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					                         Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules                                          78281

      DEPARTMENT OF HEALTH AND                                   • FAX: 301–827–6870.                               II. Background
      HUMAN SERVICES                                             • Mail/Hand delivery/Courier [For                  A. History of the Review
                                                              paper, disk, or CD-ROM submissions]:
      Food and Drug Administration                            Division of Dockets Management, 5630                     In the Federal Register of February
                                                              Fishers Lane, rm. 1061, Rockville, MD                 13, 1973 (38 FR 4319), FDA issued
      21 CFR Parts 201 and 610                                20852.                                                procedures for the review by
      [Docket No. 1980N–0208]                                                                                       independent advisory review panels of
                                                                 Instructions: All submissions received             the safety, effectiveness, and labeling of
                                                              must include the agency name and                      biological products licensed before July
      Biological Products; Bacterial
                                                              Docket No. for this proposal. All                     1, 1972. This process was eventually
      Vaccines and Toxoids; Implementation
                                                              comments received will be posted                      codified in § 601.25 (21 CFR 601.25) (38
      of Efficacy Review
                                                              without change to http://www.fda.gov/                 FR 32048 at 32052, November 20, 1973).
      AGENCY:    Food and Drug Administration,                ohrms/dockets/default.htm, including                  Under the panel assignments published
      HHS.                                                    any personal information provided. For                in the Federal Register of June 19, 1974
      ACTION:   Proposed rule and proposed                    detailed instructions on submitting                   (39 FR 21176), FDA assigned the
      order.                                                  comments and additional information                   biological product review to one of the
                                                              on the process, see the ‘‘Comments’’                  following groups: (1) Bacterial vaccines
      SUMMARY: The Food and Drug                              heading of the SUPPLEMENTARY                          and bacterial antigens with ‘‘no U.S.
      Administration (FDA) is proposing to                    INFORMATION section of this document.                 standard of potency,’’ (2) bacterial
      amend the biologics regulations in                         Docket: For access to the docket to                vaccines and toxoids with standards of
      response to the report and                              read background documents or                          potency, (3) viral vaccines and
      recommendations of the Panel on                         comments received, go to http://                      rickettsial vaccines, (4) allergenic
      Review of Bacterial Vaccines and                        www.fda.gov/ohrms/dockets/                            extracts, (5) skin test antigens, and (6)
      Toxoids (the Panel). The Panel reviewed                 default.htm and insert the docket                     blood and blood derivatives.
      the safety, efficacy, and labeling of                   number found in brackets in the                          Under § 601.25, FDA assigned
      bacterial vaccines and toxoids with                     heading of this document, into the                    responsibility for the initial review of
      standards of potency, bacterial                         ‘‘Search’’ box and follow the prompts                 each of the biological product categories
      antitoxins, and immune globulins. On                    and/or go to the Division of Dockets                  to a separate independent advisory
      the basis of the Panel’s findings and                   Management, 5630 Fishers Lane, rm.                    panel consisting of qualified experts to
      recommendations, FDA is proposing to                    1061, Rockville, MD 20852.                            ensure objectivity of the review and
      classify these products as Category I                                                                         public confidence in the use of these
      (safe, effective, and not misbranded),                  FOR FURTHER INFORMATION CONTACT:
                                                                                                                    products. Each panel was charged with
      Category II (unsafe, ineffective, or                    Astrid Szeto, Center for Biologics
                                                                                                                    preparing an advisory report to the
      misbranded), or Category IIIB (off the                  Evaluation and Research (HFM–17),
                                                                                                                    Commissioner of Food and Drugs which
      market pending completion of studies                    Food and Drug Administration, 1401
                                                                                                                    was to: (1) Evaluate the safety and
      permitting a determination of                           Rockville Pike, Suite 200N, Rockville,
                                                                                                                    effectiveness of the biological products
      effectiveness). On December 13, 1985,                   MD 20852–1448, 301–827–6210.
                                                                                                                    for which a license had been issued, (2)
      FDA proposed to amend the biologics                     SUPPLEMENTARY INFORMATION:                            review their labeling, and (3) identify
      regulations and proposed to classify the                                                                      the biological products that are safe,
      bacterial vaccines and toxoids. After                   I. Introduction
                                                                                                                    effective, and not misbranded. Each
      reviewing the Panel’s report and                                                                              advisory panel report was also to
      comments on the proposal, FDA                             In this document, FDA is issuing a
                                                              proposed rule and proposed order to:                  include recommendations classifying
      published a final rule and final order on                                                                     the products reviewed into one of three
                                                                 1. Categorize those bacterial vaccines and
      January 5, 2004. The court vacated the                                                                        categories.
                                                              toxoids licensed before July 1972 according
      January 5, 2004 (69 FR 255) final rule.                 to the evidence of their safety and                      • Category I designating those
      Therefore, elsewhere in this issue of the               effectiveness, thereby determining whether            biological products determined by the
      Federal Register, FDA is withdrawing                    they may remain licensed and on the market;           panel to be safe, effective, and not
      the January 5, 2004, final rule. FDA is                    2. Issue a proposed response to                    misbranded.
      issuing this proposed rule and proposed                 recommendations made in the Panel’s                      • Category II designating those
      order again to provide notice and to give               report.1 These recommendations concern                biological products determined by the
      interested persons an opportunity to                    conditions relating to active components,
                                                                                                                    panel to be unsafe, ineffective, or
      comment.                                                labeling, tests required before release of
                                                              product lots, product standards, or other
                                                                                                                    misbranded.
      DATES:  Submit written or electronic                    conditions considered by the Panel to be                 • Category III designating those
      comments on the proposed rule and                       necessary or appropriate for assuring the             biological products determined by the
      proposed order by March 29, 2005.                       safety and effectiveness of the reviewed              panel not to fall within either Category
      ADDRESSES: You may submit comments,                     products;                                             I or Category II on the basis of the
      identified by Docket No. 1980N–0208,                       3. Revise the standard for potency of              panel’s conclusion that the available
      by any of the following methods:                        Tetanus Immune Globulin in § 610.21 (21               data were insufficient to classify such
        • Federal eRulemaking Portal: http://                 CFR 610.21); and                                      biological products, and for which
      www.regulations.gov. Follow the                            4. Apply the labeling requirements in              further testing was therefore required.
      instructions for submitting comments.                   §§ 201.56 and 201.57 (21 CFR 201.56 and               Category III products were assigned to
        • Agency Web site: http://                            201.57) to bacterial vaccines and toxoids by          one of two subcategories. Category IIIA
                                                              amending the implementation dates in
      www.fda.gov/dockets/ecomments.                                                                                products were those that would be
                                                              § 201.59 (21 CFR 201.59).
      Follow the instructions for submitting                                                                        permitted to remain on the market
      comments on the agency Web site.                          1 The Panel was convened on July 12, 1973, in an
                                                                                                                    pending the completion of further
        • E-mail: fdadockets@oc.fda.gov.                      organizational meeting, followed by multiple
                                                                                                                    studies. Category IIIB products were
      Include Docket No. in the subject line of               working meetings until February 2, 1979. The Final    those for which the panel recommended
      your e-mail message.                                    Report of the Panel was completed in August 1979.     license revocation on the basis of the


