approve t h a t inves-
                   shall n o t be employees or officers of             tigation without 'equiriiig t h a t iii-
                   t h e Federal Government (other t h a n             formecl consent of a l l research subjects
                   for purposes of nieinbership on the IRB)            be obtained if t h e IRB (with t h e coii-
                   and shall be required t o obtain a n y              currence of a licensed physician who i s




© 2002 by CRC Press LLC
        208      Clinical Research Coordinator Handbook




                                                                                    21 CFR Ch. 1 (4-1-01 Edition)
                   a member of or consultant t o the IRB                tacted for consent within t h a t window
                   and who is not otherwise participating               'ather t h a n proceeding without con-
                   in the clinical investigation) finds and             sent. The investigator will sunnnarize
                   clocunieiits each of t h e followiiig:               efforts niacle to contact legally author-
                      ( I ) The human subjects are i n a life-          ized representatives and make this in-
                   threateiiiiig situatioii. available t r e a t -      formation available to t h e IRB a t the
                   ments are unproven or unsatisfactory,                time of continuing review.
                   and the collection of valid scientific                  (6) The IRB has reviewed and ap-
                   evidence, which may include evidence                 proved informed consent procedures
                   obtained through randomized placebo-                 and a n iiifornied consent clocunieiit
                   controlled investigations, i s necessary             consistent with $50.25. These proce-
                                             e
                   t o ~ l e t e ~ i n i i ithe safety and effective-   dures and t h e iiiforinecl coiisent clocu-
                   ness of particular interventions.                    inent are t o be used with subjects or
                      (2) Obtaining iiiforined coiisent i s n o t       their legally authorized represeiita-
                   feasible because:                                    tives i n situations where use of such
                      (i) The subjects will n o t be able t o           procedures and clocunients i s feasible.
                   give their informed consent a s a result             The IRB has reviewed and approved
                   of their medical conditioii:                         procedures and iiiforniation t o be used
                      (ii) The intervention under investiga-            when providing a n opportunity for a
                   tion must be administered before con-                family nieinber t o object t o a subject's
                   sent from the subjects' legally author-              participation i n t h e clinical investiga-
                   ized representatives i s feasible: and               tion coiisisteiit with paragraph ( a ) ( 7 ) ( v )
                      (iii) There is no reasonable way t o              of this section.
                   identify prospectively the iiidivicluals                (7) Aclditioiial protectioiis of the
                   likely t o become eligible for participa-            rights and welfare of the subjects will
                   tion i n t h e clinical investigatioii.              be provided. iiiclucling. a t least:
                      (3) Participation i n the research                   ( i ) Consultation (including, where ap-
                   holds out t h e prospect of direct benefit           propriate. consultation carried o u t by
                   t o t h e subjects because:                          t h e IRB) with representatives of the
                      (i) Subjects are facing a life-threat-            coinniunities in which t h e clinical iii-
                   ening situation t h a t necessitates inter-          vestigation will be conducted and from
                   vention:                                             which t h e subjects will be clrawii:
                      (ii) Appropriate animal and other                    (ii) Public disclosure t o t h e coinmu-
                   preclinical studies have been coii-                  nities i n which the clinical iiivestiga-
                   cluctecl, and the information derived                tion will be conducted and from which
                   froin those studies and related evicleiice           t h e subjects will be drawn. prior t o iiii-
                   support t h e potential for t h e interven-          tiation of t h e clinical investigation, of
                   tion t o provide a direct benefit to t h e           plans for the investigation and i t s risks
                   individual subjects: and                             and expected benefits:
                      (iii) Risks associated with t h e iiives-            (iii) Public clisclosure of sufficient iii-
                   tigation are reasonable i n relation t o             formation following completion of the
                   what is known about the medical coii-                clinical investigation t o apprise the
                   clition of t h e potential class of subjects,        colninunity and researchers of the
                   t h e risks and beiiefits of staiidarcl ther-        study. including the demographic char-
                   apy, if a n y , and what is known about              acteristics of the research population,
                   t h e risks and beiiefits of t h e proposed          and i t s
                   intervention or activity.                               (iv) Establishment of a n independent
                      (4) The clinical investigation could              d a t a moiiitoring conimittee to exercise
                   n o t practicably be carried out without             oversight of the clinical investigation:
                   t h e waiver.                                        and
                      (5) The proposecl investigational plan               (v) If obtaining informed consent i s
                   clefiiies the length of the potential                n o t feasible aiicl a legally authorized
                   therapeutic winclow based on scientific              representative is n o t reasonably avail-
                   evidence. and t h e investigator has coin-           able. t h e investigator has conimitted.
                   inittecl to a t t e m p t i n g to contact a le-     if feasible, to atteinpting t o contact
                   gally authorized representative for                  within the therapeutic winclow t h e sub-
                   each subject within t h a t window of                ject's family member who i s not a le-
                   tinie and. if feasible. t o asking t h e le-         gally authorized representative. and
                   gally authorized representative con-                 asking whether he or she objects t o t h e




© 2002 by CRC Press LLC
                                                                          Appendix A: FDA Regulations                     209




                   Food and Drug Administration, HHS
                   subject's participation in t h e clinical         tocols t h a t m a y include subjects who
                   investigatioii. The iiivestigator will            are unable to conseiit. The subniission
                   sunnnarize efforts made t o contact               of those protocols in a separate IND
                   fainily menibers and make this infor-             IDE i s                 even if a n IND for the
                   mation available t o the IRB a t the              same drug product or a n IDE for the
                   time of coiitiiiuing review.                      same clevice already exists. Applica-
                      (b) The IRB i s responsible for ensur-         tions for investigatioiis under this sec-
                   ing t h a t procedures are i n place t o iii-     tion m a y n o t be submitted a s ainend-
                   form, a t the earliest feasible oppor-            inents under 55312.30 or 812.35 of this
                   t u n i t y . each subject. or if the subject     chapter.
                   remains incapacitatecl, a legally au-                (e) If a n IRB deterniiiies t h a t i t can-
                   thorized                      of t h e subject.   n o t approve a clinical iiivestigation be-
                   or if such a representative is not rea-           cause the investigation does not meet
                   sonably available. a fainily meniber. of          t h e criteria i n the exception provided
                   t h e subject's inclusion i n the clinical        under paragraph ( a ) of this section or
                   investigatioii. t h e details of the iiives-      because of other relevant ethical con-
                   tigation and other information con-               cerns, t h e IRB must document i t s find-
                   tained in the iiifornied coiisent clocu-          ings and provide these findings proinpt-
                   inent. The IRB shall also ensure t h a t          ly i n writing to the clinical investi-
                   there is a procedure t o inforin t h e sub-       gator and to the sponsor of the clinical
                   ject, or if the subject remains incapaci-         investigatioii. The sponsor of the cliii-
                   tated. a legally authorized represeiita-          ical iiivestigation niust promptly dis-
                   tive of t h e subject, or if such a rep-          close this information t o FDA and t o
                   resentative i s n o t reasoiiably available.      t h e spoiisor's clinical investigators who
                   a family member, t h a t he or she m a y          are participating or a r e asked t o par-
                   discoiitiiiue the subject's participation         ticipate i n this or a substantially
                   a t a n y time without penalty or loss of         equivalent clinical investigation of the
                   benefits t o which the subject is other-          sponsor, and to other IRB's t h a t have
                   wise entitled. If a legally authorized            been, or are, asked to review t h i s or a
                   representative or faniily member i s              substantially equivalent investigation
                   told about t h e clinical investigation           by t h a t ~ p o i i s o ~ .
                   and the subject's condition iniproves.            [61 FR 51528. Oct. 2. 19961
                   t h e subject i s also t o be informed a s
                   soon a s feasible. If a subject i s entered       4 50.25 Elements of informed consent.
                   into a clinical investigation with                   ( a ) B m i c elements o f informed cement.
                   waived conseiit and t h e subject dies be-        In seeking informed coiiseiit. the fol-
                   fore a legally authorized representative          lowing information shall be proviclecl t o
                   or fainily nieinber can be coiitactecl. iii-      each subject:
                   formation about the clinical investiga-               (1) A s t a t e m e n t t h a t the study iii-
                   tion is t o be provided to the subject's          volves research, a n explanation of the
                   legally authorized representative or              purposes of the research and the ex-
                   fainily nieinber. if feasible.                    pected duration of t h e subject's partici-
                      ( c ) The IRB determinations required          pation. a description of the procedures
                   by paragraph ( a ) of this section and the        t o be followed, and identification of
                   documentation required by paragraph               aiiy procedures which are experi-
                   ( e ) of this section are t o be retained by      mental.
                   t h e IRB for a t least 3 years after coin-           (2) A description of aiiy reasoiiably
                   pletion of t h e clinical iiivestigation.         foreseeable risks or discomforts t o the
                   and the records shall be accessible for           subject.
                   inspection aiicl copying by FDA in ac-                (3) A clescription of a n y benefits t o
                   cordance with §56.115(b) of this chap-            t h e subject or t o others which m a y rea-
                   ter.                                              sonably be expected froin the research.
                      (d) Protocols involving a n exception              (4) A disclosure of appropriate alter-
                   t o the infornied consent requirement             native procedures or courses of t r e a t -
                   under this section must be performed              m e n t , if a n y , t h a t might be aclvan-
                   under a separate investigational new              tageous t o t h e subject.
                   drug application (IND) or investiga-                  (5) A s t a t e m e n t describing t h e ex-
                   tional clevice exemption (IDE) t h a t            t e n t . if aiiy. t o which coiificleiitiality of
                   clearly identifies such protocols a s pro-        records identifying the subject will be




© 2002 by CRC Press LLC
        210      Clinical Research Coordinator Handbook




                                                                                        21 CFR Ch. 1 (4-1-01 Edition)

                   maintained and t h a t notes the possi-                  eral, State, or local laws which require
                   bility t h a t the Food and Drug Adniinis-               additional information to be disclosed
                   tration may inspect the records.                         for infornied consent to be legally ef-
                      (6) For research involving more than                  fective.
                   minimal risk, a n explanation as to                        (d) Nothing in these regulations is iii-
                   whether any conipensation and a n ex-                    tended to liniit the authority of a phy-
                   planation as to whether any medical                      sician t o provide emergency medical
                   treatments are available if injury oc-                   care to the extent the physician is per-
                   curs and, if so, what they consist of, or                mitted to clo so under applicable Fecl-
                   where further information may be ob-                     eml. State. or local law.
                   tained.
                      (7) An explanation of whom to con-                    4 50.27 Documentation           of    informed
                   t a c t for answers to pertinent questions                   consent.
                   about the research and research sub-
                   jects' rights. and whoin to contact in                      ( a ) Except as provided in §56.109(c).
                   t h e event of a research-related injury                 inforinecl consent shall be documented
                   to the subject.                                          by the use of a written consent form
                       (8) A statenient t h a t participation is            approvecl by the IRB and signecl and
                   voluntary, t h a t refusal to participate                dated by the subject or the subject's le-
                   will involve no penalty or loss of bene-                 gally authorized representative a t the
                   fits to which the subject is otherwise                   tinie of consent. A copy shall be given
                   entitled. and t h a t the subject niay clis-             to the person signing the form.
                   continue participation a t any time                         (b) Except as provided in §56.109(c).
                   without penalty or loss of benefits to                   the consent form may be either of the
                   which t h e subject i s otherwise entitled.              following:
                       (b) Additioncll elements of i n f o ~ n z e dcolz-      ( I ) A written consent document t h a t
                   s e n t . When appropriate, one or more of               embodies the elements of informed
                   the following elenients of information                   consent required by $50.25. This form
                   shall also be provicled to each subject:                 niay be read to the subject or the sub-
                       (1) A statement t h a t the particular               ject's legally authorized representa-
                   treatment or procedure may involve                       tive. but. in any event. the investigator
                   risks to the subject (or to the embryo                   shall give either the subject or the rep-
                   or fetus, if the subject is or may be-
                   come pregnant) which are currently                       resentative adequate opportunity t o
                   unforeseeable.                                           read i t before i t is signecl.
                       (2) Anticipated circumstances under                     (2) A short form written consent clocu-
                   which the subject's participation may                    inent stating t h a t the elements of in-
                   be terminated by the investigator                        formed consent required by $50.25 have
                   without regard to the subject's con-                     been presented orally to the subject or
                   sent.                                                    the subject's legally authorized rep-
                       (3) Any aclditional costs to the sub-                resentative. When this method is used,
                   ject t h a t niay        froin participation             there shall be a witness to the oral
                   in the research.                                         presentation. Also, the IRB shall ap-
                       (4) The consequences of a subject's                  prove a w i t t e n sunimary of what is to
                   decision to withdraw from the research                   be said to the subject or the represent-
                   and procedures for orderly termination                   ative. Oiily the short forin itself is to
                   of participation by the subject.                         be signecl by the subject or the rep-
                       (5) A statement t h a t significant new              resentative. However, the witness shall
                   findings developed during the course of                  sign both the short form and a copy of
                   the research which may relate to the                     the sunnnary. and the person actually
                   subject's willingness to continue par-                    obtaining t h e consent shall sign a copy
                   ticipation will be provided to the sub-                   of the summary. A copy of the suni-
                   ject.                                                    inary shall be given to the subject or
                       (6) The approximate number of sub-                   the representative in acldition to a
                   jects involved in the study.                             copy of the short form.
                       (c) The inforinecl consent
                   inents in these regulations are not in-                  146 FR 8951. J a n . 27. 1981, a s arnellded a t 61
                   tended to preempt any applicable Fed-                    FR 57280. Noa. 5. 19961




© 2002 by CRC Press LLC
                                                                               Appendix A: FDA Regulations                       2 11




                   Pt. 56                                                              21 CFR Ch. 1 (4-1-01 Edition)
                   pertaining t o t h e financial interests of            56.113 Snspension or terniiilation of IRB ap-
                   clinical investigators who coiiducted                      proval of research.
                   studies on which t h e application relies              56.114 Cooperative research.
                                            or
                   and who are n o t f ~ d l part-time ein-                     Subpart D-Records        and Reports
                   ployees of the applicant, a s follows:
                      (1) Coinplete records showing a n y fi-             56.115 IRB records.
                   nancial interest or arrangement a s de-
                   scribed i n §54.4(a)(3)(i) paid t o such                  Subpart E-Administrative Actions for
                   clinical investigators by the sponsor of                            Noncompliance
                   t h e covered study.                                   56.120 Lesser administrative actions.
                      (2) Coinplete records showing signifi-              56.121 Disqnalification of a n IRB or a n insti-
                   c a n t payments of other sorts, a s de-                   tntion.
                   scribed i n §54.4(a)(3)(ii). niacle by t h e           56.122 Public disclosure of information re-
                   sponsor of the covered clinical study t o                  garding revocation.
                                                                          56.123 Reinstatement of a n IRB or a n insti-
                   t h e clinical investigator.                               tntion.
                      (3) Coinplete records showing a n y fi-             56.124 Actions alternative or aclclitioi~alt o
                   nancial interests held by clinical inves-                  disqualification.
                   tigatom a s set forth i n §54.4(a)(3)(iii)                             21
                                                                            AUTHORITY: U.S.C. 321. 346. 346a. 348. 351
                   and (a)(3)(iv).                                        352. 353. 355. 360. 360c-360f. 360h-3603. 371. 379e.
                      (b) Regziirenzents for nzaintenance of              381: 42 U.S.C. 216. 241. 262. 2631s-26311.
                                                     '
                   clinical i n ~ e s t i g a t o r sfinancic~lrecords.     SOURCE: FR 8975. J a n . 27. 1981. unless
                                                                                     46
                      ( I ) For a n y application submitted for           otherwise noted.
                   a covered procluct. a n applicant shall
                   retain records a s described i n para-                    Subpart A-General              Provisions
                   graph ( a ) of this section for 2 years
                   after t h e date of approval of the appli-             4 56.101 Scope.
                   cation.
                                                                             ( a ) This p a r t contains t h e general
                      (2) The person maiiitaiiiiiig these                 standards for the composition, oper-
                   records shall, upon request from a n y                 ation, and responsibility of a n Institu-
                   properly authorized officer or employee                tional Review Board (IRB) t h a t reviews
                   of FDA, a t reasonable times, permit                   clinical investigations regulated by the
                   such officer or employee to have access                Food and Drug Adniinistration under
                   t o and copy and verify these records.                 sections 505(i) and 520(g) of the a c t , a s
                                                                          well a s clinical iiivestigations t h a t sup-
                     PART 56-INSTITUTIONAL                   REVIEW       port applications for research or mar-
                                 BOARDS                                   keting permits for products regulated
                                                                          by t h e Food and Drug Administration,
                            Subpart A-General         Provisions          including food and color additives.
                                                                          drugs for human use, medical devices
                   Sec.                                                   for human use. biological proclucts for
                   56.101 Scope.
                                                                          human use, and electronic proclucts.
                   56.102 Definitions.
                   56.103 Circumstances in which IRB review ie
                                                                          Conipliance with this part i s intended
                       required.                                          t o protect t h e rights and welfare of
                   56.104 Exeniptions from IRB reqnirenient.              human subjects involved i n such iiives-
                   56.105 Kaiver of IRB reqnirenient.                     tigations.
                                                                             (b) References i n this part to regu-
                     Subpart B-Organization and Personnel                 latory sectioiis of the Code of Federal
                                                                          Regulations are to chapter I of t i t l e 21,
                   56.107 IRB membership.                                 unless otherwise noted.
                    Subpart C-IRB       Functions and Operations          [46 F R 8975. J a n . 27. 1981. a s amended a t 64
                                                                          F R 399. J a n . 5. 19991
                   56.108 IRB f~uictions    and operations.
                   56.109 IRB review of research.                         S 56.102 Definitions.
                   56.110 Expedited review procednres for cer-
                       t a i n kinds of research inaolviilg no more         As used in this part:
                       t h a n minimal risk. and for minor                  ( a ) Act meaiis the Federal Food.
                       changes in approved research.                      Drug, and Cosmetic Act, a s amended
                   56.111 Criteria for IRB approval of research.          (sees. 201-902. 52 S t a t . 1040 et seg., a s
                   56.112 Review h g institution.                         amended (21 U. S.C. 321-392)).




© 2002 by CRC Press LLC
        2 12     Clinical Research Coordinator Handbook




                   Food and Drug Administration, HHS
                     (b) Application for l-eseal-ch ol- nml--        inittecl a s part of t h e proceclures for
                   keting permit includes:                           classifyiiig such devices. described i n
                      ( I ) A color additive petition, de-           part 860.
                   scribed i n part 71.                                  (14) Data and iiiforniation                  a
                      (2) Data and information regarding a           medical device for human use sub-
                   substance subniittecl a s part of t h e pro-      niittecl a s part of the procedures for es-
                   cedures for establishing t h a t a sub-           tablishing, amending, or repealing a
                   stance i s generally recognized a s safe          standard for such device. described i n
                   for a use which results or m a y reason-          part 861.
                   ably be expected t o              directly or         (15) An application for preniarket ap-
                   indirectly, i n i t s becoming a compo-           proval of a medical device for human
                   nent or otherwise affecting the charac-           use. described i n section 515 of the a c t .
                   teristics of a n y foocl, described i n               (16) A product development protocol
                   § 170.35.                                         for a niedical device for human use. de-
                      (3) A food additive petition, described        scribed i n section 515 of t h e act.
                   in part 171.                                          (17) Data and inforniation regarcliiig
                      (4) Data and information regarding a           a n electronic procluct submitted a s
                   foocl additive subniittecl a s part of t h e      part of the procedures for establishing.
                   proceclures regarding foocl additives             amending, or repealing a standard for
                   permitted to be used 011 a n interim              such products. described in section 358
                   basis pending additional study, de-               of the Public Health Service Act.
                   scribed i n § 180.1.                                  (18) Data and inforniation regarcliiig
                      (5) Data and information regarding a           a n electronic procluct submitted a s
                   substance subniittecl a s part of t h e pro-      part of the procedures for obtaining a
                   cedures for establishing a tolerance for          variance froin a n y electronic procluct
                   unavoidable coiitaniinaiits i n foocl and         performalice standard. a s described i n
                   food-wackao'ino' materials, described i n         § 1010.4.
                   s e c t i k 406bf the a c t .                         (19) Data and inforniation regarcliiig
                      (6) An investigational new drug appli-         a n electronic procluct submitted a s
                   cation. clescribecl i n part 312 of this          part of t h e procedures for granting.
                   chapter.                                          amending, or extending a n exemption
                      (7) A new drug application. described          froin a radiation safety perforniaiice
                   in part 314.                                      standard, a s described in § 1010.5.
                      (8) Data and information regarcliiig               (20) Data and inforniation regarcliiig
                   t h e bioavailability or bioequivalence of        a n electronic procluct submitted a s
                   drugs for human use subniittecl a s p a r t       part of t h e procedures for obtaining a n
                   of the proceclures for issuing, ainend-           exeinption from notification of a racli-
                   ing. or repealing a bioequivaleiice re-           ation safety defect or failure of compli-
                   quirement, clescribed i n p a r t 320.            ance with a radiation safety perforin-
                      (9) Data and information regarcliiig           aiice staiidard. described i n subpart D
                   a n over-the-counter drug for human               of p a r t 1003.
                   use subniittecl a s part of the procedures            (c) Cliniccll investigation nieans a n y
                   for classifying such drugs a s generally          experiment t h a t involves a t e s t article
                                  a s safe and effective and n o t   and one or niore human subjects. aiicl
                   misbranded, described i n part 330.               t h a t either must meet t h e require-
                      (10) An application for a biologics li-        nieiits for prior submission t o t h e Food
                   cense, described i n p a r t 601 of this          and Drug Administration uncler section
                   chapter.                                          505(i) or 520(g) of t h e a c t . or need n o t
                      (11) Data and information regarding a          meet the requirements for prior sub-
                   biological product submitted a s p a r t of       niission t o the Food and Drug Adniiiiis-
                   t h e proceclures for determining t h a t li-     t r a t i o n uncler these sections of t h e a c t ,
                   ceiisecl biological products are safe and         but the results of which are inteiiclecl t o
                   effective and n o t misbranclecl, a s de-         be l a t e r submitted t o , or held for in-
                   scribed i n part 601 of this chapter.             spection by. the Food and Drug Aclmiii-
                      (12) An Application for a n Investiga-         istration a s part of a n application for a
                   tional Device Erenzption, described i n           research or niarketing permit. The
                   parts 812 and 813.                                t e r m does n o t include experiments t h a t
                      (13) Data and iiiforniation               a    niust nieet t h e provisioiis of part 58. re-
                   medical device for human use sub-                 garding nonclinical laboratory studies.




© 2002 by CRC Press LLC
                                                                                  Appendix A: FDA Regulations                          2 13




                                                                                          21 CFR Ch. 1 (4-1-01 Edition)
                   The terms research, clinical research.                   iininediate clirection of another incli-
                   cliniccll s t u d y , s t u d y , and cliniccll inves-   vidual. A person other than a n incli-
                   tigation are deemed t o be synonymous                    vidual (e.g., a corporation or agency)
                   for purposes of this part.                               t h a t uses one or more of i t s own eni-
                      (d) Enzergeizcy use ineans the use of a               ployees to conduct a n investigation
                   test article on a hunian subject in a                    t h a t i t has initiated is considered to be
                   life-threatening situation in which no                   a sponsor (not a sponsor-investigator),
                   stanclard acceptable treatnieiit is avail-               and the employees are considered t o be
                   able, and in which there is not suffi-                   investigators.
                   cient time t o obtain IRB approval.                         ( k ) Sponsor-investigator means a n in-
                      (el Hzinzan subject ineans a n incli-                 dividual who both initiates and actu-
                   vidual who is or beconies a participant                  ally conducts, alone or with others, a
                   in research, either a s a recipient of the                                                          le~
                                                                            clinical investigation. i.e.. ~ ~ i i cwhose
                   test article or a s a control. A subject                 iininediate clirection the test article is
                   inay be either a healthy individual or a                 adniinisterecl or dispensed to. or used
                   patient.                                                 involving, a subject. The term cloes not
                      (f) Institzition ineans any public or                 include aiiy person other than a n indi-
                   private entity or ageiicy (including                     vidual, e.g., i t cloes not include a cor-
                   Federal, S t a t e , and other agencies).                poration or ageiicy. The obligatioiis of
                   The term facility a s used in section                    a sponsor-investigator under this part
                   520(g) of the a c t is deemed t o be syn-                include both those of a sponsor and
                   oiiynious with the term institzition for                 those of a n investigator.
                   purposes of this part.                                      (1) Test cuticle meaiis aiiy drug for
                      (g) Institzitional R e v i e ~ u Boclrd ( I R B )     human use, biological product for
                   ineans any board, committee, or other                    human use. medical device for human
                   group formally designated by a n insti-                  use, human food additive, color acldi-
                   tution t o review, to approve the initi-                 tive. electronic product. or a n y other
                   ation of. and t o conduct periodic re-                   article subject t o regulation under the
                   view of, biomedical research involving                   a c t or under sections 351 or 354-360F of
                   human subjects. The primary purpose                      the Public Health Service Act.
                   of such review is t o assure the protec-                    (in) I R B approval nieans the deter-
                   tion of the rights and welfare of the                    mination of the IRB t h a t the clinical
                   human subjects. The term has the                         investigation has been reviewed and
                   sanie nieaniiig a s the phrase institu-                  inay be conducted a t a n institution
                   tional reviezc conzmittee a s usecl in sec-                                              ts
                                                                            within the ~ o i i s t ~ a i i iset forth by the
                   tion 520(g) of the act.                                  IRB and by other institutional and
                      ( h ) Investigator ineans a n individual              Federal requirenieiits.
                   who actually conducts a clinical iiives-                 [46 F R 8975. J a n . 27. 1981. a s a m e n d e d a t 54
                   tigation (i.e., under whose immediate                    F R 9038. Mar. 3. 1989: 56 F R 28028. J u n e 18.
                   clirection the test article is aclmiiiis-                1991: 64 FR 399. Jan. 5, 1999: 64 FR 56448. Oct.
                   terecl or dispensed to, or used involv-
                   ing. a subject) or. in the event of a n iii-
                   vestigation conducted by a team of in-                   4 56.103 Circumstances in which IRB
                   dividuals. is the responsible leader of                       review is required.
                   t h a t team.                                              ( a ) Except a s provided in @56.104 aiicl
                      (i) Mininwl risk meaiis t h a t the prob-             56.105, any clinical investigation which
                   ability and magnitude of harm or dis-                    niust meet the requirenieiits for prior
                   comfort anticipated in the research are                  submission (as required in parts 312,
                   not greater in and of themselves than                    812. and 813) t o the Foocl and Drug Acl-
                   those ordinarily encountered in daily                    ministration shall not be initiated un-
                   life or during the performance of rou-                   less t h a t investigation has been re-
                   tine physical or psychological exanii-                   viewed and approved by, and remains
                   nations or tests.                                        subject t o continuing review by. a n
                      ( j ) Sponsor meaiis a person or other                IRB meeting the requirements of this
                   entity t h a t initiates a clinical inves-               part.
                   tigation. but t h a t does not actually                    (b) Except a s provided in @56.104 aiicl
                   conduct the investigation, i.e., the test                56.105, the Foocl and Drug Adininistra-
                                                       or
                   article is a d n i i i i i ~ t e ~ e d dispensed to.     tion may decide not t o coiisicler in sup-
                   or usecl involving, a subject under the                  port of a n application for a research or




© 2002 by CRC Press LLC
        214      Clinical Research Coordinator Handbook




                   Food and Drug Administration, HHS
                   marketing permit any d a t a or informa-                    spection Service of the U.S. Depart-
                   tion t h a t has been derived froin a clin-                 nieiit of Agriculture.
                   ical investigation t h a t has not been ap-                 [46 FR 8975. J a n . 27. 1981. a s a m e n d e d nt 56
                   proved by. aiicl t h a t was iiot subject t o               F R 28028. J u n e 18. 19911
                   initial and continuing review by, a n
                   IRB nieetiiig the requirements of t h i s                   4 56.105 Waiver of IRB requirement.
                   part. The determination t h a t a clinical
                                                                                  On t h e application of a sponsor or
                   investigation may iiot be considered in
                                                                               sponsor-investigator, the Foocl and
                   support of a n application for a research
                                                                               Drug Adniinistration niay waive a n y of
                   or marketing perniit does iiot. how-
                                                                               t h e requirements contained i n these
                   ever, relieve the applicant for such a
                                                                                                   including t h e require-
                   perniit of any obligation under any
                                                                               ments for IRB review, for specific re-
                   other applicable regulations t o submit
                                                                               search activities or for classes of re-
                   t h e results of the investigation to the
                   Foocl and Drug Administration.                              search activities, otherwise covered by
                                                                               these r e g ~ ~ l a t i o i i s .
                      ( c j Coinpliance with these regula-
                   tions will i n no way render inapplicable
                   pertinent Federal, S t a t e , or local laws                    Subpart B-Organization                   and
                   or r e g ~ ~ l a t i o i i s .                                           Personnel
                   146 F R 8975. J a n . 27. 1981: 46 F R 14340, F e h . 27,   S 56.107 IRB membership.
                   19811
                                                                                   ( a ) Each IRB shall have a t least five
                   4 56.104 Exemptions from IRB require-                       members, with varying backgrounds t o
                         ment.                                                 promote coniplete and adequate review
                                                                               of research activities colninonly con-
                      The following categories of clinical                     ducted by t h e iiistitutioii. The IRB
                   investigatioiis are exenipt froin t h e re-                 shall be sufficiently qualified through
                   quirements of this part for IRB review:                     t h e experience aiicl expertise of i t s
                      ( a ) Aiiy investigation which coni-                     members, and t h e diversity of the
                   inencecl before J u l y 27, 1981 and was                    nieinbers. including coiisideration of
                   subject t o requirements for IRB review                     race, gender, cultural backgrounds, and
                   under FDA regulations before t h a t                        seiisitivity t o such issues a s coinniu-
                   date. provided t h a t the iiivestigation                   n i t y attitudes, t o promote respect for
                   remains subject t o review of a n IRB                       i t s advice and c o ~ m s e li n s a f e g ~ ~ a ~ c l i i i g
                   which meets the FDA requirenieiits i n                      t h e rights and welfare of human sub-
                   effect before J u l y 27, 1981.                             jects. In addition t o possessiiig t h e pro-
                      (bj Aiiy investigation coinmeiiced be-                   fessional competence necessary t o re-
                   fore J u l y 27, 1981 and was not otherwise                 view the specific research activities.
                   subject t o requirements for IRB review                     t h e IRB shall be able t o ascertain the
                   under Food and Drug Acllninistration                        acceptability of proposed research i n
                                  before t h a t date.                         terms of institutional connnitinents
                      ( c j Emergency use of a test article,                   and regulations. applicable law. aiicl
                   provided t h a t such emergency use is re-                  standards or professional conduct and
                   ported t o the IRB within 5 working                         practice. The IRB shall therefore in-
                   clays. Aiiy subsequent use of the test                      clude persons knowledgeable in these
                   article a t the institution is subject t o                  areas. If a n IRB                   reviews re-
                   IRB review.                                                 search t h a t involves a vulnerable
                      (dj Taste aiicl foocl quality evalua-                    catgory of subjects. such a s children.
                   tions and consumer acceptance studies,                      prisoners, pregnant women, or handi-
                   if wholesome foods without additives                        capped or mentally disabled persons.
                   are consumed or if a foocl is consumed                      coiisideration shall be given t o t h e in-
                   t h a t contains a food ingredient a t or                   clusion of one or more individuals who
                   below t h e level and for a use found t o                   are knowledgeable about and experi-
                   be safe. or agricultural. chemical. or                      enced in working with those subjects.
                   environmental contaminant a t or                                (b) Every nondiscriminatory effort
                   below the level found t o be safe. by the                   will be made t o ensure t h a t no IRB
                   Foocl and Drug Acllninistration or ap-                      consists entirely of men or entirely of
                   proved by t h e Environnieiital Protec-                     women. including t h e institutoii's con-
                   tion Agency or the Food Safety and In-                      sideration of qualified persons of both




© 2002 by CRC Press LLC
                                                                               Appendix A: FDA Regulations                        2 15




                                                                                       21 CFR Ch. 1 (4-1-01 Edition)
                   sexes, so long a s no selection is made                  (b) Follow written proceclures for en-
                   t o the IRB on the basis of gender. No                suring pronipt reporting to the IRB.
                   IRB may consist entirely of members                   appropriate iiistitutioiial officials. and
                   of one profession.                                                                                       n
                                                                         t h e Food and Drug A ~ l i n i i i i s t ~ a t i oof:
                      (c) Each IRB shall include a t least               (1) Any unanticipated problems involv-
                   oiie meniber whose priniary coiicerns                 ing risks t o human subjects or others:
                   are i n the scientific area and a t least             (2) any instance of serious or con-
                   oiie meniber whose priniary coiicerns                 tinuing noiiconipliance with these reg-
                   are in nonscientific areas.                                                                      ts
                                                                         ulatioiis or the r e q ~ ~ i r e n i e i i or deter-
                      (d) Each IRB shall iiiclucle a t least             minations of the IRB: or (3) aiiy sus-
                   one member who is not otherwise affili-               pension or termination of IRB ap-
                   ated with the institution and who is                  proval.
                   not part of t h e immediate family of a                  ( c j Except when a n expedited review
                   person who is affiliated with the insti-              procedure is used (see $56.1101, review
                   tution.                                               proposecl research a t convened ineet-
                      (e) No IRB niay have a nieinber par-               ings a t which a majority of the n i e n -
                   ticipate in t h e IRB's initial or coii-              bers of t h e IRB are present. iiicludiiig
                   tinuiiig review of aiiy project i n which             a t least one nieinber whose priniary
                   t h e nieinber has a conflicting interest.            concerns are i n nonscientific areas. In
                   except t o provide information re-                    order for t h e research to be approved,
                   quested by t h e IRB.
                                                                         i t shall receive the approval of a ma-
                      ( f ) An IRB may, i n i t s discretion, in-        jority of those menibers present a t t h e
                   vite individuals with competence i n                  meeting.
                   special areas t o assist i n the review of
                   complex issues which require expertise                (Information collection requirements in this
                   beyond or i n addition t o t h a t available          section were aggroved by the Office of Man-
                   on t h e IRB. These inclividuals niay not             agement and Bndget (OMB) and assigned
                   vote with the IRB.                                    OMB control nnmber 0910-0130)

                   146 F R 8975, J a n 27. 1981, as amended a t 56 F R   [46 FR 8975. J a n . 27. 1981. a s amended a t 56
                   28028, June 18. 1991: 56 F R 29756, June 28. 19911    FR 28028. June 18. 19911

                                                                         4 56.109 IRB review of research.
                      Subpart C-IRB Functions and
                                                                            ( a ) An IRB shall 'eview and have au-
                               Operations
                                                                         thority t o approve, require inodifica-
                   4 56.108 IRB functions and operations.                tions in ( t o secure approval), or dis-
                                                                         approve all research activities covered
                      In order to fulfill t h e requirements of          by these regulations.
                   these regulations, each IRB shall:                       (b) An IRB shall require t h a t iiifor-
                      ( a ) Follow written procedures: (1)For            niation given to subjects a s part of iii-
                   coiiducting i t s initial and coiitiiiuiiig           formed coiisent is in accordance with
                   review of research and for reporting i t s            $50.25. The IRB may require t h a t infor-
                   fiiidiiigs and actions t o the iiivestigator
                                                                         mation, i n addition t o t h a t specifically
                   and t h e institution: (2) for cleterininiiig
                                                                         nieiitionecl in $50.25. be given t o the
                   which projects require review more
                                                                         subjects when in t h e IRB's juclgnieiit
                   often t h a n annually and which projects
                   need verification from sources other                  t h e information would i n e a n i n g f ~ ~ l l y
                   t h a n t h e investigator t h a t no inaterial       add t o t h e protection of t h e rights and
                   changes have occurred since previous                  welfare of subjects.
                   IRB review: (3) for ensuring prompt re-                  (c) An IRB shall require clocunieiita-
                   porting to t h e IRB of changes in re-                tion of informed consent i n accordance
                   search activity: and (4) for eiisuriiig               with $50.27 of this chapter, except a s
                   t h a t changes in approved research, dur-            follows:
                   ing the period for which IRB approval                    (1) The IRB niay. for sonie or all sub-
                   has already been given, may not be ini-               jects, waive the requirement t h a t the
                   tiated without IRB review and ap-                     subject, or the subject's legally author-
                   proval except where necessary to eliini-              ized representative. sign a written coii-
                   n a t e apparent iinniediate hazards t o              sent forin if i t finds t h a t the research
                   t h e human subjects.                                 presents no more t h a n minimal risk of




© 2002 by CRC Press LLC
        2 16     Clinical Research Coordinator Handbook




                   Food and Drug Administration, HHS
                   h a r m t o subjects and involves no proce- copies of the information disclosed t o
                   dures for which written consent i s nor- FDA.
                   mally required outside the research                   [46 F R 8975. J a n . 27. 1981. a s a m e n d e d a t 61
                   context: or                                           F R 51529. O c t . 2. 19961
                      (2) The IRB niay. for sonie or all sub-
                   jects. find t h a t the r e q ~ ~ i ~ e n i e i i ns 4 56.110 Expedited review procedures
                                                                     t
                   s50.24 of this chapter for a n exception                   for certain kinds of research involv-
                   froin iiifornied coiisent for emergency                    ing no more than minimal risk, and
                                                                              for minor changes in approved re-
                   research are niet.                                         search.
                      (d) In cases where the documentation
                   requirement i s waived under paragraph                  ( a ) The Food and Drug Adininistra-
                   ( c ) ( l ) of this section, the IRB inay re- tion has established. and published in
                   quire the investigator t o provide sub- t h e FEDERAL                       REGISTER.a list of cat-
                                                                         egories of research t h a t m a y be re-
                   jects with a written s t a t e m e n t regard-
                                                                         viewed by the IRB through a n expe-
                   ing t h e research.
                                                                         dited review procedure. The list will be
                      (e) An IRB shall notify i i i v e ~ t i g a t o ~ samended. a s appropriate. through peri-
                   and the institution in writing of i t s cle- odic republication i n t h e FEDERAL                       REG-
                   cision t o approve or disapprove t h e pro- ISTER.
                   posed research activity. or of modifica-                (b) An IRB m a y use t h e expedited re-
                   tions                  t o secure IRB approval view proceclure t o review either or both
                   of t h e research activity. If the IRB de- of the followiiig: (1) Some or all of the
                   cides t o clisapprove a research activity, research appearing on the list and
                   i t shall include i n i t s written notifica- found by t h e reviewer(s) t o iiivolve no
                   tion a s t a t e m e n t of t h e reasons for i t s more t h a n minimal risk, (2) minor
                   decision and give the investigator a n changes in previously approved re-
                   opportunity t o respond i n person or i n search during the period (of I year or
                   writing. For investigations involving less) for which approval is authorized.
                                                                         e~
                   a n exception t o iiifornied coiisent ~ ~ i i d Under a n expeditecl review procedure,
                   s50.24 of this chapter. a n IRB shall t h e review m a y be carried out by the
                   promptly notify i n writing t h e investi- IRB chairperson or by one or more ex-
                   gator and the spoiisor of t h e research              perienced reviewers designated by the
                   when a n IRB determines t h a t i t cannot IRB chairperson from among t h e mem-
                   approve the research because i t does bers of the IRB. I n                                           the re-
                   n o t meet the criteria i n t h e exception search, the reviewers inay exercise all
                   provided under 0 50.24(a) of this chapter             of the authorities of t h e IRB except
                   or because of other relevant ethical t h a t t h e reviewers m a y n o t clisapprove
                   concerns. The written notification t h e research. A research activity niay
                   shall include a s t a t e m e n t of the rea- be disapproved only after review i n ac-
                   sons for the IRB's deterniination.                    cordance with t h e nonexpedited review
                      (f) An IRB shall conduct coiitinuiiig proceclure set forth in §56.lO8(c).
                   review of research covered by these                     (c) Each IRB which uses a n expeditecl
                                      a t intervals appropriate t o review procedure shall adopt a method
                   t h e degree of risk. but n o t less t h a n for keeping a l l nieinbers advised of re-
                   once per year, and shall have a u t h o r i t y search proposals which have been ap-
                   t o observe or have a third party ob- proved ~ ~ i i ctl e ~                h e procedure.
                   serve t h e consent process and t h e re-               (d) The Food and Drug Adininistra-
                   search.                                               tion niay restrict. suspend. or ternii-
                      (g) An IRB shall provide in writing t o n a t e a n institution's or IRB's use of
                   t h e sponsor of research involving a n t h e expeditecl review procedure when
                   exception to iiifornied coiiseiit under necessary t o protect the rights or wel-
                   s50.24 of this chapter a copy of iiifor- fare of subjects.
                   niation t h a t has been publicly disclosed           146 FR 8975. J a n . 27. 1981, a s a m e l i d e d a t 56
                   under §50.24(a)(7)(ii)aiicl (a)(7)(iii) of F R 28029. J u n e 18. 19911
                   this chapter. The IRB shall provide
                   this information to t h e sponsor $56.111 Criteria for IRB approval of
                   promptly so t h a t t h e sponsor is aware                 research.
                   t h a t such disclosure has occurred.                   ( a ) I n order t o approve research cov-
                   Upon receipt, t h e sponsor shall provide ered by these regulations the IRB shall




© 2002 by CRC Press LLC
                                                                                Appendix A: FDA Regulations                           2 17