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      78282              Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules

      panel’s assessment of potential risks and               into Category IIIA to the Vaccines and                 Category IIIA products in the above-
      benefits.                                               Related Biological Products Advisory                   noted process.
         In its report, the panel could also                  Committee. FDA has addressed the                          (Comment 2) In response to FDA’s
      include recommendations concerning                      review and reclassification of bacterial               proposal that Pertussis Immune
      any condition relating to active                        vaccines and toxoids classified into                   Globulin (Human) be placed into
      components, labeling, tests appropriate                 Category IIIA through a separate                       Category IIIA because of insufficient
      before release of products, product                     administrative procedure (see the                      evidence of efficacy, one comment
      standards, or other conditions necessary                Federal Register of May 15, 2000 (65 FR                stated that FDA should permit
      or appropriate for a biological product’s               31003), and May 29, 2001 (66 FR                        manufacture of Pertussis Immune
      safety and effectiveness.                               29148)). Therefore, FDA does not                       Globulin (Human) for export only. The
         In accordance with § 601.25, after                   further identify or discuss in this                    comment noted that medical practices
      reviewing the conclusions and                           document any bacterial vaccines and                    in other countries may differ from those
      recommendations of the review panels,                   toxoids classified into Category IIIA.                 in the United States and that in some
      FDA would publish in the Federal                                                                               countries Pertussis Immune Globulin
      Register a proposed order containing:                   B. Comments on the December 1985                       (Human) plays an important role in the
      (1) A statement designating the                         Proposal                                               augmentation of therapy with
      biological products reviewed into                          FDA received four letters of                        antibiotics in young, very ill infants
      Categories I, II, IIIA, or IIIB, (2) a                  comments in response to the December                   with pertussis.
      description of the testing necessary for                1985 proposal. One letter from a                          Since that time, FDA has revoked all
      Category IIIA biological products, and                  licensed manufacturer of bacterial                     licenses for Pertussis Immune Globulin
      (3) the complete panel report. Under the                vaccine and toxoid products concerned                  (Human) at the requests of the
      proposed order, FDA would propose to                    the confidentiality of information it had              individual manufacturers. The FDA
      revoke the licenses of those products                   submitted for the Panel’s review. As                   Export Reform and Enhancement Act of
      designated into Category II and Category                provided in § 601.25(b)(2), FDA                        1996 (Public Law 104–134, as amended
      IIIB. After reviewing public comments,                  considered the extent to which the                     by Public Law 104–180) amended
      FDA would publish a final order on the                  information fell within the                            provisions of the Federal Food, Drug,
      matters covered in the proposed order.                  confidentiality provisions of 18 U.S.C.                and Cosmetic Act (the act) pertaining to
         In the Federal Register of November                  1905, 5 U.S.C. 552(b), or 21 U.S.C.                    the export of certain unapproved
      21, 1980 (45 FR 77135), FDA issued a                    331(j), before placing the information in              products. Section 802 of the act contains
      notice of availability of the Panel’s final             the public docket for the December 1985                requirements for the export of products
      report. In the Federal Register of                      proposal. Another comment from a                       not approved in the United States.
      December 13, 1985 (50 FR 51002), FDA                    member of the Panel provided an                        Under these provisions, products such
      issued a proposed rule that contained                   update of important scientific                         as Pertussis Immune Globulin (Human)
      the full Panel report2 and FDA’s                        information related to bacterial vaccines              can be exported to other countries, if the
      response to the recommendations of the                  and toxoids that had accrued since the                 requirements of section 802 are met.
      Panel (the December 1985 proposal)                      time of the Panel’s review. The letter                    (Comment 3) One comment
      (Ref. 1). In the December 1985 proposal,                did not comment on the December 1985                   concerned the generic order and
      FDA proposed regulatory categories                      proposal nor did it contend that the                   wording for product labeling
      (Category I, Category II, or Category IIIB              newly available information should                     recommended by the Panel and which
      as defined previously in this document)                 result in modification of the Panel’s                  FDA proposed to adopt in its response
      for each bacterial vaccine and toxoid                   recommendations or FDA’s proposed                      to the Panel recommendation. The
      reviewed by the Panel, and responded                    actions. FDA’s responses to the                        comment recommended that a labeling
      to other recommendations made by the                    comments contained in the remaining                    section concerning ‘‘Overdose’’ be
      Panel. The public was offered 90 days                   two letters follow.                                    included only when circumstances
      to submit comments in response to the                      (Comment 1) One comment from a                      dictate. The comment stated that
      December 1985 proposal.                                 licensed manufacturer of bacterial                     because all biological products are
         The definition of Category IIIA as                   vaccines and toxoids objected to the                   prescription products administered by
      described previously in this document,                  proposed classification into Category                  health care providers, the risk of
      was applied at the time of the Panel’s                  IIIA of several of its products for use in             overdose should be greatly reduced.
      review and served as the basis for the                  primary immunization.                                     FDA agrees that, in many cases, a
      Panel’s recommendations. In the                            As described previously in this                     labeling section in part 201 (21 CFR part
      Federal Register of October 5, 1982 (47                 document, FDA is considering those                     201) entitled ‘‘Overdosage’’ is not
      FR 44062), FDA revised § 601.25 and                     products proposed for Category IIIA in                 necessary. Section 201.56(d)(3) (21 CFR
      codified § 601.26, which established                    a separate rulemaking process.3 This                   201.56(d)(3)) of the labeling regulations
      procedures to reclassify those products                 proposal does not propose any action                   provides that the labeling may omit any
      in Category IIIA into either Category I or              regarding the further classification of                section or subsection of the labeling
      Category II based on available evidence                 those products proposed for Category                   format (outlined in § 201.56) if clearly
      of effectiveness. The Panel                             IIIA, including those proposed for                     inapplicable. The ‘‘Overdosage’’ section,
      recommended that a number of                            Category IIIA for primary immunization.                provided for in § 201.57(i) of the
      biological products be placed into                      All manufacturers and others in the                    regulations, is omitted for many
      Category IIIA. FDA assigned the review                  general public have been offered                       bacterial vaccine and toxoid products.
      of those products previously classified                 additional opportunity to comment on                      (Comment 4) One letter of comment
                                                              the final categorization of specific                   objected to several statements made by
         2 In addition to publication in the Federal                                                                 the Panel and provided in the written
      Register of December 13, 1985 (50 FR 51002), FDA           3 See the Federal Register of May 15, 2000 (65 FR
                                                                                                                     report, but did not object to or comment
      is making the full Panel report available on FDA’s      31003), containing the proposed order to reclassify    on FDA’s proposed responses to the
      Website at http://www.fda.gov/ohrms/dockets/            Category IIIA products into Category I and Category
      default.htm. A copy of the Panel report is also         II based on the review and recommendation of the       Panel’s recommendations.
      available at the Division of Dockets Management,        Vaccines and Related Biological Products Advisory         FDA is not considering comments on
      5630 Fishers Lane, rm. 1061, Rockville, MD 20852.       Committee.                                             the Panel’s report in this proposed rule


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                         Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules                                               78283

      and proposed order. The Panel’s                           In this proposal, FDA is again                       which FDA’s proposed category differs
      recommendations are not binding but                     providing the opportunity for comment                  from that recommended by the Panel.
      represent the scientific opinions of a                  on FDA’s proposals.                                    Products for which the licenses were
      panel of experts. FDA believes that the                                                                        revoked before the December 1985
                                                              III. Proposed Categorization of
      agency should not modify the                                                                                   proposal and that were already
                                                              Products—Proposed Order
      statements and recommendations of the                                                                          identified in the December 1985
      Panel as provided in its report,                           Category I. Licensed biological                     proposal are not listed in the tables
      including through public comment. The                   products determined to be safe and                     below. Products for which the licenses
      purpose of the opportunity for comment                  effective and not misbranded. Table 1 of               were revoked after the December 1985
      is to allow comment on FDA’s responses                  this document is a list of those products              proposal are identified in the
      to the Panel’s report and not on the                    proposed in December 1985 by FDA for                   ‘‘Comments’’ column. FDA proposes to
      Panel’s report directly.                                Category I. Under the ‘‘Comments’’                     adopt Category I as the final category for
                                                              column, FDA notes those products for                   the following products.
                                                                         TABLE 1.—CATEGORY I
                Manufacturer/License No.                                       Products                                              Comments

       Alpha Therapeutic Corp., License No.               Tetanus Immune Globulin (Human)                     Although the Panel recommended that Tetanus Im-
         744                                                                                                    mune Globulin (Human), manufactured by Alpha
                                                                                                                Therapeutic Corp., be placed in Category IIIB,
                                                                                                                FDA proposed that it be placed in Category I1

       Advance Biofactures Corp., License No.             Collagenase
         383

       Armour Pharmaceutical Co., License No.             Tetanus Immune Globulin (Human)                     Manufacturer’s licensed name is now Centeon L. L.
         149                                                                                                   C. On July 26, 1999, FDA revoked the license for
                                                                                                               Tetanus Immune Globulin (Human) at the request
                                                                                                               of the manufacturer

       Connaught Laboratories, Inc., License              Diphtheria and Tetanus Toxoids and Per-             On December 9, 1999, a name change to Aventis
         No. 711                                            tussis Vaccine Adsorbed, and Diphtheria            Pasteur, Inc. with an accompanying license num-
                                                            Antitoxin                                          ber change to 1277 was granted to Connaught
                                                                                                               Laboratories, Inc. FDA revoked the licenses for
                                                                                                               these products at the request of the manufacturer
                                                                                                               on July 6, 2001, and August 2, 2001, respectively

       Connaught Laboratories, Ltd., License              BCG Vaccine, Botulism Antitoxin (Types A,           On February 24, 2000, a name change to Aventis
         No. 73                                            B, and E), Botulism Antitoxin (Type E),             Pasteur, Ltd. with an accompanying license num-
                                                           Tetanus Toxoid                                      ber change to 1280 was granted. On December
                                                                                                               21, 2000, FDA revoked the license for Tetanus
                                                                                                               Toxoid at the request of the manufacturer

       Cutter Laboratories, Inc., License No. 8           Plague Vaccine, Tetanus Immune Globulin             On October 5, 1994, the manufacturing facilities and
                                                            (Human)                                            process for Plague Vaccine were transferred to
                                                                                                               Greer Laboratories, Inc., License No. 308. On
                                                                                                               May 24, 1995, FDA revoked Cutter’s license for
                                                                                                               Plague Vaccine at the request of Cutter, the pre-
                                                                                                               vious manufacturer; the license for Greer Labs,
                                                                                                               Inc. remains in effect. Bayer Corporation now
                                                                                                               holds the license for Tetanus Immune Globulin
                                                                                                               (Human) under License No. 8

       Eli Lilly & Co., License No. 56                    Diphtheria and Tetanus Toxoids and Per-             On December 2, 1985, FDA revoked the license for
                                                            tussis Vaccine Adsorbed                            Diphtheria and Tetanus Toxoids and Pertussis
                                                                                                               Vaccine Adsorbed at the request of the manufac-
                                                                                                               turer

       Glaxo Laboratories, Ltd., License No.              BCG Vaccine                                         On July 17, 1990, FDA revoked the license for BCG
         337                                                                                                   Vaccine at the request of the manufacturer

       Istituto Sieroterapico Vaccinogeno                 Diphtheria Antitoxin, Diphtheria Toxoid Ad-         On July 17, 1990, FDA revoked the license for Diph-
          Toscano Sclavo, License No. 238                   sorbed, Tetanus Toxoid Adsorbed                    theria Antitoxin at the request of the manufacturer.
                                                                                                               On July 27, 1993, FDA revoked the licenses for
                                                                                                               Diphtheria Toxoid Adsorbed and Tetanus Toxoid
                                                                                                               Adsorbed at the request of the manufacturer