                                                                                        21 CFR Ch. 1 (4-1-01 Edition)
                   determine t h a t all of the following re-             women, handicapped, or mentally dis-
                   quirements are satisfied:                              abled persons, or economically or eclu-
                       ( I ) Risks t o subjects a r e minimized:          cationally clisadvantagecl persons. are
                   ( i ) By using procedures which are coii-              likely t o be vulnerable to coercion or
                   sistent with sound research design and                 undue influence additional safeguards
                   which do not unnecessarily expose sub-                 have been included i n the study t o pro-
                   jects to risk, and (ii) whenever appro-                tect the rights and welfare of these
                   priate. by using procedures already                    subjects.
                   being performecl on the subjects for di-
                   agnostic or treatment purposes.                        146 FR 8975. J a n . 27. 1981, a s a m e l i d e d a t 56
                       (2) Risks t o subjects are reasonable              FR 28029. J u n e 18. 19911
                   in relation t o anticipated benefits. if
                   any, t o subjects, and the importance of               4 56.112 Review by institution.
                   t h e knowledge t h a t niay be expected t o              Research covered by these regula-
                   result. In evaluating risks and benefits,              tions t h a t has been approved by a n IRB
                   t h e IRB should consider only those                                                    appropriate
                                                                          niay be subject t o f ~ ~ r t h e '
                   risks and benefits t h a t may result from             review and approval or clisapproval by
                   t h e research (as clistinguishecl froin               officials of t h e institution. However,
                   risks and benefits of therapies t h a t                those officials niay not approve the re-
                   subjects would receive even if not par-                search if i t has not been approved by
                   ticipating in t h e research). The IRB                 a n IRB.
                   should not consider possible long-range
                   effects of applying knowledge gained i n               S 56.113 Suspension or termination of
                   t h e research (for exaniple. the possible                  IRB approval of research.
                   effects of the research on public policy)                 An IRB shall have authority t o sus-
                   a s among those research risks t h a t fall
                                                                          pend or terminate approval of research
                   within t h e purview of i t s responsi-
                                                                          t h a t is not being conducted in accord-
                   bility.
                                                                          ance with the IRB's requirenieiits or
                       (3) Selection of subjects is equitable.
                   In making this assessnient the IRB                     t h a t has been associatecl with unex-
                   should t a k e into account the purposes               pected serious harm to subjects. Any
                   of the research and the setting i n                    suspension or termination of approval
                   which t h e research will be conducted                 shall iiiclucle a statement of the rea-
                   and should be particularly cognizant of                sons for the IRB's action and shall be
                   t h e special problems of research in-                 reported proniptly to t h e investigator.
                   volving vulnerable populations. such a s               appropriate iiistitutioiial officials. and
                   children, prisoners, pregnant women,                   t h e Food and Drug Administration.
                   handicapped. or mentally clisabled per-
                   sons, or economically or eclucationally                S 56.114 Cooperative research.
                   clisaclvaiitagecl persons.                               In complyiiig with these 'egulations.
                       (4) Informed consent will be sought                institutions involved i n niulti-institu-
                   froin each prospective subject or the                  tional studies may use joint review, re-
                   subject's legally authorized representa-               liance upon the review of another
                   tive. i n accorclance with and t o t h e ex-           qualified IRB. or similar arraiigenieiits
                   t e n t required by part 50.                           aimed a t avoidance of duplication of ef-
                       (5) Informed coiiseiit will be appro-              fort.
                   priately documented, i n accordance
                   with and t o the extent required by
                   § 50.27.
                                                                           Subpart D-Records                 and Reports
                       (6) Where appropriate. the research                S 56.115 IRB records.
                   plan makes adequate provision for
                   n i o n i t ~ ~ i i itg e d a t a collected t o eii-
                                         h                                   ( a ) An iiistitutioii. or where appro-
                   sure the safety of subjects.                           priate a n IRB. shall prepare and maiii-
                       (7) Where appropriate. there are ade-              t a i n adequate documentation of IRB
                   quate provisions to protect t h e privacy              activities. iiiclucliiig the followiiig:
                   of subjects and to niaiiitain the con-                    ( I ) Copies of all research proposals re-
                   fidentiality of data.                                  viewed. scientific evaluatioiis. if any.
                       (b) When sonie or all of t h e subjects.           t h a t accompany the proposals, ap-
                   such a s children, prisoners, pregnant                 proved sample consent clocuinents,




© 2002 by CRC Press LLC
        2 18     Clinical Research Coordinator Handbook




                   Food and Drug Administration, HHS
                   progress reports submitted by inves-                Subpart E-Administrative Actions
                   tigators. and reports of injuries t o sub-                for Noncompliance
                   jects.
                     (2) Minutes of IRB meetings which                 4 56.120 Lesser administrative actions.
                   shall be in sufficient detail t o show a t -           ( a ) If apparent noncompliance with
                   teiidaiice a t t h e meetiiigs: actions             these regulations i n t h e operation of a n
                   taken by t h e IRB: t h e vote on these ac-         IRB is observed by a n FDA investi-
                   tions including the number of members               gator during a n inspection, the inspec-
                   voting for, against, and abstaining: the            t o r will present a n oral or written suin-
                   basis for               changes i n or dis-         inary of observations t o a n appropriate
                   approving research: and a written suni-             'epresentative of the IRB. The Food
                   niary of the cliscussioii of controverted           and Drug Aclmiiiistration niay subse-
                   issues and their resolution.                        quently send a letter describing t h e
                     (3) Records of coiitiiiuing review ac-            noiiconipliaiice t o t h e IRB and to the
                   tivities.                                           parent iiistitutioii. The agency will re-
                                                                       quire t h a t the IRB or t h e parent insti-
                     (4) Copies of all correspondelice be-
                                                                       tution respond t o this l e t t e r within a
                   tween t h e IRB and t h e investigators.            time period specified by FDA and de-
                     (5) A list of IRB nieinbers identified            scribe t h e corrective actions t h a t will
                   by name: earned degrees: representa-                be taken by the IRB, the institution, or
                   tive capacity: indications of experience            both to achieve compliance with these
                   such a s board certifications, licenses,            regulations.
                   etc.. sufficient to describe each niein-               (b) On the basis of t h e IRB's or t h e
                   ber's chief anticipated contributions t o           institution's response, FDA may sched-
                   IRB deliberations: and any eniploy-                 ule a reinspection to confirm the ade-
                   inent or other relationship between                 quacy of corrective actions. In acldi-
                   each member and the institution: for                tion, until t h e IRB or t h e parent insti-
                   example: full-time einployee, part-time             tution takes appropriate corrective ac-
                   eniployee. a meniber of governing panel             tion. the agency may:
                   or board. stockholder. paid or unpaid                  ( I ) Withhold approval of new studies
                   coiisultant.                                                                                 ts
                                                                       subject t o the r e q ~ ~ i r e n i e i iof this part
                     (6) Written procedures for the IRB a s            t h a t are conducted a t the institution
                                                                       or reviewed by t h e IRB:
                              by s56.108 ( a ) and (b).
                                                                          (2) Direct t h a t no new subjects be
                     (7) Statements of significant new                 added to ongoing studies subject t o
                   findings provided t o subjects, a s re-             this part:
                   quired by § 50.25.                                     (3) Terminate ongoing studies subject
                     (b) The records required by this regu-            t o this part when doing so would not
                   lation shall be retained for a t least 3            endanger t h e subjects: or
                   years after coinpletion of the research,               (4) When t h e apparent noncoinpliaiice
                   and the records shall be accessible for             creates a significant t h r e a t t o t h e
                   inspection aiicl copying by authorized              rights and welfare of human subjects.
                   representatives of t h e Food and Drug              notify relevant S t a t e and Federal regu-
                   Administration a t reasonable times                 latory agencies and other parties with
                   and i n a reasoilable maliner.                      a direct interest i n t h e agency's action
                     (c) The Food and Drug Adniinistra-                of the deficiencies i n the operation of
                   tion may r e f ~ ~ s o consider a clinical
                                        te                             t h e IRB.
                   investigation i n support of a n applica-              (c) The parent institution is pre-
                   tion for a research or marketing per-               sumed to be responsible for the oper-
                   niit if t h e institution or the IRB t h a t        ation of a n IRB. and t h e Food and Drug
                   reviewed t h e investigation r e f ~ ~ s et s
                                                               o       Administration will ordinarily direct
                   allow a n inspection under this section.            any aclmiiiistrative action ~ u ? d et h i s      ~
                                                                       subpart against the institution. How-
                   (Information collection requirements i n this       ever. depeiidiiig on the evidence of re-
                   section were aggroved by t h e Office of Man-       sponsibility for deficiencies, deter-
                   ngement rind Budget (OMB) and assigned              niinecl cluriiig t h e investigatioii. the
                   OMB control number 0910-0130)                       Food and Drug Administration may re-
                   [46 FR 8975. J a n . 27. 1981. a s amended n t 56   strict its a~liniiiist~ative       actions to t h e
                   FR 28029. J u n e 18. 19911                         IRB or t o a component of the parent




© 2002 by CRC Press LLC
                                                                               Appendix A: FDA Regulations                 2 19




                                                                                      21 CFR Ch. 1 (4-1-01 Edition)
                   institution determined t o be respon-                  4 56.122 Public disclosure of informa-
                   sible for formal designation of the IRB.                   tion regarding revocation.
                                                                             A determination t h a t the Foocl and
                   $56.121 Disqualification of an IRB or                  Drug Adniinistratioii has disqualified
                      an institution.
                                                                          a n institution and the administrative
                      ( a ) Whenever t h e IRB or t h e institu-          record regarding t h a t deterniiiiation
                   tion has failed t o t a k e adequate steps             are clisclosable t o the public under p a r t
                   t o correct t h e iioncoinpliaiice s t a t e d i n     20.
                   t h e l e t t e r sent by t h e agency uncler
                   §56.120(aj, and the Colninissioner of                  S 56.123 Reinstatement of an IRB or an
                   Food and Drugs deterniiiies t h a t t h i s                  institution.
                   noiiconipliaiice niay justify t h e dis-                  An IRB or a n institution m a y be re-
                   qualification of the IRB or of the par-                instated if the Coniniissioiier deter-
                   e n t institution, the Colnmissioner will              mines, upon a n evaluation of a written
                   i n s t i t u t e proceedings i n accordance           submission froin t h e IRB or iiistitutioii
                   with the r e q ~ ~ i r e n i e i i for a regulatory
                                                      ts                  t h a t explains the corrective action
                   hearing s e t forth i n part 16.                       t h a t the iiistitutioii or IRB plans t o
                      (b) The Colnmissioner m a y disqualify              t a k e , t h a t t h e IRB or institution has
                   a n IRB or t h e parent institution if the             provided adequate assurance t h a t i t
                   Coniinissioiier cleteriniiies t h a t :                will operate i n compliance with the
                                                                          stanclards set forth i n this part. Notifi-
                                                         cl
                      (1) The IRB has r e f ~ ~ s eor repeatedly          cation of reinstatement shall be pro-
                   failed t o comply with a n y of the regu-              vided t o all persons notified under
                   lations s e t forth i n this p a r t , and             5 56.121(c).
                      (2) The noiiconipliaiice adversely af-
                   fects the rights or welfare of the                     S 56.124 Actions alternative or addi-
                   human subjects in a clinical investiga-                       tional to disqualification.
                   tion.                                                     Disqualification of a n IRB or of a n
                                                            ~
                      (c) If the C o i n n i i ~ s i o n ecleteriniiies   institution is iiidependeiit of. aiicl nei-
                   t h a t disqualification is appropriate.               t h e r in lieu of nor a precondition t o ,
                   t h e Coinmissioner will issue a n order               other proceecliiigs or actions authorized
                   t h a t explains the basis for the deter-              by the a c t . The Foocl and Drug Aclmin-
                   mination aiicl t h a t prescribes a n y ac-            istration niay. a t a n y time. through
                   tions t o be t a k e n with regard t o ongo-           t h e Department of Justice i n s t i t u t e
                   ing clinical research conducted uncler                 a n y appropriate judicial proceecliiigs
                   t h e review of t h e IRB. The Food and                (civil or criminal j and a n y other appro-
                   Drug Aclininistratioii will send notice                priate                action. in addition t o
                   of t h e clisqualification to t h e IRB and            or i n lieu of, and before, a t the time of,
                   t h e parent iiistitution. Other parties               or after. disqualificatioii. The agency
                   with a direct interest. such a s spoiisors             inay also refer pertinent m a t t e r s to an-
                   and clinical investigators, m a y also be              other Federal. S t a t e . or local goverii-
                   sent a notice of t h e disqualificatioii. In           inent agency for a n y action t h a t t h a t
                   adclition. the agency m a y elect t o pub-             agency determines t o be appropriate.
                   lish a notice of i t s action i n t h e FED-
                   ERAL REGISTER.                                         PART 58-GOOD      LABORATORY
                      (d) The Food and Drug Adininistra-                    PRACTICE FOR NONCLlNlCAL
                   tioii will not approve a n application for               LABORATORY STUD1ES
                   a research permit for a clinical inves-
                   tigation t h a t i s to be uncler the review                 Subpart A-General     Provisions
                   of a disqualified IRB or t h a t is t o be             Sec.
                   conducted a t a disqualified institution,              58.1 Scope.
                   and i t inay refuse t o consider i n sup-              58.3 Definitions.
                   port of a marketing perinit the d a t a                58.10 Applicability t o studies performed
                   from a clinical investigation t h a t was                  under g r a n t s and contracts.
                   reviewed by a clisqualifiecl IRB a s con-              58.15 Illspection of a testing facility.
                   ducted a t a disqualified iiistitutioii. LX-
                                                                            Subpart B-Organization    and Personnel
                   less the IRB or the parent institution
                   is reinstated a s provided in s56.123.




© 2002 by CRC Press LLC
        220      Clinical Research Coordinator Handbook




                                                                                      21 CFR Ch. 1 (4-1-01 Edition)
                   312.41 Conirnent and advice on a n IND.              Subpart G-Drugs for Investigational Use in
                   312.42 Clinical holds and requests for niodi-           Laboratory Research Animals or in
                       fication.                                           Vitro Tests
                   312.44 Termination.
                   312.45 Inactive status.                              312.160 Drugs for investigatiollal use i n lals-
                   312.47 Meetings.                                         oratory research anirnals or i n vitro
                   312.48 Dispute resolution.                               tests.
                                                                                        21
                                                                          AUTHORITY: U.S.C. 321. 331. 351. 352. 353.
                     Subpart D-Responsibilities of Sponsors             355. 371: 42 U.S.C. 262.
                               and Investigators                          SOURCE: F R 8831. Mar. 19, 1987. unless
                                                                                   52
                   312.50 General responsibilities of sponsors.         otherwise noted.
                   312.52 Transfer of obligations t o a coiltract
                       research organization.                              Subpart A-General                Provisions
                   312.53 Selecting investigators and monitors.
                   312.54 Emergency research ~ u i d e r550.24 of       4 312.1 Scope.
                       this chapter.                                       ( a ) This p a r t contains procedures and
                   312.55 Iilforrning investigators.                    'equirenients governing t h e use of ill-
                   312.56 Review of ongoing investigations.             vestigational new drugs, including pro-
                   312.57 Recordkeeping and record retention.           cedures aiicl requirenieiits for t h e sub-
                   312.58 Inspection of sponsor's records and           mission t o , and review by, the Food
                       reports.
                   312.59 Disposition of unused supply of inaes-        and Drug Adniinistration of iiivestiga-
                       tigatioiral drug.                                tional new drug applications (IND's).
                   312.60 General resgonsihilities of investiga-        An investigatioiial new drug for which
                       tors.                                            a n IND is i n effect i n accordance with
                   312.61 Control of t h e investigatioilal drng.       this part is exempt froni t h e preniar-
                   312.62 Investigator       recordkeeging      and     keting approval requirements t h a t are
                        record retention.                               otherwise applicable aiicl niay be
                   312.64 Investigator regorts.                                                 ly
                                                                        shipped l a w f ~ ~ lfor the purpose of con-
                   312.66 Assurance of IRB review.                      ducting clinical investigatioiis of t h a t
                   312.68 Inspection of investigator's records          drug.
                        and reports.                                       ( b ) References i n this n a r t t o regula-
                   312.69 Haildling of coiltrolled snhstances.          tions in t h e Code of F'ecleral Regula-
                   312.70 Disqualification of a clinical investi-       tions are t o chapter I of t i t l e 21. ~ m l e s s
                        gator.
                                                                        otherwise noted.
                   Subpart E-Drugs Intended to Treat Life-              S 312.2 Applicability.
                      threatening and Severely-debilitating
                      Illnesses                                            (a j Applicubility. Except a s provided
                                                                        in this section, this part applies t o all
                   312.80 Purpose.                                      clinical investigations of products t h a t
                   312.81 Scope.                                        are subject t o section 505 of the Federal
                   312.82 Early consnltation.                           Food. Drug. and Cosmetic Act or t o the
                   312.83 T r e a t m e n t protocols.                  licensing provisions of the Public
                   312.84 Risk-benefit analysis i n review of           Health Service Act (58 S t a t . 632. a s
                       marketing applications for drugs t o t r e a t   amended (42 U.S.C. 201 et seq. 1).
                       life-threatening and severely-delsilitatillg
                       illnesses.                                          (b) Eaenzptions. (1)The clinical inves-
                   312.85 Phase 4 stndies.                              tigation of a drug product t h a t i s law-
                   312.86 Focused FDA regulatory research.              fully marketed i n the United S t a t e s i s
                   312.87 Active rnoilitoring of condnct and            exenipt froin the                             of t h i s
                        evaluation of clinical trials.                  part if all the following apply:
                   312.88 Safeguards for patient safety.                   ( i j The investigation i s n o t intended
                                                                        t o be reported to FDA a s a well-coii-
                             Subpart F-Miscellaneous                    trolled study i n support of a new indi-
                                                                        cation for use llor intended t o be used
                   312.110 Import and exgort requirements.
                                                                        t o support a n y other significant change
                   312.120 Foreign clinical studies n o t con-
                       ducted under a n IND.                            in the labeling for the drug:
                   312.130 Availability for public disclosure of                                                            ing
                                                                           (iij If the drug t h a t i s ~ ~ i i c l e ~ g o iii-
                       d a t a and infornlation in a n IND.             vestigation is lawfully marketed a s a
                   312.140 Address for correspondence.                  prescript'ion drug product. the inves-
                   312.145 Guidance docnnients.                         tigation is not intended t o support a




© 2002 by CRC Press LLC
                                                                                 Appendix A: FDA Regulations                         22 1




                   Food and Drug Administration, HHS
                   significant change i n the advertising                  cation of a new drug product approved
                   for the product:                                        under p a r t 314 or of a liceiised biologi-
                      (iii) The investigation does n o t in-               cal procluct.
                   volve a route of administration or clos-                  (e) Gutdance. FDA niay. on i t s own
                   age level or use i n a patient population               initiative, issue guidance on the appli-
                   or other factor t h a t significantly iii-              cability of this part t o particular iii-
                   creases the risks (or decreases t h e ac-               vestigational uses of drugs. On
                   ceptability of the risks) associated                    FDA will advise on the applicability of
                   with t h e use of t h e drug procluct:                  this part to a plaiiiied clinical iiives-
                      (iv) The investigation i s concluctecl i n           tigation.
                   compliance with the requirements for
                   institutional review s e t forth i n part 56            152 F R 8831. M a r . 19, 1987. as anieiided a t 61
                   and with the requirements for informed                  F R 51529. O c t . 2, 1996:64 F R 401. J a n . 5. 19991
                   coiisent s e t forth i n p a r t 50: and
                      (v) The investigation i s conducted i n              S 312.3 Definitions and interpretations.
                                                                      s
                   coinpliaiice with t h e r e q ~ ~ i r e n i e i i tof      ( a ) The clefiiiitioiis and iiiterpreta-
                   § 312.7.                                                tions of terins contained i n section 201
                      (2)(i) A cliiiical investigation involv-             of the Act apply t o those terins when
                   ing a n i n vitro cliagnostic biological                used i n this part:
                   product listed i n paragraph (b)(2)(ii)of                  (b) The following definitions of terins
                   this section i s exempt from t h e re-                  also apply t o this part:
                   quirements of this part if ( a ) i t i s iii-              Act nieans t h e Federal Food. Drug.
                   tended t o be used i n a diagnostic proce-              and Cosinetic Act (sees. 201-902. 52
                   dure t h a t confirnis the diagnosis inacle             S t a t . 1040 et seg.. a s amended (21 U.S.C.
                   by another, medically established, di-                  301-392) ).
                   agnostic product or procedure aiicl (b) i t                Clinical investiyation means a n y ex-
                   is shipped i n compliance with S312.160.                periment in which a drug i s adininis-
                      (ii) I n accordaiice with paragraph                  terecl or dispensed t o , or used involv-
                   (b)(2)(i) of this section, the following                ing, one or more human subjects. For
                   products are exenipt froni t h e require-               t h e purposes of this part, a n experi-
                   ments of this part: ( a ) blood grouping                ment i s a n y use of a clrug except for t h e
                   serum: ( b )              red blood cells: and          use of a inarketecl drug in the course of
                   (c) anti-human globulin.                                medical practice.
                      (3) A drug inteiidecl solely for t e s t s in
                                                                              Contrc~ct   researclz organiic~tionnieans a
                   vitro or in laboratory research animals
                                                                           person t h a t assumes. a s a n inclepeiiclent
                   is exenipt froin the requireinelits of
                                                                           contractor with t h e spoilsor. one or
                   this part if shipped in accordance with
                   § 312.160.
                                                                           more of t h e obligations of a sponsor,
                      (4) FDA will n o t accept a n applica-               e.g., design of a protocol, selection or
                   tion for a n iiivestigation t h a t i s ex-             monitoring of investigations, evalua-
                   empt under t h e provisions of paragraph                tion of reports, and preparation of ma-
                   ( b ) ( l )of this section.                             terials t o be submitted t o the Food and
                      (5) A clinical investigation involving               Drug Aclministration.
                   use of a placebo i s exenipt froin t h e re-               FDA ineaiis t h e Food aiicl Drug Acl-
                   quirements of this part if t h e inves-                 niinistration.
                   tigation does not otherwise require                        IYD ineaiis a n iiivestigational new
                   submission of a n IND.                                  drug application. For purposes of this
                      (6) A cliiiical investigation iiivolviiig            part, "IND" i s synonymous with "No-
                   a n exception from informed consent                     tice of Claimed Investigational Exeinp-
                   under S50.24 of this chapter i s n o t ex-              tion for a New Drug."
                   empt froin t h e requirements of this                      Investigationc~lnezv dl-ziy means a new
                   part.                                                   clrug or biological clrug t h a t i s used in
                      ( c ) Bioavailability stzidies. The applica-         a clinical iiivestigation. The tern? also
                   bility of this part to i n vivo bio-                    includes a biological product t h a t i s
                   availability studies i n humans i s sub-                used i n vitro for diagnostic purposes.
                   ject to the provisions of § 320.31.                     The ternis ..investigatioiial drug" aiicl
                      (d) Unlabeled indication. This part                  ..iiivestigational new drug" are deemed
                   does n o t apply to t h e use i n the prac-             t o be synonymous for purposes of this
                   tice of medicine for a n unlabeled incli-               part.




© 2002 by CRC Press LLC
        222      Clinical Research Coordinator Handbook




                                                                                   21 CFR Ch. 1 (4-1-01 Edition)
                       Investigator means a n individual who             (b) The label or labeling of a n inves-
                   actually coiiducts a clinical investiga- tigational new clrug shall n o t bear a n y
                   tion (i.e.. under whose inimecliate cli- s t a t e m e n t t h a t i s false or inisleacling i n
                   'ectioii t h e drug i s aclininisterecl or dis- a n y particular and shall n o t represent
                   peiisecl t o a subject). I n t h e event a n iii- t h a t t h e investigational new drug i s
                   vestigation is coiicluctecl by a teain of safe or effective for t h e purposes for
                   individuals. the investigator i s t h e re- which i t i s being iiivestigatecl.
                   sponsible leader of the team. "Sub-
                   investigator" includes a n y other incli- 4 312.7 Promotion and charging for in-
                   vidual inember of t h a t team.                          vestigational drugs.
                       Marketing upplication nieaiis a n appli-          ( a ) Promotion of a n investigc~tionaln e t t
                   cation for a iiew drug submitted under drug. A sponsor or investigator. or a n y
                   section 505(b) of the a c t or a biologics person acting on behalf of a sponsor or
                   license application for a biological               investigator. shall iiot                    in a
                   product submitted under t h e Public promotional context t h a t a n investiga-
                   Health Service Act.
                       Sponsor nieans a person who t a k e s re- tional iiew drug is safe or effective for
                   sponsibility for and initiates a clinical t h e purposes for which i t i s ~ m d e rin-
                   investigation. The sponsor m a y be a n vestigation or otherwise promote the
                   individual or pharmaceutical company. clrug. This provision is not intended t o
                   governmental agency, academic insti- restrict t h e full exchange of scientific
                   tution. private orgaiiizatioii. or other information concerning the drug, in-
                   organization. The sponsor does n o t ac- cluding dissemination of scientific
                   tually conduct the investigation ~ ~ i i l e s sfindings i n scientific or l a y media.
                   t h e sponsor is a sponsor-investigator. A Rather. i t s i n t e n t is t o restrict pro-
                   person other t h a n a n individual t h a t niotioiial claims of safety or effective-
                   uses one or more of i t s own employees ness of the drug for a use for which i t
                   t o conduct a n investigation t h a t i t has is under iiivestigation aiicl to preclude
                   initiated i s a sponsor, n o t a sponsor-in- coinniercialization of the drug before i t
                   vestigator. and the eniployees are iii- is approvecl for colninercial clistribu-
                   vestigators.                                       tion.
                       Sponsor-Investigc~tor means a n incli-            (b) Conznzel-cia1 distl-ibzition of a n inves-
                   vidual who both initiates and conducts tigational nezv dl-zig. A sponsor or inves-
                   a n iiivestigatioii. and under whose ini- tigator shall not connnercially clis-
                   mediate direction t h e investigational tribute or t e s t niarket ail investiga-
                   drug i s adniinisterecl or clispeiised. The tioiial iiew drug.
                   t e r m does n o t include a n y person other         (c) Prolonging a n investigution. A
                                                                                                       ly
                   t h a n a n iiidiviclual. The requireinelits spoiisor shall n o t ~ ~ i i c l u prolong a n iii-
                   applicable t o a sponsor-investigator              vestigation after fiiicliiig t h a t the re-
                   under this part include both those ap- sults of the investigation appear t o es-
                   plicable to a n investigator and a spon- tablish sufficient d a t a t o support a
                   Sol'.                                              marketing application.
                       Szibject means a human who partici-               (d) Charging for and conlnlel-cialiaatiolz
                   pates in a n investigatioii. either a s a o f investiuc~tional dl-zius-(1)                  Clinical
                   recipient of the investigational new t&ls z ~ n d e iu n I,VD. Chay-ging for a n in-
                   drug or a s a control. A subject niay be vestigational drug i n a clinical t r i a l
                   a healthy human or a patient with a under a n IND is iiot permitted without
                   disease.                                           t h e prior written approval of FDA. In
                   1 2 FR 8831. Mar. 19, 1987. as anieiided at 64
                     5                                                               such approval. t h e sponsor
                                                                                              written explanation
                   FR 401. J a n . 5. 1999: 64 FR 56449.Oct.20. 19991 shall provide a f ~ ~ l l
                                                                      of why charging i s necessary i n order
                   S 312.6 Labeling of an investigational for the spoiisor t o undertake or coii-
                          new drug.                                   tinue the clinical t r i a l , e.g., why dis-
                       ( a ) The ininiediate package of a n in- tribution of the drug to t e s t subjects
                   vestigational new drug intended for should n o t be considered p a r t of t h e
                   human use shall bear a label with the normal cost of cloiiig business.
                   s t a t e m e n t "Caution: New Drug-Liin-            (2) Tl-eatnzent protocol or tl-eatnlent
                   ited by Federal (or United S t a t e s ) law I,VD. A sponsor or investigator niay
                   t o investigational use."                          charge for a n investigational clrug for a




© 2002 by CRC Press LLC
                                                                               Appendix A: FDA Regulations                  223




                   Food and Drug Administration, HHS
                   t r e a t m e n t use under a t r e a t m e n t pro-     (3) Other information justifying a
                   tocol or t r e a t m e n t IND provided: ( i )         waiver.
                   There is adequate enrollment i n the                     (b) FDA niay grant a waiver if i t
                   ongoing clinical iiivestigatioiis under                finds t h a t t h e sponsor's noncompliance
                   t h e authorized IND: ( i i ) charging does            would iiot pose a sigiiificaiit and unrea-
                   not constitute coinmenial marketing                    sonable risk t o human subjects of the
                   of a new clrug for which a marketing                   investigation and t h a t one of the fol-
                   application has iiot been approved: (iii)              lowing is met:
                   t h e drug is not being colninercially                   (1)The sponsor's compliance with the
                   promoted or advertised: and (iv) t h e                 requirement is unnecessary for the
                   sponsor of the drug is actively pursuing               agency t o evaluate t h e application. or
                   marketing approval with clue diligence.                compliance cannot be achieved:
                   FDA must be notified i n writing i n ad-                 (2) The sponsor's proposed alter-
                   vance of conimencing a n y such                        native satisfies the requirement: or
                   charges, i n a n information alnenclment                 (3) The applicant's subniission other-
                   submitted ~ u ? d e 312.31. Authorization
                                           §~                             wise justifies a waiver.
                   for charging goes into effect autoinati-
                                                                          (Collection of information reqnirements ag-
                   cally 30 clays after receipt by FDA of
                                                                          groved hy the Office of Management and
                   t h e information ainenclment, unless the              Budget under control numlser 0910-0014)
                   spoiisor is notified t o t h e contrary.
                       (3) Nonco??~??~ercialiic~tio?zinvestiga-
                                                       of                 [52 F R 8831. Mar. 19. 1987. as amended a t 52
                                                                          F R 23031. June 17. 19871
                   tional d n i g . Under this section, the
                   spoiisor may iiot coininercialize a n in-
                   vestigational drug by charging a price                   Subpart B-Investigational New
                   larger t h a n t h a t necessary t o recover                Drug Application (IND)
                   costs of manufacture, research, clevel-
                   opnieiit. and halidling of the investiga-              4 312.20 Requirement for a n IND.
                   tional drug.
                                                                             ( a ) A sponsor shall submit a n IND t o
                       (4) Witlzdruwal o f uutlzori%utio?z. ALP           FDA if t h e sponsor intends t o conduct
                   thorization t o charge for a n investiga-              a clinical iiivestigation with a n inves-
                                            this section may be
                   tional drug ~ ~ i i c l e r                            tigational new clrug t h a t is subject t o
                   withdrawn by FDA if t h e agency finds                 § 312.2(a).
                   t h a t the coliclitions underlying t h e au-
                                                                             (b) A sponsor shall not begin a clin-
                   thorization are no longer satisfied.
                                                                          ical iiivestigation subject t o §312.2(a)
                   (Collection of information reqnirements ag-            until the investigation is subject to a n
                   proved Isy the Office of Management and                IND which is i n effect i n accordaiice
                   Bndget under control nnmher 0910-0014)                 with § 312.40.
                   152 F R 8831. Mar. 19, 1987. as amended a t 52            ( c ) A sponsor shall submit a separate
                   F R 19476. May 22. 19871                               IND for any clinical iiivestigation in-
                                                                          volving a n exception froin informed
                   S 312.10 Waivers.                                                         $50.24 of this chapter.
                                                                          coiisent ~ ~ i i c l e ~
                     ( a ) A sponsor may request FDA t o                  Such a clinical investigation is not
                   waive applicable 'equireinent under                    perniittecl t o proceed without t h e prior
                   this part. A waiver request may be sub-                written authorization froin FDA. FDA
                   niittecl either i n a n IND or i n a n iiifor-         shall provide a written deterniination
                   ination ainenclment to a n IND. In a n                 30 days after FDA receives the IND or
                   eniergency. a request may be niacle by                 earlier.
                   telephone or other rapid communica-                    [52 F R 8831. Mar. 19. 1987. as amended a t 61
                   tion mealis. A waiver                  is re-          F R 51529, Oct. 2. 1996: 62 F R 32479. June 16,
                   quired t o contain a t least one of the                19971
                   following:
                     ( I ) An explanation why t h e sponsor's             S 312.21 Phases of an investigation.
                   compliaiice with the requirement is LX-                  An IND niay be submitted for one or
                   necessary or cannot be achieved:                       more phases of a n investigation. The
                     (2) A clescription of a n alternative                clinical iiivestigation of a previously
                   submission or course of action t h a t                 untested clrug is generally divided into
                   satisfies the purpose of the require-                  three phases. Although i n general the
                   ment: or                                               phases are conducted sequentially,




© 2002 by CRC Press LLC
        224      Clinical Research Coordinator Handbook




                                                                                       21 CFR Ch. 1 (4-1-01 Edition)
                   they m a y overlap. These three phases 4312.22 General principles of the IND
                   of a n investigation are a follows:                            submission.
                      ( a ) Phase I . (1) Phase 1 includes t h e               ( a ) FDA's primary objectives in re-
                   initial iiitroductioii of a n investiga- viewing a n IND are. in all phases of the
                   tional iiew drug i n t o hunians. Phase 1 investigation, t o assure the safety and
                   studies are typically closely nioiiitored                'ights of subjects. aiicl. i n Phase 2 and
                   and may be conducted in patients or 3, t o help assure t h a t t h e quality of the
                   normal volunteer subjects. These stud- scientific evaluation of drugs i s acle-
                   ies are designed t o determine the me- quate t o permit a n evaluation of the
                   tabolisni and pharniacologic actions of drug's effectiveness and safety. There-
                   t h e drug in hunians. the sicle effects as- fore, although FDA's review of Phase 1
                   sociated with iiicreasiiig doses. aiicl. if subinissioiis will focus on assessing the
                   possible, to gain early evidence on ef- safety of Phase 1 investigations, FDA's
                   fectiveness. During Phase 1, sufficient review of Phases 2 and 3 submissions
                   information about the drug's phar- will also include a n assessment of the
                   niacokinetics and pharniacological ef- scientific quality of the clinical inves-
                   fects should be obtained to perniit the tigations and the likelihood t h a t the
                   clesign of w e l l - ~ o i i t ~ o l l e scieiitifically investigatioiis will yield data capable
                                                            d.
                   valid, Phase 2 studies. The t o t a l num- of meeting s t a t u t o r y standards for
                                                                            niarketing approval.
                   ber of subjects and patients included i n
                                                                               (b) The amount of iiiforination on a
                   Phase 1 studies varies with the clrug,
                                                                            particular drug t h a t must be submitted
                   but is generally i n t h e range of 20 t o 80.
                                                                            in a n IND t o assure t h e accoinplish-
                      (2) Phase 1 studies also include stud- inent of t h e objectives described i n
                   ies of drug metabolisni. structure-ac- paragraph ( a ) of this section depends
                   tivity relatioiiships. aiicl niechanisni of upon such factors a s t h e novelty of the
                   action i n huinaiis. a s well a s studies in drug. t h e extent to which i t has been
                   which investigational drugs are used a s studiecl previously, the known or sus-
                   research tools to explore biological                     pected risks. and the clevelopnieiital
                   phenomena or disease processes.                          phase of the clrug.
                      (b) Phase 2. Phase 2 includes t h e con-                 ( c j The central focus of t h e initial
                   trolled clinical studies conducted t o IND submission should be on the gen-
                   evaluate t h e effectiveness of the drug eral investigational plan and t h e proto-
                   for a particular indication or iiiclica- cols for specific hunian studies. Subse-
                   tioiis in patients with the disease or quent amendments t o t h e IND t h a t
                   condition under study and t o deter- contain iiew or revised protocols shoulcl
                   mine the common short-term sicle ef- build logically on previous submissions
                   fects and risks associatecl with the and should be supported by additional
                   drug. Phase 2 studies are typically well information, including the results of
                   ~ o i i t ~ o l l e closely nionitorecl. aiicl con- aiiinial toxicology studies or other
                                       d.
                   ducted i n a relatively sinall iiuniber of human studies a s appropriate. Annual
                   patients, usually involving no more reports t o t h e IND should serve a s the
                   t h a n several hundred subjects.                        focus for reporting t h e s t a t u s of stuclies
                                                                            being coiiducted under t h e IND and
                      ( c j Phase 3. Phase 3 stuclies are ex-
                                                                            should update the general investiga-
                   panded controlled and uncontrolled                       tional plan for t h e coniing year.
                   trials. They are performed after pre-                       (d) The IND format s e t forth in
                   liiniiiary evidence suggesting effective- s312.23 should be followed                                   by
                   ness of t h e drug has been obtained. and sponsors i n t h e interest of fostering a n
                   are intended t o gather the additional efficient review of applicatioiis. Spoii-
                   information about effectiveness and sors a r e expected t o exercise consicler-
                   safety t h a t i s needed t o evaluate the able ~ l i s c ~ e t i o ihowever. regarding the
                                                                                               i.
                   overall benefit-risk relationship of the content of information submitted i n
                   drug and t o provide a n adequate basis each section. depending upon t h e kind
                   for physician labeling. Phase 3 studies of drug being studiecl and the nature of
                   usually iiiclucle froni several h ~ m d ~ e d h e available information. Section
                                                                            t
                   t o several thousand subjects.                           312.23 outlines t h e information needed




© 2002 by CRC Press LLC
                                                                           Appendix A: FDA Regulations                  225




                   Food and Drug Administration, HHS
                   for a connnercially sponsored IND for a                (viij The naine(s) and title(s) of the
                   new niolecular e n t i t y . A spoiisor-inves-                                           §r
                                                                      person(s j 'esponsible ~ ~ i i d e 312.32 for
                   tigator who uses, a s a research tool, a n         review and evaluation of information
                   investigational new drug t h a t i s al-                          to the safety of t h e drug.
                   ready subject t o a manufacturer's IND                 (viiij If a sponsor has transferrecl a n y
                   or marketing application should follow             obligations for t h e conduct of aiiy clin-
                   t h e same general format, but orcli-              ical stucly t o a contract research orga-
                   narily niay. if authorized by the maiiu-           nization. a s t a t e m e n t containing the
                   facturer, refer t o the manufacturer's             name and address of the contract re-
                   IND or marketing application i n pro-              search organization. identification of
                   viding the technical information sup-              t h e clinical study, and a listing of the
                   porting the proposed clinical investiga-           obligations transferrecl. If all obliga-
                   tion. A sponsor-investigator who uses              tions governing t h e conduct of t h e
                   a n investigatioiial drug not subject t o          study have been transferred. a general
                   a manufacturer's IND or marketing ap-              s t a t e m e n t of this transfer-in lieu of a
                   plication is orcliiiarily              t o sub-    listing of t h e specific obligations trans-
                   m i t all technical information sup-               ferrecl-may be subinittecl.
                                                  such iiifornia-
                   porting t h e IND. ~ ~ i i l e s s                     (ixj The signature of t h e spoiisor or
                   tion m a y be referenced froin the sci-            t h e sponsor's authorized representa-
                   entific literature.                                tive. If t h e person signing the applica-
                                                                      tion does n o t reside or have a place of
                   4 312.23 IND content and format.                   business within the United States. the
                       ( a ) A sponsor who intends t o concluct       IND is required t o contain the name
                   a clinical iiivestigation subject to t h i s       and address of. and be countersigned
                   part shall submit a n "Investigational             by, a n a t t o r n e y , agent, or other au-
                   New Drug Application" (INDj includ-                thorized official who resides or main-
                   ing, in the following order:                       t a i n s a place of business within the
                       ( I ) Cover sheet (Fornz FDA-1571). A          United States.
                   cover sheet for t h e application coii-                (2)A table o f contents.
                   taining the following:                                 (3) Introductory statement and general
                       (i) The name. address. and telephone           investigatioizal plan. ( i j A brief introduc-
                   number of the sponsor, t h e date of the           tory statenleiit giving the naine of the
                   application. and the iianie of t h e iiives-       clrug and all active ingredients, the
                   tigational new clrug.                              drug's pharniacological              class. the
                       (ii) Identification of the phase or            structural formula of t h e drug (if
                   phases of the clinical investigation t o           known). the forniulation of t h e dosage
                   be conducted.                                      form(s) t o be used, the route of aclmin-
                       (iii) A colnmitinent not t o begin clin-       istration. and the broad objectives and
                   ical investigations until a n IND cov-             planned duration of t h e proposed clin-
                   ering the investigations i s i n effect.           ical investigatioii(s).
                       (iv) A coininitment t h a t a n Institu-           (ii) A brief summary of previous
                   tioiial Review Board (IRB) t h a t coni-           human experience with t h e drug. with
                   plies with t h e requirements set forth i n        reference to other IND's if pertinent,
                   part 56 will be respoiisible for the ini-          and to investigational or marketing ex-
                   t i a l and continuing review and ap-              perience i n other countries t h a t m a y
                   proval of each of the studies i n the pro-         be relevant t o the safety of t h e pro-
                   posed clinical investigation and t h a t           posed clinical investigation(sj.
                   t h e investigator will report t o the IRB             (iiij If the drug has been withdrawn
                   proposecl changes i n the research activ-          from investigation or marketing i n a n y
                   i t y in accordance with the require-              co~mtry       for aiiy reason related to safe-
                   ments of p a r t 56.                               t y or effectiveness, identification of
                       (v) A commitment to conduct t h e in-          t h e co~u?try(iesjwhere t h e drug was
                   vestigation i n accordance with all                withdrawn and the reasons for the
                   other applicable regulatory require-               withdrawal.
                   nients.                                                (iv) A brief description of t h e overall
                       (vij The naine and t i t l e of t h e person   plan for investigating the drug product
                   responsible for monitoring t h e concluct          for the following year. The plan should
                   and progress of t h e clinical investiga-          include the following: ( a j The
                   tions.                                             for the drug or t h e research stucly: (6)




© 2002 by CRC Press LLC
        226      Clinical Research Coordinator Handbook




                                                                                         21 CFR Ch. 1 (4-1-01 Edition)
                   t h e inclication(s1 t o be studiecl: ( c j the            those elements of the stucly t h a t are
                   general approach t o be followecl i n                      critical t o safety. such a s necessary
                   evaluating the drug: (dl the kinds of                      monitoring of vital signs and blood
                   clinical trials to be coiiducted i n the                   cheniistries. Moclificatioiis of the ex-
                   first year following t h e submission (if                  perimental design of Phase I studies
                   plans are n o t developed for the entire                   t h a t do not affect critical safety as-
                   year, t h e sponsor shoulcl so indicate):                  sessments a r e required t o be reported
                   (e) the estimated number of patieiits t o                  t o FDA only in the aiinual report.
                   be given the drug i n those studies: and                      (ii) In Phases 2 and 3, detailed proto-
                   (f~ a n y risks of particular severity or                  cols describing all aspects of t h e study
                   seriousness anticipated on t h e basis of                  shoulcl be submitted. A protocol for a
                   t h e toxicological data in aniinals or                    Phase 2 or 3 investigation shoulcl be de-
                   prior studies in humans with the drug                      signed i n such a way t h a t , if the spon-
                   or related drugs.                                          sor anticipates t h a t some cleviation
                      (4)[Reserved]                                           from the stucly clesign m a y become nec-
                      (5) I?zvestigc~tor'sbroclzure. If required              essary a s the investigation progresses.
                   under Q312.55,a copy of the investiga-                     alternatives or contingencies to pro-
                   tor's brochure. containing the fol-                        vide for such deviation are built i n t o
                   lowing information:                                        t h e protocols a t the outset. For exain-
                                                          of
                      (i) A brief ~ l e s c ~ i p t i o i i the drug          ple. a protocol for a controlled short-
                   substance and the formulation, includ-                     t e r m study might include a plan for a n
                   ing t h e structural formula. if kiiown.                                                                rs
                                                                              early crossover of n o i ~ ~ e s p o n d e t o a n
                      (ii) A sulninary of the pharma-                         alternative therapy.
                   cological and toxicological effects of                        (iii) A protocol is required t o contain
                   t h e drug i n animals and, t o t h e extent               t h e following, with the specific ele-
                   kiiown. i n hunians.                                       nieiits aiicl detail of t h e protocol re-
                      (iii) A sulnlnary of the pharmaco-                      flecting the above distinctions depend-
                   kinetics and biological disposition of                     ing on the phase of study:
                   t h e clrug i n animals and, if known, i n                    ( a ) A s t a t e m e n t of the objectives and
                   h~~inaiis.                                                 purpose of the study.
                      (iv) A summary of information relat-                       (6)The naine and address and a state-
                   ing to safety and effectiveness i n hu-                    nieiit of t h e qualifications ( c ~ ~ r ~ i c ~ ~ l ~ ~ i n
                   mans obtained from prior clinical stud-                    vitae or other s t a t e m e n t of qualifica-
                   ies. (Reprints of published articles on                    tions) of each investigator. and the
                   such studies m a y be appended when                        name of each subinvestigator (e.g., re-
                   useful.)                                                   search fellow. resident) working under
                      (v) A description of possible risks and                 t h e supervision of the investigator: the
                   side effects t o be anticipated on the                     naine and address of t h e research fa-
                   basis of prior experience with t h e drug                  cilities to be used: and the name and
                   under iiivestigation or with related                       address of each                      Institutional
                   drugs, and of precautions or special                       Review Board.
                                       ig
                   n i o n i t ~ ~ i i t o be clone a s p a r t of the iii-      (c) The criteria for patient selection
                   vestigational use of the clrug.                            and for exclusion of patients and a n es-
                      (6) Protocols. ( i ) A protocol for each                tiniate of the iiuniber of patieiits to be
                   planned study. (Protocols for studies                      studiecl.
                   n o t subniittecl initially i n the IND                       (cl) A description of the design of the
                   shoulcl be submitted in accordance with                    study, inclucling the kind of control
                   §312.30(a).) In general. protocols for                     group t o be used. if any. and a clescrip-
                   Phase 1 studies m a y be less cletailed                    tion of methods t o be used to minimize
                   and niore flexible t h a n protocols for                   bias on the part of subjects. iiivestiga-
                   Phase 2 and 3 studies. Phase I protocols                   tors, and analysts.
                   shoulcl be directed priniarily a t pro-                                                                    g
                                                                                 (e) The method for ~ l e t e ~ i n i i i i nthe
                   viding a n outline of t h e investigation-                 close(s1 t o be aclministered, t h e planned
                   a n estimate of the iiuniber of patieiits                  niaxiniuni dosage. and the duration of
                   t o be involved, a description of safety                   individual patient exposure to the
                   exclusions. and a description of the                       drug.
                   closing plan inclucling duration, dose, or                    ( f j A description of the observations
                   niethocl t o be used in deterniiniiig                                                     o s
                                                                              and m e a s ~ ~ ~ e i n etn t be inacle to fulfill
                   close-and shoulcl specify i n detail only                  t h e objectives of t h e stucly.