       Lederle Laboratories, Division American            Cholera Vaccine, Tetanus Immune Globulin            On December 23, 1992, FDA revoked the license
         Cyanamid Co., License No. 17                       (Human)                                            for Tetanus Immune Globulin (Human) at the re-
                                                                                                               quest of the manufacturer. On October 23, 1996,
                                                                                                               FDA revoked the license for Cholera Vaccine at
                                                                                                               the request of the manufacturer




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      78284              Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules

                                                                   TABLE 1.—CATEGORY I—Continued
                Manufacturer/License No.                                        Products                                              Comments

       Massachusetts Public Health Biologic               Diphtheria and Tetanus Toxoids Adsorbed,             Although the Panel recommended that Tetanus Anti-
        Laboratories, License No. 64                        Diphtheria and Tetanus Toxoids and Per-              toxin be placed in Category IIIB, FDA proposed in
                                                            tussis Vaccine Adsorbed, Tetanus and                 the December 1985 proposal that it be placed in
                                                            Diphtheria Toxoids Adsorbed (For Adult               Category I. On October 26, 1988, FDA revoked
                                                            Use), Tetanus Antitoxin, Tetanus Immune              the license for Typhoid Vaccine at the request of
                                                            Globulin (Human), Tetanus Toxoid Ad-                 the manufacturer. On January 10, 1994, FDA re-
                                                            sorbed, Typhoid Vaccine                              voked the license for Tetanus Antitoxin at the re-
                                                                                                                 quest of the manufacturer. On December 22,
                                                                                                                 1998, FDA revoked the license for Diphtheria and
                                                                                                                 Tetanus Toxoids and Pertussis Vaccine Adsorbed
                                                                                                                 at the request of the manufacturer. On August 3,
                                                                                                                 2000, FDA revoked the license for Diphtheria and
                                                                                                                 Tetanus Toxoids Adsorbed at the request of the
                                                                                                                 manufacturer

       Merck Sharp & Dohme, Division of                   Tetanus Immune Globulin (Human)                      The manufacturer is now known as Merck & Co.,
        Merck & Co., Inc, License No. 2                                                                          Inc. On January 31, 1986, FDA revoked the li-
                                                                                                                 cense for Tetanus Immune Globulin (Human) at
                                                                                                                 the request of the manufacturer

       Michigan Department of Public Health,              Anthrax Vaccine Adsorbed, Diphtheria and             On November 11, 1998, a name change to BioPort
         License No. 99                                     Tetanus Toxoids and Pertussis Vaccine               Corporation (BioPort) with an accompanying li-
                                                            Adsorbed, Pertussis Vaccine Adsorbed,               cense number change to 1260 was granted. The
                                                            Typhoid Vaccine                                     license for Typhoid Vaccine was revoked on June
                                                                                                                25, 1985, at the request of the manufacturer. The
                                                                                                                license for Diphtheria and Tetanus Toxoids and
                                                                                                                Pertussis Vaccine Adsorbed was revoked at the
                                                                                                                request of the manufacturer (BioPort) on Novem-
                                                                                                                ber 20, 2000. The license for Pertussis Vaccine
                                                                                                                Adsorbed was revoked at the request of the man-
                                                                                                                ufacturer (BioPort) on April 22, 2003

       Parke-Davis, Division of Warner-Lambert            Tetanus Immune Globulin (Human)                      On November 19, 1983, FDA revoked the license
         Co., License No. 1                                                                                     for Tetanus Immune Globulin (Human) at the re-
                                                                                                                quest of the manufacturer

       Swiss Serum and Vaccine Institute                  Tetanus Antitoxin                                    Although the Panel recommended that Tetanus Anti-
        Berne, License No. 21                                                                                    toxin be placed in Category IIIB, FDA proposes
                                                                                                                 that it be placed in Category I. On March 13,
                                                                                                                 1980, FDA revoked the license for Tetanus Anti-
                                                                                                                 toxin at the request of the manufacturer

       Travenol Laboratories, Inc., Hyland                Tetanus Immune Globulin (Human)                      The manufacturer is now known as Baxter
         Therapeutics Division, License No.                                                                      Healthcare Corporation. On July 27, 1995, FDA
         140                                                                                                     revoked the license for Tetanus Immune Globulin
                                                                                                                 (Human) at the request of the manufacturer

       University of Illinois, License No. 188            BCG Vaccine                                          On May 29, 1987, FDA revoked the license for BCG
                                                                                                                Vaccine at the request of the manufacturer

       Wyeth Laboratories, Inc, License No. 3             Cholera Vaccine, Tetanus Immune Globulin             On December 23, 1992, FDA revoked the license
                                                           (Human), Typhoid Vaccine (acetone inac-              for Tetanus Immune Globulin (Human) at the re-
                                                           tivated), Typhoid Vaccine (heat-phenol in-           quest of the manufacturer. On September 11,
                                                           activated)                                           2001, FDA revoked the licenses for Cholera Vac-
                                                                                                                cine and Typhoid Vaccine (both forms) at the re-
                                                                                                                quest of the manufacturer
         1 The Panel recommended that Tetanus Immune Globulin (Human) manufactured by Alpha Therapeutic Corporation be placed in Category
      IIIB, products for which available data are insufficient to classify their safety and effectiveness and which should not continue in interstate com-
      merce. In the December 1985 proposal, the agency disagreed with the Panel’s recommendation as the product was manufactured only as a par-
      tially processed biological product and was intended for export and further manufacture (50 FR 51002 at 51007). The agency continues to agree
      with this approach inasmuch as the manufacturer continues to export the product as a partially processed biological. The product is not available
      as a finished product in the United States.


        Category II. Licensed biological                         Category IIIB. Biological products for              listed products for which FDA revoked
      products determined to be unsafe or                     which available data are insufficient to               the licenses before the December 1985
      ineffective or to be misbranded and                     classify their safety and effectiveness                proposal but we identified them in the
      which should not continue in interstate                 and should not continue in interstate                  proposal. Products for which FDA
      commerce. FDA does not propose that                     commerce. Table 2 of this document is                  revoked the licenses after the December
      any products be placed in Category II.                  a list of those products proposed by                   1985 proposal are identified in the
                                                              FDA for Category IIIB. We have not                     ‘‘Comments’’ column.


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                         Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules                                                  78285

        FDA has revoked the licenses of all                   IIIB. FDA proposes Category IIIB as the
      products proposed by FDA for Category                   final category for the listed products.

                                                                          TABLE 2.—CATEGORY IIIB
                Manufacturer/License No.                                        Products                                              Comments

       Istituto Sieroterapico Vaccinogeno                 Diphtheria Toxoid                                    On July 27, 1993, FDA revoked the license for Diph-
          Toscano Sclavo, License No. 238                                                                       theria Toxoid at the request of the manufacturer

       Connaught Laboratories, Inc., License              Diphtheria Toxoid, Pertussis Vaccine                 On June 21, 1994, FDA revoked the license for
         No. 711                                                                                                Diphtheria Toxoid and on December 19, 1997,
                                                                                                                FDA revoked the license for Pertussis Vaccine, in
                                                                                                                both cases at the request of the manufacturer

       Massachusetts Public Health Biologic               Tetanus Toxoid                                       On October 11, 1989, FDA revoked the license for
        Laboratories, License No. 64                                                                            Tetanus Toxoid at the request of the manufacturer

       Merck Sharpe & Dohme, Division of                  Cholera Vaccine, Diphtheria and Tetanus              The manufacturer is now known as Merck & Co.,
        Merke & Co., Inc., License No. 2                    Toxoids and Pertussis Vaccine Adsorbed,              Inc. On January 31, 1986, FDA revoked the li-
                                                            Tetanus and Diphtheria Toxoids Adsorbed              censes for all the listed products at the request of
                                                            (For Adult Use), Tetanus Toxoid, Typhoid             the manufacturer
                                                            Vaccine

       Michigan Department of Public Health,              Diphtheria Toxoid Adsorbed                           On November 12, 1998, the name of the manufac-
         License No. 99                                                                                         turer was changed to BioPort, and the license
                                                                                                                number was changed to 1260. On November 20,
                                                                                                                2000, FDA revoked the license for Diphtheria Tox-
                                                                                                                oid Adsorbed at the request of the manufacturer

       Wyeth Laboratories, Inc., License No.3             Diphtheria Toxoid, Diphtheria Toxoid Ad-             On May 19, 1987, FDA revoked the licenses for all
                                                            sorbed, Pertussis Vaccine                           listed products at the request of the manufacturer



      IV. Anthrax Vaccine Adsorbed—                           identified points of disagreement with                  protection against inhalation anthrax.
      Proposed Order                                          statements in the Panel report. However,                On December 22, 2003, the Court issued
                                                              FDA proposes that the data do support                   a preliminary injunction enjoining
      A. The Panel Recommendation that
                                                              the safety and efficacy of the vaccine                  inoculations under the AVIP in the
      Anthrax Vaccine Adsorbed be Placed in
                                                              and, thus, FDA continues to accept the                  absence of informed consent or a
      Category I (Safe, Effective, and Not                    Panel’s recommendation and proposes                     Presidential waiver.
      Misbranded)                                             to place AVA in Category I.4                               In the Federal Register of January 5,
         In its report, the Panel found that                     On October 12, 2001, a group of                      2004 (69 FR 255), FDA published a final
      Anthrax Vaccine Adsorbed (AVA),                         individuals filed a citizen petition                    rule and final order amending the
      manufactured by Michigan Department                     requesting that FDA find AVA, as                        biologics regulations in response to the
      of Public Health (MDPH, now BioPort)                    currently manufactured by BioPort,                      report and recommendations of the
      was safe and effective for its intended                 ineffective for its intended use, classify              Panel. The final order placed AVA into
      use and recommended that the vaccine                    the product as Category II, and revoke                  Category I. Following FDA’s issuance of
      be placed in Category I. In the December                the license for the vaccine. The                        the final rule and final order, the Court
      1985 proposal, FDA agreed with the                      petitioners complained that the                         lifted the preliminary injunction on
      Panel’s recommendation. During the                      December 1985 proposal that placed                      January 7, 2004, except as it applied to
      comment period for the December 1985                    AVA in Category I had not been                          the six Doe plaintiffs.
      proposal, FDA received no comments                      finalized. FDA responded separately in                     On October 27, 2004, the Court issued
      opposing the placement of AVA into                      a written response to the petitioners on                a memorandum opinion vacating and
      Category I.                                             August 28, 2002 (Docket No. 2001P–                      remanding the January 2004 final rule
         The Panel based its evaluation of the                0471), and FDA will not further address
                                                                                                                      and final order to FDA for
                                                              those issues in this proposal.
      safety and efficacy of AVA on two                                                                               reconsideration, following an
                                                                 In March 2003, six plaintiffs, known
      studies: A well-controlled field study                                                                          appropriate notice and comment period.
                                                              as John and Jane Doe ι1 through ι6, filed
      conducted in the 1950s, ‘‘the Brachman                  suit in the United States District Court                FDA is reopening the comment period
      study’’ (Ref. 1a) and an open-label safety              for the District of Columbia (the Court)                on the entire Bacterial Vaccine and
      study conducted by the National Center                  seeking the Court to enjoin the Anthrax                 Toxoids efficacy review document for
      for Disease Control (CDC, now the                       Vaccination Immunization Program                        90 days.
      Centers for Disease Control and                         (AVIP) of the Department of Defense                     B. Efficacy of Anthrax Vaccine
      Prevention) (50 FR 51002 at 51058). The                 (DoD), and to declare AVA an                            Adsorbed
      Panel also considered surveillance data                 investigational drug when used for
      on the occurrence of anthrax disease in                                                                           The Brachman study included 1,249
      the United States in at-risk industrial                      4 In
                                                                     October 2000, the Institute of Medicine (IOM)    workers in four textile mills in the
      settings as supportive of the                           convened the Committee to Assess the Safety and         northeastern United States that
      effectiveness of the vaccine (50 FR                     Efficacy of the Anthrax Vaccine. In March 2002, the     processed imported goat hair. Of these
      51002 at 51059). In its proposed                        Committee issued its report: The Anthrax Vaccine:       1,249 workers, 379 received anthrax
                                                              Is It Safe? Does It Work? (Ref. 2). The report
      determination that the data support the                 concluded that the vaccine is acceptably safe and       vaccine, 414 received placebo, 116
      safety and efficacy of AVA, FDA has                     effective in protecting humans against anthrax.         received incomplete inoculations of