© 2002 by CRC Press LLC
                                                                         Appendix A: FDA Regulations                 227




                   Food and Drug Administration, HHS
                      (gj A description of clinical proce-          formation appropriate to the expanded
                   dures. laboratory tests. or other nieas-         scope of t h e investigation.
                   ures to be t a k e n t o monitor t h e effects      (iv) Reflecting the clistinctions de-
                   of t h e drug i n human subjects aiicl t o       scribed i n this paragraph (aj(7). and
                   minimize risk.                                   based on the phase(s) t o be studied, t h e
                      (7j Clzemistry, n~unzifucturing,und con-      submission i s                t o contain the
                   trol infornmtion. ( i j As appropriate for       following:
                   t h e particular iiivestigations covered                                     A
                                                                       ( a ) Drzig ~zib~tunce. description of
                   by the IND, a section describing the             t h e clrug substance, inclucling i t s phys-
                   composition. maiiufacture. and control           ical. chemical. or biological character-
                   of the clrug substance and the drug              istics: the name and address of i t s man-
                   product. Although i n each phase of the          ufacturer: the general method of prepa-
                   investigation sufficient information i s         ration of t h e drug substance: t h e ac-
                                 to be submitted to assure the      ceptable liniits and analytical niethods
                   proper identification, quality, purity,          used t o assure the identity, strength,
                   and strength of the investigatioiial             quality. and purity of the drug sub-
                   clrug, t h e amount of information need-         stance: and information sufficient t o
                   ed t o niake t h a t assurance will vary         support stability of the drug substaiice
                   with the phase of the investigation, t h e       cluring the toxicological studies and
                   proposed duration of the iiivestigation.         t h e plaiiiied clinical studies. Reference
                   t h e dosage form, and the amount of in-         t o t h e current edition of the United
                   formation otherwise available. FDA               S t a t e s Pharinacopeia-National        For-
                   recognizes t h a t moclifications to the         inulary m a y satisfy relevant require-
                   niethocl of preparation of the iiew drug         nieiits in this paragraph.
                   substance and closage form and changes              ( 6 ) Drzig prodzict. A list of all coinpo-
                   in t h e closage forin itself are likely a s     nents. which niay iiiclucle reasonable
                   t h e investigation progresses. There-           alternatives for inactive compounds,
                   fore. t h e eniphasis i n a n initial Phase 1    used i n the nianufact~weof t h e inves-
                   submission should generally be placed            tigational drug procluct, including both
                   on t h e icleiitification aiicl control of the   those conipoiieiits inteiiclecl to appear
                   raw ~ n a t e r i a l sand the new clrug sub-    in t h e clrug product and those which
                   stance. Filial specificatioiis for the           niay n o t appear but which are used in
                   clrug substance and drug product are             t h e inanufacturing process, and, where
                   n o t expected until the end of the iiives-      applicable. t h e quantitative composi-
                   tigational process.                              tion of the investigational drug prod-
                      (ii) I t should be eniphasizecl t h a t the   uct. including a n y reasonable vari-
                   amount of information t o be submitted           ations t h a t may be expected cluring the
                   clepeiicls upon the scope of the proposed        investigational stage: the name and ad-
                   clinical investigation. For example, al-         dress of the clrug product manufac-
                   though stability data are                   in   turer: a brief general clescription of the
                   all phases of the IND t o demonstrate            inanufacturing and packaging proce-
                   t h a t t h e iiew drug substaiice aiicl drug    dure a s appropriate for the product: the
                   product a r e within acceptable chemical         acceptable l i m i t s and analytical meth-
                   and physical liniits for the planned clu-        ods used t o assure t h e identity.
                   ration of t h e proposed clinical inves-         strength, quality, and purity of the
                   tigation. if very short-tern? t e s t s are      drug product: and iiiforniation suffi-
                   proposecl, the supporting stability d a t a      cient t o assure t h e product's stability
                                                      limited.
                   can be c ~ ~ r e s p o n c l i n g l y           cluriiig the plaiiiied clinical studies.
                      (iii) As drug development proceeds            Reference to the current edition of the
                   and a s the scale or production is               United S t a t e s Pharniacopeia-National
                   changed froin t h e pilot-scale produc-          Formulary m a y satisfy certain require-
                   tion appropriate for the limited initial         nieiits in this paragraph.
                   clinical investigations t o the larger-             (c) A brief general description of the
                   scale production needed for expanded             composition. maiiufacture. and control
                   clinical trials, t h e sponsor should sub-       of a n y placebo used in a controlled
                   niit iiiforniation aniendnieiits to sup-         clinical trial.
                   plement t h e initial information sub-              (d) Labeling. A copy of all labels and
                   niittecl on t h e cheniistry. nianufac-          labeling t o be provided t o each investi-
                   turing, and control processes with in-           gator.




© 2002 by CRC Press LLC
        228      Clinical Research Coordinator Handbook




                                                                                     21 CFR Ch. 1 (4-1-01 Edition)
                     ( e ) Environmental aizalysis reqziire-               (iii) For each nonclinical laboratory
                   nzents. A claini for categorical exclu-              study subject t o the good laboratory
                   sion under Q25.30or 25.31 or a n environ-            practice regulations under p a r t 58, a
                                                   s
                   nieiital assessnieiit ~~iicle'25.40.                 stateineiit t h a t t h e study was con-
                       (8) Phc~rmc~cology     and toxicology infor-     cluctecl in compliance with t h e good
                   nzution. Adequate information about                  laboratory practice regulatioiis in p a r t
                   pharmacological             and    toxicological     58, or, if the study was n o t conducted
                   studies of the drug involving labora-                in conipliance with those                        a
                   t o r y animals or i n vitro, on the basis of        brief s t a t e m e n t of the reason for t h e
                   which t h e sponsor has coiicluclecl t h a t         noiiconipliaiice.
                   i t is reasonably safe to conduct the                   (9) Previozis hzinzaiz e,rperience w i t h t h e
                   proposecl cliiiical investigatioiis. The             investigutio?zal drug. A summary of pre-
                   kind, duration, and scope of animal and              vious human experience known t o the
                   other t e s t s required varies with t h e clu-      applicant. if any. with the investiga-
                   ration and n a t u r e of the proposecl clin-        tional clrug. The information i s re-
                   ical iiivestigations. Guidance clocu-                quired t o iiiclude t h e following:
                   inents are available from FDA t h a t de-               ( i j If the investigational clrug has
                   scribe ways in which these                           been investigated or inarketecl pre-
                   ments may be m e t . Such information i s            viously, either i n t h e United S t a t e s or
                                 t o iiiclucle t h e ideiitificatioii   other countries. detailed iiiforination
                   and qualifications of the individuals                about such experience t h a t is relevant
                   who evaluated the                  of such stud-     t o the safety of t h e proposed iiivestiga-
                   ies and concluded t h a t i t i s reasonably         tion or to the investigation's rationale.
                   safe to begin t h e proposecl investiga-             If t h e durg has been t h e subject of con-
                   tions and a s t a t e m e n t of where t h e in-     trolled trials, detailed information on
                   vestigations were conducted and where                such trials t h a t is relevant t o a n as-
                   t h e records are available for inspec-              sessment of the clrug's effectiveness for
                   tion. As drug developnieiit proceeds.                t h e proposed iiivestigational use(s j
                   t h e sponsor i s required t o submit infor-         shoulcl also be provided. Any publishecl
                   niatioiial anieiiclineiits. a s appropriate.         material t h a t i s relevant t o t h e safety
                   with additional information pertinent                of the proposed investigation or t o a n
                   t o safety.                                          assessnieiit of the drug's effectiveness
                       ( i j Phc~rn~ucology   and drug disposition.     for i t s proposecl investigational use
                   A section describing t h e pharina-                                                          l.
                                                                        shoulcl be provided i n f ~ ~ l Published
                   cological effects and mechanism(s) of                material t h a t i s less clirectly relevant
                   action of the drug in aiiinials. aiicl iii-          niay be supplied by a bibliography.
                   formation on t h e absorption, distribu-                (ii) If t h e clrug i s a combination of
                   tion. nietabolisni. and excretion of the             drugs previously investigated or niar-
                   clrug, if known.                                     keted, t h e information required under
                       (ii j Toxicology. ( a j An integrated sum-       paragraph (aj(9j(i) of this section
                   mary of the toxicological effects of the             shoulcl be provided for each active drug
                   drug i n aniinals and i n vitro. Depeiid-            coinponent. However. if a n y coinponent
                   ing on the n a t u r e of the clrug and the          in such combination i s subject t o a n
                   phase of the investigatioii. the descrip-            approved inarketiiig application or i s
                   tion i s to include the results of acute,            otherwise lawfully marketed in the
                   subacute. aiicl chronic toxicity tests:              United States. t h e spoilsor is n o t re-
                   t e s t s of the drug's effects on reproduc-         quired t o submit published material
                   tion and t h e developing fetus: a n y spe-                              tg
                                                                        ~ o i i c e ~ i i i nh a t active drug coinponent
                   cial toxicity t e s t related to the drug's          unless such material relates clirectly t o
                   particular inode of adniiiiistration or              t h e proposed iiivestigatioiial use (iii-
                   conditions of use (e.g., inhalation, cler-           clucling publications relevant t o corn-
                   nial. or ocular toxicology): and a n y i n           ponent-component interaction).
                   vitro studies intencled t o evaluate clrug              (iii) If the clrug has been marketed
                   toxicity.                                            outside the United States. a list of the
                       ( 6 ) For each toxicology study t h a t i s      countries i n which t h e drug has been
                   intended primarily t o support the safe-             marketed and a list of t h e countries i n
                   t y of the proposed clinical investiga-              which the drug has been withdrawn
                   tion. a full tabulation of data suitable             froin marketing for reasons potentially
                   for detailed review.                                 related t o safety or effectiveness.




© 2002 by CRC Press LLC
                                                                                 Appendix A: FDA Regulations                       229




                   Food and Drug Administration, HHS
                       (10) Additional iizfol-mation. In certain            of all submissions t o the IND file, in-
                   applicatioiis. a s described below. infor-               cluding t h e original submission and all
                   mation on special topics may be need-                    ainenclinents and 'eports.
                   ed. Such information shall be sub-                          (el Yunzbel-ing of LVD siibnzissions.
                   m i t t e d i n this section a s follows:                Each submission relating to a n IND i s
                       (i) Drug depe?zde?zce cmd clbuse poten-              required t o be numbered serially using
                   tial. If the drug is a psychotropic sub-                 a single. three-digit serial iiumber. The
                   stance or otherwise has abuse poteii-                    initial IND is              t o be numbered
                   t i a l , a section describing relevant clin-            000: each subsequent submission (e.g.,
                   ical studies aiicl experience and studies                ainenclinent. report. or correspoiidence)
                   in t e s t animals.                                      is required t o be numbered chrono-
                       (iij Radioactive drugs. If the drug i s a            logically i n sequence.
                   radioactive drug, sufficient clata from                     (fj Identification of e,rception from i n -
                   aiiinial or hunian studies t o allow a                   formed consent. If the investigation iii-
                   reasonable calculation of racliation-ab-                 volves a n exception froin informed con-
                   sorbed close t o the whole body aiicl crit-              sent under 950.24 of this chapter. t h e
                   ical organs upon administration t o a                    sponsor shall proininently iclentify on
                   human subject. Phase 1 studies of ra-                    t h e cover sheet t h a t the iiivestigation
                   dioactive drugs must include studies                     is subject to t h e requirements i n $50.24
                   which will obtain sufficient clata for                   of this chapter.
                   closiinetry calculations.                                (Collection of information reqnirements ap-
                       (iii j Pediatric studies. Plans for assess-          proved h y the Office of Management and
                   ing pediatric safety and effectiveness.                  Budget under control numlser 0910-0014)
                       (iv j Other i nformcltion. A brief s t a t e -       [52 F R 8831. Mar. 19. 1987. as ameilcled a t 52
                   ment of a n y other information t h a t                  FR 23031. J ~ m e 1987: 53 FR 1918, Jan. 25.
                                                                                                17,
                   would aid evaluation of the proposed                     1988: 61 F R 51529. Oct. 2. 1996. 62 F R 40599.
                   clinical investigations with respect t o                 J u l y 29. 1997. 63 F R 66669. Dec. 2. 1998: 65 F R
                   their safety or their design and poten-                  56479, Sept. 19, 20001
                   t i a l a s controlled clinical t r i a l s t o sup-
                   port marketing of the drug.                              S 312.30 Protocol amendments.
                       (11) Relevant i n f o m a t i o n . If requested        Once a n IND i s in effect, a sponsor
                   by FDA. a n y other                         iiifornia-   shall anieiicl i t a s needed t o ensure t h a t
                   tion needed for review of the applica-                   t h e clinical investigations are con-
                   tion.                                                    ducted according to protocols included
                       (b) I n f o ~ m a t i o n p~eviozisly siibnzitted.   in t h e application. This section sets
                   The spoiisor ordinarily is n o t required                forth t h e provisioiis ~ m d e rwhich new
                   t o resubmit information previously                      protocols m a y be subinittecl and
                   submitted. but m a y incorporate t h e iii-              changes i n previously subinittecl proto-
                   formation by reference. A reference t o                  cols m a y be made. Whenever a sponsor
                   inforniation submitted previously niust                  intends t o conduct a clinical iiivestiga-
                   iclentify the file by name, reference                    tion with a n exception froin informed
                   number. volunie. and page number                         coiisent for eniergeiicy research a s s e t
                   where the information can be found. A                    forth i n $50.24 of this chapter, t h e spon-
                   reference to information submitted t o                   sor shall subniit a separate IND for
                   t h e agency by a person other t h a n the               such investigation.
                   spoiisor i s required t o coiitain a writ-                  ( a ) S e x protocol. Whenever a sponsor
                   t e n s t a t e m e n t t h a t authorizes t h e ref-    intencls t o conduct a stucly t h a t i s not
                   erence and t h a t i s signed by the person              covered by a protocol already coii-
                   who subinittecl the information.                         tained i n the IND, the sponsor shall
                       (c) iWcltericll i n a foreign lc11~g~age.     The    submit t o FDA a protocol ainenclinent
                   sponsor shall submit a n accurate and                    containing the protocol for the stucly.
                   complete English translation of each                     Such study m a y begin provided two
                   part of the IND t h a t i s n o t in English.            conditions are met: (1)The sponsor has
                   The spoiisor shall also submit a copy of                 submitted the protocol t o FDA for i t s
                   each original literature publication for                 review: and (2) the protocol has been
                   which a n English traiislation i s sub-                  approved by t h e Institutional Review
                   mitted.                                                  Board (IRB) with responsibility for re-
                       (dj Number of copies. The spoiisor                   view aiicl approval of t h e study i n ac-
                   shall submit a n original and two copies                 cordance with the requirements of p a r t




© 2002 by CRC Press LLC
        230      Clinical Research Coordinator Handbook




                                                                                      21 CFR Ch. 1 (4-1-01 Edition)
                   56. The sponsor m a y coinply with these               investigator and the investigator may
                   two conditioiis i n either order.                      begin participating i n t h e study. The
                      (b) Chunyes i n CL p ~ o t o c o l .(1) A sponsor   spoiisor shall notify FDA of the new in-
                   shall submit a protocol ainenclment de-                vestigator within 30 clays of t h e inves-
                   scribing aiiy change i n a Phase 1 pro-                tigator being adclecl.
                   tocol t h a t significantly affects the                   (dj Content a n d fornzclt. A protocol
                   safety of subjects or aiiy chaiige in a                amenclment i s required t o be proini-
                   Phase 2 or 3 protocol t h a t significantly            nently identified a s such (i.e., "Pro-
                   affects the safety of subjects. the scope              tocol Amendment: New Protocol",
                   of the investigation, or t h e scientific
                                                                          ..Protocol Amendnieiit: Change i n Pro-
                   quality of t h e study. Exaniples of
                   changes requiring a n amendment uncler                 tocol". or ..Protocol Anieiidnieiit: New
                   this paragraph iiiclucle:                              Investigator"). and t o contain the fol-
                      ( i j Any increase i n clrug dosage or clu-         lowing:
                   ration of exposure of individual sub-                     (lj(ij In the case of a iiew protocol. a
                   jects t o the clrug beyond t h a t i n the             copy of the new protocol and a brief de-
                   current protocol. or a n y significant ill-            scription of the most clinically signifi-
                   crease i n t h e number of subjects uncler             c a n t differences between i t and pre-
                   study.                                                 vious protocols.
                      (iij Any sigiiificaiit chaiige in t h e de-            (ii) In the case of a change i n pro-
                   sign of a protocol (such a s t h e acldition           tocol. a brief clescription of the chaiige
                   or dropping of a control group).                       and reference (date aiicl iiuniber) t o t h e
                      (iii) The acldition of a new t e s t or                                 t
                                                                          s ~ ~ b m i s s i o nh a t contained t h e pro-
                   procedure t h a t i s intended t o improve             tocol.
                   monitoring for, or reduce the risk of, a                  (iiij In the case of a iiew investigator.
                   side effect or adverse event: or the                   t h e investigator's name, the qualifica-
                   dropping of a t e s t intended t o monitor             tions t o conduct t h e investigation, ref-
                   safety.                                                erence to t h e previously submitted pro-
                      (2)(i) A protocol change uncler para-
                                                                          tocol. and all aclditioiial information
                   graph ( b ) ( l ) of this section niay be
                   made proviclecl two conditions are met:                about the iiivestigator's study a s i s re-
                      ( a ) The sponsor has submitted the                 quired under §312.23(aj(6j(iii j.   j(h
                   chaiige t o FDA for i t s review: and                     (2) Reference. if necessary. t o specific
                      ( 6 ) The change has been approved by               technical information in t h e IND or i n
                   t h e IRB with respoiisibility for review              a concurrently submitted information
                   and approval of t h e study. The sponsor               amenclment t o t h e IND t h a t the spon-
                   niay coniply with these two conclitioiis               sor relies on t o support a n y clinically
                   in either order.                                       sigiiificaiit chaiige i n the iiew or
                      (ii j    Notwithstanding               paragraph    amended protocol. If the reference i s
                   (bj(2)(ij of this section, a protocol                                                 iig
                                                                          niacle to s ~ ~ p p o ~ t i information al-
                   chaiige iiiteiidecl t o eliiniiiate a n appar-         ready i n t h e IND, t h e sponsor shall
                   e n t immediate hazard t o subjects m a y              identify by name, reference number,
                   be iniplenieiitecl iinniediately provided              volume, and page number t h e location
                   FDA is subsequently notified by pro-                   of the iiiforniatioii.
                   tocol anieiidnieiit aiicl t h e reviewing                 (3) If t h e sponsor desires FDA t o corn-
                   IRB i s notified i n accordance with                                                     a
                                                                          nieiit on the s~~binissioii. request for
                   § 56.lO4(cj.
                                                                          such coinnieiit and the specific ques-
                      (c) S e x investigc~tor. A spoiisor shall
                                                                          tions FDA's response should address.
                   submit a protocol amendment when a
                   new iiivestigator is added to carry o u t                 (e) W h e n submitted. A sponsor shall
                   a previously submitted protocol, except                submit a protocol anieiidnieiit for a
                   t h a t a protocol anieiiclinent i s n o t re-         new protocol or a change i n protocol
                   quired when a licensed practitioner i s                before i t s implementation. Protocol
                   added i n t h e case of a t r e a t m e n t pro-       amenclments t o acld a new investigator
                   tocol under s312.34. Once t h e investi-               or to provide additional iiiforniatioii
                   gator i s acldecl t o the study. the iiives-           about investigators niay be grouped
                   tigational clrug m a y be shipped to the               and subniittecl a t 30-clay intervals.




© 2002 by CRC Press LLC
                                                                                Appendix A: FDA Regulations                    23 1




                   Food and Drug Administration, HHS
                   When several submissions of new proto-                    Associated w i t h t h e zise of t h e dl-zig.
                   cols or protocol changes a r e aiitici-                 There i s a reasonable possibility t h a t
                   pated during a short period, t h e spon-                t h e experience m a y have been caused
                   sor is eiicouraged. t o t h e extent fea-               by the drug.
                   sible, to include these a l l i n a single                 Disability. A substantial disruption of
                   subinissioii.                                           a person's ability t o coiiduct iiorinal
                   (Collection of information reqnirements ap-             life f ~ m c t i o n s .
                   proved Isy the Office of Mnnagement nnd                   Life-tkrecltening cldverse drug experi-
                   Bndget under control nnmher 0910-0014)                  ence. Any adverse drug experience t h a t
                                                                           places t h e patient or subject. in t h e
                   [52 F R 8831. Mar. 19. 1987. ns nmencled a t 52
                   F R 23031. J u n e 17. 1987: 53 F R 1918. Jnn. 25.
                                                                           view of t h e investigator, a t immediate
                   1988: 61 FR 51530, Oct. 2, 19961                        risk of death froin the reaction a s i t oc-
                                                                           curred, i.e., i t does n o t inclucle a reac-
                   S 312.31 Information amendments.                        tion t h a t . had i t occurred i n a inore se-
                                                                           vere form, might have caused death.
                      ( a ) Requirement for infornmtion anzend-
                   nlent. A sponsor shall report i n a n in-                   Serious cldverse drug experience: Any
                                                                           adverse clrug experience occurring a t
                   formation ainendnieiit essential infor-
                                                                           a n y dose t h a t          i n a n y of the fol-
                   mation on the IND t h a t is n o t within
                                                                           lowing outcomes: Death, a life-threat-
                   t h e scope of a protocol ainenclinent.
                                                                           ening adverse drug experience. inpa-
                   IND safety reports, or annual report.
                                                                           t i e n t hospitalization or prolongation of
                   Exaniples of iiiforniatioii                        an
                                                                           existing hospitalizatioii. a persistent or
                   information amendment inclucle:
                                                                           significant disability incapacity, or a
                      ( I ) New toxicology, chemistry, or
                                                                           coiigenital aiioinaly birth defect. Ini-
                   other technical iiiforniatioii: or
                                                                           portant medical events t h a t inay n o t
                      (2) A report regarcliiig t h e cliscoiitiiiu-
                                                                                      in death. be life-threatening. or
                   ance of a clinical investigation.
                                                                           require hospitalization m a y be consid-
                      (b) Content a n d fol-mat of a n infol-ma-           ered a serious adverse drug experience
                   tion anzendnzent. An iiiforination ainend-              when, based upon appropriate medical
                   inent is required to bear prominent
                                                                           judgment. they m a y jeopardize the pa-
                   icleiitificatioii of i t s contents (e.g.. .'Ill-
                                                                           t i e n t or subject and inay require ined-
                   formation Amendment:                   Chemistry,
                                                                           ical or surgical iiiterventioii to prevent
                   Manufacturing. and Coiitrol". "Infor-
                                                                           one of t h e outcomes listed i n this defi-
                   mation Ainenclment: Pharinacology-
                                                                           nition. Exaniples of such ineclical
                   Toxicology".           "Iiiforniatioii       Ainend-
                                                                           events include allergic bronchospasm
                   ment: Clinical"), and t o contain the                                  intensive treatnieiit i n a n
                   following:
                                                                           emergency room or a t home, blood
                      ( I ) A s t a t e m e n t of t h e n a t u r e and   dyscrasias or convulsioiis t h a t do n o t
                   purpose of the ainendnieiit.                            result i n inpatient hospitalization, or
                      (2) An organized submission of the                   t h e developnieiit of drug depeiidency or
                   d a t a i n a format appropriate for sci-               clrug abuse.
                   entific review.                                           Unexpected cldverse drug experience:
                      (3) If t h e spoilsor desires FDA t o coin-          Any adverse clrug experience, the speci-
                   inent on a n information amendment, a                   ficity or severity of which i s n o t coii-
                               for such coniinent.                         sistent with the current investigator
                      ( c ) W h e n subnzitted. Information                brochure: or. if a n investigator bro-
                   ainenclinents t o the IND should be sub-                chure is n o t required or available, the
                   m i t t e d a s necessary b u t , to t h e extent       specificity or severity of which is n o t
                   feasible. n o t inore t h a n every 30 clays.           consistent with the risk information
                   (Collection of informntion requirements np-             clescribecl i n t h e general iiivestiga-
                   proved hy the Office of Management and                  tional plan or elsewhere i n the current
                   Budget under control numlser 0910-0014)                 application. a s amended. For exaniple.
                   [52 F R 8831. Mar. 19. 1987. ns nmencled a t 52         under this definition, hepatic necrosis
                   F R 23031. J u n e 17. 1987: 53 F R 1918. Jnn. 25.      would be unexpected (by virtue of
                                                                           greater severity) if the investigator
                                                                           brochure only referred to elevated he-
                   4 312.32 IND safety reports.                            patic enzymes or hepatitis. Similarly,
                      ( a ) Definitions. The following clefiiii-           cerebral throinboenibolisin aiicl cere-
                   tions of t e r m s apply to this section:-              bral vasculitis would be unexpected (by




© 2002 by CRC Press LLC
        232      Clinical Research Coordinator Handbook




                                                                                        21 CFR Ch. 1 (4-1-01 Edition)
                   virtue of greater specificity) if t h e in- mines t h a t additional d a t a are needed,
                   vestigator brochure only listed cere- t h e agency m a y require further data t o
                   bral vascular accidents. "Unexpected,"                           be submitted.
                   a s used i n this definition. refers t o a n                       (ii) In each written IND safety re-
                   adverse drug experience t h a t has n o t port, the sponsor shall identify all safe-
                   been previously observed (e.g.. included t y reports previously filed with the
                   in t h e investigator brochure) r a t h e r IND concerning a similar adverse expe-
                   t h a n from the perspective of such expe- rience. and shall analyze t h e signifi-
                   rience n o t being anticipated from the cance of the adverse experience i n light
                   pharniacological          properties of the                      of the previouos. siniilar reports.
                   pharmaceutical product.                                            (2) Telephone a n d facsinlile trans-
                       (b) Review o f sclfety infornmtion. The nzission safety reports. The sponsor shall
                   sponsor shall promptly review all infor- also notify FDA by telephone or by fac-
                   niation relevant t o t h e safety of t h e siniile transniission of a n y ~mexpected
                   drug obtained or otherwise receivecl by fatal or life-threatening experience as-
                   t h e spoiisor froni a n y source. foreign or sociated with the use of t h e drug a s
                   domestic, including information cle- soon a s possible but i n no event l a t e r
                             froni a n y clinical or epicleiniolog- t h a n 7 calendar days after t h e spoii-
                   ical investigations, animal investiga- sor's initial receipt of t h e information.
                   tions. coinniercial niarketiiig experi- Each telephone call or facsiniile trans-
                   ence, reports i n the scientific lit- mission t o FDA shall be transmitted t o
                   erature. and unpublished scientific pa- t h e FDA iiew drug review division i n
                   pers, a s well a s reports from foreign t h e Center for Drug Evaluation and Re-
                                    authorities t h a t have iiot search or the procluct review clivision
                   already been previously reported to the in the Center for Biologics Evaluation
                   agency by the sponsor.                                           and Research t h a t has responsibility
                       ( c j LVD safety reports. (1) Written re-                    for review of the IND.
                   ports-(i) The sponsor shall notify FDA                             ( 3j Reporting format or frequency. FDA
                   and all participating investigators i n a may request a sponsor to submit IND
                   written IND safety report of:                                    safety reports i n a forinat or a t a fre-
                       ( A ) Any adverse experience associ- quency clifferent t h a n t h a t required
                   ated with t h e use of t h e drug t h a t i s under this paragraph. The sponsor niay
                   both serious and unexpectecl: or                                 also propose and adopt a clifferent re-
                       (B) Any fiiidiiig from t e s t s i n labora- porting format or frequency if t h e
                   t o r y animals t h a t suggests a signifi- change i s agreed t o i n advance by the
                   c a n t risk for huniaii subjects iiiclucliiig director of t h e new drug review divi-
                   reports               of         mutagenicity, sion i n t h e Center for Drug Evaluation
                   teratogenicity.          or   ~ a ~ c i i i o g e i i i c i t y .and Research or the director of t h e
                   Each notification shall be made a s soon products review division in the Center
                   a s possible and i n no event later t h a n for Biologics Evaluation and Research
                   15 calendar days after t h e sponsor's ini- which i s responsible for review of the
                   t i a l receipt of t h e information. Each IND.
                   written notification m a y be submitted                            (4) A sponsor of a clinical study of a
                   on FDA Forin 3500A or i n a narrative marketed drug i s iiot required t o niake
                   format (foreign events m a y be sub- a safety report for a n y adverse experi-
                   niittecl either on a n FDA Forni 3500A ence associated with use of t h e drug
                   or, if preferred, on a CIOMS I form: re- t h a t is n o t from t h e clinical study
                   ports froni aiiinial or epideniiological itself.
                   studies shall be submitted in a nar-                               (d) Follozuzip. (1) The sponsor shall
                   m t i v e forniat) aiicl shall bear pronii- promptly investigate all safety iiifor-
                   nent identification of i t s contents, i.e., ination receivecl by i t .
                   ..IND Safety Report." Each written no-                             (2) Followup information t o a safety
                   tification to FDA shall be transmitted                           report shall be submitted a s soon a s
                   t o t h e FDA iiew drug review clivision in t h e relevant inforniation i s available.
                   t h e Center for Drug Evaluation and Re-                           (3) If t h e results of a sponsor's inves-
                   search or the procluct review clivision tigation show t h a t a n adverse drug ex-
                   in the Center for Biologics Evaluation perience n o t initially determined t o be
                   and Research t h a t has responsibility                          reportable under paragraph (c) of this
                   for review of the IND. If FDA cleter- section is so reportable, the sponsor




© 2002 by CRC Press LLC
                                                                                             Appendix A: FDA Regulations                        233




                   Food and Drug Administration, HHS
                   shall report such experience in a writ-                             description of a n y available study re-
                   ten safety report a s soon a s possible.                            sults.
                   but in no event later than 15 calendar                                                                         n.
                                                                                          (b) S u n n n m y i n f o ~ n ~ a t i o Information
                   clays after the deterniiiiation is niacle.                          obtained during the previous year's
                      (4) Results of a sponsor's investiga-                            clinical and nonclinical investigations,
                   tion of other safety information shall                              including:
                   be subniittecl. a s appropriate. in a n in-                            ( I ) A narrative or tabular summary
                   formation anieiidnieiit or annual re-                               showing the inost frequent aiicl inost
                   port.                                                               serious adverse experiences by body
                      (el Disclainzel-. A safety report or                             system.
                   other information submitted by a spon-
                   sor ~~iicler part (and aiiy release by
                               this                                                       (2) A suininary of all IND safety re-
                   FDA of t h a t report or iiiforniatioii)                            ports submitted cluriiig the past year.
                   does iiot necessarily reflect a coiiclu-                               (3) A list of subjects who died cluring
                   sion by the sponsor or FDA t h a t the re-                          participation in the iiivestigation. with
                   port or iiiforination coiistitutes a n ad-                          the cause of death for each subject.
                   niission t h a t the drug caused or coii-                              (4) A list of subjects who dropped out
                   tributed to a n adverse experience. A                               cluring the course of the investigation
                   sponsor need not admit, and may deny,                               in association with any adverse experi-
                   t h a t the report or information sub-                              ence. whether or iiot thought t o be
                   mitted by the sponsor constitutes a n                               drug related.
                   admission t h a t the drug caused or con-                              (5) A brief description of what, if any-
                   tributed t o a n adverse experience.                                thing, was obtained t h a t is pertinent t o
                   (Collection of informntion requirements np-                         a n understanding of the drug's actions.
                   proved hy t h e Office of Management and                            including, for example, information
                   Bndget under control nnmher 0910-0014)                              about dose response, information from
                   152 FR 8831. Mar. 19. 1987. ns nmenclecl a t 52                     coiitrolled trails. aiicl iiiforination
                   FR 23031. J u n e 17. 1987. 55 FR 11579. Mnr. 29.                   about bioavailability.
                   1990: 62 FR 52250, Oct. 7, 19971                                       (6) A list of the precliiiical studies
                                                                                       (including animal studies) completed
                   S 312.33 Annual reports.                                            or in progress cluriiig the past year and
                      A sponsor shall within 60 days of the                            a suniniary of the major preclinical
                   aiiiiiversary date t h a t the IND went                             findings.
                   into effect, submit a brief report of the                              (7) A summary of a n y significant
                   progress of the investigation t h a t iii-                          manufacturing              or       inicrobiological
                   clucles:                                                            changes inacle cluriiig the past year.
                                                              n
                      ( a ) I n d i v i d ~ i a l s t ~ i d i~ f o ~ n w t i o n . A      (c) A description of the general iiives-
                   brief suininary of the s t a t u s of each                          tigational plan for the coining year t o
                   study in progress and each study coin-                              replace t h a t submitted I year earlier.
                   pletecl cluring the previous year. The                              The general investigational plan shall
                   sunimary is                         t o include the fol-            contain the information required under
                   lowing information for each study:                                  § 312.23(a)(3)(iv).
                      ( I ) The title of the study (with any
                   appropriate study identifiers such a s                                 (d) If the investigator brochure has
                   protocol number), i t s purpose, a brief                            been revised, a description of the revi-
                   statement identifying the patient pop-                              sion and a copy of the new brochure.
                   ulation, and a statement a s t o whether                                                           ii
                                                                                          (e) A ~ l e s c ~ i p t i o of any significant
                   the study is conipleted.                                            Phase 1 protocol inoclifications made
                      (2) The total number of subjects ini-                            cluring the previous year and not pre-
                   tially plaiinecl for inclusion in the                               viously reported t o the IND in a pro-
                   study: the nuinber entered into the                                 tocol ainenclment.
                   study t o date. tabulated by age group.                                (f) A brief suininary of significant
                   gender, and race: the nuinber whose                                 foreign niarketiiig clevelopinents with
                   participation in the study was coni-                                the drug during the past year. such a s
                   pletecl a s planned: and the number who                             approval of marketing in aiiy country
                   dropped out of the study for any rea-                               or withdrawal or suspeiision froin niar-
                   son.                                                                keting in aiiy c o ~ m t r y .
                      (3) If the study has been completed.                                (g) If desired by the sponsor, a log of
                   or if interim results are known, a brief                            any outstanding business with respect




© 2002 by CRC Press LLC
        234      Clinical Research Coordinator Handbook




                                                                                        21 CFR Ch. 1 (4-1-01 Edition)
                   t o t h e IND for which t h e sponsor re-                  (ii) There is no comparable or satis-
                   quests or expects a reply. coinnieiit. or              factory alternative drug or other ther-
                   meeting.                                               apy available to t r e a t t h a t stage of t h e
                   (Collection of informntion requirements np-            disease i n t h e intended patieiit popu-
                   proved Isy t h e Office of Mnnagement nnd              lation:
                   Budget under control numlser 0910-0014)                    (iii) The drug is ~ u ? d e ~        investigation
                                                                          in a controlled clinical trial under a n
                   [52 F R 8831. Mar. 19. 1987. ns nmencled a t 52
                   F R 23031. J u n e 17. 1987: 63 F R 6862. Fels. 11.    IND in effect for t h e trial. or all cliii-
                                                                          ical trials have been completed: and
                                                                              (iv) The spoiisor of the controlled
                   4 312.34 Treatment use of an investiga-                clinical trial is actively pursuing mar-
                           tional new drug.                               keting approval of t h e investigational
                       ( a ) G e n e m l . A drug t h a t is iiot ap-     clrug with clue diligence.
                   proved for marketing niay be under                         (2) Seriozis diseuse. For a drug in-
                   clinical investigation for a serious or                tended t o t r e a t a serious disease, the
                   ininiediately life-threatening clisease                Conimissioiier niay cleny a request for
                   condition i n patients for whom no coin-               t r e a t m e n t use under a t r e a t m e n t pro-
                   parable or satisfactory alternative                    tocol or t r e a t m e n t IND if there is in-
                   clrug or other therapy is available. Dur-              sufficient evidence of safety and effec-
                   ing the clinical investigation of the                  tiveness to support such use.
                   clrug, i t may be appropriate to use the                   (3) I n m e d i a t e l y life-threuteiziizg diseuse.
                   clrug in the t r e a t m e n t of patients not         ( i ) For a drug intended t o t r e a t a n ini-
                   in the clinical trials. in accordance                  mediately life-threatening clisease, the
                   with a treatment protocol or t r e a t -               Conimissioiier niay cleny a request for
                   ment IND. The purpose of this section                  t r e a t m e n t use of a n investigational
                   is t o facilitate the availability of                  drug under a treatment protocol or
                   promising new drugs t o desperately ill                t r e a t m e n t IND if the available sci-
                   patieiits a s early i n t h e drug develop-            entific evidence. taken a s a whole. fails
                   ment process a s possible, before gen-                 t o provide a reasonable basis for con-
                   eral marketing begins. aiicl t o obtain                cluding t h a t the drug:
                   additional d a t a on the drug's safety                    ( A ) May be effective for i t s intended
                   and effectiveness. In the case of a seri-              use i n i t s iiiteiidecl patieiit population:
                   ous disease, a clrug orclinarily may be                or
                   niacle available for treatnieiit use under                 (B) Woulcl iiot expose the patieiits t o
                   this section during Phase 3 investiga-                 whom t h e drug is to be administered t o
                   tions or after all clinical trials have                                                 aiicl
                                                                          a n ~ ~ i i ~ e a s o n a b l e sigiiificaiit adcli-
                   been completecl: however, in appro-                    tional risk of illness or injury.
                   priate ~ i ~ c ~ ~ i n s t a na e s .
                                                   c drug niay be             (ii) For the purpose of this section.
                   made available for t r e a t m e n t use dur-          a n "iininediately life-threatening" clis-
                   ing Phase 2. In the case of a n iinnie-                ease nieans a stage of a clisease i n
                   cliately life-threatening disease, a clrug             which there is a reasonable likelihood
                   niay be made available for treatnieiit                 t h a t death will occur within a niatter
                   use under this section earlier t h a n                 of months or i n which premature death
                   Phase 3. but ordinarily iiot earlier t h a n           is likely without early treatment.
                   Phase 2. For purposes of this section,                     ( c j S u f e g ~ i u r d s .Treatment use of a n
                   t h e "treatment use" of a drug iiiclucles             investigational drug is coiiditioned on
                   t h e use of a drug for diagnostic pur-                t h e sponsor and investigators corn-
                   poses. If a protocol for ail investiga-                plying with t h e safeguards of the IND
                   tional drug meets t h e criteria of this               process, including t h e regulations gov-
                   section. t h e protocol is t o be submitted            erning iiifornied consent (21 CFR part
                   a s a t r e a t m e n t protocol under the pro-        50) and institutional review boards (21
                   visions of this section.                               CFR part 56) and t h e applicable provi-
                       (b) Criteria. (1) FDA shall permit a n             sions of part 312, including distribution
                   investigational drug to be used for a                  of the drug through qualified experts.
                   t r e a t m e n t use under a t r e a t m e n t pro-   maintenance of adequate manufac-
                   tocol or treatnieiit IND if:                           turing facilities. and subniission of IND
                       ( i j The drug is intended to t r e a t a se-      safety reports.
                   rious or inimecliately life-threatening                    (d) Clinicul hold. FDA may place on
                   clisease:                                              clinical hold a proposecl or ongoing




© 2002 by CRC Press LLC
                                                                                      Appendix A: FDA Regulations                        235




                   Food and Drug Administration, HHS
                   t r e a t m e n t protocol or t r e a t m e n t IND              (3) A licensed practioner who receives
                   in accordaiice with $312.42.                                  a n iiivestigational drug for treatnieiit
                   [52 FR 19476. Mny 22. 1987. as nmended a t 57                 use under a t r e a t m e n t protocol i s a n
                   FR 13248. Apr. 15. 19921                                                                     the
                                                                                 ..iiivestigator" ~ u ? d e ~ protocol and
                                                                                 is responsible for meeting all applica-
                   4 312.35 Submissions                     for treatment       ble investigator responsibilities under
                           use.                                                  this part and 21 CFR parts 50 and 56.
                       ( a ) T r e u t n ~ e n t p r o t o ~ o l submitted by       (b) Trecltment I,VD submitted by li-
                    I,XD sponsor. Any sponsor of a clinical                      censed piactitionel-. ( I ) If a licensed med-
                   investigation of a drug who i~itenclsto                      ical practitioner wants t o obtain a n ill-
                   spoiisor a treatinent use for the drug                       vestigational drug subject t o a con-
                   shall submit to FDA a treatinent pro-                        trolled clinical t r i a l for a treatnieiit
                   tocol ~ ~ i i d e ~ if the sponsor be-
                                         9312.34                                use, t h e practitioner should first a t -
                   lieves the criteria of s312.34 a r e satis-                  t e m p t to obtain the drug froin t h e
                   fied. If a protocol is n o t submitted                       sponsor of the controlled t r i a l under a
                   under s312.34, but FDA believes t h a t                      treatineiit protocol. If t h e sponsor of
                   t h e protocol should have been sub-                         t h e controlled clinical investigation of
                   m i t t e d uncler t h i s section, FDA inay                 t h e drug will n o t establish a treatinent
                   cleeni the protocol to be submitted                          protocol for t h e clrug under paragraph
                   under $312.34. A t r e a t m e n t use uncler a              ( a ) of this section. t h e licensed medical
                   t r e a t m e n t protocol niay begin 30 days                practitioner inay seek to obtain t h e
                   after FDA receives the protocol or on                        drug froin t h e sponsor and subniit a
                   earlier notification by FDA t h a t the                      t r e a t m e n t IND to FDA requesting au-
                   t r e a t m e n t use described in the protocol              thorization t o use t h e investigational
                   niay begin.                                                  drug for t r e a t m e n t use. A treatinent
                       ( I ) A treatinent protocol is required                  use ~ m d a ~     e treatinent IND niay begin
                   t o contain the following:                                   30 days after FDA receives the IND or
                       (i) The intended use of the drug.                        on earlier notification by FDA t h a t the
                       (ii) An explanation of t h e rationale                   t r e a t m e n t use under the IND m a y
                   for use of the drug. iiicludiiig. a s appro-                 begin. A treatnieiit IND i s                        to
                   priate, either a list of what available                      contain t h e following:
                   reginlens ordinarily should be tried be-                         (i) A cover sheet (Form FDA 1571)
                   fore using t h e investigational drug or                     meeting $312.23(g)(l).
                   a n explaiiation of why t h e use of the                         (ii) Iiiforniation (when not provided
                   investigational drug is preferable t o                       by the sponsor) on t h e drug's chem-
                   t h e use of available marketed t r e a t -                  istry. manufacturing. and controls. and
                   ments.                                                       prior clinical and nonclinical experi-
                       (iii) A brief clescription of the criteria               ence with the drug subniittecl i n ac-
                   for patient selection.                                       cordance with $312.23. A sponsor of a
                       (iv) The method of administration of                     clinical iiivestigation subject t o a n IND
                   t h e drug and the dosages.                                  who supplies a n investigational clrug t o
                       (v) A description of clinical proce-                     a liceiised niedical practitioner for puY-
                   dures. laboratory tests. or other nieas-                     poses of a separate t r e a t m e n t clinical
                   ures t o monitor the effects of t h e clrug                  investigation shall be deemed t o au-
                   and t o miiiiinize risk.                                     thorize the incorporation-by-reference
                       (2) A treatinent protocol i s t o be sup-                of the technical iiiforination contained
                   ported by the followiiig:                                    in t h e sponsor's IND into t h e medical
                       (i) Informational brochure for sup-                      practitioner's t r e a t m e n t IND.
                   plying t o each treating physician.                              (iii) A s t a t e m e n t of t h e steps t a k e n
                       (ii) The technical inforniation t h a t i s              by t h e practitioner to obtain the drug
                   relevant t o safety and effectiveness of                     under a treatinent protocol from the
                   t h e drug for the iiitended t r e a t m e n t               drug spoiisor.
                   purpose. Information contained in the                            (iv) A treatinent protocol containing
                   sponsor's IND m a y be incorporated by                       t h e same inforniation listed i n para-
                   reference.                                                   graph ( a ) ( l )of this section.
                       (iii) A conimitmeiit by t h e spoilsor t o                   (v) A s t a t e m e n t of the practitioner's
                   assure compliance of all participating                       qualifications to use t h e investiga-
                   investigators with the informed c o w                        tional drug for t h e iiitended treatnieiit
                   sent requirements of 21 CFR part 50.                         use.




© 2002 by CRC Press LLC
        236      Clinical Research Coordinator Handbook




                                                                                     21 CFR Ch. 1 (4-1-01 Edition)
                      (vi) The practitioner's s t a t e m e n t of      a s practicable after receiving t h e au-
                   familiarity with information on the                  thorization.
                   drug's safety and effectiveness derived              (Collection of information reqnirements ag-
                   froin previous clinical and nonclinical              groved h y t h e Office of Management and
                   experience with the drug.                            Budget under control numlser 0910-0014)
                      (vii) Agreenieiit t o report to FDA
                                                                        [52 F R 8831. Mar. 19. 1987. a s amended a t 52
                   safety information in accordance with                F R 23031. J u n e 17. 1987: 55 F R 11579. Mar. 29,
                   0 312.32.                                            19901
                      (2) A licensed practitioner who sub-
                   m i t s a t r e a t m e n t IND under t h i s sec-   S 312.38 Withdrawal of an IND.
                   tion i s the sponsor-investigator for                  ( a ) At a n y tiine a sponsor niay with-
                   such IND aiicl i s respoiisible for nieet-           draw a n effective IND without preju-
                   ing all applicable sponsor and investi-              dice.
                   gator respoiisibilities under this p a r t             (b) If a n IND is withdrawn, FDA shall
                   and 21 CFR parts 50 and 56.                          be so notified, all clinical investiga-
                   (Collection of information requirements ap-                                     the
                                                                        tions coiiclucted ~ u ? d e ~ IND shall be
                   proved Isy t h e Office of Management and            ended, all current investigators noti-
                   Budget under control numlser 0910-0014)              fied, and all stocks of the clrug re-
                   [52 F R 19477. May 22. 1987. a s amended a t 57      turned t o the sponsor or otherwise dis-
                   F R 13249. Apr. 15. 19921                            posed of a t the request of the sponsor
                                                                        in accordance with s312.59.
                   4312.36 Emergency use of an inves-                     ( c ) If a n IND is withdrawn because of
                        tigational new drug.                            a safety reason. the spoiisor shall
                      Need for a n investigational clrug m a y          promptly so inform FDA. all partici-
                   arise i n a n emergency situation t h a t            pating investigators, and all reviewing
                   does not allow tiine for submission of               Institutional Review Boards. together
                   a n IND i n accordaiice with $312.23 or              with t h e reasons for such withdrawal.
                   s312.34. I n such a case. FDA niay au- (Collection of information reqnirements ag-
                   thorize shipment of t h e drug for a spec- proved Isy t h e Office of Management and
                   ified use i n advance of submission of a n Budget under control numlser 0910-0014)
                   IND. A request for such authorization              152 F R 8831. Mar. 19, 1987. a s amended a t 52
                   niay be transniitted t o FDA by tele- F R 23031. J u n e 17. 19871
                   phone or other rapid coinniunication
                   nieans. For investigatioiial biological            Subpart C-Administrative Actions
                   drugs, t h e request should be directed t o
                   t h e Division of Biological Investiga- 4 312.40 General requirements for use
                   tional New Drugs (HFB-2301, Center for                  of an investigational new drug in a
                   Biologics Evaluation and Research.                      clinical investigation.
                   8800 Rockville Pike. Bethescla. MD                   ( a ) An investigatioiial new drug niay
                   20892. 301-443-4864. For a l l other iiives- be used i n a clinical investigation if
                   tigational drugs, t h e request for au- t h e following conditions are met:
                   thorization should be directed to t h e              ( I ) The sponsor of the investigation
                   Document Management and Reporting                  submits a n IND for t h e drug t o FDA:
                   Branch (HFD-53). Center for Drug Eval- t h e IND i s in effect ~mde' paragraph (b)
                   uation and Research. 5600 Fishers Lane. of this section: and t h e sponsor corn-
                   Rockville. MD 20857. 301-443-4320. After plies with a l l applicable requirements
                   normal working hours, eastern stand- in this part and parts 50 and 56 with re-
                   ard tiine, the request should be cli- spect t o the conduct of the clinical in-
                   rected t o the FDA Division of Emer- vestigations: and
                   gency and Epideniiological Operations.               (2) Each participating investigator
                   202-857-8400. Except in e ~ t ~ a o r d i i i a r ycoiiducts his or her investigation i n
                   circumstances. such authorization will compliance with t h e requirements of
                   be conditioned on the sponsor making this part and parts 50 and 56.
                   a n appropriate IND submission a s soon              (b) An IND goes i n t o effect:




© 2002 by CRC Press LLC
                                                                              Appendix A: FDA Regulations                      237




                   Food and Drug Administration, HHS
                      ( I ) T h i r t y days after FDA receives          4 312.42 Clinical holds and requests for
                   t h e IND. ~ ~ i i l e FDA notifies the spon-
                                           ss                                modification.
                   sor t h a t the investigations clescribecl i n            ( a ) Genercll. A clinical holcl i s a n orcler
                   t h e IND are subject t o a clinical hold             issued by FDA t o the sponsor to delay
                   under $ 312.42: or                                    a proposecl clinical investigation or t o
                      (2) On earlier notification by FDA                 suspencl a n ongoing investigation. The
                   t h a t the clinical investigations i n the           clinical hold order m a y apply t o one or
                   IND m a y begin. FDA will notify the                  more of the investigations covered by
                   sponsor in writing of the date i t re-                a n IND. When a proposed study i s
                   ceives the IND.                                       placed on clinical holcl, subjects m a y
                      ( c ) A sponsor m a y ship a n investiga-          n o t be given t h e investigational drug.
                   tional new drug t o investigators named               When a n ongoing study i s placecl on
                   in the IND:                                           clinical holcl. no new subjects m a y be
                      (1) T h i r t y days after FDA receives            recruited to the stucly and placecl on
                   t h e IND: or                                         t h e investigational drug: patients al-
                      (2) On earlier FDA authorization t o               ready in the stucly should be t a k e n off
                   ship the drug.                                        therapy involving the investigational
                                                                         drug unless specifically permitted by
                      (d) An iiivestigator niay not adniiii-
                                                                         FDA i n t h e interest of patient safety.
                   ister a n iiivestigatioiial new drug t o
                                                                             (b) Grounds for imposition of cliniccll
                                                l
                   human subjects ~ m t i the IND goes i n t o
                                                                         hold-(1) Clinical hold of a Phase I study
                   effect under paragraph ( b ) of this sec-             tinder an I Y D . FDA niay place a pro-
                   tion.                                                 posed or ongoing Phase I investigation
                                                                         on clinical holcl if i t finds t h a t :
                   $312.41 Comment and advice on an
                         IND.                                                (i) Hunian subjects are or would be
                                                                         exposed t o a n unreasonable and signifi-
                      ( a ) FDA m a y a t a n y tinie during the         c a n t risk of illness or injury:
                   course of the investigation coniniu-                      (ii) The clinical investigators named
                   nicate with the sponsor orally or i n                 in t h e IND are n o t qualified by reason
                   writing about deficiencies i n t h e IND              of their scientific training and experi-
                   or about FDA's need for more d a t a or               ence to conduct t h e investigation de-
                   information.                                          scribed i n the IND:
                      (b) On the sponsor's request, FDA                      (iii) The investigator brochure i s
                   will provide advice on specific m a t t e r s         niisleacliiig. erroneous. or materially
                   relating t o a n IND. Exaniples of such               incomplete: or
                   advice m a y include advice on the acle-                  (iv) The IND does n o t contain suffi-
                   quacy of technical data t o support a n               cient information required under
                   investigational plan, on the design of a              $312.23 t o assess the risks t o subjects of
                   clinical trial, and on whether proposed               t h e proposed studies.
                   investigations are likely to produce the                  (v) The IND is for t h e stucly of a n in-
                   d a t a aiicl iiiforniation t h a t is needed t o     vestigational drug inteiided t o t r e a t a
                   nieet r e q ~ ~ i r e n i e i i for a marketing ap-
                                                   ts                    life-threatening clisease or condition
                   plication.                                            t h a t affects both genders. and inen or
                      (c) Uiiless the conim~u?icationi s ac-             women with reprocluctive potential
                   companied by a clinical hold order                    who have the disease or coiidition
                   under $ 312.42, FDA communications                    being studied are excluded from eligi-
                   with a sponsor under this section are                 bility because of a risk or potential
                   solely advisory and do not require a n y              risk from use of the investigational
                   nioclification i n t h e planned or ongoing           drug of                      toxicity (i.e.. af-
                                                                         fecting reproductive organs) or clevel-
                   clinical investigatioiis or response t o
                                                                         opnieiital toxicity (i.e.. affecting poten-
                   t h e agency.                                         t i a l offspring). The phrase "women
                   (Collection of information reqnirenients ap-          with                      potential" does n o t
                   proved hy t h e Office of Management and              include pregnant women. For purposes
                   Bndget under control nnniher 0910-0014)               of this paragraph. ..life-threatening ill-
                   [52 FR 8831. Mar. 19. 1987. a s amended a t 52        nesses or diseases" are defined a s "dis-
                   FR 23031. J u n e 17. 19871                           eases or conditioiis where t h e likeli-
                                                                         hood of death i s high unless t h e course




© 2002 by CRC Press LLC
        238      Clinical Research Coordinator Handbook




                                                                                       21 CFR Ch. 1 (4-1-01 Edition)
                   of the disease i s interrupted." The clin-             keting application have been coin-
                   ical holcl would iiot apply ~~iicle'           this    pletecl, or a clinical stucly under the
                   paragraph to clinical studies con-                     IND has been placed on clinical holcl:
                   ducted:                                                    (C) The sponsor of t h e controlled
                       ( A ) Under special circumstances,                 clinical trial is n o t pursuing marketing
                   such a s studies pertinent only t o one                approval with clue diligence:
                   gender (e.g., studies evaluating the ex-                   (D) If t h e t r e a t m e n t IND or t r e a t -
                   cretion of a drug i n semen or t h e ef-               ment protocol i s intended for a serious
                   fects on menstrual f ~ m c t i o n j :                 disease. there i s insufficient evidence
                       (B) Only in inen or women. a s long a s            of safety and effectiveness to support
                   a stucly t h a t cloes not exclude members             such use: or
                   of the other gender with reproductive                      (E) If the treatnieiit protocol or
                   potential i s being concluctecl concur-                t r e a t m e n t IND was based on a n imme-
                   rently. has been concluctecl. or will                  diately life-threatening disease. the
                   t a k e place within a reasonable time                 available scientific eviclence, t a k e n a s
                   agreed upon by t h e agency: or                        a whole. fails t o provide a reasonable
                       (C) Only i n subjects who do n o t suffer          basis for concluding t h a t t h e clrug:
                   froin the disease or coiidition for which                  ( 1 ) May be effective for i t s intended
                   t h e drug i s being studied.                          use i n i t s inteiiclecl populatioii: or
                       (2) Clinical hold of a Pkclse 2 or 3 s t u d y
                                                                              ( 2 ) Would not expose the patients t o
                   zinder a n IAVD. FDA inay place a pro-                 whoin t h e drug i s to be aclmiiiistered t o
                   posed or oiigoing Phase 2 or 3 inves-                  a n unreasonable and significant adcli-
                   tigation on clinical hold if i t finds
                                                                          tioiial risk of illness or injury.
                   that:
                       ( i ) Any of t h e conditions i n para-                (iii) F D A m a y place a proposecl or oii-
                   graphs (b)(l)(i) through (b ) ( l)(v) of t h i s       going treatinent IND or treatinent pro-
                   section apply: or                                      tocol on clinical hold if i t fiiicls t h a t
                       (ii) The plan or protocol for t h e iii-           a n y of t h e conditions i n paragraph
                   vestigation i s clearly deficient i n de-              (b)(4)(i)     through (b)(4)(viii)of this sec-
                   sign t o nieet i t s s t a t e d objectives.           tion apply.
                       (3) Clinical hold of a treatinent IND                 (4) Clinical hold o f a n y s t u d y t h a t is
                   or t r e a t m e n t protocol.                         n o t designed to be adeyuclte a n d well-colz-
                       ( i j Proposed use. FDA inay place a               trolled. FDA m a y place a proposecl or
                   proposecl treatnieiit IND or treatnieiit               oiigoing iiivestigation t h a t i s n o t de-
                   protocol on clinical hold if i t is deter-             signed t o be adequate and well-con-
                   niinecl t h a t :                                      trolled on clinical holcl if i t finds t h a t :
                       ( A ) The           pertinent    criteria i n         ( i ) Any of t h e conditions i n para-
                   §312.34(b) for perniitting t h e t r e a t m e n t     graph ( b ) ( l ) or (bj(2) of t h i s section
                   use t o begin are n o t satisfied: or                  apply: or
                       (B) The treatnieiit protocol or t r e a t -           (ii) There i s reasonable evidence the
                   ment IND cloes n o t contain the infor-                investigation t h a t i s n o t designed t o be
                   niation                   under $312.35 ( a ) or (b)   adequate and well-controlled i s imped-
                   t o m a k e t h e specified determination              ing enrollnieiit in. or otherwise inter-
                   under § 312.34(b).                                     fering with the conduct or completion
                       (ii) Ongoing use. FDA m a y place a n              of. a study t h a t i s designed t o be a n
                   ongoing treatnient protocol or treat-                  adequate and well-controlled investiga-
                   ment IND on clinical hold if i t is deter-             tion of the sanie or another iiivestiga-
                   niinecl t h a t :                                      tional drug: or
                       ( A ) There becomes available a corn-                 (iii) Insufficient quantities of the in-
                   parable or satisfactory alternative                    vestigational drug exist t o adequately
                   clrug or other therapy t o t r e a t t h a t           conduct both the investigation t h a t i s
                   stage of the disease i n the intended pa-              n o t clesigiied to be adequate and well-
                   t i e n t population for which t h e inves-            controlled and the investigations t h a t
                   tigational drug i s being used:                        are clesigiied to be adequate and well-
                       ( B ) The investigational clrug is n o t           controlled: or
                   under investigation i n a controlled                      (iv) The drug has been studied i n one
                   clinical t r i a l under a n IND in effect for         or more adequate and well-controlled
                   t h e t r i a l aiicl iiot all controlled clinical     investigatioiis t h a t strongly suggest
                   trials necessary t o support a mar-                    lack of effectiveness: or




© 2002 by CRC Press LLC
                                                                                    Appendix A: FDA Regulations                   239




                   Food and Drug Administration, HHS
                      (v) Another clrug under investigation                    holcl FDA will, unless patients are ex-
                   or approved for the saine indication                        posed to ininiediate and serious 'isk.
                   and available t o the saine patient popu-                   a t t e m p t t o discuss and satisfactorily
                   lation has denionstratecl a better po-                      resolve the m a t t e r with the spoiisor be-
                   tential benefit risk balance: or                            fore issuing t h e clinical hold orcler.
                      (vij The drug has received marketing                         (dj Imposition of clinical hold. The
                   approval for the saine indication i n the                   clinical hold orcler m a y be made by
                   sanie patient population: or                                telephone or other meaiis of rapid c o n -
                      (viij The sponsor of the study t h a t i s               inunication or i n writing. The clinical
                   clesigiied to be a n adequate and well-                     holcl order will identify the studies
                   controlled investigation i s n o t actively                 under the IND to which t h e holcl ap-
                   pursuing marketing approval of the iii-                     plies. and will briefly explain the basis
                   vestigational clrug with due diligence:                     for t h e action. The clinical holcl order
                   or                                                          will be niacle by or on behalf of the Di-
                      (viiij The Colninissioner determines                     vision Director with responsibility for
                   t h a t i t would n o t be i n the public inter-            review of the IND. As soon a s possible.
                   e s t for t h e study to be conducted or                    and no more t h a n 30 clays after imposi-
                   coiitiiiued. FDA ordinarily intends t h a t                 tion of t h e clinical hold. the Division
                   clinical       holds      under     paragraphs              Director will provide the sponsor a
                   (b)(4j(ii).(bj(4j(iiij and (b)(4)(v) of t h i s             written explaiiation of the basis for the
                   section would only apply t o additional                     holcl.
                   enrollment i n noncoiicurrently con-                            (e) Restinzption of clinicul investigc~-
                   trolled trials r a t h e r t h a n eliminating              tions. An investigation m a y only re-
                   coiitiiiued access t o iiiclividuals already                sunie after FDA (usually the Division
                   receiving the investigational clrug.                        Director, or t h e Director's designee,
                      (5) Clinical hold of m y investigution i?z-              with respoiisibility for review of t h e
                   uolving a n exception from i n f o m e d con-               INDj has notified t h e sponsor t h a t the
                   sent tinder $50.24 of t h i s chapter. FDA                  investigation niay proceed. Resump-
                   may place a proposed or ongoing inves-                      tion of t h e affected investigation(s)
                   tigation involving a n exception froin                      will be authorized when t h e sponsor
                   informed consent under Q50.24 of this                       corrects the cleficiency(iesj previously
                   chapter on clinical hold if i t i s deter-                  cited or otherwise satisfies t h e agency
                   ininecl t h a t :                                           t h a t the investigation(s) can proceed.
                      (i) Any of t h e conditioiis i n para-                   FDA niay notify a spoiisor of i t s deter-
                   graphs ( b j ( l j or (b)(2j of this section                mination regarding t h e clinical holcl by
                   apply: or                                                   telephone or other meaiis of rapid c o n -
                      (ii) The pertinent criteria i n $50.24 of                inunication. If a sponsor of a n IND t h a t
                   this chapter for such a n iiivestigation                    has been placed on clinical hold re-
                   t o begin or continue are n o t submitted                   quests in writing t h a t the clinical hold
                   or n o t satisfied.                                         be reniovecl and submits a complete re-
                      (6) Clinical holcl of a n y investigation                                                )
                                                                               sponse to the i s s u e ( ~identified i n the
                   involving a n exception from iiiforined                     clinical hold orcler. FDA shall respoiicl
                   consent under §50.23(clj of this chapter.                   in writing t o t h e sponsor within 30-cal-
                   FDA niay place a proposed or ongoing                        enclar clays of receipt of t h e request and
                   investigation involving a n exception                       t h e coinplete response. FDA's response
                   froin infornied consent under § 50.23(dj                    will either remove or niaiiitain the
                   of this chapter on clinical hold if i t i s                 clinical hold, and will s t a t e t h e reasons
                   cleterininecl t h a t :                                     for such deterniiiiation. Notwith-
                      ( i j Any of t h e conditions i n para-                  standing t h e 30-calendar day response
                   graphs (b)(l) or (bj(2) of this section                     tinie. a sponsor m a y n o t proceed with a
                   apply: or                                                   clinical t r i a l on which a clinical holcl
                      (iij A cleterinination by the President                  has been iniposecl until the sponsor has
                   t o waive t h e prior consent requirement                   been notified by FDA t h a t the hold has
                                                           i
                   for t h e a ~ l m i i i i s t ~ a t i oofi a n investiga-   been lifted.
                   tional new clrug has not been made.                             (fj Appeal. If t h e sponsor disagrees
                      (c) Discussion o f deficiency. Whenever                  with the reasons cited for the clinical
                   FDA concludes t h a t a deficiency exists                   holcl, the sponsor m a y request recon-
                   in a clinical iiivestigation t h a t m a y be                                   of
                                                                               s i ~ l e ~ a t i o i i the decision i n accord-
                   grounds for t h e iinposition of clinical                   ance with § 312.48.




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                                                                                 21 CFR Ch. 1 (4-1-01 Edition)
                     ( g ) Conve?szon of LYD o n clznzcul hold             (vi) The IND, or a n y amendment or
                   to znactzve stutzis. If all investigations           'eport t o the IND. contains a n ~ ~ i i t r u e
                   covered by a n IND remain on cllnical s t a t e m e n t of a material fact or omits
                   hold for 1 year or more, the IND inay niaterial iiiforniation required by this
                   be placed on inactlve s t a t u s by FDA part.
                   under Q 312.45.                                         (vii) The spoiisor fails proniptly t o iii-
                                                                        vestigate and inform t h e Food and
                   [52 F R 8831. M a r . 19. 1987. n s nmenclecl a t 52
                   F R 19477. M a y 22, 1987: 57 F R 13249. Apr. 15.
                                                                        Drug Adniiiiistration and all investiga-
                   1992: 61 F R 51530. O c t . 2. 1996: 63 F R 68678,   tors of serious and unexpected adverse
                   Dec. 14. 1998: 64 FR 54189. Oct. 5. 1999: 65 F R     experiences i n accordance with $312.32
                   34971, J u n e 1. 20001                              or fails t o m a k e a n y other report re-
                                                                        quired under this part.
                   S 312.44 Termination.                                   (viii) The sponsor fails t o submit a n
                      ( a ) General. This section describes the accurate annual report of the inves-
                   procedures ~~iicle'      which FDA niay ter- tigations i n accordance with $ 312.33.
                   minate a n IND. If a n IND i s terini-                  (ix) The sponsor fails to comply with
                   natecl. the sponsor shall elid all clinical a n y other applicable requirement of
                   investigations concluctecl under the this part. part 50. or part 56.
                   IND aiicl recall or otherwise provide for               (x) The IND has remained on inactive
                   t h e disposition of all unused supplies of s t a t u s for 5 years or more.
                   t h e drug. A termination action m a y be               (xi) The sponsor fails t o delay a pro-
                   based on deficiencies i n the IND or i n posed investigation under the IND or
                   t h e conduct of a n investigation ~ ~ i i d t o~ suspencl a n ongoing investigation
                                                                        e
                   a n IND. Except a s provided i n para- t h a t has been placed 011 clinical hold
                   graph (d) of this section. a terniiiiation           under Q 312.42(b)(4).
                   shall be preceded by a proposal t o ter-                (2) Phase 2 or 3. FDA inay propose t o
                   niinate by FDA and a n ~ p p o ~ t ~ ~ fori t yterminate a n IND during Phase 2 or
                                                                    ii
                   t h e sponsor to respond. FDA will, i n Phase 3 if FDA finds t h a t :
                   general. only i n i t i a t e a n action under          ( i ) Any of t h e conditions i n para-
                   this section after first a t t e m p t i n g t o graphs ( b ) ( l ) ( i )  through (b)(l)(xi)of this
                   resolve cliffereiices infornially or. when section apply: or
                   appropriate, through t h e clinical hold                (ii) The investigational plan or pro-
                   procedures clescribecl i n § 312.42.                 t o c o l ( ~i)s not reasonable a s a bona ficle
                      (b) Grounds for terminatio?z-(1) Plzclse scientific plan t o determine whether or
                   I . FDA m a y propose t o terminate a n n o t t h e drug i s safe aiicl effective for
                   IND during Phase 1 if i t finds t h a t :            use: or
                      (i) Human subjects would be exposed                  (iii) There i s convincing evidence
                   t o a n unreasonable and significant risk t h a t the drug i s n o t effective for the
                   of illness or unjury.                                purpose for which i t i s being inves-
                      (ii) The IND cloes n o t contain suffi- tigated.
                   cient information required under                        (3) FDA m a y propose t o termiiiate a
                   $312.23 t o assess the safety to subjects t r e a t m e n t IND if i t finds t h a t :
                   of the clinical investigations.                         ( i ) Any of t h e conditions i n para-
                      (iii) The niethocls. facilities. and coii- graphs ( b ) ( l ) ( i )      through (x) of this sec-
                   trols used for the manufacturing, proc- tion apply: or
                   essing. and packing of the investiga-                   (ii) Any of the conditions i n
                   tional drug are inadequate t o establish § 312.42(b)(3)apply.
                   and maintain appropriate standards of                   (c) Opportunity for sponsor response.
                   identity, strength, quality, and purity              (1) If FDA proposes t o terminate a n
                   a s needed for subject safety.                       IND. FDA will notify the sponsor i n
                      (iv) The clinical investigatioiis are writing, and invite correction or expla-
                   being concluctecl in a manner substan- nation within a period of 30 days.
                   tially different t h a n t h a t described i n          (2) On such notificatioii. the sponsor
                   t h e protocols submitted i n t h e IND.             inay provide a written explanation or
                      (v) The drug i s being promoted or dis- correction or m a y request a conference
                   tributed for commercial purposes n o t with FDA t o provide t h e requested ex-
                   justified by t h e requirements of the iii- planation or correction. If the sponsor
                   vestigation or permitted by $ 312.7.                 cloes n o t respond t o t h e notification




© 2002 by CRC Press LLC
                                                                           Appendix A: FDA Regulations                   24 1




                   Food and Drug Administration, HHS
                   within t h e allocated tiine, the IND              a s t o why t h e IND should continue to
                   shall be terininatecl.                             'einain active.
                      (3) If the sponsor responds but FDA                 (b) If a n IND i s placed on inactive
                   does not accept the explanation or cor-            s t a t u s , all investigators shall be so no-
                   'ectioii submitted. FDA shall inforin              tified and all stocks of the drug shall
                   t h e sponsor in writing of t h e reason for       be returned or otherwise disposed of in
                   t h e iioiiacceptance and provide the              accordance with § 312.59.
                   sponsor with a n opportunity for a regu-               ( c j A sponsor is n o t required t o sub-
                   latory hearing before FDA ~ m d e rpart            m i t annual reports t o a n IND on inac-
                   16 on the question of whether the IND              tive s t a t u s . An inactive IND is, how-
                   shoulcl be termiiiated. The sponsor's re-          ever, still in effect for purposes of t h e
                   quest for a regulatory hearing must be             public disclosure of d a t a and infornia-
                   niacle within 10 days of t h e sponsor's           tion under § 312.130.
                   receipt of FDA's notification of non-                  (d) A sponsor who intends to resume
                   acceptance.                                        clinical investigation under a n IND
                      (d) Immediate tel-mination of IAVD. Not-        placed on inactive s t a t u s shall submit
                   withstaiicliiig paragraphs ( a ) through           a protocol ainenclinent ~ ~ i i c l$312.30e~
                   (c) of this section, if a t a n y tiine FDA        coiitainiiig the proposed general inves-
                   coiicludes t h a t coiitiiiuation of t h e iii-    tigational plan for t h e coining year and
                   vestigation presents a n immediate and             appropriate protocols. If the protocol
                   substantial danger to t h e health of iii-         ainenclinent relies on iiiforination pre-
                   clividuals, t h e agency shall imme-               viously subniittecl. the plan shall ref-
                                                                      erence such information. Additional in-
                   diately. by written notice t o t h e spoii-
                   sor from the Director of t h e Center for          formation supporting t h e proposecl in-
                                                                      vestigation, if a n y , shall be submitted
                   Drug Evaluation and Research or the
                                                                      in a n information amendment. Not-
                   Director of the Center for Biologics
                                                                      withstanding the provisions of $312.30,
                   Evaluation and Research. terminate                 clinical investigations under a n IND on
                   t h e IND. An IND so terininatecl i s sub-
                                                                      inactive s t a t u s niay only resume (1)30
                   ject to reinstatement by the Director              clays after FDA receives t h e protocol
                   on the basis of additional submissions             ainenclinent. unless FDA notifies the
                   t h a t eliminate such danger. If a n IND          spoiisor t h a t t h e investigatioiis de-
                   is terininatecl under this paragraph, the          scribed i n the anieiidnieiit are subject
                   agency will afford the spoiisor a n op-            t o a clinical hold ~ u ? d e ~  $312.42. or (2)
                   portunity for a regulatory hearing                 on earlier notification by FDA t h a t the
                   under part 16 on t h e question of wheth-          clinical investigations described i n the
                   e r the IND should be reinstated.                  protocol amendment m a y begin.
                   (Collection of informntion requirements np-            (e) An IND t h a t remains on inactive
                   proved hy the Office of Management and             s t a t u s for 5 years or more m a y be ter-
                   Budget under control numlser 0910-0014)            minated under § 312.44.
                   [52 F R 8831. Mar. 19. 1987. ns nmenclecl a t 52   (Collection of informntion requirements np-
                   FR 23031. June 17. 1987: 55 FR 11579. Mar. 29,     proved hy the Office of Management and
                   1990: 57 F R 13249. hpr. 15. 19921                 Bndget under control nnmher 0910-0014)
                                                                      [52 F R 8831. Mar. 19. 1987. ns nmenclecl a t 52
                   4 312.45 Inactive status.                          F R 23031. June 17. 19871
                      ( a ) If 110 subjects are entered i n t o
                   clinical studies for a period of 2 years           4 312.47 Meetings.
                                       a
                   or more ~ m d e r n IND. or if all iiives-            ( a ) General. Meetings between a spon-
                   tigations under a n IND remain on clin-            sor and the agency are frequently use-
                   ical hold for 1 year or more. the IND              f~11i n resolving questions and issues
                   may be placed by FDA on inactive sta-              raised during the course of a clinical
                   tus. This action niay be t a k e n by FDA          investigation. FDA encourages such
                   either on request of t h e sponsor or on           meetings t o t h e extent t h a t they aid in
                   FDA's own initiative. If FDA seeks t o             t h e evaluation of t h e drug and i n the
                   a c t on i t s own initiative under this sec-      solution of scientific problems con-
                   tion. i t shall first notify the spoiisor i n      cerning the drug. to t h e extent t h a t
                   writing of the proposed inactive s t a t u s .     FDA's resources permit. The general
                   Upon receipt of such notification. the                                         the conduct of
                                                                      principle ~ m d e ~ l y i n g
                   sponsor shall have 30 days t o respond             such meetings i s t h a t there should be




© 2002 by CRC Press LLC
        242      Clinical Research Coordinator Handbook




                                                                                    21 CFR Ch. 1 (4-1-01 Edition)
                   free, full, and open colninunication                 inaries of the Phase 1 and 2 investiga-
                   about aiiy scientific or medical ques-               tions. the specific protocols for Phase 3
                   tion t h a t m a y arise during the clinical         clinical studies, plans for a n y acldi-
                   investigation. These meetiiigs shall be              tioiial noncliiiical studies. plans for pe-
                   conducted and documented i n accord-                 diatric studies, including a time line
                   ance with part 10.                                   for protocol finalizatioii. enrollment.
                     (b) "Eizd-of-Phase 2" meetings and                 completion, and d a t a analysis, or infor-
                   nzeetings held before submission of c1 111ar-        niation t o support aiiy planned request
                   ketiizg application. At specific times               for waiver or deferral of pediatric stud-
                   during the drug investigation process.               ies. aiicl. if available. tentative labeling
                   meetings between FDA and a sponsor                   for the drug. The reconnnencled con-
                                                      i l
                   can be especially h e l p f ~ ~n miniiniziiig                                                n
                                                                        t e n t s of such a s ~ ~ b m i s s i o are de-
                   wasteful expenditures of tiine and                   scribed more fully i n FDA Staff Man-
                   nioney and t h u s i n speecliiig t h e drug         ual Guide 4850.7 t h a t i s publicly avail-
                   development and evaluation process. In               able under FDA's public information
                   particular. FDA has found t h a t nieet-                             i n p a r t 20.
                   ings a t the end of Phase 2 of a n inves-                (v) Coizdzict of meeting. Arrangements
                   tigation (end-of-Phase 2 meetings) are               for a n end-of-Phase 2 nieeting are t o be
                   of considerable assistance i n planning              made with the division i n FDA's Center
                   later studies and t h a t meetings held              for Drug Evaluation and Research or
                   near completion of Phase 3 and before                t h e Center for Biologics Evaluation
                                      of
                   s ~ ~ b m i s s i o n a niarketiiig application      and Research which i s responsible for
                   (.'pre-NDA" meetings) are helpful i n                review of t h e IND. The ineeting will be
                   developing methods of presentation                   scheduled by FDA a t a tiine conveiiieiit
                   and submission of d a t a in the mar-                t o both FDA and t h e sponsor. Both the
                   keting application t h a t facilitate re-            spoiisor and FDA niay bring consult-
                   view and allow timely FDA response.                  a n t s t o the meeting. The ineeting
                      (1) End-of-Plzclse 2 meetings-(i) Pur-            should be directed priinarily a t estab-
                   pose. The purpose of a n end-of-phase 2              lishing agreement between FDA and
                                                         e
                   nieeting i s to ~ l e t e ~ i n i i ithe safety of   t h e sponsor of the overall plan for
                   proceeding t o Phase 3, t o evaluate the             Phase 3 and t h e objectives and clesign
                   Phase 3 plan and protocols and the ade-              of particular studies. The adequacy of
                   quacy of current studies and plans t o               t h e technical information t o support
                   assess pediatric safety aiicl effective-             Phase 3 studies ancllor a marketing ap-
                   ness, and t o identify a n y additional in-          plication m a y also be cliscussed. FDA
                   formation necessary t o support a niar-              will also provide i t s best judgment. a t
                   keting application for t h e uses under              t h a t tiine, of t h e pediatric studies t h a t
                   investigation.                                       will be required for t h e drug product
                      (ii) Eligibility for meeting. While the           and whether their submission will be
                   encl-of-Phase 2 nieeting is designed pri-            cleferred until after approval. Agree-
                   marily for IND's involving new inolec-               ments reached a t t h e meeting on these
                   ular entities or niajor new uses of niar-            niatters will be recorded i n niiiiutes of
                   keted drugs, a sponsor of a n y IND m a y            t h e conference t h a t will be t a k e n by
                               and obtain a n encl-of-Phase 2           FDA i n accordance with § 10.65 and pro-
                   meeting.                                             vided t o t h e sponsor. The minutes
                      (iii) Timing. To be most u s e f ~ ~o thet l      along with aiiy other written niaterial
                   sponsor, end-of-Phase 2 meetings                     provided t o t h e sponsor will serve a s a
                   should be held before major conimit-                 pernianent record of aiiy agreenieiits
                   inents of effort and resources t o spe-              reached. Barring a significant sci-
                   cific Phase 3 t e s t s are made. The schecl-        entific clevelopnient t h a t              oth-
                   uling of a n end-of-Phase 2 ineeting i s             erwise, stuclies conducted i n accord-
                   not. however. intended t o delay the                 ance with t h e agreement shall be pre-
                   transition of a n investigation from                 sumed t o be sufficient i n objective and
                   Phase 2 t o Phase 3.                                 clesign for the purpose of obtaining
                      (iv) Advance infornzatioiz. At least I            marketing approval for the drug.
                   nionth i n aclvaiice of a n eiicl-of-Phase 2             (2) "Pre-SDA" a n d "pre-BLA" meet-
                   meeting, the sponsor should submit                   ings. FDA has found t h a t delays associ-
                   background information on the spoii-                 ated with the initial review of a mar-
                   sor's plan for Phase 3, including sum-               keting application m a y be reduced by




© 2002 by CRC Press LLC
                                                                          Appendix A: FDA Regulations                         243




                   Food and Drug Administration, HHS
                   exchanges of information about a pro-             with t h e clivision i n FDA's Center for
                   posed marketiiig applicatioii. The pri-           Drug Evaluation aiicl Research or Ceii-
                   niary purpose of this kind of exchange            t e r for Biologics Evaluation and Re-
                   is t o uncover any major ~mresolved               search which is responsible for review
                   problenis. t o identify those studies t h a t     of the IND, beginning with t h e con-
                   t h e sponsor is relying on a s adequate          sumer safety officer assigned t o t h e ap-
                   and well-coiitrollecl to establish the            plication. If the dispute is not resolved,
                   drug's effectiveness, t o identify t h e          t h e spoiisor niay raise t h e niatter with
                   s t a t u s of ongoing or needed stuclies         t h e person clesigiiatecl a s o n i b ~ ~ d s m a n .
                   adequate t o assess pediatric safety and
                                                                     whose f~mctioiishall be t o investigate
                   effectiveness, to acquaint FDA review-
                   ers with t h e general information to be          what has happened and t o facilitate a
                   submitted i n the marketing applica-              tiinely and equitable resolution. Appro-
                   tion (iiiclucling technical iiiforniatioiij.      priate issues t o raise with the oinbuds-
                   t o discuss appropriate niethods for sta-         nian iiiclucle resolving difficulties i n
                   tistical analysis of the data. and to dis-        scheduliiig meetings and obtaining
                   cuss the best approach to the preseii-            timely replies t o inquiries. Further de-
                   t a t i o n aiicl formatting of clata i n t h e   tails on this procedure are contained i n
                   niarketing application. Arraiigenieiits           FDA Staff Manual Guide 4820.7 t h a t is
                   for such a meeting are t o be initiated           publicly available under FDA's public
                   by t h e sponsor with t h e clivision re-         inforniation regulations i n part 20.
                   sponsible for review of the IND. To per-             ( c j Scientific and medical disputes. ( 1 )
                   m i t FDA t o provide the sponsor with            When scientific or nieclical disputes
                   t h e most useful aclvice on preparing a          arise during the drug iiivestigation
                   marketing application, the sponsor                process. spoiisors shoulcl discuss the
                   shoulcl submit to FDA's reviewing divi-           m a t t e r directly with t h e responsible
                   sion a t least 1 moiith i n advance of the        reviewing officials. If necessary, spon-
                   meeting the following information:
                       ( i j A brief sulninary of the clinical       sors may request a meeting with the
                   studies t o be submitted i n the applica-         appropriate reviewing officials and
                   tion.                                             nianagenient representatives i n order
                       (ii) A proposed forinat for organizing                                        i.
                                                                     t o seek a r e s o l ~ ~ t i o iRequests for such
                   t h e submission, including methods for           meetings shall be directed t o the clirec-
                   presenting t h e clata.                           t o r of the clivision i n FDA's Center for
                       (iii) Information on t h e s t a t u s of     Drug Evaluation and Research or Cen-
                   neeclecl or ongoing pediatric stuclies.           t e r for Biologics Evaluation and Re-
                       (ivj Any other inforniation for discus-       search which is responsible for review
                   sion a t the meeting.                             of the IND. FDA will make every a t -
                   (Collection of information reqnirenients ap-      tempt t o grant requests for meetings
                   proved hy the Office of Management and            t h a t involve important issues and t h a t
                   Bndget under control nnniher 0910-0014)           can be scheduled a t inutually conven-
                   1 2 F R 8831. Mar. 19, 1987. as aniended a t 52
                    5                                                ient times.
                   F R 23031.June 17. 1987: 55 F R 11580. Mar. 29,      (2) The "end-of-Phase 2" and "pre-
                   1990:63 F R 66669,Dec. 2,19981                    NDA" meetiiigs clescribecl i n §312.47(b)
                                                                     will also provide a tiinely forum for
                   4 312.48 Dispute resolution.                      cliscussing aiicl                  scientific and
                      ( a ) Genel-al. The Food and Drug Ad-          medical issues on which the sponsor
                   ministration is connnitted to resolving           disagrees with t h e agency.
                   differences between sponsors and FDA                 (3) In requesting a meeting designed
                   reviewing divisions with respect to re-           t o resolve a scientific or medical dis-
                   quirements for IND's a s quickly and              pute, applicants may suggest t h a t FDA
                   amicably a s possible through t h e coop-
                                                                     seek the aclvice of outside experts. in
                   erative exchange of information and
                   views.                                            which case FDA may. i n i t s discretion.
                      (b) Adnziizistl-ative and pl-ocedziml          invite t o the meeting one or more of i t s
                   isszies. When administrative or proce-            advisory connnittee members or other
                   dural disputes arise, t h e sponsor should        consultants, a s designated by t h e agen-
                   first a t t e m p t t o resolve t h e inatter     cy. Applicants may rely on, and may