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      78286              Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules

      either vaccine or placebo, and 340                      anthracis, independent of the route of                   1971 in which approximately 7,000
      received no treatment but were                          exposure.5                                               persons, including textile employees,
      monitored for the occurrence of anthrax                    As stated previously in this                          laboratory workers, and other at-risk
      disease as an observational group. The                  document, the Panel also considered                      individuals, were vaccinated with
      Brachman study used an earlier version                  epidemiological data—sometimes called                    anthrax vaccine and monitored for
      of the protective antigen-based anthrax                 surveillance data—on the occurrence of                   adverse reactions to vaccination. The
      vaccine administered subcutaneously at                  anthrax disease in at-risk industrial                    vaccine was administered in 0.5-mL
      0, 2, and 4 weeks and 6, 12, and 18                     settings collected by the CDC and                        doses according to a 0-, 2-, and 4-week
      months. During the trial, 26 cases of                   summarized for the years 1962-1974 as                    initial dose schedule followed by
      anthrax were reported across the four                   supportive of the effectiveness of AVA.                  additional doses at 6, 12, and 18 months
                                                              In that time period, individuals received                with annual boosters thereafter. Several
      mills: 5 inhalation and 21 cutaneous
                                                              either vaccine produced by MDPH, now                     lots, approximately 15,000 doses, of
      anthrax cases. Prior to vaccination, the
                                                              BioPort, or an earlier version of anthrax                AVA manufactured by MDPH were used
      yearly average number of human                          vaccine. Twenty-seven cases of anthrax
      anthrax cases was 1.2 cases per 100                                                                              in this study period. In its report, the
                                                              disease were identified. Three cases                     Panel found that the CDC data ‘‘suggests
      employees in these mills. Of the five                   were not mill employees but people
      inhalation anthrax cases (four of which                                                                          that this product is fairly well tolerated
                                                              who worked in or near mills; none of                     with the majority of reactions consisting
      were fatal), two received placebo and                   these cases had been vaccinated.                         of local erythema and edema. Severe
      three were in the observational group.                  Twenty-four cases were mill employees;                   local reactions and systemic reactions
      Of the 21 cutaneous anthrax cases, 15                   three were partially immunized (one                      are relatively rare’’ (50 FR 51002 at
      received placebo, 3 were in the                         with one dose, two with two doses); the                  51059).
      observational group, and 3 received                     remainder (89 percent) were                                Subsequent to the publication of the
      anthrax vaccine. Of the three cases in                  unvaccinated (50 FR 51002 at 51058).                     Panel’s recommendations, DoD
      the vaccine group, one case occurred                    These data provide confirmation that                     conducted a small, randomized clinical
      just prior to administration of the third               the risk of disease still existed for those              study of the safety and immunogenicity
      dose, one case occurred 13 months after                 persons who were not vaccinated and                      of AVA. (See summary in product label.
      the individual received the third of the                that those persons who had not received                  (Ref. 6)) These more recent DoD data as
      six doses (but no subsequent doses), and                the full vaccination series (six doses)                  well as post licensure adverse event
      one case occurred prior to receiving the                were susceptible to anthrax infection,                   surveillance data available from the
      fourth dose of vaccine.                                 while no cases occurred in those who                     Vaccine Adverse Event Reporting
                                                              had received the full vaccination series.                System (VAERS) further support the
         In its report, the Panel stated that the                In 1998, the DoD initiated the Anthrax
      Brachman study results demonstrate ‘‘a                                                                           safety of AVA (Ref. 7). These data are
                                                              Vaccination Program, calling for                         regularly reviewed by FDA, and
      93 percent (lower 95 percent confidence                 mandatory vaccination of service
      limit = 65 percent) protection against                                                                           provided the basis for a description of
                                                              members. Thereafter, concerns about the                  the types and severities of adverse
      cutaneous anthrax’’ and that ‘‘inhalation               vaccine caused the U.S. Congress to
      anthrax occurred too infrequently to                                                                             events associated with administration of
                                                              direct DoD to support an independent                     AVA included in labeling revisions
      assess the protective effect of vaccine                 examination of AVA by the IOM. The
      against this form of the disease.’’ (50 FR                                                                       approved by FDA in January 2002 (Ref.
                                                              IOM committee reviewed all available                     6).
      51002 at 51058). On the latter point,                   data, both published and unpublished,
      FDA does not agree with the Panel                       heard from Federal agencies, the                         D. The Panel’s General Statement:
      report. Because the Brachman                            manufacturer, and researchers. The                       Anthrax Vaccine, Adsorbed, Description
      comparison of anthrax cases between                     committee in its published report                        of Product
      the placebo and vaccine groups                          concluded that AVA, as licensed, is an                     The Panel report states:
      included both inhalation and cutaneous                  effective vaccine to protect humans                         ‘‘Anthrax vaccine is an aluminum
      cases, FDA has determined that the                      against anthrax, including inhalation                    hydroxide adsorbed, protective,
      calculated efficacy of the vaccine to                   anthrax (Ref. 2). FDA agrees with the                    proteinaceous, antigenic fraction prepared
      prevent all types of anthrax disease                    report’s finding that certain studies in                 from a nonproteolytic, nonencapsulated
      combined was, in fact, 92.5 percent                     humans and animal models support the                     mutant of the Vollum strain of Bacillus
                                                              conclusion that AVA is effective against                 anthracis’’ (50 FR 51002 at 51058).
      (lower 95 percent confidence interval =                                                                            FDA would like to clarify that while
      65 percent). The efficacy analysis in the               B. anthracis strains that are dependent
                                                              upon the anthrax toxin as a mechanism                    the B. anthracis strain used in the
      Brachman study includes all cases of                                                                             manufacture of BioPort’s AVA is the
      anthrax disease regardless of the route                 of virulence, regardless of the route of
                                                              exposure.6                                               nonproteolytic, nonencapsulated strain
      of exposure or manifestation of disease.                                                                         identified in the Panel report, it is not
      FDA agrees that the five cases of                       C. Safety of Anthrax Vaccine Adsorbed                    a mutant of the Vollum strain but was
      inhalation anthrax reported in the                        CDC conducted an open-label study                      derived from a B. anthracis culture
      course of the Brachman study are too                    under an investigational new drug                        originally isolated from a case of bovine
      few to support an independent                           application (IND) between 1967 and                       anthrax in Florida.
      statistical analysis. However, of these
      cases, two occurred in the placebo                         5 The Panel noted that it would be very difficult,
                                                                                                                       E. The Panel’s Specific Product Review:
      group, three occurred in the                            if not impossible, to clinically study the efficacy of   Anthrax Vaccine Adsorbed: Efficacy
      observational group, and no cases                       any anthrax vaccine (50 FR 51058). Further study           The Panel report states:
                                                              raises ethical considerations, and the low incidence       3. Analysis—a. Efficacy—(2) Human. The
      occurred in the vaccine group.                          and sporadic occurrence of anthrax disease also
      Therefore, we propose the indication                    makes further adequate and well-controlled clinical
                                                                                                                       vaccine manufactured by the Michigan
      section of the labeling for AVA not                     studies of effectiveness not possible.                   Department of Public Health has not been
                                                                 6 For example: The Brachman study (Ref. 1a); the      employed in a controlled field trial. A similar
      specify the route of exposure, and the                                                                           vaccine prepared by Merck Sharp & Dohme
                                                              CDC epidemiological data described in the
      vaccine be indicated for active                         December 1985 proposal; Fellows (2001) (Ref. 3);         for Fort Detrick was employed by Brachman
      immunization against Bacillus                           Ivins (1996) (Ref. 4); Ivins (1998) (Ref. 5).            * * * in a placebo-controlled field trial in