© 2002 by CRC Press LLC
        244      Clinical Research Coordinator Handbook




                                                                                         21 CFR Ch. 1 (4-1-01 Edition)
                   bring t o any meeting, their own con-                    in this part apply t o a contract re-
                   sultaiits. For niajor scientific and nied-               search orgaiiizatioii to the extent t h a t
                   ical policy issues not resolved by infor-                i t assumes one or more obligations of
                   nial ineetiiigs. FDA may refer the niat-                 the sponsor.
                   ter to one of i t s staiicliiig advisory coni-
                   niittees for i t s coiisideratioii aiid rec-             S 312.53 Selecting            investigators and
                   oinnieiiclations.                                                monitors.
                   1 2 FR 8831. M a r . 19, 1987. as anieiided a t 55
                    5                                                           ( a ) Selecting investigators. A sponsor
                   FR 11580.M a r . 29.19901                                shall select only investigators qualified
                                                                            by training aiicl experience a s appro-
                       Subpart D-Responsibilities of                        priate experts to investigate the clrug.
                        Sponsors and Investigators                              (b) Control of dl-zig. A sponsor shall
                                                                            ship iiivestigational new drugs only t o
                   4 312.50 General               responsibilities of       investigators participating in the in-
                          sponsors.                                         vestigation.
                       Spoiisors are 'esponsibile for select-                   (c) Obtuining infornzation from the i?z-
                   ing qualified investigators. providing                   vestigatol-. Before permitting a n investi-
                   them with the information they need                      gator t o begin participation in a n in-
                   t o conduct a n investigation properly,                  vestigation, the sponsor shall obtain
                   ensuring proper monitoring of the in-                    the following:
                   v e s t i g a t i o n ( ~ )ensuring t h a t the inves-
                                              ,                                 (1) A signed investigator statenient
                   t i g a t i o n ( ~ is conducted in accordance
                                        )                                   (Form FDA-1572) containing:
                   with the general investigational plan                        ( i ) The naine and acldress of the in-
                   and protocols coiitainecl in the IND.                    vestigator
                   niaiiitainiiig ail effective IND with re-                    (ii) The iianie and code iiuniber. if
                   spect t o the iiivestigations. and ensur-                any, of the protocol(sj in the IND iclen-
                   ing t h a t FDA and all participating iii-               tifyiiig the study(ies) t o be coiiducted
                   vestigators are proniptly inforniecl of                  by the investigator:
                   sigiiificaiit new adverse effects or risks                   (iii) The naine and acldress of any
                   with respect to the clrug. Additional                    medical school. hospital. or other re-
                   specific responsibilities of sponsors are                search facility where the clinical inves-
                   described elsewhere in this part.                                            )
                                                                            t i g a t i o n ( ~ will be coiiducted:
                   $312.52 Transfer of obligations to a
                                                                                (iv) The nanie and address of any
                      contract research organization.                       clinical laboratory facilities t o be used
                                                                            in the study:
                      ( a ) A sponsor may transfer responsi-                    (v) The name and address of the IRB
                   bility for a n y or all of the obligations               t h a t is responsible for review and ap-
                   set forth in this part t o a contract re-                proval of the stucly(ies):
                   search organization. Any such transfer
                   shall be described in writing. If not all                    (vi) A coniinitnieiit by the investi-
                   obligations are transferred. the writing                 gator t h a t he or she:
                   is required t o describe each of the obli-                   ( a ) Will conduct the stucly(iesj in ac-
                   gations being assunied by the contract                   cordance with the relevant. current
                   research organization. If all obligatioiis               protocol(s) and will only make changes
                   are transferred. a general statenient                    in a protocol after notifying the spoii-
                   t h a t all obligatioiis have been trans-                sor, except when necessary to protect
                   ferred is acceptable. Any obligation not                 the safety. the rights. or welfare of
                   covered by the written description                       subjects:
                   shall be cleeinecl not t o have been trans-                  (6)   Will comply with all requirements
                   ferred.                                                                    the obligations of clinical iii-
                      (b) A contract research organization                  vestigators and all other pertinent re-
                   t h a t assumes any obligation of a spon-                quirements in this part:
                   sor shall comply with the specific regu-                     (c) Will personally conduct or super-
                   lations in this chapter applicable t o                   vise the described investigation(s):
                   this obligation and shall be subject t o                     (d) Will inform any potential subjects
                   the same regulatory action a s a spon-                   t h a t the drugs are being used for inves-
                   sor for failure t o coinply with any obli-               tigational purposes and will ensure
                                                 ~
                   gation assuinecl ~ u ? d ethese regula-                  t h a t the req~~irenieiits       relating t o ob-
                   tions. Thus, all references t o "sponsor"                taining informed consent (21 CFR part




© 2002 by CRC Press LLC
                                                                           Appendix A: FDA Regulations                  245




                   Food and Drug Administration, HHS
                   50) and institutional review board re-             clinical observations and laboratory
                   view and approval (21 CFR part 56) are             t e s t s to be conducted: t h e estiniated
                   met:                                               duration of the study: and copies or a
                      (e) Will 'eport t o the sponsor adverse         description of case report forms t o be
                   experiences t h a t occur i n the course of        used.
                   t h e investigatioii(s) i n accordance with            ( 4 ) Financiul discloszire infornmtion.
                   0 312.64:                                          Sufficient accurate financial infornia-
                     a     Has 'eacl and understands the iii-         tion to allow the sponsor t o submit
                   formation in t h e investigator's bro-             complete and accurate certification or
                   chure. including t h e potential risks             clisclosure s t a t e m e n t s required under
                   and side effects of t h e clrug: and               part 54 of this chapter. The sponsor
                      (g) Will ensure t h a t all associates.         shall obtain a coinniitinent froin t h e
                   colleagues, and employees assisting in             clinical investigator t o promptly up-
                   t h e conduct of the study(ies) are in-            date t h i s information if a n y relevant
                   formed about their obligations i n                 changes occur cluriiig the course of the
                   nieeting the above coinniitinents.                 investigation and for 1 year followiiig
                      (vii) A connnitinent by the investi-            t h e coinpletion of the study.
                   gator t h a t . for a n investigation subject
                   t o a n institutional review requirement               (d) Selecting nzonitors. A sponsor shall
                   under part 56. ail IRB t h a t coniplies           select a monitor qualified by training
                   with the requirements of t h a t part will         and experience t o nioiiitor the progress
                   be responsible for the initial and con-            of the investigation.
                   tinuing review and approval of the clin-           (Collection of information requirements ap-
                   ical investigation and t h a t the investi-        proved Isy the Office of Management and
                   gator will promptly report t o t h e IRB           Budget under control numlser 0910-0014)
                   all changes in the research activity and           152 F R 8831. Mar. 19, 1987. as amelided a t 52
                   all unanticipated probleins involving              F R 23031, June 17, 1987: 61 F R 57280. Nor. 5,
                   risks t o human subjects or others. and            1996: 63 FR 5252. Feb. 2. 19981
                   will n o t make a n y changes i n t h e re-
                   search without IRB approval. except                4 312.54 Emergency         research under
                   where necessary t o eliminate apparent                   # 50.24 of this chapter.
                   ininiediate hazards to the human sub-                 ( a ) The sponsor shall monitor the
                   jects.                                             progress of all investigations involving
                      (viii) A list of the nanies of t h e sub-       a n exception froin iiiforined coiiseiit
                   investigators (e.g., research fellows,             under 050.24 of this chapter. When the
                                  who will be assisting the iii-      sponsor receives from the IRB inforina-
                   vestigator i n the conduct of the inves-
                                                                      tion coiiceriiing the public disclosures
                   tigation(~).
                                                                      required by § 50.24(a)(7)(ii)and (a)(7)(iii)
                      (2) Czirriczilzim vitae. A curriculum
                   vitae or other statenleiit of qualifica-           of this chapter, t h e sponsor proinptly
                   tions of t h e investigator showing the            shall subniit t o the IND file and t o
                   education. training. and experience                Docket Number 958-0158 i n the Dockets
                   t h a t qualifies t h e investigator a s a n ex-   Management Branch (HFA-305), Food
                   pert i n t h e clinical investigation of the       and Drug Adniinistration. 12420 P a r k -
                   clrug for the use under investigation.             lawn Dr., rm. 1-23, Rockville, MD 20857,
                      (3) Clinical protocol. (i) For Phase 1 iii-     copies of the information t h a t was dis-
                   vestigations, a general outline of t h e           closed. identified by the IND iiuniber.
                   planned investigation iiiclucliiig t h e es-          (b) The spoiisor also shall monitor
                   timated duration of the study and the              such investigations to identify when a n
                   niaxiniuni number of subjects t h a t will         IRB determines t h a t i t cannot approve
                   be involved.                                       t h e research because i t does n o t nieet
                      (ii) For Phase 2 or 3 investigations.           t h e criteria in the exception in
                   a n outline of the study protocol includ-          §50.24(a) of this chapter or because of
                   ing a n approxiination of t h e iiuniber of        other relevant ethical concerns. The
                   subjects t o be treated with t h e clrug           spoiisor proniptly shall provide t h i s in-
                   and t h e iiumber t o be employed a s con-         formation i n writing t o FDA, inves-
                   trols, if any: the clinical uses t o be in-        tigatom who are asked to participate
                   vestigated: characteristics of subjects            in this or a substantially equivalent
                   by age, sex, and condition: the kind of            clinical investigation, and other IRB's




© 2002 by CRC Press LLC
        246      Clinical Research Coordinator Handbook




                                                                                                         21 CFR Ch. 1 (4-1-01 Edition)
                   t h a t are asked t o review this or a sub-                          t o FDA regarding information relevant
                   stantially equivalent investigatioii.                                t o t h e safety of the drug a s are re-
                                                                                        quired under $312.32. The spoiisor shall
                   161 FR 51530, Oct. 2, 19961
                                                                                        niake annual reports on t h e progress of
                   4 312.55 Informing investigators.                                    t h e investigation i n accordance with
                                                                                        § 312.33.
                      ( a ) Before t h e investigation begins. a                           (dl A snonsor who deterniines t h a t i t s
                   sponsor (other t h a n a sponsor-investi-                            investigational drug presents a n uiirea-
                   gator) shall give each participating                                 sonable and significant risk t o subjects
                   clinical investigator a n investigator                               shall cliscoiitiiiue those investigations
                   brochure coiitainiiir t h e information                              t h a t present t h e risk. notify FDA. all
                   described i n §312.23(ij(5).                                         institutional review boards. and all in-
                      (b) The spoiisor shall. a s the overall                           vestigators who have a t any time par-
                   investigation proceeds, keep each par-                               ticipated i n t h e investigation of t h e
                   ticipating iiivestigator iiifornied of iiew                          discontinuance, assure the disposition
                   observations discovered by or reported                               of all stocks of t h e clrug outstanding a s
                   t o t h e spoiisor on the drug. particu-                             requirecl by $312.59, and furnish F D A
                   larly with respect t o adverse effects                               with a full report of t h e sponsor's ac-
                   and safe use. Such iiiforniation may be                              tions. The spoiisor shall discontinue
                   clistributecl to investigators by means                              t h e iiivestigation a s soon a s possible.
                   of periodically revised investigator                                 and i n no event later t h a n 5 working
                   brochures, reprints or published stud-                               clays after niakiiig the deterniiiiation
                   ies. reports or letters t o clinical inves-                          t h a t the iiivestigation should be dis-
                   tigators, or other appropriate means.                                coiitiiiued. Upon request. FDA will con-
                   Iniportaiit safety information is re-                                fer with a sponsor on the need to dis-
                   quired to be relayed to investigators i n                            continue a n investigation.
                   accordance with § 312.32.
                                                                                        (Collection of i n f o r m a t i o n r e q n i r e m e n t s a p -
                   (Collection of i n f o r m a t i o n r e q u i r e m e n t s a p -   proved h y t h e Office of M a n a g e m e n t a n d
                   proved h y t h e Office of M a n a g e m e n t a n d                 B n d g e t u n d e r c o n t r o l n n m h e r 0910-0014)
                   B u d g e t u n d e r c o n t r o l numlser 0910-0014)
                                                                                        152 FR 8831. M a r . 19, 1987. a s a m e n d e d a t 52
                   [52 F R 8831. M a r . 19. 1987. a s a m e n d e d a t 52             F R 23031. J u n e 17. 19871
                   F R 23031. J u n e 17. 19871
                                                                                        4 312.57 Recordkeeping and record re-
                   4 312.56 Review of ongoing investiga-                                     tention.
                         tions.                                                           ( a ) A sponsor shall maintain acle-
                      ( a ) The sponsor shall moiiitor the                              quate 'ecords showing the receipt.
                   progress of all clinical investigations                              shipment, or other disposition of t h e
                   being coiiducted ~mde' i t s IND.                                    investigational drug. These records are
                      (b) A sponsor who discovers t h a t a n                           requirecl t o include, a s appropriate, the
                   investigator is not coniplying with the                              name of the investigator to whoin the
                   signed agreement (Form FDA-1572), the                                clrug is shipped, and t h e date, quantity,
                   general investigational plan. or t h e re-                           and batch or code niark of each such
                   quirements of this part or other appli-                              shipment.
                   cable parts shall promptly either se-                                  (b) A spoiisor shall niaiiitain coni-
                   cure compliance or discontinue ship-                                 plete and accurate recorcls showing any
                   nieiits of t h e investigational iiew drug                           financial interest in § 54.4(a)(3)(i           ).
                   t o t h e investigator and end the inves-                            (aj(3)(iij, (a)(3j(iiij,and (a)(3)(iv)of this
                   tigator's participation i n the investiga-                           chapter paid t o clinical i i i v e ~ t i g a t o ~ s
                   tion. If the investigator's participation                            by the sponsor of the covered study. A
                   in the investigation is eiiclecl. t h e spoii-                       spoiisor shall also maintain complete
                   sor shall require t h a t the investigator                           and accurate recorcls concerning all
                   dispose of or return the investigational                             other financial interests of investiga-
                   clrug i n accordance with t h e require-                             tors subject t o part 54 of this chapter.
                   nieiits of S312.59 and shall notify FDA.                               (c) A spoiisor shall retain the records
                      ( c j The sponsor shall review and                                and reports requirecl by this part for 2
                   evaluate the evidence relating to t h e                              years after a marketing application is
                   safety and effectiveness of t h e clrug a s                          approvecl for t h e clrug: or, if a n applica-
                   i t is obtained from the investigator.                               tion is not approvecl for the drug. until
                   The sponsors shall make such reports                                 2 years after shipment and delivery of




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                   Food and Drug Administration, HHS
                   t h e clrug for investigational use i s dis-                         other securely locked, substantially
                   coiitiiiued and FDA has been so iioti-                               coiistr~~ctecl  eiiclosure. access to which
                   fiecl.                                                               is liniited. t o prevent theft or diversion
                      (d) A sponsor shall 'etain reserve                                of t h e substance into illegal channels
                   samples of a n y t e s t article and ref-                            of distribution.
                   erence staiiclard identified in. aiicl used
                   in a n y of t h e bioequivalence or bio-                             S 312.59 Disposition of unused supply
                   availability      studies described in.                                  of investigational drug.
                   0320.38 or S320.63 of this chapter, and                                The sponsor shall assure the return
                   release t h e reserve saniples to FDA
                                                                                        of all mused supplies of the investiga-
                   upon request, in accordance with, and
                                                                                        tional drug froni each iiidiviclual inves-
                   for the period specified in § 320.38.
                                                                                        tigator whose participation i n t h e iii-
                   (Collection of i n f o r m a t i o n r e q n i r e m e n t s a p -   vestigation i s discontinued or terini-
                   proved h y t h e Office of M a n a g e m e n t a n d                 natecl. The sponsor may authorize al-
                   B u d g e t u n d e r c o n t r o l numlser 0910-0014)
                                                                                        ternative clisposition of unused supplies
                   [52 F R 8831. M a r . 19. 1987. a s a m e n d e d a t 52             of t h e investigatioiial drug provided
                                      e
                   F R 23031, J ~ m 17. 1987: 58 F R 25926. Apr. 28,                    this alternative disposition does n o t
                   1993: 63 F R 5252. F e b . 2. 19981
                                                                                        expose huniaiis t o risks froni the drug.
                   S 312.58 Inspection          of     sponsor's                        The sponsor shall maintain written
                          records and reports.                                          records of a n y clisposition of the clrug
                       ( a ) FDA inspection. A sponsor shall                            in accordance with § 312.57.
                   upon request from a n y properly au-                                 (Collection of i n f o r m a t i o n r e q u i r e m e n t s a p -
                   thorized officer or employee of the                                  proved Isy t h e Office of M a n a g e m e n t a n d
                   Food and Drug Administration, a t rea-                               B u d g e t u n d e r c o n t r o l numlser 0910-0014)
                   sonable times. perniit such officer or
                                                                                        152 F R 8831. M a r . 19, 1987. a s a m e n d e d a t 52
                   einployee t o have access t o and copy                               F R 23031. J u n e 17. 19871
                   and verify a n y records and reports re-
                   lating t o a clinical investigation con-                             4 312.60 General responsibilities of in-
                                      le~
                   ducted ~ ~ i i c this part. Upon written                                  vestigators.
                   request by FDA, t h e sponsor shall sub-
                   niit t h e records or reports (or copies of                             An investigator is respoiisible for eii-
                   t h e m ) t o FDA. The sponsor shall dis-                            suring t h a t a n investigation i s con-
                   coiitiiiue shipments of the drug t o a n y                           cluctecl according t o the signed investi-
                   investigator who has failed t o maintain                             gator s t a t e m e n t , the investigational
                   or m a k e available            or reports of                        plan. and applicable regulations: for
                   t h e investigation a s required by this                             protecting the rights. safety. and wel-
                   part.                                                                fare of subjects uncler t h e investiga-
                       (b) Controllecl substances. If a n inves-                        tor's care: and for the control of drugs
                   tigational new clrug is a substance list-                            under investigatioii. An iiivestigator
                   ed i n a n y schedule of t h e Coiitrollecl                          shall. in accordance with t h e provi-
                   Substances Act (21 U.S.C. 801: 21 CFR                                sions of part 50 of this chapter, obtain
                   part 1308). records concerning ship-                                 t h e informed consent of each human
                   m e n t , delivery, receipt, and clisposition                        subject to whoin the drug i s aclmiiiis-
                   of the drug. which are required to be                                tered. except a s provided in $950.23 or
                   kept uncler this part or other applica-                              50.24 of this chapter. Additional spe-
                   ble parts of this chapter shall. upon the                            cific responsibilities of clinical inves-
                   request of a properly authorized ein-                                tigatom are set forth i n this part and
                   ployee of t h e Drug Eiiforceinent Acl-                              in parts 50 and 56 of this chapter.
                   ministration of the U.S. Department of
                   Justice. be made available by the in-                                [52 F R 8831. M a r . 19. 1987. a s a m e n d e d a t 61
                   vestigator or sponsor t o whom t h e re-                             F R 51530. O c t . 2. 19961
                   quest i s niade. for inspection and copy-
                   ing. I n addition, the sponsor shall as-                             4 312.61 Control of the investigational
                                                                                            drug.
                   sure t h a t adequate precautions are
                   t a k e n , including storage of t h e inves-                          An investigator shall administer the
                   tigational drug i n a securely locked.                               clrug only t o subjects uncler the inves-
                   substantially constructed cabinet, or                                tigator's personal supervision or under




© 2002 by CRC Press LLC
        248      Clinical Research Coordinator Handbook




                                                                                                         21 CFR Ch. 1 (4-1-01 Edition)
                   t h e supervision of a subinvestigator re-                           lecting and evaluating the results ob-
                   spoiisible t o the iiivestigator. The iii-                           tained. The sponsor is required uncler
                   vestigator shall not supply the inves-                               0312.33 t o submit annual reports t o
                   tigational drug t o any person not au-                               FDA on the progress of the clinical in-
                                    this
                   thorized ~ u ? d e ~ part t o receive i t .                          vestigations.
                                                                                           (b) S a f e t y reports. An iiivestigator
                   4 312.62 Investigator         recordkeeping                          shall proniptly report t o the sponsor
                          and record retention.
                                                                                        any adverse effect t h a t niay reasonably
                      ( a ) Disposition of drzig. An investi-                           be regarded a s caused by. or probably
                   gator is required t o niaiiitain adequate                            caused by. the drug. If the adverse ef-
                   'ecords of t h e disposition of t h e drug.                          fect is alarniiiig. t h e investigator shall
                   including dates. quantity. and use by                                report t h e adverse effect iinmecliately.
                   subjects. If t h e investigation is terini-                             ( c ) Final report. An investigator shall
                   natecl, suspended, discontinued, or                                  provide t h e sponsor with a n adequate
                   completed, the investigator shall re-
                                                                                        report shortly after coinpletion of t h e
                   t u r n t h e unused supplies of t h e clrug t o
                                                                                        investigator's participation i n the in-
                   t h e sponsor, or otherwise provide for
                                                                                        vestigation.
                   clisposition of t h e unused supplies of
                   t h e drug under § 312.59.                                              (d) Financicll discloszire reports. The
                      (b) Case histories. An investigator is                            clinical iiivestigator shall provide the
                   required to prepare and maintain acle-                               spoiisor with sufficient accurate finan-
                   quate and accurate case histories t h a t                            cial information t o allow a n applicant
                   record all observations and other clata                              t o submit complete and accurate cer-
                   pertinent t o the investigation on each                              tification or clisclosure statements a s
                   individual adniinisterecl t h e investiga-                           required uncler part 54 of this chapter.
                   tional drug or employed a s a control i n                            The clinical investigator shall proinpt-
                   t h e investigation. Case histories iii-                             ly update this information if any rel-
                   clucle the case report forins aiicl sup-                             evant changes occur during t h e course
                   porting clata including. for exaniple.                               of the investigation and for 1 year fol-
                   signed and dated consent forms and                                   lowiiig the coinpletion of the study.
                   niedical records iiiclucliiig. for exaniple.                         (Collection of i n f o r m a t i o n r e q n i r e m e n t s a p -
                   progress notes of the physician, the in-                             proved h y t h e Office of M a n a g e m e n t a n d
                   dividual's hospital chart(s). and the                                B u d g e t u n d e r c o n t r o l numlser 0910-0014)
                   nurses' notes. The case history for each
                   individual shall document t h a t iii-                               152 F R 8831. M a r . 19, 1987. a s a m e n d e d a t 52
                                                                                        F R 23031. J u n e 17. 1987: 63 F R 5252. F e b . 2.
                   formed consent was obtained prior t o                                19981
                   participation i n the study.
                      (c) Record retention. An investigator                             S 312.66 Assurance of IRB review.
                   shall retain records required t o be
                   niaiiitainecl under this part for a period                             An iiivestigator shall assure t h a t a n
                   of 2 years following t h e date a mar-                               IRB t h a t coinplies with t h e require-
                   keting application is approved for the                               nieiits set forth i n part 56 will be re-
                   clrug for the indication for which i t is                            sponsible for the initial and continuing
                   being investigated: or. if no application                            review aiicl approval of t h e proposed
                   is to be filed or if the application is not                          clinical study. The investigator shall
                   approved for such inclicatioii. until 2                              also assure t h a t he or she will pronipt-
                   years after the investigation is cliscon-                            ly report t o t h e IRB all changes in t h e
                   tinuecl and FDA is iiotifiecl.                                       research activity and all ~maiiticipatecl
                                                                                        problems involving risk t o human sub-
                   (Collection of i n f o r m a t i o n r e q u i r e m e n t s a p -   jects or others. and t h a t he or she will
                   proved h y t h e Office of M a n a g e m e n t a n d
                   B u d g e t u n d e r c o n t r o l numlser 0910-0014)
                                                                                        not make any changes i n t h e research
                                                                                        without IRB approval. except where
                   [52 F R 8831. M a r . 19. 1987. a s a m e n d e d a t 52             necessary to eliminate apparent imine-
                   F R 23031, J u n e 17, 1987: 61 F R 57280. N o r . 5,                cliate hazards to hunian subjects.
                   19961
                                                                                        (Collection of i n f o r m a t i o n r e q n i r e m e n t s a p -
                   S 312.64 Investigator reports.                                       proved h y t h e Office of M a n a g e m e n t a n d
                      ( a ) Progress reports. The investigator                          B u d g e t u n d e r c o n t r o l numlser 0910-0014)
                                       all
                   shall f ~ ~ r i i i s h 'eports t o the sponsor                      152 F R 8831. M a r . 19, 1987. a s a m e n d e d a t 52
                   of t h e clrug who is responsible for col-                           F R 23031. J u n e 17. 19871




© 2002 by CRC Press LLC
                                                                          Appendix A: FDA Regulations                             249




                   Food and Drug Administration, HHS

                   4 312.68 Inspection       of investigator's         (b) After evaluating all available in-
                         records and reports.                       formation, inclucling a n y explanation
                      An iiivestigator shall upon request           preseiitecl by the iiivestigator. if the
                   froin a n y properly authorized officer or       Coniinissioiier determines t h a t the iii-
                   einployee of FDA, a t reasonable times,          vestigator has repeatedly or clelib-
                   permit such officer or employee t o              erately failecl t o comply with the re-
                   have access to, and copy and verify a n y        quirements of this part. part 50. or part
                   records or reports made by the investi-          56 of this chapter. or has deliberately
                   gator pursuant t o s312.62. The investi-         or repeatedly subinittecl false inforina-
                   gator i s n o t required t o divulge subject     tion to FDA or t o t h e sponsor in a n y
                   names unless the records of particular                         report. the Coniniissioner will
                   individuals               a niore detailed       notify the iiivestigator aiicl t h e sponsor
                   study of the cases. or unless there is           of a n y investigation in which the in-
                   reason to believe t h a t the records do         vestigator has been named a s a partici-
                   not               actual case studies. or do     pant t h a t the iiivestigator i s not enti-
                   n o t represent actual           obtained.       tled t o receive investigatioiial drugs.
                                                                    The notification will provide a s t a t e -
                   4312.69 Handling of controlled sub-              ment of basis for such determination.
                        stances.                                       ( c ) Each IND and each approved ap-
                      If the iiivestigational drug i s subject      plication subniitted under part 314 coii-
                   t o t h e Coiitrolled Substances Act. t h e      taiiiing data reported by a n investi-
                   investigator shall t a k e adequate pre-         gator who has been determined t o be
                   cautions, inclucling storage of the in-          ineligible t o receive investigational
                   vestigational drug i n a securely locked,        drugs will be exainiiied to ~ l e t e ~ i n i i i e
                   substantially constructed cabinet, or            whether the iiivestigator has submitted
                   other securely locked. substantially             unreliable d a t a t h a t are essential t o
                   constructed enclosure, access to which           t h e continuation of the investigation
                   is liniited. t o prevent theft or diversion      or essential t o the approval of a n y
                   of t h e substance into illegal channels         marketing application.
                   of d i ~ t ~ i b u t i o i i .                      (d) If t h e Commissioner determines,
                                                                    after the unreliable d a t a submitted by
                   4 312.70 Disqualification of a clinical          t h e investigator a r e eliiniiiated froin
                         investigator.
                                                                    coiisideration. t h a t the d a t a reinainiiig
                      ( a ) If FDA has information indicating       are inadequate t o support a conclusion
                   t h a t a n investigator (including a spon-      t h a t i t i s reasonably safe t o continue
                   sor-investigator) has repeatedly or cle-         t h e iiivestigation. the Coniinissioiier
                   liberately failecl t o coniply with t h e re-    will notify t h e sponsor who shall have
                   quirements of this part, part 50, or part        a n opportunity for a regulatory hear-
                   56 of this chapter. or has subniittecl t o       ing under part 16. If a danger t o t h e
                   FDA or t o the sponsor false informa-            public health exists. however. t h e Coni-
                   tion i n a n y            report. the Center     niissioner shall teriniiiate t h e IND iin-
                   for Drug Evaluation and Research or
                                                                    mediately and notify t h e sponsor of the
                   t h e Center for Biologics Evaluation
                   and Research will furnish t h e investi-         determination. In such case, t h e spon-
                   gator written notice of the niatter              sor shall have a n opportunity for a reg-
                   complained of and offer the investi-                                                          ea
                                                                    ulatory hearing before FDA ~ ~ i i c l p r r t
                   gator a n opportunity to explain the             16 on the question of whether the IND
                   m a t t e r i n writing, or, a t the option of   should be reinstated.
                   t h e investigator. i n a n iiifornial coii-        (e) If t h e Coniniissioiier ~ l e t e ~ i n i i i e s .
                   ference. If a n explanation i s offered but                                    data submitted by
                                                                    after the ~ ~ i i r e l i a b l e
                   n o t accepted by the Center for Drug            t h e investigator a r e eliminated from
                   Evaluation and Research or t h e Center          consideration, t h a t the continued ap-
                   for Biologics Evaluation and Research.           proval of the drug product for which
                   t h e investigator will be given a n oppor-      t h e d a t a were subinittecl cannot be jus-
                   t u n i t y for a               hearing under    tified, the Coinmissioner will proceed
                   part 16 on t h e question of whether the         t o withdraw approval of the drug prod-
                   investigator i s entitled t o receive iii-       uct i n accordance with t h e applicable
                   vestigational new drugs.                         provisions of the a c t .




© 2002 by CRC Press LLC
        250      Clinical Research Coordinator Handbook




                                                                                       21 CFR Ch. 1 (4-1-01 Edition)
                      (fj An investigator who has been cle-               ease being treated. The procedure out-
                   terniinecl t o be ineligible to receive iii-           lined in this section shoulcl be inter-
                   vestigational drugs may be reinstated                  preted consistent with t h a t purpose.
                                                                  de-
                   a s eligible when the C o i n n i i ~ s i o n e ~
                   termines t h a t the investigator has pre-             S 312.81 Scope.
                   seiitecl adequate assurances t h a t the iii-             This section applies to iiew drug aiicl
                   vestigator will eniploy investigatioal                 biological proclucts t h a t are being stud-
                   clrugs solely i n compliance with the                  ied for their safety and effectiveness in
                   provisioiis of this part and of parts 50               treating life-threateiiiiig or severely-
                   and 56.                                                clebilitatiiig diseases.
                   (Collection of informntion requirements np-               ( a ) For purposes of this sectioii. the
                   proved hy t h e Office of Management and               tern? ..life-threatening" nieans:
                   Bndget under control nnmher 0910-0014)                    ( I ) Diseases or conclitions where the
                                                                          likelihood of death is high unless the
                   [52 F R 8831. Mar. 19. 1987. ns nmenclecl a t 52
                   F R 23031. J u n e 17. 1987. 55 F R 11580. Mnr. 29.    course of the disease is interrupted:
                   1990: 62 FR 46876, Sept. 5. 19971                      and
                                                                             (2)Diseases or conclitions with poten-
                                                                          tially fatal outcomes, where t h e end
                   Subpart E-Drugs      Intended to                       point of clinical trial analysis is sur-
                      Treat Life-threatening and Se-                      vival.
                      verely-debilitating Illnesses                          (b) For purposes of this section, the
                                                                          t e r m "severely debilitating" means
                     AUTHORITY: U.S.C. 351. 352. 353. 355. 371:
                                  21                                      diseases or conclitions t h a t cause major
                   42 U.S.C. 262.                                         irreversible morbidity.
                     SOURCE: FR 41523, Oct. 21. 1988. unless
                              53                                             ( c j Sponsors are encouraged t o con-
                   otherwise noted.                                       sult with FDA on t h e applicability of
                                                                          these procedures t o specific proclucts.
                   S 312.80 Purpose.                                      [53 F R 41523. Oct. 21. 1988. a s amended a t 64
                       The purpose of this section is to es-              F R 401. J n n . 5. 19991
                   tablish procedures designed to expedite
                   t h e clevelopment, evaluation, and mar-               S 312.82 Early consultation.
                   keting of iiew therapies iiiteiidecl t o                   For proclucts intended t o t r e a t life-
                   t r e a t persons with life-threatening and            threateiiiiig or severely-clebilitatiiig ill-
                   severely-debilitating illiiesses. espe-                nesses. sponsors niay                    t o meet
                   cially where no satisfactory alter-                    with FDA-reviewiiig officials early in
                   native therapy exists. As stated                       t h e drug developnieiit process t o review
                   §314.105(cj of this chapter, while t h e               and reach agreenieiit on t h e clesign of
                   s t a t u t o r y staiiclards of safety aiicl effec-   necessary preclinical and clinical stud-
                   tiveness apply t o all clrugs, t h e many              ies. Where appropriate, FDA will invite
                   kinds of drugs t h a t are subject t o                 t o such meetings one or more outside
                   them, and the wide range of uses for                   expert scientific consultants or advi-
                   those drugs. cleinaiid flexibility i n ap-             sory coininittee menibers. To the ex-
                   plying t h e standards. The Food and                   t e n t FDA resources permit, agency re-
                   Drug Aclministration (FDA) has deter-                  viewing officials will hollor requests
                   ininecl t h a t i t is appropriate t o exercise        for such meetings
                   t h e broadest flexibility in applying t h e               ( a ) Pre-investigc~tion(II n e w clrug (I,VDj
                   s t a t u t o r y standards, while preserving          meetings. Prior t o t h e submission of t h e
                   appropriate guarantees for safety and                  initial IND. t h e sponsor may request a
                   effectiveness. These procedures reflect                meeting with FDA-reviewing officials.
                   t h e recognition t h a t physicians and pa-           The primary purpose of this meeting is
                   tients are generally willing t o accept                t o review and reach agreement on the
                   greater risks or side effects froin pro&               clesign of aiiinial studies needed to iiii-
                   ucts t h a t t r e a t life-threatening and se-        t i a t e human testing. The meeting may
                   verely-debilitating illiiesses. t h a n they           also provide a n opportunity for dis-
                   would accept from products t h a t t r e a t           cussing the scope and design of phase I
                   less serious illnesses. These procedures               testing. plans for studying t h e drug
                   also reflect the recognition t h a t the               product i n pediatric populations, and
                   benefits of t h e drug need t o be evalu-              t h e best approach for presentation and
                   ated i n light of the severity of t h e dis-           formatting of d a t a i n t h e IND.




© 2002 by CRC Press LLC
                                                                                  Appendix A: FDA Regulations                  25 1




                   Food and Drug Administration, HHS
                       (b) End-of-phase I meetings. When d a t a             risks and benefits of the drug, t a k i n g
                   froin phase 1 clinical testing are avail-                 into consideration t h e severity of the
                   able. the sponsor niay again request a                    disease and t h e absence of satisfactory
                   nieeting with FDA-reviewing officials.                    alternative therapy.
                   The primary purpose of this meeting i s                      (b) I n making clecisioiis on whether
                   t o review aiicl reach agreenieiit on the                 t o grant niarketiiig approval for pro&
                   clesign of phase 2 controlled clinical                    ucts t h a t have been t h e subject of a n
                   trials, with t h e goal t h a t such testing              end-of-phase I meeting uncler $ 312.82,
                   will be adequate t o provicle sufficient
                                                                             FDA will usually seek t h e advice of
                   clata on the drug's safety and effective-
                   ness to support a clecision on i t s ap-                  outside expert scientific consultaiits or
                   provability for marketing. and to dis-                    advisory coinmittees. Upon t h e filiiig
                   cuss t h e neecl for, a s well a s the clesign            of such a marketing application under
                   and timing of. studies of the drug i n pe-                $ 314.101 or part 601 of this chapter, FDA
                   diatric patients. For drugs for life-                     will notify the inembers of the relevant
                   threateiiiiig diseases. FDA will provide                  standing advisory committee of t h e ap-
                   i t s best judgment, a t t h a t time, wheth-             plication's filiiig and i t s availability
                   er pediatric studies will be required                     for review.
                   and whether their submission will be                         (c) If FDA conclucles t h a t t h e clata
                   cleferred until after approval. The pro-                  preseiitecl are not sufficient for niar-
                   cedures outlined i n $312.47(b)(l) with                   keting approval. FDA will issue (for a
                   respect to end-of-phase 2 conferences.                    clrug) a not approvable l e t t e r pursuant
                   including clocuinentation of agree-                       t o $314.120 of this chapter, or (for a bio-
                   nieiits reached. would also be used for                   logic) a deficiencies l e t t e r consistent
                   end-of-phase I meetings.                                  with the biological product licensing
                   [53 F R 41523. O c t . 21. 1988. a s al-nenclecl a t 63   procedures. Such l e t t e r . in clescribiiig
                   F R 66669. Dec. 2. 19981                                  t h e deficiencies i n t h e applicatioii. will
                                                                             address why the results of t h e research
                   4 312.83 Treatment protocols.                             clesign agreed t o uncler $312.82, or i n
                      If t h e preliiniiiary aiialysis of phase 2            subsequent meetings, have n o t pro-
                   t e s t results appears promising, FDA                    vided sufficient evicleiice for marketing
                   niay a s k t h e spoiisor to submit a treat-              approval. Such l e t t e r will also describe
                   ment protocol t o be reviewed under the                   a n y recoinnieiiclations niacle by the ad-
                   procedures and criteria listed in                         visory connnittee regarding the appli-
                   SS312.34 and 312.35. Such a t r e a t m e n t             cation.
                   protocol. if requested aiicl granted.                        (d) Marketing applications submitted
                   would norlnally remain i n effect while                   under t h e procedures contained in this
                   t h e coniplete clata necessary for a niar-
                                                                             section will be subject to t h e require-
                   keting application a r e being assembled
                                                                             nieiits aiicl procedures contained i n part
                   by the sponsor and                    by FDA
                   (unless grounds exist for clinical hold                   314 or part 600 of this chapter. a s well
                   of ongoing protocols. a s provided i n                    a s those in this subpart.
                   $ 312.42(b)(3)(ii)).
                                                                             4 312.85 Phase 4 studies.
                   S 312.84 Risk-benefit analysis in review                     Concurrent with marketing approval,
                          of marketing applications for drugs                FDA m a y seek agreement from the
                          to treat life-threatening and se-                  spoiisor to coiicluct certain post-
                          verely-debilitating illnesses.
                                                                             niarketing (phase 4) studies t o cleliii-
                       ( a ) FDA's application of the s t a t u -            e a t e additional information about the
                   tory staiiclards for niarketiiig approval                 drug's risks, benefits, and optimal use.
                   shall recognize the need for a medical                    These studies could include, but would
                   risk-beiiefit juclgnieiit in makiiig the                  n o t be limited t o , studying different
                   final clecision on approvability. As p a r t
                                                                             closes or schedules of adniiiiistration
                   of this evaluation. consistent with the
                   s t a t e m e n t of purpose i n $312.80, FDA             t h a n were used i n phase 2 studies. use
                   will consider whether the benefits of                     of the drug in other patient popu-
                   t h e clrug outweigh the known and po-                    lations or other stages of t h e disease,
                   tential risks of the drug aiicl the neecl                 or use of the drug over a longer period
                   t o answer remaining questions about                      of time.