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                         Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules                                          78287

      mills processing imported goat hair * * *.              similar with respect to peak antibody                 A. Generic Order and Wording of
      The Michigan Department of Public Health                response and seroconversion.                          Labeling; Amendment of § 201.59
      vaccine is patterned after that of Merck Sharp
      & Dohme with various minor production                   F. The Panel’s Specific Product Review:                  The Panel recommended changes to
      changes.                                                Anthrax Vaccine Adsorbed: Labeling                    the labeling of the biological products
      (50 FR 51002 at 51059).                                                                                       under review. The Panel also
         FDA has found that contrary to the                        The Panel report states:                         recommended a generic order and
      Panel’s statement, the vaccine used in                    3. Analysis—d. Labeling: The labeling               wording for information in the labeling
      the Brachman study was not                              seems generally adequate. There is a conflict,        of bacterial vaccines. In the December
      manufactured by Merck Sharp &                           however, with additional standards for                1985 proposal, FDA agreed with the
      Dohme, but instead this initial version                 anthrax vaccine. Section 620.24 (a) (21 CFR           labeling changes recommended by the
      was provided to Dr. Brachman by Dr. G.                  620.24(a)) defines a total primary
                                                                                                                    Panel.
      Wright of Fort Detrick, U.S. Army, DoD                  immunizing dose as 3 single doses of 0.5 mL.
      (Ref. 1a). The DoD version of the                       The labeling defines primary immunization                In the December 1985 proposal, FDA
      anthrax vaccine used in the Brachman                    as 6 doses (0, 2, and 4 weeks plus 6, 12, and         proposed that 6 months after
      study was manufactured using an                         18 months).                                           publication of a final rule,
      aerobic culture method (Ref. 8).                                                                              manufacturers of products subject to
                                                              (50 FR 51002 at 51059).                               this Panel review submit, for FDA’s
      Subsequent to the Brachman trial, DoD
                                                                 The dosing schedule for AVA has                    review and approval, draft labeling
      modified the vaccine’s manufacturing
      process to, among other things, optimize                always consisted of six doses, a 0.5-mL               revised in conformance with the Panel’s
      production of a stable and immunogenic                  dose at 0, 2, and 4 weeks, and then at                report and with the regulations. FDA
      formulation of vaccine antigen and to                   6, 12, and 18 months, followed by a                   proposed to require that the revised
      increase the scale of manufacture. In the               subsequent 0.5-mL dose at 1 year                      labeling accompany all products
      early 1960s, DoD entered into a contract                intervals to maintain immunity.                       initially introduced or initially
      with Merck Sharp & Dohme to                             Prelicensure labels described the                     delivered for introduction into interstate
      standardize the manufacturing process                   vaccination schedule as three initial                 commerce 30 months after the date of
      for large-scale production of the anthrax               doses, followed by three additional                   publication of the final rule. The
      vaccine and to produce anthrax vaccine                  doses, and yearly subsequent doses,                   proposed labeling review schedule was
      using an anaerobic method. Thereafter,                  which is consistent with the additional               consistent with the scheduling provided
      in the 1960s, DoD entered into a similar                standards of AVA that were originally                 in § 201.59 of the regulations.
      contract with MDPH to further                           published in October 1970, immediately                   Since the time of the Panel’s
      standardize the manufacturing process                   before the licensure of AVA. The 1979                 recommendation, FDA has made a
      and to scale up production for further                  labeling referred to ‘‘primary                        number of changes to the labeling
      clinical testing and immunization of                    immunization’’ as consisting of six                   regulations and related regulatory
      persons at risk of exposure to anthrax                  injections, with recommended yearly                   policies. FDA has added or revised the
      spores. This DoD-MDPH contract                          subsequent injections. The 1987                       requirements in § 201.57 for including
      resulted in the production of the                       labeling of AVA, subsequent to the                    in the labeling, in standardized
      anthrax vaccine that CDC used in the                    Panel’s report, described the vaccination             language, the information concerning
      open-label safety study and that was                    schedule as ‘‘primary immunization’’                  use during pregnancy, pediatric use,
      licensed in 1970.                                       consisting of three doses followed by                 and geriatric use. Section 201.57
         While the Panel attributes the                       three additional doses for a total of six             requires a specific order and content for
      manufacture of the vaccine used in the                  doses followed by annual injections.                  drug product labeling. A number of
      Brachman study to Merck Sharp &                         The labeling is not inconsistent with                 labeling sections included in § 201.57
      Dohme, FDA has reviewed the historical                  § 620.24(a) (21 CFR 620.24(a)) before it              were not included in the Panel’s
      development of AVA and concluded                        was revoked by FDA in 1996 as part of                 recommended ordering and wording of
      that DoD’s continuous involvement                       a final rule that revoked 21 CFR part 620             the labeling but are now required to
      with, and intimate knowledge of, the                    and other biologics regulations because               help ensure clarity in the labeling. FDA
      formulation and manufacturing                           they were obsolete or no longer                       has also provided guidance regarding
      processes of all of these versions of the               necessary (Ref. 9). Thus while use of the             the wording of sections in which the
      anthrax vaccine provide a foundation                    term ‘‘primary’’ has varied over time in              agency believes complete and consistent
      for a determination that the MDPH                       reference to the AVA vaccination                      language is important. Because FDA
      anthrax vaccine is comparable to the                    schedule, the licensed schedule itself                regularly monitors labeling for the
      original DoD vaccine. See Berlex                                                                              products subject to this Panel review to
                                                              has always consisted of six doses of 0.5
      Laboratories, Inc. v. FDA, 942 F. Supp.                                                                       determine if the labeling is consistent
                                                              mL administered at 0, 2, and 4 weeks
      19 (D.D.C. 1996). The comparability of                                                                        with applicable labeling requirements,
                                                              and 6, 12, and 18 months, followed by
      the MDPH anthrax vaccine to the DoD                                                                           FDA does not believe that a labeling
                                                              additional doses on an annual basis to
      vaccine has been verified through                                                                             review is necessary at this time.
                                                              maintain immunity.
      potency data that demonstrate the                                                                             Accordingly, FDA proposes to amend
      ability of all three versions of the                    V. FDA’s Responses to Additional Panel                the table in § 201.59 by providing that
      vaccine to protect guinea pigs and                      Recommendations                                       the labeling requirements in §§ 201.56,
      rabbits against challenge with virulent                                                                       201.57, and 201.100(d)(3) (21 CFR
      B. anthracis. In addition, there are data                 In the December 1985 proposal, FDA                  201.100(d)(3)) become effective on the
      comparing the safety and                                responded to the Panel’s general                      date 30 months after the date of
      immunogenicity of the MDPH vaccine                      recommendations regarding the                         publication of the final rule. Because
      with the DoD vaccine. These data, while                 products under review and to the                      FDA regularly monitors the labeling of
      limited in the number of vaccines and                   procedures involved in their                          all products on an ad hoc basis, FDA
      samples evaluated, reveal that the                      manufacture and regulation. Below,                    also proposes to explain in a footnote to
      serological responses to the MDPH                       FDA responds again with its proposal to               the table in § 201.59(a)(3) that
      vaccine and the DoD vaccine were                        the general recommendations.                          specification of a date for submission of