© 2002 by CRC Press LLC
© 2002 by CRC Press LLC
                                                                                  Appendix A: FDA Regulations                       253




                   Food and Drug Administration, HHS
                   consignee in t h a t country. Such a re-                 should FDA request, case records main-
                   quest shall specify the q u a n t i t y of drug          tained by the investigator or acldi-
                   t o be shipped per shipment and t h e fre-               tioiial background d a t a such a s hos-
                   quency of expected shipineiits.                          pital or other iiistitutioiial records:
                      (iii) Authorization t o export a n iii-                   (4) A description of the drug sub-
                   vestigational clrug under paragraph                      stance and drug product used i n the
                   (b)(2)(i)or (ii) of this section niay be                 study, including a description of com-
                   revoked by FDA if t h e agency finds                     ponents, formulation, specifications,
                   t h a t the conditioiis underlying i t s au-             and bioavailability of t h e specific clrug
                   thorization are n o t longer met.
                                                                            product used i n the clinical study. if
                      (3) This paragraph applies only where
                                                                            available: and
                   t h e clrug is t o be used for the purpose of
                   clinical iiivestigatioii.                                    (5) If t h e study i s inteiiclecl t o support
                      (4) This paragraph does not apply t o                 t h e effectiveness of a drug product. iii-
                   t h e export of iiew drugs (including bio-               formation showing t h a t t h e study i s
                   logical proclucts, antibiotic drugs, and                 adequate and well controlled uncler
                   insulin) approved or authorized for ex-                  § 314.126.
                   port uncler section 802 of the a c t (21                                            w            ~l
                                                                                (c)C o n f o ~ v m n c e ith etl~iccp~inciples.
                   U.S.C. 382) or section 351(h)(l)(A) the  of              (1)Foreign clinical research i s required
                   Public Health Service Act (42 U.S.C.                     t o have been conducted i n accordance
                   262(h)(l)(A)).                                           with t h e ethical principles s t a t e d i n
                   (Collection of information reqnirements ag-              t h e "Declaration of Helsinki" (see
                   proved Isy the Office of Management and                  paragraph (c)(4) of this section) or the
                   Budget under control numlser 0910-0014)                  laws and                                           in
                                                                                                            of the c o ~ m t r y
                   [52 F R 8831. Mar. 19. 1987. as amended a t 52           which the research was conducted,
                   F R 23031. J u n e 17. 1987: 64 F R 401. Jan. 5. 19991   whichever represents t h e greater pro-
                                                                            tection of the iiidiviclual.
                   S 312.120 Foreign clinical studies not                       (2) For each foreign clinical study
                         conducted under an IND.                            submitted uncler this section, the spon-
                      ( a ) Introdzictioiz. This section cle-               sor shall explain how t h e research con-
                   scribes t h e criteria for acceptance by                 formed to the ethical principles coii-
                   FDA of foreign clinical studies n o t con-               taiiied i n the "Declaration of Helsinki"
                   ducted under a n IND. In general. FDA                    or t h e foreign country's stanclarcls,
                   accepts such studies provided they are                   whichever were used. If the foreign
                   well clesigiied. well concluctecl. per-                  c o ~ m t r y ' s staiidarcls were used. the
                   formed by qualified investigators, and                   spoiisor shall explain i n detail how
                   conducted i n accordance with ethical                    those stanclarcls differ from the "Dec-
                   principles acceptable to the world coin-                 laration of Helsinki" and how they
                   niunity. Studies nieetiiig these criteria                offer greater protection.
                   may be utilized t o support clinical in-                     (3) When the research has been ap-
                   vestigations i n t h e United S t a t e s and            proved by a n iiiclepeiident review coni-
                   or marketing approval. Marketing ap-                     inittee, the sponsor shall submit t o
                   proval of a iiew drug based solely on
                                                                            FDA documentation of such review and
                   foreign clinical d a t a i s governed by
                                                                            approval. iiiclucliiig the names and
                   § 314.106.
                      (b) Data submissions. A sponsor who                   qualificatioiis of t h e menibers of the
                   wishes t o rely on a foreign clinical                    cominittee. I n this regard, a "review
                   study t o support a n IND or t o support                 committee" means a connnittee coin-
                   a n application for marketing approval                   posed of scientists aiicl. where prac-
                   shall subniit t o FDA the following iii-                 ticable. iiidivicluals who are otherwise
                   formation:                                               qualified (e.g., other health profes-
                      ( I ) A description of t h e investigator's           sionals or laymen). The investigator
                   qualificatiolis:                                         niay not vote on a n y aspect of the re-
                      (2) A ~ l e s c ~ i p t i oof the research fa-
                                                  ii                        view of his or her protocol by a review
                   cilities:                                                committee.
                      (3) A detailed summary of the pro-                        (4) The "Declaration of Helsinki"
                   tocol and                     of t h e study. and.       s t a t e s a s follows:




© 2002 by CRC Press LLC
                 Clinical Research Coordinator Handbook




                                                                                   21 CFR Ch. 1 (4-1-01 Edition)
                                                                        2. The design and performance of each ex-
                                                                      perimental procednre iilvolving human sub-
                                                                      jects should he clearly formnlated in a n ex-
                                                                      perimental protocol which should he trans-
                                                                      mitted for consideration. comment and guicl-
                      I t is the mission of the physician t o safe-   a w e t o a specially appointed committee
                   guard the health of the people. His or her         independent of the investigator and the
                   knowledge and conscience are dedicated t o         sponsor provided t h a t this independent com-
                   the fulfillment of this mission.                   mittee is in conformity with the laws and
                      The Declaration of Geneva of the Korld          regulations of the country in which the re-
                   Medical Association hinds the physician with       search experiment is performed.
                   the words, "The health of my patient will he         3. Biomedical research involving human
                   m y first consideration," and the Inter-           subjects should be conducted only by sci-
                   national Code of Medical Ethics declares           entifically qualified persons and under t h e
                   t h a t . "A physician shall a c t only in the pa- supervision of a clinically competent mecl-
                   tient's interest when providing medical care       ical person. The responsilsility for the human
                   which might have the effect of weakening           subject must always rest with a medically
                   the physical and mental condition of the pa-       qnalified person and never rest on the suh-
                   tient."                                            ject of the research, even thong11 the snhject
                      The purpose of hioniedical research involv-     has given his or her consent.
                                                                        4. Biomedical research involving human
                   ing human sulsjects must be t o improve diag-
                                                                      subjects cannot legitimately Ise carried out
                   nostic. therapeutic and prophylactic proce-
                                                                      unless the importance of the olsjectiae is in
                   dnres and the understanding of the aetiology
                                                                      proportion t o the inherent risk t o the suls-
                   and pathogenesis of disease.
                                                                      ject.
                      In current medical practice most diag-            5 . Eaery lsiomedical research project in-
                   nostic. therapeutic or prophylactic proce-         volving human subjects should Ise preceded
                   dnres involve hazards. This applies espe-          by careful assessment of predictable risks in
                   cially t o biomedical research.                    comparison with foreseealsle lsenefits t o the
                      Medical progress is based on research           subject or t o others. Concern for the inter-
                   which ultimately must rest in part on ex-          ests of the subject must always prevail over
                   perimentation iilvolving hnman subjects.           the interests of science and society.
                      In the field of hioniedical research a f~uida-    6. The right of the research subject t o safe-
                   mental distinction niust be recognized he-         guard his or her integrity must always be re-
                   tween medical research in which the aim is         spected. Eaery precaution should be taken t o
                   essentially diagnostic or therapeutic for a        respect the privacy of the sulsject and t o
                   patient. and medical research. the essential       minimize the impact of the study on the sub-
                   object of which is purely scientific and with-     ject's physical and mental integrity and on
                   ont implying direct diagnostic or thera-           the personality of the subject.
                   peutic value t o the person subjected t o the        7. Physicians shonld abstain frorn engaging
                   research.                                          in research projects involving human sub-
                      Special caution must be exercised in the        jects unless they are satisfied t h a t the haz-
                   conduct of research which may affect the en-       ards involved are believed t o be predictable.
                   viromnent. and the welfare of anirnals nsed        Physicians should cease any investigation if
                   for research must Ise respected.                   the hazards are found t o outweigh the poten-
                      Because i t is essential t h a t the results of tial benefits.
                   lalsoratory experiments Ise applied t o human        8. I11 pulslication of the results of his or her
                   beings t o further scientific knowledge and t o    research. the physician is obliged t o preserve
                   help suffering humanity. the World Medical         the accuracy of the results. Reports of ex-
                   Association has prepared the following rec-        perimentation not in accordance with the
                   onirnendations as a gnide t o every physician      principles laid down in this Declaration
                   in biomedical research involving humall sub-       shonld not be accepted for publication.
                   jects. They should be kept under review in           9. In any research on human beings. each
                   the future. I t niust he stressed t h a t the      potential snhject niust he adeqnately in-
                   standards a s drafted are only a guide t o phy-    formed of the aims, methods. anticipated
                   sicians all over the world. Physicialls are not    benefits and potential hazards of the study
                   relieved frorn criminal, civil and ethical re-     and the discomfort i t may entail. He or she
                   sponsibilities under the laws of their ow11 shonld he informed t h a t he or she is a t lih-
                   countries.                                         erty t o abstain from participation in the
                                    I. Basic Principles               stndy and t h a t he or she is free t o withdraw
                                                                      his or her conseilt t o participation a t any
                      1. Biomedical research involving human          time. The physician should then obtain t h e
                   subjects niust conform t o generally accepted      subject's freely-given informed consent. pref-
                   scientific principles and shonld be based on       erably in writing.
                   aclecluately performed lEtborat0ry and animal        10. When olstaining informed consent for
                   experimentation and on a thorough knowl-           the research project the physician shonld be
                   edge of the scientific literature.                 particularly cautious if the subject is in a




© 2002 by CRC Press LLC
                                                                              Appendix A: FDA Regulations                  255




                   Food and Drug Administration, HHS
                   dependent relationship t o him or her or may          the experimental design is not related t o the
                   conseilt ~ u i d e rduress. In t h a t case the in-   patient's illness.
                   formed consent shonld he obtained hy a phy-             3. The investigator or the investigating
                   sician who is not engaged in the investiga-           team should discontinue the research if in
                   tion and who is completely independent of             his her or their judgment i t may. if contin-
                   this official relationship.                           ued. be harmful t o the individual.
                      11. In case of legal incompetence, informed
                                                                           4. In research on man. the interest of
                   conseilt should he ohtained from the legal
                   gnardian in accordance with national legis-           science and society should never t a k e prece-
                   lation. IVhere physical or mental incapacity          dence over considerations related t o the
                   makes i t irnpossihle t o obtain informed con-        well-lseing of the sulsject.
                   sent. or when the subject is a minor. permis-         (Collection of information requirements ap-
                   sion from the responsilsle relative replaces          proved Isy the Office of Management and
                   t h a t of the subject in accordance with 11%-        Budget under control numlser 0910-0014)
                   tional legislation.
                      IVhenever the minor child is in fact able t o      152 FR 8831. Mar. 19, 1987. as amended a t 52
                   give a consent. the minor's consent mnst he                             17.
                                                                         FR 23031, J ~ u i e 1987: 56 FR 22113. May 14,
                   obtained in addition t o the consent of the           1991: 64 FR 401, Jan. 5, 19991
                   minor's legal guardian.
                      12. The research protocol shonld always            S 312.130 Availability for public disclo-
                   contain a statement of the ethical consider-                sure of data and information in an
                   ations involved and shonld indicate t h a t the             IND.
                   principles enunciated in the present Declara-
                   tion are complied with.                                  ( a ) The existelice of a n investiga-
                                                                         tional new drug application will not be
                                                                         clisclosed by FDA unless i t has pre-
                                                                         viously been publicly clisclosecl or ac-
                      1. In the treatment of the sick person. the
                   physician must be free t o use a new diag-            knowledged.
                   nostic and therapeutic measure. if in his or             (b) The availability for public disclo-
                   her jndgment i t offers hope of saving life. re-      sure of all d a t a and information in a n
                   establishing health or alleviating snffering.         investigational new drug application
                      2. The potential benefits. hazards and dis-        for a new drug will be handled i n ac-
                   comfort of a new method should Ise weighed
                   against the advantages of the best current            cordance with t h e provisions estab-
                   diagnostic and therapeutic methods.                   lished i n § 314.430 for the coiifideiitiality
                      3. In any medical stndy, every patient-iii-        of d a t a and information i n applications
                   clnding those of a control group. if any-             submitted in p a r t 314. The availability
                   should be assured of the best proven diag-            for public disclosure of all d a t a and in-
                   nostic and therapeutic method.
                      4. The refusal of the patient t o participate      formation in a n investigatioiial new
                   in a study mnst never interfere with the phy-         drug application for a biological prod-
                   sician-patient relationsl~ip.                         uct will be governed by the provisions
                      5 . If the physician considers i t essential       of §§ 601.50 and 601.51.
                   not t o obtain informed consent. the specific            (c) Notwithstanding t h e provisioiis of
                   reasons for this proposal should be stated in
                   the experimental protocol for trailsniission          $314.430, FDA shall disclose upon re-
                   t o the independent committee (I. 2).                 quest t o a n individual t o whom a n in-
                      6. The physician can combine medical re-           vestigational new drug has been given
                   search with professional care. the olsjectiae         a copy of a n y IND safety report relat-
                   being the acquisition of new medical knowl-           ing t o t h e use i n t h e individual.
                   edge. only t o t h e extent t h a t medical re-
                   search is jnstified hy its potential diagnostic          (d) The availability of information
                   or therapeutic value for the patient.                             t o be publicly disclosed for iii-
                                                                         vestigations iiivolviiig a n exception
                                                                         from informed consent under Q50.24of
                                                                         this chapter will be hanclled a s follows:
                                                                         Persons wishing to request the publicly
                      1. In t h e purely scientific application of       clisclosable information i n t h e IND t h a t
                   medical research carried ont on a hnman
                   being. i t is the duty of the physician t o re-       was required t o be filed i n Docket
                   main the protector of the life and health of          Nuniber 958-0158 in t h e Dockets Mali-
                   t h a t person on whom biomedical research is         ageinent Branch (HFA-305), Food and
                   being carried out.                                    Drug Administration, 12420 Parklawn
                      2. The snhjects shonld be vol~uiteers-ei-          Dr., r m . 1-23, Rockville, MD 20857, shall
                   ther healthy persons or patients for whom




© 2002 by CRC Press LLC
        256      Clinical Research Coordinator Handbook




                                                                                       21 CFR Ch. 1 (4-1-01 Edition)
                   submit a request under t h e Freedom of             Racliopharlnaceutical Drug Products
                   Information Act.                                    (HFD-150). Center for Drug Evaluation
                   152 F R 8831, Mar. 19, 1987. Redesignated a t 53    and Research. Food and Drug Adniiiiis-
                   F R 41523. Oct. 21. 1988. a s nmencled n t 61 F R   tration. 5600 Fishem Lane. Rockville.
                   51530. Oct. 2. 1996: 64 FR 401. J n n . 5. 19991    MD 20857, except t h a t applications for
                                                                       couplecl antibodies shall be submitted
                   4 312.140 Address for correspondence.               in accordance with paragraph ( b j of
                       ( a ) Except a s provided in paragraph          this sectioii.
                   (bj of this section, a sponsor shall send             (d) All correspondence relating t o ex-
                   a n initial IND submission to t h e Ceii-           port of a n iiivestigatioiial drug under
                   t r a l Document Room, Center for Drug              §312.110(b)(2)shall be subniitted t o the
                   Evaluation and Research. Food and                   Interiiatioiial Affairs Staff (HFY-50).
                   Drug Administration, P a r k Blclg., R1n.           Office of Health Affairs, Food and Drug
                   214. 12420 Parklawn Dr.. Rockville. MD              Aclministration, 5600 Fishers Lane,
                   20852. On receiving the IND, FDA will               Rockville, MD 20857.
                   infom? the sponsor which one of the cli-
                   visions i n the Center for Drug Evalua-             (Collection of i n f o r m n t i o n r e q u i r e m e n t s np-
                   tion aiicl Research or the Center for               proved Isy t h e Office of M n n a g e m e n t n n d
                   Biologics Evaluation and Research i s               B u d g e t u n d e r c o n t r o l numlser 0910-0014)
                   responsible for the IND. Aniendnieiits.             152 F R 8831. Mar. 19, 1987. a s amelided a t 52
                   reports, and other correspondence re-               F R 23031. J u n e 17. 1987: 55 F R 11580. M a r . 29,
                   lating t o m a t t e r s covered by the IND         19901
                   shoulcl be directed to t h e appropriate
                   division. The outside wrapper of each               S 312.145 Guidance documents.
                   submission shall s t a t e what is con-                ( a ) FDA has niacle available guidance
                   tained in the subniission. for example.             clocunieiits under § 10.115 of this chapter
                   ..IND Application", "Protocol Amend-
                                                                       t o help you t o comply with certain re-
                   nieiit". etc.
                       (b) Applicatioiis for t h e products list-      quirements of this part.
                   ecl below shoulcl be submitted to the Di-              (b) The Center for Drug Evaluation
                   vision of Biological Investigational                and Research (CDER) and t h e Center
                   New Drugs (HFB-2301, Center for Bio-                for Biologics Evaluation and Research
                   logics Evaluation and Research. Food                (CBER) maintain lists of guidance cloc-
                   and Drug Aclministration, 8800 Rock-                unieiits t h a t apply t o the centers' regu-
                   ville Pike. Bethesda. MD 20892. (1)                 lations. The lists are maintained on
                   Proclucts subject t o the licensing provi-          t h e Internet and a r e published aniiu-
                   sioiis of the Public Health Service Act             ally i n the FEDERAL        REGISTER.A re-
                   of J u l y 1, 1944 (58 S t a t . 682, a s amended   quest for a copy of t h e CDER list
                   (42 U.S.C. 201 et sey. j j or subject t o part      shoulcl be clirected t o the Office of
                   600: (2) ingredients packaged together              Training and Coinniunications. Divi-
                   with containers inteiiclecl for the collec-         sion of Conim~~iiicatioiis     Management.
                   tion, processing, or storage of blood or            Drug Information Branch (HFD-210).
                   blood conipoiieiits: (3) urokinase prod-            Center for Drug Evaluation and Re-
                   ucts: (4) plasma volume expanders and               search, Foocl and Drug Aclministration,
                   hydroxyethyl starch for leukapheresis:              5600 Fishers Lane, Rockville, MD 20857.
                   and (5) couplecl antibodies, i.e., prod-            A request for a copy of t h e CBER list
                   ucts t h a t consist of a n antibody coni-          shoulcl be directed t o the Office of Coni-
                   ponent coupled with a drug or radio-                niunication. Training. and M a i i u f a c t ~ w
                   nuclide component i n which both coin-
                                                                       ers Assistance (HFM-401, Center for
                   ponents provide a pharmacological ef-
                                                                       Biologics Evaluation and Research,
                   fect but t h e biological coniponent cle-
                                                                       Foocl and Drug Administration, 1401
                   terinines the site of action.
                       (c) All correspondelice relating t o bi-        Rockville Pike. Rockville. MD 20852-
                   ological products for human use which               1448.
                   are also radioactive drugs shall be sub-            165 F R 56479, S e p t . 19, 20001
                   m i t t e d to the Division of Oncology and




© 2002 by CRC Press LLC
                                                                               Appendix A: FDA Regulations                  257




                   Food and Drug Administration, HHS                                                             Pt. 314

                   Subpart G-Drugs   for Investiga-                          ( I ) The sponsor of the investigation
                      tional Use in Laboratory Re-                        has failed to comply with any of the
                      search Animals or In Vitro                          conditions for shipment established
                                                                          under this section: or
                      Tests                                                  (2) The continuance of the investiga-
                   S 312.160 Drugs for investigational use                                    fe
                                                                          tion is ~ ~ i i s a or otherwise contrary t o
                        in laboratory research animals or                 t h e public interest or the clrug is used
                        in vitro tests.                                   for purposes other t h a n boiia ficle sci-
                     ( a ) Azithol-ization t o ship. ( l ) ( i j A per-   entific investigation. FDA will notify
                   son may ship a drug intended solely for                t h e person shipping the drug of i t s fiiid-
                   tests in vitro or i n animals used only                ing and invite iininediate correction. If
                   for laboratory research purposes if i t is             correction is not iininecliately niacle.
                   labeled a s follows:                                   t h e person shall have a n opportunity
                                                                          for a regulatory hearing before FDA
                     CAUTION: Contains a new drng for inves-              pursuant t o part 16.
                   tigational use only in laboratory research
                   animals. or for tests in vitro. Not for use in            ( c j Disposition o f zinzised drzig. The
                   humans.                                                                                        para-
                                                                          person who ships t h e drug ~ ~ i i c l e r
                                                                          graph ( a ) of this section shall assure
                     (ii) A person inay ship a biological                 the           of all unused supplies of the
                   product for investigational in vitro cli-              clrug from individual investigators
                   agnostic use       t h a t is listed i n               whenever the iiivestigation cliscoii-
                                  if
                   §312.2(b)(2)(ii) i t is labeled a s follows:           tinues or the investigation is terini-
                     CAUTION. Contains a lsiological product              natecl. The person who ships t h e drug
                   for investigational in vitro diagnostic tests          inay authorize i n writing alternative
                   only.                                                  clispositioii of mused supplies of the
                      (2) A person shipping a drug under                  clrug provided this alternative disposi-
                   paragraph ( a ) of t h i s section shall use           tion does not expose huinaiis to risks
                   clue diligence to assure t h a t t h e con-            from t h e drug, either directly or incli-
                   signee is regularly engaged i n con-                   rectly (e.g.. through food-producing
                   ducting such tests and t h a t t h e ship-             animals). The shipper shall maintain
                   ment of t h e new clrug will actually be               records of any alternative clispositioii.
                   used for tests i n vitro or i n animals                (Collection of information reqnirements ag-
                   used only for laboratory research.                     proved Isy the Office of Management and
                      (3) A person who ships a clrug under                Budget under control numlser 0910-0014)
                   paragraph ( a ) of this section shall
                                                                          152 FR 8831. Mar. 19, 1987. as amended a t 52
                   maintain adequate records showing the                  FR 23031. J ~ m e 17, 1987. Redesignated a t 53
                   name and post office address of the ex-                FR 41523. Oct. 21. 19881
                   pert t o whom the clrug is shipped and
                   t h e date. quantity. and batch or code
                   niark of each shipnieiit aiicl delivery.               PART 3 14-APPLICATIONS FOR FDA
                   Records of shipments ~ ~ i i c l e r    paragraph        APPROVAL TO MARKET A NEW
                   ( a ) ( l j ( i )of this section are t o be main-        DRUG
                   tained for a period of 2 years after the
                   shipment. Records aiicl reports of d a t a                   Subpart A-General      Provisions
                   and           shipments       under     paragraph      Sec.
                   (aj(l)(iij of this section are to be main-             314.1 Scope of this part.
                   tained in accordance with §312.57(b).                  314.2 Purpose.
                   The person who ships t h e clrug shall                 314.3 Definitions.
                   upon request from any properly au-
                   thorized officer or employee of the                              Subpart B-Applications
                   Food and Drug Aclmiiiistration. a t rea-
                   sonable times. permit such officer or                  314.50 Content and format of a11 application.
                   eniployee t o have access t o and copy                 314.52 Notice of certification of invalidity
                                                                              or noninfringement of a patent.
                   and verify records required t o be niaiii-             314.53 Snhmission of patent information.
                   tained under this section.                             314.54 Procedure for submission of a11 appli-
                      (bj Ternzinc~tion of c~utlzorization t o                cation requiring iilvestigations for ag-
                   ship. FDA inay terminate authoriza-                        proaal of a new indication for. or other
                   tion to ship a drug under this section if                  change from. a listed drug.
                   i t finds t h a t :                                    314.55 Pediatric use information.




© 2002 by CRC Press LLC
        258      Clinical Research Coordinator Handbook




                   Department of Health and Human Services                                                          546.101
                   46.404 Research n o t involving g r e a t e r t h a n         t o regulation by t h e federal govern-
                       minimal risk.                                              ment outside t h e United States.
                   46.405 Research involving g r e a t e r t h a n                  (1) Research t h a t is conducted or sup-
                       m i n i m a l r i s k b u t presenting t h e prospect     ported by a federal department or
                       of direct benefit t o t h e individual sub-
                       jects.                                                     agency, whether or not i t is regulated
                   46.406 Research involving g r e a t e r t h a n                as defined in S46.102(e), must comply
                       m i n i m a l r i s k a n d no prospect of direct         with all sections of this policy.
                       benefit t o individual subjects, b u t l i k e l y           (2) Research t h a t is neither con-
                       t o yield generalizable knowledge a b o u t                ducted nor supported by a federal de-
                       t h e subject's disorder o r condition.                   partment or agency but is subject t o
                   46.407 Research n o t otherxvise approvable                    regulation as defined in S46.102(e) must
                       which presents a n o p p o r t u n i t y t o under-       be reviewed and approved, in compli-
                       s t a n d , prevent, o r alleviate a serious               ance with 546.101, 546.102, and 546.107
                       problem affecting t h e h e a l t h o r welfare
                       of children.
                                                                                 through S46.117 of this policy, by an in-
                   46.408 Requirements for permission by p a r -
                                                                                 stitutional review board (IRB) t h a t op-
                       e n t s o r guardians and for a s s e n t by chil-         erates in accordance with the pertinent
                       dren.                                                      requirements of this policy.
                   46.409 Wards.                                                    (b) Unless otherwise required by de-
                                                                                 partment or agency heads, research ac-
                             5
                     AUTHORITY: U.S.C. 301; 42 U.S.C. 289.                       tivities in which t h e only involvement
                      EDITORIAL NOTE: T h e D e p a r t m e n t of                of human subjects will be in one or
                   H e a l t h a n d H u m a n Services issued a n o t i c e      more of t h e following categories are
                   of xvaiver regarding t h e r e q u i r e m e n t s s e t       exempt from this policy:
                   f o r t h i n p a r t 46, r e l a t i n g t o protection of      (1) Research conducted in established
                   h u m a n subjects, a s t h e y p e r t a i n t o dem-
                   o n s t r a t i o n projects, approved under section
                                                                                  or commonly accepted educational set-
                   1115 of t h e Social S e c u r i t y A c t , which t e s t    tings, involving normal educational
                   t h e use of cost-sharing, s u c h a s deductibles,           practices, such as (i) research on reg-
                   copayment a n d coinsurance, i n t h e Medicaid               ular and special education instruc-
                   program. F o r f u r t h e r information see 47 F R           tional strategies, or (ii) research on t h e
                   9208, Mar. 4, 1982.                                            effectiveness of or t h e comparison
                                                                                  among instructional techniques, cur-
                   Subpart A-Basic   HHS Policy for                               ricula, or classroom management
                      Protection of Human Research                                methods.
                      Subjects                                                      (2) Research involving t h e use of edu-
                                                                                  cational tests (cognitive, diagnostic,
                                                                                  aptitude, achievement), survey proce-
                    AUTHORITY: U.S.C. 301: 42 U.S.C. 289, 42
                                      5                                           dures, interview procedures or observa-
                   U.S.C. 3 0 0 ~ ~ - l ( b ) .                                  tion of public behavior, unless:
                     SOURCE: F R 28012, 28022, J u n e 18, 1991,
                              56                                                    (i) Information obtained is recorded
                   unless otherwise noted.                                        in such a manner t h a t human subjects
                                                                                  can be identified, directly or through
                  $46.101 To what does this policy                                identifiers linked t o t h e subjects: and
                        apply?                                                    (ii) any disclosure of t h e human sub-
                     (a) Except as provided in paragraph                         jects' responses outside t h e research
                   (b) of this section, this policy applies                       could reasonably place t h e subjects a t
                  t o all research involving human sub-                           risk of criminal or civil liability or be
                  jects conducted, supported or otherwise                         damaging t o t h e subjects' financial
                  subject t o regulation by any federal de-                      standing, employability, or reputation.
                  partment or agency which takes appro-                             (3) Research involving t h e use of edu-
                  priate administrative action t o make                           cational tests (cognitive, diagnostic,
                  t h e policy applicable t o such research.                      aptitude, achievement), survey proce-
                  This includes research conducted by                             dures, interview procedures, or obser-
                  federal civilian employees or military                         vation of public behavior t h a t is not
                  personnel, except t h a t each department                       exempt under paragraph (b)(2) of this
                  or agency head may adopt such proce-                           section, if:
                  dural modifications as may be appro-                              (i) The human subjects are elected or
                  priate from an administrative stand-                            appointed public officials or candidates
                  point. I t also includes research con-                         for public office: or (ii) federal s t a t -
                  ducted, supported, or otherwise subject                                 )
                                                                                 u t e ( ~require(s) without exception t h a t




© 2002 by CRC Press LLC
                                                                       Appendix A: FDA Regulations                   259




                                                                      45 CFR Subtitle A (10-1-00 Edition)
                  t h e confidentiality of t h e personally           (f) This policy does not affect any
                   identifiable information will be main-         s t a t e or local laws or regulations which
                  tained throughout t h e research and            may otherwise be applicable and which
                  thereafter.                                     provide additional protections for
                      (4) Research, involving t h e collection    human subjects.
                   or study of existing data, documents,              (g) This policy does not affect any
                   records, pathological specimens, or di-        foreign laws or regulations which may
                   agnostic specimens, if these sources are       otherwise be applicable and which pro-
                  publicly available or if t h e information      vide additional protections t o human
                   is recorded by t h e investigator in such      subjects of research.
                   a manner t h a t subjects cannot be iden-
                  tified, directly or through identifiers             (h) When research covered by this
                   linked t o t h e subjects.                     policy takes place in foreign countries,
                      (5) Research and demonstration              procedures normally followed in t h e
                  projects which are conducted by or sub-         foreign countries t o protect human
                  ject t o t h e approval of department or        subjects may differ from those set
                   agency heads, and which are designed           forth in this policy. [An example is a
                  t o study, evaluate, or otherwise exam-         foreign institution which complies
                   ine:                                           with guidelines consistent with t h e
                      (i) Public benefit or service pro-          World Medical Assembly Declaration
                  grams; (ii) procedures for obtaining            (Declaration of Helsinki amended 1989)
                  benefits or services under those pro-           issued either by sovereign states or by
                  grams; (iii) possible changes in or al-         an organization whose function for the
                  ternatives t o those programs or proce-         protection of human research subjects
                   dures; or (iv) possible changes in meth-       is internationally recognized.] In these
                   ods or levels of payment for benefits or       circumstances, if a department or
                  services under those programs.                  agency head determines t h a t t h e proce-
                      (6) Taste and food quality evaluation       dures prescribed by t h e institution af-
                   and consumer acceptance studies, (i) if        ford protections t h a t are a t least
                  wholesome foods without additives are           equivalent t o those provided in this
                   consumed or (ii) if a food is consumed         policy, t h e department or agency head
                  t h a t contains a food ingredient a t or       may approve t h e substitution of the
                  below t h e level and for a use found t o
                                                                  foreign procedures in lieu of t h e proce-
                  be safe, or agricultural chemical or en-
                  vironmental contaminant a t or below            dural requirements provided in this
                  t h e level found t o be safe, by t h e Food    policy. Except when otherwise required
                   and Drug Administration or approved            by s t a t u t e , Executive Order, or t h e de-
                  by t h e Environmental            Protection    partment or agency head, notices of
                  Agency or the Food Safety and Inspec-           these actions as they occur will be pub-
                  tion Service of t h e U.S. Department of        lished in t h e FEDERAL                 or
                                                                                               REGISTER will
                  Agriculture.                                    be otherwise published as provided in
                      (c) Department or agency heads re-          department or agency procedures.
                  t a i n final judgment as t o whether a             (i) Unless otherwise required by law,
                  particular activity is covered by this          department or agency heads may waive
                  policy.                                         t h e applicability of some or all of the
                      (d) Department or agency heads may          provisions of this policy t o specific re-
                   require t h a t specific research activities   search activities or classes of research
                   or classes of research activities con-         activities otherwise covered by this
                   ducted, supported, or otherwise subject        policy. Except when otherwise required
                  t o regulation by t h e department or           by s t a t u t e or Executive Order, t h e de-
                   agency but not otherwise covered by            partment or agency head shall forward
                  this policy, comply with some or all of         advance notices of these actions t o t h e
                  t h e requirements of this policy.              Office for Protection from Research
                      (e) Compliance with this policy re-         Risks, Department of Health and
                   quires compliance with pertinent fed-
                                                                  Human Services (HHS), and shall also
                   eral laws or regulations which provide
                                                                  publish them in t h e FEDERAL       REGISTER
                   additional protections for human sub-
                  jects.




© 2002 by CRC Press LLC
        260      Clinical Research Coordinator Handbook




                   Department of Health and Human Services                                                         5 46.102
                   or in such other manner as provided in                      ministration). I t does not include re-
                   department or agency procedure^.^                           search activities which are inciden-
                   [56 F R 28012, 28022, J u n e 18, 1991; 56 F R 29756,
                                                                               tally regulated by a federal department
                   J u n e 28, 19911                                           or agency solely as part of t h e depart-
                                                                               ment's or agency's broader responsi-
                   S 46.102 Definitions.                                       bility t o regulate certain types of ac-
                      (a) Department or agency head means                      tivities whether research or non-re-
                   t h e head of any federal department or                     search in nature (for example, Wage
                   agency and any other officer or em-                         and Hour requirements administered
                   ployee of any department or agency t o                      by t h e Department of Labor).
                   whom authority has been delegated.                              (Q Human subject means a living indi-
                      (b) Institution means any public or                      vidual about whom an investigator
                   private entity or agency (including fed-                    (whether professional or student) con-
                   eral, s t a t e , and other agencies).                      ducting research obtains
                      (c) Legally authorized representative                        (1) Data through intervention or
                   means an individual or judicial or                          interaction with the individual, or
                   other body authorized under applicable                          (2) Identifiable private information.
                   law t o consent on behalf of a prospec-                     Intervention includes both physical pro-
                   tive subject t o t h e subject's participa-                 cedures by which data are gathered (for
                   tion in t h e procedure(s) involved in t h e                example, venipuncture) and manipula-
                   research.                                                   tions of the subject or t h e subject's en-
                      (d) Research means a systematic in-                      vironment t h a t are performed for re-
                   vestigation, including research devel-                      search purposes. Interaction includes
                   opment, testing and evaluation, de-                         communication or interpersonal con-
                   signed t o develop or contribute t o gen-                   t a c t between investigator and subject.
                   eralizable knowledge. Activities which                      Private inforniation includes informa-
                   meet this definition constitute re-                         tion about behavior t h a t occurs in a
                   search for purposes of this policy,                         context in which an individual can rea-
                   whether or not they are conducted or                        sonably expect t h a t no observation or
                   supported under a program which is                          recording is taking place, and informa-
                   considered research for other purposes.                     tion which has been provided for spe-
                   For example, some demonstration and                         cific purposes by an individual and
                   service programs may include research                       which t h e individual can reasonably
                   activities.                                                 expect will not be made public (for ex-
                      (e) Research subject to regulation, and                  ample, a medical record). Private infor-
                   similar terms are intended t o encom-                       mation must be individually identifi-
                   pass those research activities for which                    able (i.e., t h e identity of t h e subject is
                   a federal department or agency has                          or may readily be ascertained by t h e
                   specific responsibility for regulating as                   investigator or associated with t h e in-
                   a research activity, (for example, In-                      formation) in order for obtaining t h e
                   vestigational New Drug requirements                         information t o constitute research in-
                   administered by t h e Food and Drug Ad-                     volving human subjects.
                                                                                   (g) I R B means an institutional review
                     '   I n s t i t u t i o n s w i t h HHS-approved assur-   board established in accord with and
                   ances o n file will abide by provisions of t i t l e        for t h e purposes expressed in this pol-
                   45 CFR p a r t 46 subparts A-D. S o m e of t h e            icy.
                   o t h e r Departments and Agencies have incor-
                   porated all provisions of t i t l e 45 CFR p a r t 46
                                                                                   (h) IRB approval means t h e deter-
                   i n t o t h e i r policies and procedures a s well.         mination of t h e IRB t h a t t h e research
                   Hoxvever, t h e exemptions a t 45 CFR 46.101(b)             has been reviewed and may be con-
                   do n o t apply t o research involving prisoners,            ducted a t an institution within t h e
                   fetuses, pregnant women, o r h u m a n i n v i t r o        constraints set forth by t h e IRB and by
                   fertilization, subparts B and C. The exemp-                 other institutional and federal require-
                   tion a t 45 CFR 46.101(b)(2), for research in-              ments.
                   volving survey o r interview procedures o r ob-
                   servation of public behavior, does n o t apply
                                                                                   (i) Minimal risk means t h a t t h e prob-
                   t o research w i t h children, s u b p a r t D, except      ability and magnitude of harm or dis-
                   for research involving observations of public               comfort anticipated in t h e research are
                   behavior when t h e investigator(s) do n o t par-           not greater in and of themselves than
                   ticipate i n t h e activities being observed.               those ordinarily encountered in daily




© 2002 by CRC Press LLC
                                                                         Appendix A: FDA Regulations               26 1




                                                                        45 CFR Subtitle A (10-1-00 Edition)
                   life or during t h e performance of rou-         lation. This may include an appro-
                   tine physical or psychological exami-            priate existing code, declaration, or
                   nations or tests.                                statement of ethical principles, or a
                       (j) Certification means t h e official no-   statement formulated by t h e institu-
                   tification by t h e institution t o t h e sup-   tion itself. This requirement does not
                   porting department or agency, in ac-             preempt provisions of this policy appli-
                   cordance with t h e requirements of this         cable t o department- or agency-sup-
                   policy, t h a t a research project or activ-     ported or regulated research and need
                   i t y involving human subjects has been          not be applicable t o any research ex-
                   reviewed and approved by an IRE in ac-           empted or waived under 846.101 (b) or
                   cordance with an approved assurance.             (i).
                                                                       (2) Designation of one or more IRBs
                   S 46.103 Assuring compliance with this           established in accordance with t h e re-
                         policy-research conducted or sup-
                         ported by any Federal Department           quirements of this policy, and for
                         or Agency.                                 which provisions are made for meeting
                                                                    space and sufficient staff t o support
                      (a) Each institution engaged in re-
                                                                    t h e IRB's review and recordkeeping du-
                   search which is covered by this policy
                                                                    ties.
                   and which is conducted or supported by
                   a federal department or agency shall                (3) A list of IRB members identified
                   provide written assurance satisfactory           by name: earned degrees: representa-
                   t o t h e department or agency head t h a t      tive capacity: indications of experience
                   i t will comply with the requirements            such as board certifications, licenses,
                   set forth in this policy. In lieu of re-         etc., sufficient t o describe each mem-
                   quiring submission of an assurance, in-          ber's chief anticipated contributions t o
                   dividual department or agency heads              IRB deliberations; and any employ-
                   shall accept t h e existence of a current        ment or other relationship between
                   assurance, appropriate for t h e research        each member and t h e institution: for
                   in question, on file with t h e Office for       example: full-time employee, part-time
                   Protection from Research Risks, HHS,             employee, member of governing panel
                   and approved for federalwide use by              or board, stockholder, paid or unpaid
                   t h a t office. When t h e existence of an       consultant. Changes in IRE member-
                   HHS-approved assurance is accepted in            ship shall be reported t o t h e depart-
                   lieu of requiring submission of an as-           ment or agency head, unless in accord
                   surance, reports (except certification)          with §46.103(a) of this policy, t h e exist-
                   required by this policy t o be made t o          ence of an HHS-approved assurance is
                   department and agency heads shall                accepted. In this case, change in IRB
                   also be made t o t h e Office for Protec-        membership shall be reported t o t h e
                   tion from Research Risks, HHS.                   Office for Protection from Research
                      (b) Departments and agencies will             Risks, HHS.
                   conduct or support research covered by              (4) Written procedures which t h e IRE
                   this policy only if t h e institution has        will follow (i) for conducting i t s initial
                   an assurance approved as provided in             and continuing review of research and
                   this section, and only if t h e institution      for reporting i t s findings and actions t o
                   has certified t o t h e department or            t h e investigator and t h e institution:
                   agency head t h a t t h e research has been      (ii) for determining which projects re-
                   reviewed and approved by an IRE pro-             quire review more often than annually
                   vided for in t h e assurance, and will be        and which projects need verification
                   subject t o continuing review by t h e           from sources other t h a n t h e investiga-
                   IRB. Assurances applicable t o federally         tors t h a t no material changes have oc-
                   supported or conducted research shall            curred since previous IRB review: and
                   a t a minimum include:                           (iii) for ensuring prompt reporting t o
                      (1) A statement of principles gov-            t h e IRB of proposed changes in a re-
                   erning t h e institution in t h e discharge      search activity, and for ensuring t h a t
                   of i t s responsibilities for protecting the     such changes in approved research,
                   rights and welfare of human subjects of          during t h e period for which IRB ap-
                   research conducted a t or sponsored by           proval has already been given, may not
                   t h e institution, regardless of whether         be initiated without IRB review and
                   t h e research is subject t o federal regu-      approval except when necessary t o




© 2002 by CRC Press LLC
        262      Clinical Research Coordinator Handbook




                   Department of Health and Human Services                                                 546.107
                  eliminate apparent immediate hazards           posal or by such later date as may be
                  t o t h e subject.                             prescribed by the department or agen-
                      (5) Written procedures for ensuring        cy t o which t h e application or proposal
                  prompt reporting t o t h e IRE, appro-         is submitted. Under no condition shall
                  priate institutional officials, and t h e      research covered by 346.103 of t h e Pol-
                  department or agency head of (i) any           icy be supported prior t o receipt of t h e
                  unanticipated problems involving risks         certification t h a t t h e research has been
                  t o subjects or others or any serious or       reviewed and approved by the IRB. In-
                  continuing noncompliance with this             stitutions without an approved assur-
                  policy or t h e requirements or deter-         ance covering t h e research shall certify
                  minations of t h e IRB and (ii) any sus-                0
                                                                 within 3 days after receipt of a request
                  pension or termination of IRB ap-              for such a certification from t h e de-
                  proval.                                        partment or agency, t h a t t h e applica-
                      (c) The assurance shall be executed        tion or proposal has been approved by
                  by an individual authorized t o a c t for      t h e IRB. If t h e certification is not sub-
                  t h e institution and t o assume on behalf     mitted within these time limits, t h e
                  of t h e institution t h e obligations im-     application or proposal may be re-
                  posed by this policy and shall be filed        turned t o t h e institution.
                  in such form and manner as t h e depart-       (Approved b y t h e Office of Management and
                  ment or agency head prescribes.                Budget under control number 9999-0020)
                      (d) The department or agency head
                  will evaluate all assurances submitted         [56 F R 28012, 28022, J u n e 18, 1991: 56 F R 29756,
                                                                 J u n e 28, 19911
                  in accordance with this policy through
                  such officers and employees of t h e de-       SS 46.10446.106 [Reserved]
                  partment or agency and such experts
                  or consultants engaged for this purpose        S 46.107 IRB membership.
                  as t h e department or agency head de-            (a) Each IRB shall have a t least five
                  termines t o be appropriate. The depart-       members, with varying backgrounds t o
                  ment or agency head's evaluation will          promote complete and adequate review
                  t a k e into consideration t h e adequacy      of research activities commonly con-
                  of the proposed IRB in light of t h e an-      ducted by t h e institution. The IRB
                  ticipated scope of t h e institution's re-     shall be sufficiently qualified through
                  search activities and t h e types of sub-      t h e experience and expertise of i t s
                  ject populations likely t o be involved,       members, and t h e diversity of t h e
                  t h e appropriateness of t h e proposed ini-   members, including consideration of
                  tial and continuing review procedures          race, gender, and cultural backgrounds
                  in light of t h e probable risks, and t h e    and sensitivity t o such issues as com-
                  size and complexity of t h e institution.      munity attitudes, t o promote respect
                      (e) On t h e basis of this evaluation,     for i t s advice and counsel in safe-
                  t h e department or agency head may            guarding t h e rights and welfare of
                  approve or disapprove t h e assurance, or      human subjects. In addition t o pos-
                  enter into negotiations t o develop an         sessing the professional competence
                  approvable one. The department or              necessary t o review specific research
                  agency head may limit t h e period dur-        activities, t h e IRE shall be able t o as-
                  ing which any particular approved as-          certain t h e acceptability of proposed
                  surance or class of approved assurances        research in terms of institutional com-
                  shall remain effective or otherwise            mitments and regulations, applicable
                  condition or restrict approval.                law, and standards of professional con-
                      (f) Certification is required when the     duct and practice. The IRB shall there-
                  research is supported by a federal de-         fore include persons knowledgeable in
                  partment or agency and not otherwise           these areas. If an IRB regularly reviews
                  exempted or waived under 346.101 (b) or        research t h a t involves a vulnerable
                   (i). An institution with an approved as-      category of subjects, such as children,
                  surance shall certify t h a t each applica-    prisoners, pregnant women, or handi-
                  tion or proposal for research covered          capped or mentally disabled persons,
                  by t h e assurance and by 946.103 of this      consideration shall be given t o t h e in-
                  Policy has been reviewed and approved          clusion of one or more individuals who
                  by the IRB. Such certification must be         are knowledgeable about and experi-
                  submitted with t h e application or pro-       enced in working with these subjects.




© 2002 by CRC Press LLC
                                                                         Appendix A: FDA Regulations                      263




                                                                         45 CFR Subtitle A (10-1-00 Edition)
                      (b) Every nondiscriminatory effort                (b) An IRB shall require t h a t infor-
                   will be made t o ensure t h a t no IRE           mation given t o subjects a s part of in-
                   consists entirely of men or entirely of          formed consent is in accordance with
                   women, including t h e institution's con-        946.116. The IRB may require t h a t in-
                   sideration of qualified persons of both          formation, in addition t o t h a t specifi-
                   sexes, so long a s no selection is made          cally mentioned i n 946.116, be given t o
                   t o t h e IRB on t h e basis of gender. No       t h e subjects when i n t h e IRB's judg-
                   IRB may consist entirely of members              ment t h e information would meaning-
                   of one profession.                               fully add t o t h e protection of t h e rights
                      (c) Each IRB shall include a t least          and welfare of subjects.
                   one member whose primary concerns                    (c) An IRB shall require documenta-
                   are i n scientific areas and a t least one       tion of informed consent or may waive
                   member whose primary concerns are i n            documentation i n accordance with
                   nonscientific areas.                             946.117.
                      (d) Each IRB shall include a t least              (d) An IRB shall notify investigators
                   one member who is not otherwise affili-          and t h e institution in writing of i t s de-
                   ated with t h e institution and who is           cision t o approve or disapprove t h e pro-
                   not part of t h e immediate family of a          posed research activity, or of modifica-
                   person who is affiliated with t h e insti-       tions required t o secure IRB approval
                   tution.                                          of t h e research activity. If t h e IRB de-
                      (e) No IRB may have a member par-             cides t o disapprove a research activity,
                   ticipate in t h e IRB's initial or con-          i t shall include i n i t s written notifica-
                   tinuing review of any project i n which          tion a s t a t e m e n t of t h e reasons for i t s
                   t h e member has a conflicting interest,         decision and give t h e investigator a n
                   except t o provide information re-               opportunity t o respond i n person or i n
                   quested by t h e IRB.                            writing.
                      (f) An IRB may, i n i t s discretion, in-         (e) An IRB shall conduct continuing
                   vite individuals with competence i n             review of research covered by t h i s pol-
                   special areas t o assist i n t h e review of     icy a t intervals appropriate t o t h e de-
                   issues which require expertise beyond            gree of risk, but not less t h a n once per
                   or i n addition t o t h a t available on t h e   year, and shall have authority t o ob-
                   IRB. These individuals may not vote              serve or have a third party observe t h e
                   with t h e IRB.                                  consent process and t h e research.
                   4 46.108 IRB functions and operations.           (Approved b y t h e Office of Management and
                                                                    Budget under control number 9999-0020)
                      In order t o fulfill t h e requirements of
                   t h i s policy each IRE shall:                   4 46.110 Expedited review procedures
                       (a) Follow written procedures i n t h e           for certain kinds of research involv-
                   same detail a s described i n 946.103(b)(4)           ing no more than minimal risk, and
                   and, t o t h e extent required by,                    for minor changes in approved re-
                   946.103(b)(5).                                        search.
                       (b) Except when a n expedited review            (a) The Secretary, HHS, has estab-
                   procedure is used (see 946.110), review          lished, and published a s a Notice i n t h e
                   proposed research a t convened meet-             FEDERAL                a
                                                                                 REGISTER, list of categories
                   ings a t which a majority of t h e mem-          of research t h a t may be reviewed by
                   bers of t h e IRB are present, including         t h e IRB through a n expedited review
                   a t least one member whose primary               procedure. The list will be amended, a s
                   concerns a r e i n nonscientific areas. In       appropriate after consultation with
                   order for t h e research t o be approved,        other      departments    and    agencies,
                   i t shall receive t h e approval of a ma-        through periodic republication by t h e
                  j o r i t y of those members present a t t h e    Secretary, HHS, i n t h e FEDERAL    REG
                   meeting.                                         ISTER A copy of t h e list is available
                                                                    from t h e Office for Protection from Re
                   S 46.109 IRB review of research.                 search Risks, National Institutes of
                       (a) An IRB shall review and have au-         Health, HHS, Bethesda, Maryland
                   t h o r i t y t o approve, require modifica-     20892.
                   tions in (to secure approval), or dis-              (b) An IRB may use t h e expedited re
                   approve all research activities covered          view procedure t o review either or both
                   by t h i s policy.                               of t h e following:




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        264      Clinical Research Coordinator Handbook




                   Department of Health and Human Services                                               546.1 13
                      (1) Some or all of t h e research ap-        gained in t h e research (for example,
                   pearing on the list and found by t h e re-      t h e possible effects of t h e research on
                              t
                   viewer(~)o involve no more t h a n mini-        public policy) as among those research
                   mal risk,                                       risks t h a t fall within t h e purview of i t s
                      (2) Minor changes in previously ap-          responsibility.
                   proved research during t h e period (of             (3) Selection of subjects is equitable.
                   one year or less) for which approval is         In making this assessment the IRB
                   authorized.                                     should t a k e into account t h e purposes
                   Under an expedited review procedure,            of t h e research and t h e setting in
                   t h e review may be carried out by t h e        which t h e research will be conducted
                   IRB chairperson or by one or more ex-           and should be particularly cognizant of
                   perienced reviewers designated by the           t h e special problems of research in-
                   chairperson from among members of               volving vulnerable populations, such as
                   t h e IRB. In reviewing t h e research, t h e   children, prisoners, pregnant women,
                   reviewers may exercise all of t h e au-         mentally disabled persons, or economi-
                   thorities of t h e IRE except t h a t the re-   cally or educationally disadvantaged
                   viewers may not disapprove t h e re-            persons.
                   search. A research activity may be dis-             (4) Informed consent will be sought
                   approved only after review in accord-           from each prospective subject or the
                   ance with the non-expedited procedure           subject's legally authorized representa-
                   set forth in 946.108(b).                        tive, in accordance with, and t o t h e ex-
                      (c) Each IRB which uses an expedited         t e n t required by § 46.116.
                   review procedure shall adopt a method               (5) Informed consent will be appro-
                   for keeping all members advised of re-          priately documented, in accordance
                   search proposals which have been ap-            with, and t o t h e extent required by
                   proved under t h e procedure.                   946.117.
                      (d) The department or agency head                (6) When appropriate, the research
                   may restrict, suspend, terminate, or            plan makes adequate provision for
                   choose not t o authorize an institu-            monitoring t h e data collected t o en-
                   tion's or IRB's use of t h e expedited re-      sure the safety of subjects.
                   view procedure.                                     (7) When appropriate, there are ade-
                                                                   quate provisions t o protect t h e privacy
                  446.111 Criteria for IRB approval of             of subjects and t o maintain t h e con-
                        research.                                  fidentiality of data.
                      (a) In order t o approve research cov-           (b) When some or all of t h e subjects
                  ered by this policy the IRB shall deter-         are likely t o be vulnerable t o coercion
                  mine t h a t all of t h e following require-     or undue influence, such as children,
                  ments are satisfied:                             prisoners, pregnant women, mentally
                      (1) Risks t o subjects are minimized:        disabled persons, or economically or
                   (i) By using procedures which are con-          educationally disadvantaged persons,
                  sistent with sound research design and           additional safeguards have been in-
                  which do not unnecessarily expose sub-           cluded in t h e study t o protect t h e
                  jects t o risk, and (ii) whenever appro-         rights and welfare of these subjects.
                  priate, by using procedures already
                  being performed on t h e subjects for di-        S 46.112 Review by institution.
                  agnostic or treatment purposes.                    Research covered by this policy t h a t
                      (2) Risks t o subjects are reasonable        has been approved by an IRB may be
                  in relation t o anticipated benefits, if         subject t o further appropriate review
                  any, t o subjects, and t h e importance of       and approval or disapproval by officials
                  t h e knowledge t h a t may reasonably be        of t h e institution. However, those offi-
                  expected t o result. In evaluating risks         cials may not approve t h e research if i t
                  and benefits, t h e IRB should consider          has not been approved by an IRB.
                  only those risks and benefits t h a t may
                  result from t h e research (as distin-           S 46.113 Suspension or termination of
                  guished from risks and benefits of                     IRB approval of research.
                  therapies subjects would receive even if            An IRB shall have authority t o sus-
                  not participating in t h e research). The        pend or terminate approval of research
                  IRB should not consider possible long-           t h a t is not being conducted in accord-
                  range effects of applying knowledge              ance with t h e IRB's requirements or




© 2002 by CRC Press LLC
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                                                                           45 CFR Subtitle A (10-1-00 Edition)
                   t h a t has been associated with unex-               (7) Statements of significant new
                   pected serious harm t o subjects. Any             findings provided t o subjects, a s re-
                   suspension or termination of approval             quired by §46.116(b)(5).
                   shall include a s t a t e m e n t of t h e rea-      (b) The records required by t h i s pol-
                   sons for t h e IRB's action and shall be          icy shall be retained for a t least 3
                   reported promptly t o t h e investigator,         years, and records relating t o research
                   appropriate institutional officials, and          which is conducted shall be retained
                   t h e department or agency head.                  for a t least 3 years after completion of
                   (Approved by t h e Office of Management and       t h e research. All records shall be acces-
                   Budget under control number 9999-0020)            sible for inspection and copying by au-
                                                                     thorized representatives of t h e depart-
                   S 46.114 Cooperative research.                    ment or agency a t reasonable times
                      Cooperative research projects a r e            and i n a reasonable manner.
                   those projects covered by t h i s policy          (Approved b y t h e Office of Management and
                   which involve more t h a n one institu-           Budget under control number 9999-0020)
                   tion. In t h e conduct of cooperative re-
                   search projects, each institution is re-          4 46.116 General requirements for in-
                   sponsible for safeguarding t h e rights                formed consent.
                   and welfare of human subjects and for
                   complying with t h i s policy. With t h e             Except a s provided elsewhere i n t h i s
                   approval of t h e department or agency             policy, no investigator may involve a
                   head, a n institution participating i n a          human being a s a subject i n research
                   cooperative project may enter into a               covered by t h i s policy unless t h e inves-
                  j o i n t review arrangement, rely upon             tigator has obtained t h e legally effec-
                   t h e review of another qualified IRB, or          tive informed consent of t h e subject or
                   make similar arrangements for avoid-               t h e subject's legally authorized rep-
                   ing duplication of effort.                         resentative. An investigator shall seek
                                                                      such consent onlv under circumstances
                   S 46.115 IRB records.                              t h a t provide theprospective subject or
                      (a) An institution, or when appro-              t h e representat&e sufficient -oppor-
                  priate a n IRB, shall prepare and main-             t u n i t y t o consider whether or not t o
                  t a i n adequate documentation of IRE               participate and t h a t minimize t h e pos-
                  activities, including t h e following:              sibility of coercion or undue influence.
                      (1) Copies of all research proposals re-        The information t h a t is given t o t h e
                  viewed, scientific evaluations, if any,             subject or t h e representative shall be
                  t h a t accompany t h e proposals, ap-              in language understandable t o t h e sub-
                  proved sample consent documents,                   j e c t or t h e representative. No informed
                  progress reports submitted by inves-                consent, whether oral or written, may
                  tigators, and reports of injuries t o sub-          include a n y exculpatory language
                  jects.                                              through which t h e subject or t h e rep-
                      (2) Minutes of IRE meetings which               resentative is made t o waive or appear
                  shall be in sufficient detail t o show a t -        t o waive any of t h e subject's legal
                  tendance a t t h e meetings: actions                rights, or releases or appears t o release
                  t a k e n by t h e IRB; t h e vote on these ac-     t h e investigator, t h e sponsor, t h e insti-
                  tions including t h e number of members             t u t i o n or i t s agents from liability for
                  voting for, against, and abstaining; t h e          negligence.
                  basis for requiring changes i n or dis-                 (a) Basic elements of informed con-
                  approving research; and a written sum-              sent. Except a s provided in paragraph
                  mary of t h e discussion of controverted            (c) or (d) of t h i s section, i n seeking in-
                  issues and their resolution.                        formed consent t h e following informa-
                      (3) Records of continuing review ac-            tion shall be provided t o each subject:
                  tivities.                                               (1) A s t a t e m e n t t h a t t h e study in-
                      (4) Copies of all correspondence be-            volves research, a n explanation of t h e
                  tween t h e IRB and t h e investigators.            purposes of t h e research and t h e ex-
                      (5) A list of IRB members in t h e same         pected duration of t h e subject's partici-
                  detail a s described is 46.lO3(b)(3).               pation, a description of t h e procedures
                      (6) Written procedures for t h e IRB i n        t o be followed, and identification of
                  t h e same detail a s described i n                 any procedures which a r e experi-
                  §46.103(b)(4) and §46.103(b)(5).                    mental:




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                   Department of Health and Human Services                                            546.1 16

                      (2) A description of any reasonably              (5) A statement t h a t significant new
                  foreseeable risks or discomforts t o the         findings developed during t h e course of
                  subject;                                         t h e research which may relate t o t h e
                      (3) A description of any benefits t o        subject's willingness t o continue par-
                  t h e subject or t o others which may rea-       ticipation will be provided t o t h e sub-
                  sonably be expected from t h e research:         ject: and
                      (4) A disclosure of appropriate alter-           (6) The approximate number of sub-
                   native procedures or courses of treat-          jects involved in t h e study.
                   ment, if any, t h a t might be advan-               (c) An IRB may approve a consent
                  tageous t o t h e subject:                       procedure which does not include, or
                      (5) A statement describing t h e ex-         which alters, some or all of t h e ele-
                  t e n t , if any, t o which confidentiality of    ments of informed consent set forth
                   records identifying the subject will be          above, or waive the requirement t o ob-
                   maintained:                                     t a i n informed consent provided t h e IRB
                      (6) For research involving more than         finds and documents t h a t :
                   minimal risk, an explanation as t o                 (1) The research or demonstration
                  whether any compensation and an ex-              project is t o be conducted by or subject
                  planation as t o whether any medical             t o t h e approval of s t a t e or local gov-
                  treatments are available if injury oc-            ernment officials and is designed t o
                   curs and, if so, what they consist of, or       study, evaluate, or otherwise examine:
                  where further information may be ob-              (i) Public benefit of service programs;
                  tained:                                           (ii) procedures for obtaining benefits or
                      (7) An explanation of whom t o con-          services under those programs; (iii)
                  t a c t for answers t o pertinent questions      possible changes in or alternatives t o
                   about t h e research and research sub-          those programs or procedures; or (iv)
                  jects' rights, and whom t o contact in           possible changes in methods or levels
                  t h e event of a research-related injury          of payment for benefits or services
                  t o t h e subject: and                           under those programs: and
                      (8) A statement t h a t participation is         (2) The research could not prac-
                  voluntary, refusal t o participate will          ticably be carried out without t h e
                   involve no penalty or loss of benefits t o      waiver or alteration.
                  which t h e subject is otherwise entitled,           (d) An IRB may approve a consent
                   and t h e subject may discontinue par-          procedure which does not include, or
                  ticipation a t any time without penalty          which alters, some or all of t h e ele-
                   or loss of benefits t o which t h e subject      ments of informed consent set forth in
                   is otherwise entitled.                          this section, or waive t h e requirements
                      (b) Additional elements of informed          t o obtain informed consent provided
                   consent. When appropriate, one or               t h e IRB finds and documents t h a t :
                   more of t h e following elements of in-             (1) The research involves no more
                  formation shall also be provided t o             t h a n minimal risk t o the subjects:
                   each subject:                                       (2) The waiver or alteration will not
                      (1) A statement t h a t t h e particular      adversely affect t h e rights and welfare
                  treatment or procedure may involve                of t h e subjects;
                   risks t o t h e subject (or t o t h e embryo        (3) The research could not prac-
                   or fetus, if t h e subject is or may be-        ticably be carried out without t h e
                   come pregnant) which are currently              waiver or alteration: and
                  unforeseeable;                                       (4) Whenever appropriate, t h e sub-
                      (2) Anticipated circumstances under          jects will be provided with additional
                  which t h e subject's participation may          pertinent information after participa-
                  be terminated by t h e investigator              tion.
                  without regard t o t h e subject's con-              (e) The informed consent require-
                  sent:                                             ments in this policy are not intended
                      (3) Any additional costs t o t h e sub-      t o preempt any applicable federal,
                  ject t h a t may result from participation       s t a t e , or local laws which require addi-
                   in t h e research;                              tional information t o be disclosed in
                      (4) The consequences of a subject's           order for informed consent t o be le-
                   decision t o withdraw from t h e research       gally effective.
                   and procedures for orderly termination              (Q Nothing in this policy is intended
                   of participation by t h e subject;              t o limit t h e authority of a physician t o




© 2002 by CRC Press LLC
                                                                       Appendix A: FDA Regulations               267




                                                                       45 CFR Subtitle A (10-1-00 Edition)
                   provide emergency medical care, t o t h e      subject will be asked whether t h e sub-
                   extent t h e physician is permitted t o do     ject wants documentation linking the
                   so under applicable federal, s t a t e , or    subject with t h e research, and t h e sub-
                   local law.                                     ject's wishes will govern: or
                   (Approved b y t h e Office of Management and     (2) That t h e research presents no
                   Budget under control number 9999-0020)         more than minimal risk of harm t o
                                                                  subjects and involves no procedures for
                   4 46.117 Documentation        of informed      which written consent is normally re-
                        consent.                                  quired outside of t h e research context.
                     (a) Except as provided in paragraph            In cases in which t h e documentation
                   (c) of this section, informed consent          requirement is waived, t h e IRB may re-
                  shall be documented by t h e use of a           quire the investigator t o provide sub-
                  written consent form approved by t h e          jects with a written statement regard-
                  IRB and signed by t h e subject or the          ing t h e research.
                  subject's legally authorized representa-
                  tive. A copy shall be given t o t h e per-      (Approved b y t h e Office of Management and
                  son signing t h e form.                         Budget under control number 9999-0020)
                     (b) Except as provided in paragraph
                   (c) of this section, t h e consent form        4 46.118 Applications   and proposals
                                                                      lacking definite plans for involve-
                  may be either of t h e following:                   ment of human subjects.
                     (1) A written consent document t h a t
                  embodies t h e elements of informed                 Certain types of applications for
                  consent required by S46.116. This form          grants, cooperative agreements, or con-
                  may be read t o t h e subject or t h e sub-     t r a c t s are submitted t o departments or
                  ject's legally authorized representa-           agencies with t h e knowledge t h a t sub-
                  tive, but in any event, t h e investigator      jects may be involved within t h e period
                  shall give either t h e subject or t h e rep-   of support, but definite plans would not
                  resentative adequate opportunity t o            normally be set forth in the applica-
                  read i t before i t is signed: or               tion or proposal. These include activi-
                     (2) A short form written consent doc-        ties such as institutional type grants
                  ument stating t h a t t h e elements of in-     when selection of specific projects is
                  formed consent required by § 46.116             t h e institution's responsibility: re-
                  have been presented orally t o t h e sub-       search training grants in which t h e ac-
                  ject or t h e subject's legally authorized      tivities involving subjects remain t o be
                  representative. When this method is             selected: and projects in which human
                  used, there shall be a witness t o t h e        subjects' involvement will depend upon
                  oral presentation. Also, t h e IRB shall        completion of instruments, prior ani-
                  approve a written summary of what is            mal studies, or purification of com-
                  t o be said t o t h e subject or t h e rep-     pounds. These applications need not be
                  resentative. Only t h e short form itself       reviewed by an IRE before an award
                  is t o be signed by t h e subject or t h e
                                                                  may be made. However, except for re-
                  representative. However, t h e witness
                  shall sign both t h e short form and a          search exempted or waived under
                  copy of t h e summary, and t h e person         546.101 (b) or (i), no human subjects
                  actually obtaining consent shall sign a         may be involved in any project sup-
                  copy of t h e summary. A copy of t h e          ported by these awards until t h e
                  summary shall be given t o t h e subject        project has been reviewed and approved
                  or t h e representative, in addition t o a      by t h e IRB, as provided in this policy,
                  copy of t h e short form.                       and certification submitted, by t h e in-
                     (c) An IRB may waive t h e require-          stitution, t o t h e department or agency.
                  ment for t h e investigator t o obtain a
                  signed consent form for some or all             4 46.119 Research undertaken without
                  subjects if i t finds either:                       the intention of involving human
                                                                      subjects.
                     (1) That t h e only record linking t h e
                  subject and t h e research would be t h e         In t h e event research is undertaken
                  consent document and t h e principal            without t h e intention of involving
                  risk would be potential harm resulting          human subjects, but i t is later pro-
                  from a breach of confidentiality. Each          posed t o involve human subjects in t h e




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                   Department of Health and Human Services                                           5 46.20 1
                   research, t h e research shall first be re-     into account, in addition t o all other
                   viewed and approved by an IRB, as pro-          eligibility requirements and program
                   vided in this policy, a certification sub-      criteria, factors such as whether t h e
                   mitted, by the institution, t o t h e de-       applicant has been subject t o a termi-
                   partment or agency, and final approval          nation or suspension under paragarph
                   given t o t h e proposed change by t h e de-    (a) of this section and whether t h e ap-
                   partment or agency.                             plicant or t h e person or persons who
                   S 46.120 Evaluation and disposition of          would direct or has have directed t h e
                        applications and proposals for re-         scientific and technical aspects of an
                        search to be conducted or sup-             activity has have, in t h e judgment of
                        ported by a Federal Department or          t h e department or agency head, mate-
                        Agency.                                    rially failed t o discharge responsibility
                     (a) The department or agency head             for t h e protection of t h e rights and
                  will evaluate all applications and pro-          welfare of human subjects (whether or
                  posals involving human subjects sub-             not the research was subject t o federal
                   mitted t o t h e department or agency           regulation).
                  through such officers and employees of
                  t h e department or agency and such ex-          S 46.124 Conditions.
                  perts and consultants as t h e depart-             With respect t o any research project
                   ment or agency head determines t o be           or any class of research projects t h e de-
                   appropriate. This evaluation will t a k e       partment or agency head may impose
                   into consideration t h e risks t o t h e sub-   additional conditions prior t o or a t t h e
                  jects, t h e adequacy of protection              time of approval when in t h e judgment
                   against these risks, t h e potential bene-      of t h e department or agency head addi-
                  fits of t h e research t o t h e subjects and    tional conditions are necessary for t h e
                   others, and t h e importance of t h e
                                                                   protection of human subjects.
                   knowledge gained or t o be gained.
                     (b) On t h e basis of this evaluation,
                  t h e department or agency head may              Subpart B-Additional Protections
                   approve or disapprove t h e application            Pertaining to Research, Devel-
                   or proposal, or enter into negotiations            opment, and Related Activi-
                  t o develop an approvable one.                      ties Involving Fetuses, Preg-
                   4 46.121 [Reserved]                                nant Women, and Human In
                                                                      Vitro Fertilization
                   4 46.122 Use of Federal funds.
                     Federal funds administered by a de-             SOURCE: FR 33528, Aug. 8, 1975, unless
                                                                              40
                   partment or agency may not be ex-               otherwise noted.
                   pended for research involving human
                   subjects unless t h e requirements of           S 46.201 Applicability.
                   this policy have been satisfied.                   (a) The regulations in this subpart
                                                                   are applicable t o all Department of
                   4 46.123 Early termination of research          Health and Human Services grants and
                       support: Evaluation of applications
                       and proposals.                              contracts supporting research, develop-
                                                                   ment, and related activities involving:
                     (a) The department or agency head             (1) The fetus, (2) pregnant women, and
                   may require t h a t department or agency
                                                                   (3) human i vitro fertilization.
                                                                                n
                   support for any project be terminated
                   or suspended in t h e manner prescribed            (b) Nothing in this subpart shall be
                   in applicable program requirements,             construed as indicating t h a t compli-
                   when t h e department or agency head            ance with t h e procedures set forth
                   finds an institution has materially             herein will in any way render inappli-
                   failed t o comply with t h e terms of this      cable pertinent S t a t e or local laws
                   policy.                                         bearing upon activities covered by this
                     (b) In making decisions about sup-            subpart.
                   porting or approving applications or               (c) The requirements of this subpart
                   proposals covered by this policy t h e de-      are in addition t o those imposed under
                   partment or agency head may t a k e             t h e other subparts of this part.




© 2002 by CRC Press LLC
                                                                            Appendix A: FDA Regulations                        269




                                                                           45 CFR Subtitle A (10-1-00 Edition)

                   4 46.202 Purpose.                                  through admixture of donor human
                                                                      sperm and ova or by any other means.
                     I t is the purpose of this subpart t o
                   provide additional safeguards in re-               L.10 F R 33528, Aug. 8 , 1975, as a m e n d e d a t 43
                   viewing activities t o which this sub-             F R 1759, J a n . 11, 19781
                   part is applicable t o assure t h a t they
                   conform t o appropriate ethical stand-             4 46.204 Ethical Advisory Boards.
                   ards and relate t o important societal            (a) One or more Ethical Advisory
                   needs.                                         Boards shall be established by t h e Sec-
                                                                  retary. Members of these board(s) shall
                   4 46.203 Definitions.                          be so selected t h a t the board(s) will be
                      As used in this subpart:                    competent t o deal with medical, legal,
                      (a) Secretary means t h e Secretary of social, ethical, and related issues and
                   Health and Human Services and any may include, for example, research sci-
                   other officer or employee of t h e De- entists, physicians, psychologists, soci-
                   partment of Health and Human Serv- ologists, educators, lawyers, and
                                                                  ethicists, as well as representatives of
                   ices t o whom authority has been dele-
                                                                  t h e general public. No board member
                   gated.
                                                                  may be a regular, full-time employee of
                      (b) Pregnancy encompasses t h e period      t h e Department of Health and Human
                   of time from confirmation of implanta- Services.
                   tion (through any of t h e presumptive            (b) At t h e request of the Secretary,
                   signs of pregnancy, such as missed t h e Ethical Advisory Board shall
                   menses, or by a medically acceptable render advice consistent with t h e poli-
                   pregnancy test), until expulsion or ex- cies and requirements of this part as t o
                   traction of t h e fetus.                       ethical issues, involving activities cov-
                      (c) Fetus means t h e product of con- ered by this subpart, raised by indi-
                   ception from t h e time of implantation        vidual applications or proposals. In ad-
                   (as evidenced by any of t h e presump- dition, upon request by t h e Secretary,
                   tive signs of pregnancy, such as missed t h e Board shall render advice as t o
                   menses, or a medically acceptable classes of applications or proposals and
                   pregnancy t e s t ) , until a determination general policies, guidelines, and proce-
                   is made, following expulsion or extrac- dures.
                   tion of the fetus, t h a t i t is viable.         (c) A Board may establish, with t h e
                      (d) Viable as i t pertains t o t h e fetus approval of t h e Secretary, classes of
                   means being able, after either sponta- applications or proposals which: (1)
                   neous or induced delivery, t o survive Must be submitted t o t h e Board, or (2)
                   (given t h e benefit of available medical      need not be submitted t o t h e Board.
                   therapy) t o t h e point of independently Where t h e Board so establishes a class
                   maintaining heart beat and respira- of applications or proposals which
                   tion. The Secretary may from time t o must be submitted, no application or
                   time, taking into account medical ad- proposal within t h e class may be fund-
                   vances, publish in t h e FEDERAL          REG- ed by t h e Department or any compo-
                   ISTER guidelines t o assist in deter-          nent thereof until t h e application or
                   mining whether a fetus is viable for proposal has been reviewed by t h e
                   purposes of this subpart. If a fetus is Board and the Board has rendered ad-
                   viable after delivery, i t is a premature vice as t o i t s acceptability from an eth-
                   infant.                                        ical standpoint.
                      (e) Nonviable fetus means a fetus ex
                   utero which, although living, is not via- [40 FR 33528, Xug. 8 , 1975, as a m e n d e d a t 43
                                                                  F R 1759, J a n . 11, 1978: 59 F R 28276, J u n e 1 ,
                   ble.
                                                                  19941
                      (Q Dead fetus means a fetus ex utero
                   which exhibits neither heartbeat, spon- 4 46.205 Additional duties of the Insti-
                   taneous respiratory activity, sponta-                tutional Review Boards in connec-
                   neous movement of voluntary muscles,                 tion    with      activities involving
                   nor pulsation of the umbilical cord (if             fetuses, pregnant women, or human
                   still attached).                                     in vitro fertilization.
                      (g) I n vitro fertilization means any fer-     (a) In addition t o t h e responsibilities
                   tilization of human ova which occurs prescribed for Institutional Review
                   outside t h e body of a female, either Boards under Subpart A of this part,




© 2002 by CRC Press LLC
        270      Clinical Research Coordinator Handbook




                   Department of Health and Human Services                                                     5 46.208
                   t h e applicant's or offeror's Board shall,              (2) Except where t h e purpose of t h e
                   with respect t o activities covered by               activity is t o meet t h e health needs of
                   this subpart, carry out t h e following              t h e mother or t h e particular fetus, t h e
                   additional duties:                                   risk t o t h e fetus is minimal and, in all
                      (1) Determine t h a t all aspects of t h e        cases, is t h e least possible risk for
                   activity meet t h e requirements of this             achieving t h e objectives of t h e activ-
                   subpart:                                             ity.
                      (2) Determine t h a t adequate consid-                (3) Individuals engaged in t h e activ-
                   eration has been given t o t h e manner              i t y will have no part in: (i) Any deci-
                   in which potential subjects will be se-              sions as t o t h e timing, method, and
                   lected, and adequate provision has been              procedures used t o terminate t h e preg-
                   made by t h e applicant or offeror for               nancy, and (ii) determining t h e viabil-
                   monitoring t h e actual informed con-                i t y of t h e fetus a t t h e termination of
                   sent process (e.g.,through such mecha-               t h e pregnancy; and
                   nisms, when appropriate, as participa-                   (4) No procedural changes which may
                   tion by t h e Institutional Review Board             cause greater than minimal risk t o t h e
                   or subject advocates in: (i) Overseeing              fetus or t h e pregnant woman will be in-
                   t h e actual process by which individual             troduced into t h e procedure for termi-
                   consents required by this subpart are                nating t h e pregnancy solely in t h e in-
                   secured either by approving induction                terest of t h e activity.
                   of each individual into t h e activity or                (b) No inducements, monetary or oth-
                   verifying, perhaps through sampling,                 erwise, may be offered t o terminate
                   t h a t approved procedures for induction            pregnancy for purposes of t h e activity.
                   of individuals into t h e activity are
                                                                        [40 F R 33528, A u g . 8 , 1975, as amended a t 40
                   being followed, and (ii) monitoring the              F R 51638, Nov. 6, 19751
                   progress of t h e activity and inter-
                   vening as necessary through such steps               S 46.207 Activities     directed toward
                   as visits t o t h e activity site and con-                 pregnant women as subjects.
                   tinuing evaluation t o determine if any                 (a) No pregnant woman may be in-
                   unanticipated risks have arisen);                    volved as a subject in an activity cov-
                      (3) Carry out such other responsibil-             ered by this subpart unless: (1) The
                   ities as may be assigned by t h e Sec-               purpose of t h e activity is t o meet t h e
                   retary.                                              health needs of t h e mother and t h e
                      (b) No award may be issued until t h e            fetus will be placed a t risk only t o t h e
                   applicant or offeror has certified t o t h e         minimum extent necessary t o meet
                   Secretary t h a t t h e Institutional Re-            such needs, or (2) t h e risk t o t h e fetus
                   view Board has made t h e determina-                 is minimal.
                   tions required under paragraph (a) of                   (b) An activity permitted under para-
                   this section and t h e Secretary has ap-             graph (a) of this section may be con-
                   proved these determinations, as pro-                 ducted only if the mother and father
                   vided in 946.120 of Subpart A of this                are legally competent and have given
                   part.                                                their informed consent after having
                      (c) Applicants or offerors seeking                been fully informed regarding possible
                   support for activities covered by this               impact on t h e fetus, except t h a t t h e fa-
                   subpart must provide for t h e designa-              ther's informed consent need not be se-
                   tion of an Institutional Review Board,               cured if: (1) The purpose of t h e activity
                   subject t o approval by t h e Secretary,             is t o meet t h e health needs of the
                   where no such Board has been estab-                  mother: (2) his identity or whereabouts
                   lished under Subpart A of this part.                 cannot reasonably be ascertained; (3)
                   [40 F R 33528, A u g . 8 , 1975, as amended a t 46   he is not reasonably available: or (4)
                   F R 8386, Jan. 26, 19811                             t h e pregnancy resulted from rape.
                   4 46.206 General limitations.                        4 46.208 Activities      directed toward
                     (a) No activity t o which this subpart                   fetuses in utero as subjects.
                   is applicable may be undertaken un-                     (a) No fetus in ntero may be involved
                   less:                                                as a subject in any activity covered by
                     (1) Appropriate studies on animals                 this subpart unless: (1) The purpose of
                   and nonpregnant individuals have been                t h e activity is t o meet t h e health needs
                   completed;                                           of t h e particular fetus and t h e fetus




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                                                                          Appendix A: FDA Regulations                  27 1




                                                                          45 CFR Subtitle A (10-1-00 Edition)
                   will be placed a t risk only t o t h e min-       ther are legally competent and have
                   imum extent necessary t o meet such               given their informed consent, except
                   needs, or (2) t h e risk t o t h e fetus im-      t h a t t h e father's informed consent need
                   posed by t h e research is minimal and            not be secured if: (1) His identity or
                   t h e purpose of t h e activity is t h e devel-   whereabouts cannot reasonably be
                   opment      of    important       biomedical      ascertained, (2) he is not reasonably
                   knowledge which cannot be obtained                available, or (3) t h e pregnancy resulted
                   by other means.                                   from rape.
                      (b) An activity permitted under para-
                   graph (a) of this section may be con-             [40 F R 33528, Xug. 8, 1975, a s amended a t 43
                                                                     F R 1759, J a n . 11, 19781
                   ducted only if the mother and father
                   are legally competent and have given              S 46.210 Activities involving the dead
                   their informed consent, except t h a t t h e          fetus, fetal material, or the pla-
                   father's consent need not be secured if:              centa.
                   (1) His identity or whereabouts cannot
                   reasonably be ascertained, (2) he is not            Activities involving t h e dead fetus,
                   reasonably available, or (3) t h e preg-          mascerated fetal material, or cells, tis-
                   nancy resulted from rape.                         sue, or organs excised from a dead fetus
                                                                     shall be conducted only in accordance
                   S 46.209 Activities       directed toward         with any applicable S t a t e or local laws
                         fetuses ex utero, including non-            regarding such activities.
                         viable fetuses, as subjects.
                      (a) Until i t has been ascertained             4 46.211 Modification or waiver of spe-
                                                                         cific requirements.
                   whether or not a fetus ex utero is via-
                   ble, a fetus ex utero may not be in-                 Upon the request of an applicant or
                   volved as a subject in an activity cov-           offeror (with t h e approval of i t s Insti-
                   ered by this subpart unless:                      tutional Review Board), t h e Secretary
                      (1) There will be no added risk t o the        may modify or waive specific require-
                   fetus resulting from t h e activity, and          ments of this subpart, with t h e ap-
                   t h e purpose of t h e activity is t h e devel-   proval of t h e Ethical Advisory Board
                   opment        of  important       biomedical      after such opportunity for public com-
                   knowledge which cannot be obtained                ment as t h e Ethical Advisory Board
                   by other means, or                                considers appropriate in t h e particular
                      (2) The purpose of t h e activity is t o       instance. In making such decisions, t h e
                   enhance t h e possibility of survival of          Secretary will consider whether t h e
                   t h e particular fetus t o t h e point of via-    risks t o t h e subject are so outweighed
                   bility.                                           by t h e sum of t h e benefit t o t h e subject
                      (b) No nonviable fetus may be in-              and t h e importance of t h e knowledge
                   volved as a subject in an activity cov-           t o be gained as t o warrant such modi-
                   ered by this subpart unless:                      fication or waiver and t h a t such bene-
                      (1) Vital functions of t h e fetus will        fits cannot be gained except through a
                   not be artificially maintained,                   modification or waiver. Any such modi-
                      (2) Experimental activities which of           fications or waivers will be published
                   themselves would terminate t h e heart-           as notices in t h e FEDERAL    REGISTER.
                   beat or respiration of t h e fetus will not
                   be employed, and                                  Subpart C-Additional Protections
                      (3) The purpose of the activity is t h e          Pertaining to Biomedical and
                   development of important biomedical                  Behavioral Research Involving
                   knowledge which cannot be obtained
                   by other means.
                                                                        Prisoners as Subjects
                      (c) In t h e event t h e fetus ex ntero is
                   found t o be viable, i t may be included             SOURCE: F R 53655, Nov. 16, 1978, unless
                                                                                        43
                   as a subject in t h e activity only t o t h e     o t h e r n i s e noted.
                   extent permitted by and in accordance
                   with t h e requirements of other sub-             4 46.301 Applicability.
                   parts of this part.                                 (a) The regulations in this subpart
                      (d) An activity permitted under para-          are applicable t o all biomedical and be-
                   graph (a) or (b) of this section may be           havioral research conducted or sup-
                   conducted only if t h e mother and fa-            ported by t h e Department of Health




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        272      Clinical Research Coordinator Handbook




                   Department of Health and Human Services                                                   5 46.305
                   and Human Services involving pris-              tutional Review Board, carrying out
                   oners as subjects.                              responsibilities under this part with re-
                      (b) Nothing in this subpart shall be         spect t o research covered by this sub-
                   construed as indicating t h a t compli-         part, shall also meet t h e following spe-
                   ance with t h e procedures set forth            cific requirements:
                   herein will authorize research involv-            (a) A majority of the Board (exclu-
                   ing prisoners as subjects, t o t h e extent     sive of prisoner members) shall have no
                   such research is limited or barred by           association with t h e prison(s) involved,
                   applicable S t a t e or local law.              apart from their membership on t h e
                      (c) The requirements of this subpart         Board.
                   are in addition t o those imposed under           (b) At least one member of the Board
                   t h e other subparts of this part.              shall be a prisoner, or a prisoner rep-
                                                                   resentative with appropriate back-
                   S 46.302 Purpose.                               ground and experience t o serve in t h a t
                      Inasmuch as prisoners may be under           capacity, except t h a t where a par-
                   constraints because of their incarcer-          ticular research project is reviewed by
                   ation which could affect their ability          more than one Board only one Board
                   t o make a truly voluntary and                  need satisfy this requirement.
                   uncoerced decision whether or not t o           [43 F R 53655, Nov. 16, 1978, as a m e n d e d a t 46
                   participate as subjects in research, i t is     F R 8386, J a n . 26, 19811
                   t h e purpose of this subpart t o provide
                   additional safeguards for t h e protec-         4 46.305 Additional duties of the Insti-
                   tion of prisoners involved in activities               tutional Review Boards where pris-
                   t o which this subpart is applicable.                  oners are involved.
                                                                       (a) In addition t o all other respon-
                   4 46.303 Definitions.                           sibilities prescribed for Institutional
                      As used in this subpart:                     Review Boards under this part, t h e
                      (a) Secretary means t h e Secretary of       Board shall review research covered by
                   Health and Human Services and any               this subpart and approve such research
                   other officer or employee of t h e De-          only if i t finds t h a t :
                   partment of Health and Human Serv-                  (1) The research under review rep-
                   ices t o whom authority has been dele-          resents one of t h e categories of re-
                   gated.                                          search permissible under §46.306(a)(2):
                      (b) DHHS means t h e Department of               (2) Any possible advantages accruing
                   Health and Human Services.                      t o t h e prisoner through his or her par-
                      (c) Prisoner means any individual in-        ticipation in t h e research, when com-
                   voluntarily confined or detained in a           pared t o t h e general living conditions,
                   penal institution. The term is intended         medical care, quality of food, amen-
                   t o encompass individuals sentenced t o         ities and opportunity for earnings in
                   such an institution under a criminal or         t h e prison, are not of such a magnitude
                   civil s t a t u t e , individuals detained in   t h a t his or her ability t o weigh t h e
                   other facilities by virtue of statutes or       risks of t h e research against the value
                   commitment procedures which provide             of such advantages in t h e limited
                   alternatives t o criminal prosecution or        choice environment of t h e prison is im-
                   incarceration in a penal institution,           paired;
                   and individuals detained pending ar-                (3) The risks involved in t h e research
                   raignment, trial, or sentencing.                are commensurate with risks t h a t
                      (d) Minimal risk is t h e probability and    would be accepted by nonprisoner vol-
                   magnitude of physical or psychological          unteers;
                   harm t h a t is normally encountered in             (4) Procedures for t h e selection of
                   t h e daily lives, or in t h e routine med-     subjects within t h e prison are fair t o
                   ical, dental, or psychological examina-         all prisoners and immune from arbi-
                   tion of healthy persons.                        t r a r y intervention by prison authori-
                                                                   ties or prisoners. Unless t h e principal
                   S 46.304 Composition of Institutional           investigator provides t o t h e Board jus-
                                                          are
                      Review Boards where ~ r i s o n e r s        tification in writing for following some
                      involved.                                    other procedures, control subjects
                    In addition t o satisfying t h e require-      must be selected randomly from t h e
                   ments in 546.107 of this part, an Insti-        group of available prisoners who meet




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                                                                        Appendix A: FDA Regulations               273




                                                                       45 CFR Subtitle A (10-1-00 Edition)
                   t h e characteristics needed for t h a t par-   example, vaccine trials and other re-
                   ticular research project:                       search on hepatitis which is much
                      (5) The information is presented in          more prevalent in prisons t h a n else-
                   language which is understandable t o            where: and research on social and psy-
                   t h e subject population;                       chological problems such as alco-
                      (6) Adequate assurance exists t h a t        holism, drug addiction and sexual as-
                   parole boards will not t a k e into ac-         saults) provided t h a t t h e study may
                   count a prisoner's participation in t h e       proceed only after t h e Secretary has
                   research in making decisions regarding          consulted with appropriate experts in-
                   parole, and each prisoner is clearly in-        cluding experts in penology medicine
                   formed in advance t h a t participation in      and ethics, and published notice, in the
                   t h e research will have no effect on his       FEDERAL                of
                                                                               REGISTER, his intent t o ap-
                   or her parole; and                              prove such research; or
                      (7) Where t h e Board finds there may            (iv) Research on practices, both inno-
                   be a need for followup examination or           vative and accepted, which have t h e in-
                   care of participants after t h e end of         t e n t and reasonable probability of im-
                   their participation, adequate provision         proving t h e health or well-being of t h e
                   has been made for such examination or           subject. In cases in which those studies
                   care, taking into account t h e varying         require t h e assignment of prisoners in
                   lengths of individual prisoners' sen-           a manner consistent with protocols ap-
                   tences, and for informing participants          proved by t h e IRE t o control groups
                   of this fact.                                   which may not benefit from t h e re-
                      (b) The Board shall carry out such           search, t h e study may proceed only
                   other duties as may be assigned by t h e        after t h e Secretary has consulted with
                   Secretary.                                      appropriate experts, including experts
                      (c) The institution shall certify t o        in penology medicine and ethics, and
                   t h e Secretary, in such form and man-          published notice, in t h e FEDERAL    REG-
                   ner as t h e Secretary may require, t h a t     ISTER, of his intent t o approve such re-
                   t h e duties of t h e Board under this sec-     search.
                   tion have been fulfilled.                           (b) Except as provided in paragraph
                                                                   (a) of this section, biomedical or behav-
                   4 46.306 Permitted research involving           ioral research conducted or supported
                         prisoners.                                by DHHS shall not involve prisoners as
                      (a) Biomedical or behavioral research        subjects.
                   conducted or supported by DHHS may
                   involve prisoners as subjects only if:          Subpart D-Additional Protections
                      (1) The institution responsible for t h e       for Children Involved as Sub-
                   conduct of t h e research has certified t o        jects in Research
                   t h e Secretary t h a t t h e Institutional
                   Review Board has approved t h e re-                SOURCE:FR 9818, Mar. 8, 1983, unless oth-
                                                                                  48
                   search under 846.305 of this subpart;           e r n i s e noted.
                   and
                      (2) In t h e judgment of t h e Secretary     446.401 To what do these regulations
                   t h e proposed research involves solely              apply?
                   t h e following:                                   (a) This subpart applies t o all re-
                      (i) Study of t h e possible causes, ef-      search involving children as subjects,
                   fects, and processes of incarceration,          conducted or supported by t h e Depart-
                   and of criminal behavior, provided t h a t      ment of Health and Human Services.
                   t h e study presents no more t h a n mini-         (1) This includes research conducted
                   mal risk and no more t h a n inconven-          by Department employees, except t h a t
                   ience t o t h e subjects;                       each head of an Operating Division of
                      (ii) Study of prisons as institutional       t h e Department may adopt such non-
                   structures or of prisoners as incarcer-         substantive, procedural modifications
                   ated persons, provided t h a t t h e study      as may be appropriate from an admin-
                   presents no more than minimal risk              istrative standpoint.
                   and no more than inconvenience t o t h e           (2) I t also includes research con-
                   subjects;                                       ducted or supported by t h e Department
                      (iii) Research on conditions particu-        of Health and Human Services outside
                   larly affecting prisoners as a class (for       t h e United States, but in appropriate




© 2002 by CRC Press LLC
        274      Clinical Research Coordinator Handbook




                   Department of Health and Human Services                                                     5 46.406
                   circumstances, t h e Secretary may,                     which satisfies the conditions of all ap-
                   under paragraph (e) of S46.101 of Sub-                  plicable sections of this subpart.
                   part A, waive t h e applicability of some
                   or all of t h e requirements of these reg-              S 46.404 Research not involving great-
                   ulations for research of this type.                           er than minimal risk.
                      (b) Exemptions a t § 46.lOl(b)(1) and                   HHS will conduct or fund research in
                   (b)(3) through (b)(6) are applicable t o                which t h e IRE finds t h a t no greater
                   this subpart. The exemption a t                         t h a n minimal risk t o children is pre-
                   5 46.101 (b)(2) regarding educational tests             sented, only if the IRB finds t h a t ade-
                   is also applicable t o this subpart. How-               quate provisions are made for solic-
                   ever, t h e exemption a t §46.lOl(b)(2) for             iting t h e assent of t h e children and t h e
                   research involving survey or interview                  permission of their parents or guard-
                   procedures or observations of public be-                ians, as set forth in § 46.408.
                   havior does not apply t o research cov-
                   ered by this subpart, except for re-                    S 46.405 Research           involving greater
                                                                                 than minimal risk but presenting
                   search involving observation of public                        the prospect of direct benefit to the
                   behavior when t h e investigator(s) do                        individual subjects.
                   not participate in t h e activities being
                   observed.                                                  HHS will conduct or fund research in
                                                                           which t h e IRE finds t h a t more than
                      (c) The exceptions, additions, and
                                                                           minimal risk t o children is presented
                   provisions for waiver as they appear in
                                                                           by an intervention or procedure t h a t
                   paragraphs (c) through (i) of 546.101 of
                                                                           holds out t h e prospect of direct benefit
                   Subpart A are applicable t o this sub-
                                                                           for t h e individual subject, or by a mon-
                   part.
                                                                           itoring procedure t h a t is likely t o con-
                   [48 F R 9818, Mar. 8, 1983; 56 F R 28032, J u n e 18,   tribute t o t h e subject's well-being, only
                   1991; 56 F R 29757, J u n e 28, 19911                   if t h e IRB finds t h a t :
                                                                              (a) The risk is justified by the antici-
                   4 46.402 Definitions.                                   pated benefit t o t h e subjects:
                      The definitions in 846.102 of Subpart                   (b) The relation of t h e anticipated
                   A shall be applicable t o this subpart as               benefit t o t h e risk is a t least as favor-
                   well. In addition, as used in this sub-                 able t o t h e subjects as t h a t presented
                   part:                                                   by available alternative approaches:
                      (a) Children are persons who have not                and
                   attained t h e legal age for consent t o                   (c) Adequate provisions are made for
                   treatments or procedures involved in                    soliciting the assent of t h e children
                   t h e research, under t h e applicable law              and permission of their parents or
                   of t h e jurisdiction in which t h e re-                guardians, as set forth in 546.408.
                   search will be conducted.
                      (b) Assent means a child's affirmative               S 46.406 Research       involving greater
                                                                               than minimal risk and no prospect
                   agreement t o participate in research.                      of direct benefit to individual sub-
                   Mere failure t o object should not, ab-                     jects, but likely to yield generaliz-
                   sent affirmative agreement, be con-                         able knowledge about the subject's
                   strued as assent.                                           disorder or condition.
                      (c) Permission means t h e agreement of                HHS will conduct or fund research in
                   parent(s) or guardian t o t h e participa-              which t h e IRE finds t h a t more than
                   tion of their child or ward in research.                minimal risk t o children is presented
                      (d) Parent means a child's biological                by an intervention or procedure t h a t
                   or adoptive parent.                                     does not hold out t h e prospect of direct
                      (e) Guardian means an individual who                 benefit for t h e individual subject, or by
                   is authorized under applicable S t a t e or             a monitoring procedure which is not
                   local law t o consent on behalf of a                    likely t o contribute t o t h e well-being
                   child t o general medical care.                         of t h e subject, only if t h e IRB finds
                                                                           that:
                   4 46.403 IRB duties.                                      (a) The risk represents a minor in-
                     In addition t o other responsibilities                crease over minimal risk:
                   assigned t o IRBs under this part, each                   (b) The intervention or procedure
                   IRB shall review research covered by                    presents experiences t o subjects t h a t
                   this subpart and approve only research                  are reasonably commensurate with




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                                                                          Appendix A: FDA Regulations                   275




                                                                          45 CFR Subtitle A (10-1-00 Edition)
                   those inherent in their actual or ex-             children, when in t h e judgment of t h e
                   pected medical, dental, psychological,            IRB t h e children a r e capable of pro-
                   social, or educational situations:                viding assent. In determining whether
                      (c) The intervention or procedure is           children a r e capable of assenting, t h e
                   likely t o yield generalizable knowledge          IRB shall t a k e i n t o account t h e ages,
                   about t h e subjects' disorder or condi-          m a t u r i t y , and psychological s t a t e of
                   tion which is of vital importance for             t h e children involved. This judgment
                   t h e understanding or amelioration of            may be made for all children t o be in-
                   t h e subjects' disorder or condition: and        volved i n research under a particular
                      (d) Adequate provisions are made for           protocol, or for each child, a s t h e IRB
                   soliciting assent of t h e children and           deems appropriate. If t h e IRE deter-
                   permission of their parents or guard-             mines t h a t t h e capability of some or
                   ians, a s s e t forth i n S 46.408.               all of t h e children is so limited t h a t
                   S 46.407 Research not otherwise ap-               t h e y cannot reasonably be consulted or
                         provable which presents an oppor-           t h a t t h e intervention or procedure in-
                         tunity to understand, prevent, or al-       volved in t h e research holds out a pros-
                         leviate a serious problem affecting         pect of direct benefit t h a t is important
                         the health or welfare of children.          t o t h e health or well-being of t h e chil-
                      HHS will conduct or fund research              dren and is available only i n t h e con-
                   t h a t t h e IRB does not believe meets          t e x t of t h e research, t h e assent of t h e
                   t h e requirements of 546.404, 546.405, or        children is not a necessary condition
                   946.406 only if:                                  for proceeding with t h e research. Even
                      (a) The IRB finds t h a t t h e research       where t h e IRE determines t h a t t h e sub-
                   presents a reasonable opportunity t o             jects are capable of assenting, t h e IRB
                   further t h e understanding, prevention,          may still waive t h e assent requirement
                   or alleviation of a serious problem af-           under circumstances i n which consent
                   fecting t h e health or welfare of chil-          may be waived i n accord with S46.116 of
                   dren: and                                         Subpart A.
                      (b) The Secretary, after consultation              (b) In addition t o t h e determinations
                   with a panel of experts i n pertinent dis-        required under other applicable sec-
                   ciplines (for example: science, medi-             tions of t h i s subpart, t h e IRB shall de-
                   cine, education, ethics, law) and fol-            termine, i n accordance with and t o t h e
                   lowing opportunity for public review              extent t h a t consent is required by
                   and comment, has determined either:               946.116 of Subpart A, t h a t adequate pro-
                      (1) T h a t t h e research in fact satisfies   visions a r e made for soliciting t h e per-
                   t h e conditions of 946.404, 846.405, or          mission of each child's parents or
                   946.406, a s applicable, or                       guardian. Where parental permission is
                      (2) The following:
                                                                     t o be obtained, t h e IRB may find t h a t
                      (i) The research presents a reasonable
                                                                     t h e permission of one parent is suffi-
                   opportunity t o further t h e under-
                   standing, prevention, or alleviation of           cient for research t o be conducted
                                                                     under 946.404 or 946.405. Where research
                   a serious problem affecting t h e health
                   or welfare of children:                           is covered by SS46.406 and 46.407 and
                      (ii) The research will be conducted in         permission is t o be obtained from par-
                   accordance with sound ethical prin-               ents, both parents must give their per-
                   ciples:                                           mission unless one parent is deceased,
                      (iii) Adequate provisions a r e made           unknown, incompetent, or not reason-
                   for soliciting t h e assent of children and       ably available, or when only one parent
                   t h e permission of their parents or              has legal responsibility for t h e care
                   guardians, a s set forth i n 946.408.             and custody of t h e child.
                                                                         (c) In addition t o t h e provisions for
                   4 46.408 Requirements for permission              waiver contained i n 846.116 of Subpart
                       by parents or guardians and for as-           A , if t h e IRB determines t h a t a re-
                       sent by children.                             search protocol is designed for condi-
                     (a) In addition t o t h e determinations        tions or for a subject population for
                   required under other applicable sec-              which parental or guardian permission
                   tions of t h i s subpart, t h e IRB shall de-     is not a reasonable requirement t o pro-
                   termine t h a t adequate provisions a r e         t e c t t h e subjects (for example, ne-
                   made for soliciting t h e assent of t h e         glected or abused children), i t may




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                   Department of Health and Human Services                                                    5 50.2
                   waive t h e consent requirements in Sub-            PART 50-U.S. EXCHANGE VISITOR
                   part A of this part and paragraph (b) of              PROGRAM-REQUEST FOR WAIV-
                   this section, provided an appropriate                         H
                                                                         ER OF T E TWO-YEAR FOREIGN
                   mechanism for protecting the children                 RESIDENCE REQUIREMENT
                   who will participate as subjects in t h e
                   research is substituted, and provided               Sec.
                   further t h a t t h e waiver is not incon-          50.1 Authority.
                   sistent with Federal, s t a t e or local law.       50.2 Exchange Visitor Waiver Review Board.
                   The choice of an appropriate mecha-                 50.3 Policy.
                                                                       50.4 Procedures for submission of applica-
                   nism would depend upon t h e nature                     t i o n t o HHS.
                   and purpose of t h e activities described           50.5 Personal hardship, persecution and visa
                   in t h e protocol, t h e risk and antici-               extension considerations.
                   pated benefit t o t h e research subjects,          50.6 Release from foreign government.
                   and their age, maturity, status, and                                    75
                                                                         AUTHORITY: S t a t . 527 (22 U.S.C. 2451 e t
                   condition.                                          seq.): 84 S t a t . 116 (8 U.S.C. 1182(e)).
                     (d) Permission by parents or guard-                 SOURCE 49 F R 9900, Mar     16, 1984, unless
                   ians shall be documented in accordance              othernise noted
                   with and t o t h e extent required by
                   546.117 of Subpart A.                               4 50.1 Authority.
                     (e) When t h e IRB determines t h a t as-           Under t h e authority of Mutual Edu-
                   sent is required, i t shall also determine          cational and Cultural Exchange Act of
                   whether and how assent must be docu-                1961 (75 S t a t . 527) and t h e Immigration
                   mented.                                             and Nationality Act as amended (84
                                                                       S t a t . 116), t h e Department of Health
                   S 46.409 Wards.                                     and Human Services is an "interested
                                                                       United States Government agency"
                       (a) Children who are wards of t h e             with t h e authority t o request t h e
                   s t a t e or any other agency, institution,         United States Information Agency t o
                   or entity can be included in research               recommend t o t h e Attorney General
                   approved under 5 46.406 or 5 46.407 only if         waiver of t h e two-year foreign resi-
                   such research is:                                   dence requirement for exchange visi-
                       (1) Related t o their s t a t u s as wards;     tors under t h e Mutual Educational and
                   or                                                  Cultural Exchange Program.
                       (2) Conducted in schools, camps, hos-
                   pitals, institutions, or similar settings           S 50.2 Exchange Visitor Waiver Review
                                                                             Board.
                   in which t h e majority of children in-
                   volved as subjects are not wards.                      (a) Establishment. The Exchange Vis-
                       (b) If t h e research is approved under         itor Waiver Review Board is estab-
                   paragraph (a) of this section, t h e IRE            lished t o carry out t h e Department's
                   shall require appointment of an advo-               responsibilities under t h e Exchange
                   cate for each child who is a ward, in ad-           Visitor Program.
                   dition t o any other individual acting                 (b) Functions. The Exchange Visitor
                                                                       Waiver Review Board is responsible for
                   on behalf of t h e child as guardian or in
                                                                       making thorough and equitable evalua-
                   loco parentis. One individual may serve             tions of applications submitted by in-
                   as advocate for more than one child.                stitutions, acting on behalf of exchange
                   The advocate shall be an individual                 visitors, t o the Department of HHS for
                   who has t h e background and experience             a favorable recommendation t o t h e
                   t o a c t in, and agrees t o a c t in, t h e best   United States Information Agency t h a t
                   interests of t h e child for t h e duration         t h e two-year foreign residence require-
                   of t h e child's participation in t h e re-         ment for exchange visitors under the
                   search and who is not associated in any             Exchanges Visitor Program be waived.
                   way (except in t h e role as advocate or                (c) Membership. The Exchange Visitor
                   member of t h e IRB) with t h e research,           Waiver Review Board consists of no
                   t h e investigator(s), or t h e guardian or-        fewer than three members and two al-
                   ganization.                                         ternates, of whom no fewer t h a n three




© 2002 by CRC Press LLC
                                    Appendix B
                                   FDA FORMS

                     Form 1571: Investigational New Drug Application

                           Form 1572: Statement of Investigator

                            MEDWATCH Adverse Event Form




© 2002 by CRC Press LLC
                                                                                                            Form Approved: OMB No. 0910-0014.
                            DEPARTMENT OF HEALTH AND HUMAN SERVICES                                         Expiration Date: September 30, 2002
                                     PUBLIC HEALTH SERVICE                                                  See OM6 Statement on Reverse.
                                        FOOD AND DRUG ADMINISTRATION
                 INVESTIGATIONAL NEW DRUG APPLICATION (IND)                                                  investigation begun until an IND for that
                    (TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312)                                   investigation is in effect (21 CFR 312.40).

         . NAME OF SPONSOR                                                                                 2 . DATE OFSUBMISSION


        I. ADDRESS (Number, Street, City, State andzip Code)                                                4. TELEPHONE NUMBER
                                                                                                               (hclude Area Code)




        j.    NAME(S) OFDRUG (Include allavailable names: Trade, Generic, Chemical, Code)                  1 6.   IND NUMBER (If previously assigned)



        '. INDICATION(S) (Covered by this submission)




        I. PHASE(S) OF CLINICAL INVESTIGATION TOBE CONDUCTED:
                                                                          U PHASE 1 U PHASE 2 U PHASE 3 U OTHER
                                                                                                                                            (Specify)
                                                                                                                                              .   .
        I.    LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC APPLICATIONS
              (21 CFR Part 314), DRUG MASTER FILES (21 CFR Part 314.420), AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED
              TO IN THIS APPLICATION.




         o.   IND submission shoyld be consecutively numbered. The initial IND should be numbered
              "Serial number: 000. The next submission (e.g., amendment, report, or correspondence)                                          SERIAL NUMBER
              should be numbered "Serial Number: 001." Subsequent submissions should be
              numbered consecutively in the order in which they are submitted.
                                                                                                                                                ---

         I . THIS SUBMISSION CONTAINS THE FOLLOWING: (Checkall that apply)
                          INITIAL INVESTIGATIONAL NEW DRUG APPLICATION (IND)                            RESPONSE TO CLINICAL HOLD

        'ROTOCOL AMENDMENT(S):                          INFORMATION AMENDMENT(S):                          IND SAFETY REPORT(S):

               NEW PROTOCOL                                  CHEMlSTRYiMlCROBlOLOGY                                 INITIAL WRITTEN REPORT
               CHANGE IN PROTOCOL                            PHARMACOLOGYflOXlCOLOGY                               FOLLOW-UP TO A WRITTEN REPORT
               NEW INVESTIGATOR                              CLINICAL


               RESPONSE TO FDA REQUEST FOR INFORMATION                                 ANNUAL REPORT                   GENERAL CORRESPONDENCE

               REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN,                             OTHER
               INACTIVATED, TERMINATED OR DISCONTINUED                                                                          (Specify)




                                                                           FOR FDA USE ONLY
        >DRIDBINDIDGD RECEIPT STAMP                         1 DDR RECEIPT STAMP                                         DIVISION ASSIGNMENT:




                                                                                                                         IND NUMBER ASSIGNED:




        ORM FDA 1571 (10199)                                             PREVIOUS EDITION IS OBSOLETE                             PAGE 1 OF 2



© 2002 by CRC Press LLC
                                                             CONTENTS OF APPLICATION
                                           This application contains the following items: (Checkall that apply)

            1. Form FDA 1571 [21 CFR 312.23(a)(l)]
            2. Table of Contents [21 CFR 312.23(a)(2)]
        q   3. Introductory statement [21 CFR 312.23(a)(3)]
            4. General Investigationalplan [21 CFR 312,23(a)(3)]
        q   5. Investigator's brochure [21 CFR 312.23(a)(5)]
            6. Protocol(s) [21 CFR 312.23(a)(6)]
                          a. Study protocol(s) [21 CFR 312.23(a)(6)]
                             b. Investigator data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572
                             c. Facilities data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572
                     q d. Institutional Review Board data [21 CFR 312,23(a)(6)(iii)(b)]or completed Form(s) FDA 1572
            7. Chemistry, manufacturing,and control data [21 CFR 312,23(a)(7)]
                         Environmental assessment or claim for exclusion [21 CFR 312.23(a)(7)(iv)(e)]
            8. Pharmacology and toxicology data [21 CFR 312.23(a)(8)]
            9. Previous human experience [21 CFR 312.23(a)(9)]
        0 1 0 . Additional information [21 CFR 312.23(a)(lO)]


        3. IS ANY PART OF THE CLINICAL STUDY TO BE CONDUCTED BY A CONTRACT RESEARCH ORGANIZATION?                              YES          NO

            IF YES, WILL ANY SPONSOR OBLIGATIONS BE TRANSFERRED TO THE CONTRACT RESEARCH ORGANIZATION?                           q    YES        NO

            IF YES, ATTACH ASTATEMENT CONTAINING THE NAME AND ADDRESS OF THE CONTRACT RESEARCH ORGANIZATION,
            IDENTIFICATION OF THE CLINICAL STUDY, AND A LISTING OF THE OBLIGATIONS TRANSFERRED.
        4. NAME AND TITLE OF THE PERSON RESPONSIBLE FOR MONITORING THE CONDUCT AND PROGRESS OF THE CLINICAL
            INVESTIGATIONS




        5 . NAME(S) AND TITLE(S) OF THE PERSON(S) RESPONSIBLE FOR REVIEW AND EVALUATION OF INFORMATION RELEVANT TO THE
            SAFETY OF THE DRUG




        I agree not to begin clinical investigations until 30 days after FDA's receipt of the IND unless I receive earlier notification
        by FDA that the studies may begin. I also agree not to begin or continue clinical investigations covered by the IND if
        those studies are placed on clinical hold. I agree that an Institutional Review Board (IRB) that complies with the
        requirements set fourth in 21 CFR Part 56 will be responsible for initial and continuing review and approval of each of the
        studies in the proposed clinical investigation. I agree to conduct the investigation in accordance with all other applicable
           -
        reaulatorv requirements.
                 - .
        6 . NAME OF SPONSOR OR SPONSOR'S AUTHORIZED                                      17. SIGNATURE OF SPONSOR OR SPONSOR'SAUTHORIZED
            REPRESENTATIVE                                                                   REPRESENTATIVE




        8. ADDRESS (Number, Street, City, State andzip Code)                             19. TELEPHONE NUMBER                            1 20. DATE
                                                                                              (Include Area Code)




        WARNING: A willfully false statement is a criminal offense. U.S.C. Title 18, Sec. 1001.)
        Public reporting burden for this collection of information is estimated to average 100 hours per response, including the time for reviewing instructions,
        searching existing data sources, gathering and maintaining the data needed, and completing reviewing the collection of information. Send comments
        regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to:
        Food and Drug Administration                                 Food and Drug Administration                         "An agency may not conduct or sponsor, and a
        CBER (HFM-99)                                                CDER (HFD-94)                                        person is not required to respond to, a
        1401 Rockville Pike                                          5516 Nicholson Lane                                  collection of information unless it displays a
        Rockville, MD 20852-1 448                                    Kensington, MD 20895                                 currently valid OMB control number."
                                                          Please DO NOT RETURN this application to this address.
        ORM FDA 1571 (10199)                                                                                                          PAGE 2 OF 2



© 2002 by CRC Press LLC
                          DEPARTMENT OF HEALTH AND HUMAN SERVICES                                Form Approved: OMB No. 0910-0014.
                                                                                                 Expiration Date: September 30, 2002.
                                   PUBLIC HEALTH SERVICE                                         See OM6 Statement on Reverse.
                                 FOOD AND DRUG ADMINISTRATION
                                                                                                 NOTE: No investigator may participate in an
                               STATEMENT OF INVESTIGATOR                                         investigation until helshe provides the sponsor with
                 (TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312)                          a completed, signed Statement of Investigator,
                               (See instructions on reverse side.)                               Form FDA 1572 (21 CFR 312.53(c)).
       1. NAME AND ADDRESS OF INVESTIGATOR




       2. EDUCATION, TRAINING, AND EXPERIENCE THAT QUALIFIES THE INVESTIGATOR AS AN EXPERT IN THE CLINICAL INVESTIGATION OF THE
          DRUG FOR THE USE UNDER INVESTIGATION. ONE OF THE FOLLOWING IS ATACHED.

                                          CURRICULUM VITAE                       OTHER STATEMENT OF QUALIFICATIONS



       3. NAME AND ADDRESS OF ANY MEDICAL SCHOOL, HOSPITAL OR OTHER RESEARCH FACILITY WHERE THE CLINICAL INVESTIGATION(S) WlLL
          BE CONDUCTED.




       4. NAME AND ADDRESS OF ANY CLINICAL LABORATORY FACILITIES TO BE USED IN THE STUDY.




       5. NAME AND ADDRESS OF THE INSTITUTIONAL REVIEW BOARD (IRB) THAT IS RESPONSIBLE FOR REVIEW AND APPROVAL OF THE STUDY(IES).




       6. NAMES OFTHE SUBINVESTIGATORS (e.g., research fellows, residents, associates) WHO WlLL BE ASSISTING THE INVESTIGATOR IN THE
          CONDUCT OF THE INVESTIGATION(S).




       7. NAME AND CODE NUMBER, IF ANY, OF THE PROTOCOL(S) IN THE IND FOR THE STUDY(IES) TO BE CONDUCTED BY THE INVESTIGATOR.




       :ORM FDA 1572 (10/99)                                   PREVIOUS EDITION IS OBSOLETE.                        PAGE 1 OF 2




© 2002 by CRC Press LLC
        I. A T A C H THE FOLLOWING CLINICAL PROTOCOL INFORMATION:

                 FOR PHASE 1 INVESTIGATIONS, A GENERAL OUTLINE OF THE PLANNED INVESTIGATION INCLUDING THE ESTIMATED DURATION OF
                 THE STUDY AND THE MAXIMUM NUMBER OF SUBJECTS THAT WILL BE INVOLVED.


                  FOR PHASE 2 OR 3 INVESTIGATIONS, AN OUTLINE OF THE STUDY PROTOCOL INCLUDING AN APPROXIMATION OF THE NUMBER OF
                  SUBJECTS TO BE TREATED WITH THE DRUG AND THE NUMBER TO BE EMPLOYED AS CONTROLS, IF ANY; THE CLINICAL USES TO BE
                  INVESTIGATED; CHARACTERISTICS OF SUBJECTS BY AGE, SEX, AND CONDITION; THE KIND OF CLINICAL OBSERVATIONS AND
                  LABORATORY TESTS TO BE CONDUCTED; THE ESTIMATED DURATION OF THE STUDY; AND COPIES OR A DESCRIPTION OF CASE
                  REPORT FORMS TO BE USED.

        ).   COMMITMENTS:
              I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying
              the sponsor, except when necessary to protect the safety, rights, or welfare of subjects.

              I agree to personally conduct or supervise the described investigation(s).

              I agree to inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and I will ensure
              that the requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional review board (IRB) review and approval in 21
              CFR Part 56 are met.

              I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFR 312.64.

              I have read and understand the information in the investigator's brochure, including the potential risks and side effects of the drug.

              I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations
              in meeting the above commitments.

              I agree to maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make those records available for inspection in
              accordance with 21 CFR 312.68.

              I will ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible for the initial and continuing review and
              approval of the clinical investigation. I also agree to promptly report to the IRB all changes in the research activity and all unanticipated
              problems involving risks to human subjects or others. Additionally, I will not make any changes in the research without IRB approval, except
              where necessary to eliminate apparent immediate hazards to human subjects.

              I agree to comply with all other requirements regarding the obligations of clinical investigators and all other pertinent requirements in 21 CFR
              Part 312.


                                                    INSTRUCTIONS FOR COMPLETING FORM FDA 1572
                                                           STATEMENT OF INVESTIGATOR:

               1. Complete all sections. Attach a separate page if additional space is needed.

               2. Attach curriculum vitae or other statement of qualifications as described in Section 2.

              3. Attach protocol outline as described in Section 8.

              4. Sign and date below.

               5. FORWARD THE COMPLETED FORM AND ATTACHMENTS TO THE SPONSOR. The sponsor will incorporate this
                  information along with other technical data into an Investigational New Drug Application (IND).


        0. SIGNATURE OF INVESTIGATOR                                                                                                11. DATE


                                                                                                                                I

        (WARNING: A willfullv false statement is a criminal offense. U.S.C. Title 18, Sec. 1001.)
        Public reporting burden for this collection of information is estimated to average 100 hours per response, including the time for reviewing instructions,
        searching existing data sources, gathering and maintaining the data needed, and completing reviewing the collection of information. Send comments
        regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to:

        Food and Drug Administration                               Food and Drug Administration                     "An agency may not conduct or sponsor, and a
        CBER (HFM-99)                                              CDER (HFD-94)                                    person is not required to respond to, a
        1401 Rockville Pike                                        5516 Nicholson Lane                              collection of information unless it displays a
        Rockville, MD 20852-1448                                   Kensington, MD 20895                             currently valid OMB control number."

                                                          Please DO NOT RETURN this application to this address.
        ORM FDA 1572 (10/99)                                                                                                         PAGE 2 OF 2




© 2002 by CRC Press LLC
                                                                                                                                                    Form +piwed: OMB No. OY'ID-O1YI Expires' oi:33,"3
                                                                                                                                                                     8- GLB sts-ement on reverse
                                                                                                                                            FDA Use On:y




    THE FDA MEDICAL PRODUCTS REPORTING PROGRAM                                      Page - of -




                                                                                                                                                                          stopped or dose reduced




    3 Date of                                   1 i Date of
      @Vent                                                                                                                                                          8. Evenn reappeared aRer
                                                                                                                          .................................
                                                                                                                         .................................
                                                                                                                                                                        reintroduction
    5, Describe event or problem




                                                                                           >
                                                                                           10. Concomitant medical products and t3erapy dates (excluderreatrnant of went)




                                                                                           12 Type of device

                                                                                           3 Manufacturer name 8 address




                                                                                                                                                                               ....
                                                                                                                                                                                ....   other:



                                                                                                                                                                          5. Expiration date
                                                                                                                                                                                 imo;ca$:y?;

                                                                                           model C
    6. Relevant testahaboratoy data, ii?cludingda%S
                                                                                           catalog %




                                                                                                                 ??o       /,returned to ??anuiadure!on .................................................................


    7. Othar relevant histoy, including preexisfing medical conditiana (e.g . aliergias.
       race, gregnancy, smoking and alcohol use, hepaticirenalclfsfznction, arc.)


                                                                                            I   game & address




    FDA Form 3500            Submission of a repor%      ep
                                                   does n t constitute an admission that medical personnel or the product caueed or contributed to the ever%,


© 2002 by CRC Press LLC
                               or2                               ith:
                               medrcations (drugs or brologrcsj                               just fill in the sections that apply to your report
                               medical devrces (rncludrng in-ntro dragnostrcs)                use section C for all products except
                               specral nutntronal products (dretary                           medical devices
                               supplements medical foods rnfan"iormulasj                      attach additional blank pages if needed
                                                                                              use a separate form for each patient
                                                                                              repoi? either 4 FDA or "re manufacbrer
                                                                                                               0
                                                                                              (or both)


                               life-threatening (real risk of dying)                                         to FAX repor!
                               hospitalizatron (rnitial or prolonged)                         1-800-FDA-7737 to report by modem
                               drsabrlrty Isrgnifrcant persrstent or permanent)               1-800-FDA-?088 to report by phone or for
                               congen~tal   anomaly
                               required intentention to prevent permanent                     1-800-822-7967
                               impairment or damage                                                                   for vaccines
                                                                                                            inwoliv           erio
                                                                                                             ano it a         in a
                               you re not certarn the product caused the                 tor's offrce, that facrlity may be legally required to report to
                               event                                                     FDA andbr the manufacturer Please not@the person rn
                               you don t have all the details                            that facility who ~vould   handle such reporiing
                                                 - quality9performance
                     or safety concerns such as                                                               : The patient's rcentity is held in strict
                                                                                         confroence by FDA and protected to the fullest extent of
                         suspected contamination                                         the law The reporter's roentrty rneluding the rdentrty of a
                         questronable stabil~ty                                          self-reporter, may be shared wrth the manufacturer unless
                         defectrve components                                            requested othewme However, FDA will not drsclose "re
                                                                                         reporter's rdentrty in response ta a request from the
                         poor packaging or labeling                                      public, pursuant to the Freedom 0 InformatianAct
                                                                                                                            4
                         therapeutic failures


                       The public repovting burden tor this collection ot information
                       has been estimated to aversge 90 minutes per Iresponse,
                       including the time tor reviwfing instructions, searching exist-
                       ing data source^, gathering and mail?taininy the data needeei.
                       and completing and reviewing the eolleetion at information,
                       Send Comments regarding this burden estimate or any other
                       aspect ot this collection at informetion, including suggestions
                       for reducing this burden to:
                                                                                                                  LJ S. DEPARTMEKTOF WEALTH A M J HUMAN SERVICES
                                                                                                                                      .
                                                                                                                  Publtt Health Serrwee F33d and D w g Adrrntslration


   FDA Form 35Wback                                                             rows



   Foad and Drug Administration
               I
               D
   Rockville, W 20857
   ...........................................................
  ............................................................

    %ici& Buginsss
   Penalty far Private Use $300
                                                                        FlRST                            LE, MD




© 2002 by CRC Press LLC
   MEDWATCH
   THE FDA MEDICAL PRODUCTS REPORTING PROGRAM
                                                                               For m e by u*er*facilities,
                                                                         ifi~riLP~.ztori manufacturer for
                                                                                     mii



                                                                                       Page - of -




      -
          Adverse event      eqdio?     /    Product problem (e.g . dede~rsi!?:sli~n~rion~)




                                                                          to
                                                    required ii?tervei?rion prave-it
                                                    nerrnane!?tirnaarrnent~maas




                                                                                           >    NDC #   - fe! product problems only (id known)
                                                                                                                -                -

                                                                                           i0. Concomitant medic81 products eqd 7herapy aates :




                                                                                                Brand name

                                                                                           ! Type of device

                                                                                           5    Manufacturer name Pn eddresa                                     id     Owrator of dsvice
                                                                                                                                                                       1health professloqal
                                                                                                                                                                       1laji useriperiert
                                                                                                                                                                       1cjihe?:


                                                                                           nodal B

      Relevant tsstfifleboratoy data, inciuding dates                                      :etalog f




                                                                                           i    taevlce aveilable lor evaluation?             (Do m t send to FDA)
                                                                                                -                               -
                                                                                                A
                                                                                                     yes         - no
                                                                                                                 7


                                                                                                                                A     rerjrned to -;anufacrurer on
                                                                                                                                                                               ,m>!X~:y?>
                                                                                               0. 6oncomltant medical producte and therapy dates (srclude tlsai-ent ot eveni)


      e%ltzerrelevant hislay, including preexisting medical canditions (s.g aiiergies
      race. pregnancy, moi.ing and alcohol use, hepatcii-enaldysfunciion etc,;




                                                                                           I. H a m Pn address                       1 phone B




                                                                                                                                                         I
                                                                                           2 Health profseslanal?          3.   Occupation                        lnitial reporter elso

   FDA                       8ubmlssle~n a repa@
                                           af        dam n d constitute en                                                                                   L
                                                                                                 -                                                                sent report ta FDA
                             admission that medical personnel, user facility,                    - ye,% 3 !10                                                     ........
                                                                                                                                                                                  no j u n k
                             dlstrlbutor, manufacturer or product caused or
                             cantrrlbuted ta the event.
                                                                                                                                                                  -
  FDA Form %BOA


© 2002 by CRC Press LLC
                                                                              S u b m i s s i o n of a repor4 d o e s n o t constitute
                                                                              a n a d m i s s i o i l that medical personnel, u s e r
                                                                             faciiitw, distributor, m a n u f a d u r e r or a r o d u c t


   Refer   ta s u i d e l i n e s f a r sseciirc ~ n s t r u c t r i l n s                           ~aae



      -

    . User facility or distributor namdaddress




                                                                                                                  Bevice evaluated by mfr'?                      4    Device manufscture dste
                                                                                                                  ........                                            :.,,<ii>l.l
                                                                                                                  I /?st returned to "rfr
                                                                                                                  A
                                                                                                                            -
                                                                                                                                                siim!wy &ached
                                                                                                                            ......... evaiilzio??
                                                                                                                  1 ! 7 o (atfdch page to expialn v7y lot)
                                                                                                                      or provide code:




                                                                                                                  If remedial action Initiated,                  2, Ufage of device
                                                                                                                  check type                                        ........
                                                                                                                  ........                                                   initiai use of device
                                                                                                                  - retail            3 i?oiificarioq




                                                                                                                   -
                                                                                                                             manufacturer narrative
                                                                                                                0 - Wdd~tlonal                                       a-mlor         '1   C Corrected date


                                                                                 Phone number


                                                                               3. RsporB source
                                                                                  (check eii i!?ai appiy)
                                                                                  7



                                                                                  d          foreigi?
                                                                                  ........

                                                                                  - stiidy
                                                                                  A




                                                                                  - iile?iili;re
                                                                                  7



                                                                                  d
                                                                                             ZO?lSLiilE?
                                                                                  7


                                                                                  ....
                                                                                   ....      health
                                                                                             professional
                                                                                  7



                                                                                  - user facility
                                                                                   ....
                                                                                  ....
                                                                                  - cc,!?:paqy
                                                                                             representative




                     -
   FDA Form 3655A back


© 2002 by CRC Press LLC
                         Appendix C
               PROTECTION OF HUMAN SUBJECTS
                  DECLARATION OF HELSINKI




© 2002 by CRC Press LLC
                                        U.S. Food and Drug Administration


                          The World Medical Association
                             Declaration of Helsinki
      World Medical Association Declaration of Helsinki: Recommendations Guiding
      Medical Doctors in Biomedical Research Involving Human Subjects

      Adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964 and as revised
      by the World Medical Assembly in Tokyo, Japan in 1975, in Venice, Italy in 1983,
      and in Hong Kong in 1989.

      Introduction
          It is the mission of the physician to safeguard the health of the people. His or her
      linowledge and conscience are dedicated to the fulfillment of this mission.
            The Declaration of Geneva of the World Medical Association binds the physician with the
      words, "The health of my patient will be my first consideration," and the International Code of
      Medical Ethics declares that, "A physician shall act only in the patient's interest when
      providing medical care which might have the effect of weakening the physical and mental
      condition of the patient."
         The Purpose of biomedical research involving human subjects must be to improve
      diagnostic, therapeutic and prophylactic procedures and the understanding of the aetiology and
      pathogenesis of disease.
          In current medical practice most diagnostic, therapeutic or prophylactic procedures involve
      hazards. This applies especially to biomedical research.
         Medical progress is based on research which ultimately must rest in part on
      experimentation involving human subjects.
            In the field of biomedical research a fundamental distinction must be recognized between
      medical research in which the aim is essentially diagnostic or therapeutic for a patient, and
      medical research, the essential object of which is purely scientific and without implying direct
      diagnostic or therapeutic value to the person subjected to the research.
          Special caution must be exercised in the conduct of research which may affect the
      environment, and the welfare of animals used for research must be respected.
            Because it is essential that the results of laboratory experiments be applied to human beings
      to further scientific knowledge and to help suffering humanity, the World Medical Association
      has prepared the following recommendations as a guide to every physician in biomedical




© 2002 by CRC Press LLC
        research involving human subjects. They should be kept under review in the future. It must be
        stressed that the standards as drafted are only a guide to physicians all over the world.
        Physicians are not relieved from criminal, civil and ethical responsibilities under the laws of
        their own countries.


        I. Basic Principles
                  Biomedical research involving human subjects must conform to generally accepted
                  scientific principles and should be based on adequately performed laboratory and
                  animal experimentation and on a thorough linowledge of the scientific literature.
                  The design and performance of each experimental procedure involving human subjects
                  should be clearly formulated in an experimental protocol which should be transmitted
                  for consideration, comment and guidance to a specially appointed committee
                  independent of the investigator and the sponsor provided that this independent
                  committee is in conformity with the laws and regulations of the country in which the
                  research experiment is performed.
                  Biomedical research involving human subjects should be conducted only by
                  scientifically qualified persons and under the supervision of a clinically competent
                  medical person. The responsibility for the human subject must always rest with a
                  medically qualified person and never rest on the subject of the research, even though
                  the subject has given his or her consent.
                  Biomedical research involving human subjects cannot legitimately be carried out unless
                  the importance of the objective is in proportion to the inherent risk to the subject.
                  Every biomedical research project involving human subjects should be preceded by
                  careful assessment of predictable rislis in comparison with foreseeable benefits to the
                  subject or to others. Concern for the interests of the subject must always prevail over
                  the interests of science and society.
                  The right of the research subject to safeguard his or her integrity must always be
                  respected. Every precaution should be taken to respect the privacy of the subject and to
                  minimize the impact of the study on the subject's physical and mental integrity and on
                  the personality of the subject.
                  Physicians should abstain from engaging in research projects involving human subjects
                  unless they are satisfied that the hazards involved are believed to be predictable.
                  Physicians should cease any investigation if the hazards are found to outweigh the
                  potential benefits.
                  In publication of the results of his or her research, the physician is obliged to preserve
                  the accuracy of the results. Reports of experimentation not in accordance with the
                  principles laid down in this Declaration should not be accepted for publication.




© 2002 by CRC Press LLC
            9. In any research on human beings, each potential subject must be adequately informed
                 of the aims, methods, anticipated benefits and potential hazards of the study and the
                 discomfort it may entail. He or she should be informed that he or she is at liberty to
                 abstain from participation in the study and that he or she is free to withdraw his or her
                 consent to participation at any time. The physician should then obtain the subject's
                 freely-given informed consent, preferably in writing.
            10. When obtaining informed consent for the research project the physician should be
                particularly cautious if the subject is in a dependent relationship to him or her or may
                consent under duress. In that case the informed consent should be obtained by a
                physician who is not engaged in the investigation and who is completely independent
                of this official relationship.
            11. In case of legal incompetence, informed consent should be obtained from the legal
                guardian in accordance with national legislation. Where physical or mental incapacity
                malies it impossible to obtain informed consent, or when the subject is a minor,
                permission from the responsible relative replaces that of the subject in accordance with
                national legislation. Whenever the minor child is in fact able to give a consent, the
                minor's consent must be obtained in addition to the consent of the minor's legal guardian.
            12. The research protocol should always contain a statement of the ethical considerations
                involved and should indicate that the principles enunciated in the present Declaration
                are complied with.


      11. Medical Research Combined with Professional Care (Clinical Research)
                 In the treatment of the sick person, the physician must be free to use a new diagnostic
                 and therapeutic measure, if in his or her judgment it offers hope of saving life,
                 reestablishing health or alleviating suffering.
                 The potential benefits, hazards and discomfort of a new method should be weighed
                 against the advantages of the best current diagnostic and therapeutic methods.
                 In any medical study, every patient-including those of a control group, if any-should
                 be assured of the best proven diagnostic and therapeutic method.
                 The refusal of the patient to participate in a study must never interfere with the
                 physician-patient relationship.
                 If the physician considers it essential not to obtain informed consent, the specific
                 reasons for this proposal should be stated in the experimental protocol for transmission
                 to the independent committee (I,2).
                 The physician can combine medical research with professional care, the objective being
                 the acquisition of new medical linowledge, only to the extent that medical research is
                 justified by its potential diagnostic or therapeutic value for the patient.




© 2002 by CRC Press LLC
        111. Non-Therapeutic Biomedical Research Involving Human Subjects
        (Non-Clinical Biomedical Research)
              1. In the purely scientific application of medical research carried out on a human being, it
                  is the duty of the physician to remain the protector of the life and health of that person
                  on whom biomedical research is being carried out.
             2. The subjects should be volunteers-either healthy persons or patients for whom the
                experimental design is not related to the patient's illness.
             3. The investigator or the investigating team should discontinue the research if in hislher
                or their judgment it may, if continued, be harmful to the individual.
             4. In research on man, the interest of science and society should never take precedence
                over considerations related to the well-being of the subject.




© 2002 by CRC Press LLC
                                    Appendix D
                          SAMPLE SCHEDULE OF STUDY VISITS
                                 AND EVALUATIONS




© 2002 by CRC Press LLC
                               Appendix D: Sample Schedule of Study Visits and Evaluations   295




                                 SAMPLE SCHEDULE OF
                             STUDY VISITS AND EVALUATIONS

            Informed Consent

            Entry Criteria

            Medical History

            Physical Exam

            Abbreviated Exam

            Chest X ray



            WBC

            Hemoglobin

            Platelet Count

            Chemistry Panel



            Alkaline Phos.

            BUN

            Creatinine

            Urinalvsis

            Adverse Event

            Dispense Drug

            Returned Drua




© 2002 by CRC Press LLC
                              Appendix E
                             ALGORITHMS

                                Surface Area
                          HeightIWeight Conversions
                                Military Time
                           Temperature Conversion




© 2002 by CRC Press LLC
                                    Appendix E: Algorithms   299




                          SURFACE AREA




© 2002 by CRC Press LLC
      300 Clinical Research Coordinator Handbook




                          HEIGHTIWEIGHT CONVERSIONS


      HEIGHT:
                           1 centimeter (cm)       = 0.39 in.
                           1 inch (in.)            = 2.54 cm




      WEIGHT:
                           1 kilogram (kg)
                           1 pound (lb)




© 2002 by CRC Press LLC
                                                          Appendix E: Algorithms   301




                             HEIGHT CONVERSION TABLE
                 Height (feetlinches)   Height (inches)             Height (cm)

                          4' 8"               56                       142.2




© 2002 by CRC Press LLC
      302 Clinical Research Coordinator Handbook




                                           MILITARY TIME
      Military time is based on the 24-hour day, and hours are numbered 1 through 24. The
      last two digits of military time indicate the minute after the hour. For example, the
      conventional times 6:30 A.M. and 11:45 P.M. would be written in military time as 0630
      and 2345, respectively.


                           l:oo A.M.   = 0100                 1:OO P.M. = 1300
                           2:00 A.M.   = 0200                 2:OO P.M.   = 1400
                           3:OO A.M.   = 0300                 3:OO P.M.   = 1500
                           4:OO A.M.   = 0400                 4:OO P.M.   = 1600
                           5:OO A.M.   = 0500                 5:OO P.M.   = 1700
                           6:OO A.M.   = 0600                 6:OO P.M.   = 1800
                           7:OO A.M.   = 0700                 7:OO P.M.   = 1900
                           8:OO A.M.   = 0800                 8:oo P.M.   = 2000
                           9:OO A.M.   = 0900                 9:OO P.M.   = 2100
                          1o:oo A.M.   = 1000                1o:oo P.M.   = 2200
                          11:00 A.M.   = 1100                11:00 P.M.   = 2300
                          12:00 A.M.   = 1200                12:OO P.M.   = 2400


      IMPORTANT: Note that 12:OO miclniglzt is written 2400 in rnilitaly time. Howe~ler-,
      military time does not esceecl 2400 hours. One minute past miclniglzt becomes 0001,
      thirty minutes past miclniglzt becomes 0030, etc. The time 1 :00 A.M. becomes 0100.




© 2002 by CRC Press LLC
                                                                  Appendix E: Algorithms   303




                           TEMPERATURE CONVERSION
            To convert Celsius degrees into Fahrenheit, multiply by 91.5 and add 32.


            To convert Fahrenheit degrees into Celsius, subtract 32 and multiply by 519.




© 2002 by CRC Press LLC

				
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