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      revised product labeling under § 201.59                 vaccines. Health care providers must                  additional data are generated is
      is unnecessary.                                         report certain adverse events included                inconsistent with the law that requires
         Section 314 of the National Childhood                in a Reportable Events Table (Ref. 10)                a determination that a biologic product
      Vaccine Injury Act (NCVIA) of 1986                      and any event listed in the vaccine’s                 is safe, pure, and potent before it is
      required FDA to review the warnings,                    package insert as a contraindication to               licensed.
      use instructions, and precautionary                     subsequent doses of the vaccine. Health
      information that are distributed with                                                                         E. Compensation for Individuals
                                                              care providers also may report other
      each vaccine listed in section 2114 of                                                                        Suffering Injury From Vaccination
                                                              clinically significant adverse events.
      the Public Health Service Act and to                    FDA and CDC receive an average of 800                    The Panel recommended that
      determine whether this information was                  to 1,000 reports each month under the                 compensation from public funds be
      adequate to warn health care providers                  VAERS program. A guidance document                    provided to individuals suffering injury
      of the nature and extent of the dangers                 is available which explains how to                    from vaccinations that were
      posed by such vaccine. Since the                        complete the VAERS form (Ref. 11).                    recommended by competent authorities,
      December 1985 proposal, FDA has                                                                               carried out with approved vaccines, and
      completed this review and labeling has                  D. Periodic Review of Product Licenses                where the injury was not a consequence
      been revised accordingly. FDA is also                      The Panel recommended that all                     of defective or inappropriate
      taking this opportunity to propose                      licensed vaccines be periodically                     manufacture or administration of the
      updating the table in § 201.59(a)(3) to                 reviewed to assure that data concerning               vaccines.
      include the current mail codes for the                  the safety and effectiveness of these                    A compensation program has been
      review of labeling for various biological               products are kept current and that                    implemented consistent with the
      products.                                               licenses be revoked for products which                Panel’s recommendation. The NCVIA
                                                              have not been marketed for years or                   established the National Vaccine Injury
      B. Periodic Review of Product Labeling                  which have never been marketed in the                 Compensation Program (NVICP)
        In its report, the Panel noted a                      licensed form. The Panel noted that, by               designed to compensate individuals, or
      number of labeling deficiencies. To                     limiting the period for which specific                families of individuals, who have been
      improve the labeling, the Panel                         vaccines may be licensed, older                       injured by childhood vaccines, whether
      recommended that labeling be reviewed                   products would be assured periodic                    administered in the private or public
      and revised as necessary at intervals of                review, and new products for which                    sector. The NVICP, administered by the
      no more than every 2 years.                             additional efficacy data are required                 Health Resources and Services
        As discussed in the December 1985                     could be provisionally licensed for a                 Administration, Department of Health
      proposal, FDA believes the current                      limited time period during which                      and Human Services (HHS), is a no-fault
      system of labeling review will                          additional data can be generated.                     alternative to the tort system for
      adequately assure accurate labeling.                       In its proposed response, FDA noted                resolving claims resulting from adverse
      Periodic review of labeling on a set                    that licensing policies in effect at the              reactions to routinely recommended
      schedule is unnecessary. Section                        time of the review resulted in licenses               childhood vaccines. The specific
      601.12(f) prescribes when revised                       being held for some products which                    vaccines and injuries covered by NVICP
      labeling must be submitted, either as a                 were never intended to be marketed as                 are identified in a Vaccine Injury Table
      supplement for FDA’s review or, if                      individual products or which were no                  that may periodically be revised as new
      changes are minor, in an annual report.                 longer being marketed as individual                   vaccines come into use or new types of
      In addition, the agency may request                     products. FDA had required that                       potential injuries are identified. The
      revision of labeling when indicated by                  manufacturers licensed for a                          NVICP has resulted in a reduction in the
      current scientific knowledge. FDA                       combination vaccine also hold a license               amount of litigation related to injury
      believes that, by these mechanisms,                     for each individual vaccine contained in              from childhood vaccines while assuring
      product labeling is kept up to date, and                the combination. For example, a                       adequate liability coverage and
      proposes that a scheduled, routine                      manufacturer of diphtheria, tetanus, and              protection. The NVICP applies only to
      review of labeling is unnecessary and                   pertussis (DTP) vaccine would also be                 vaccines routinely recommended for
      burdensome for both the agency and                      required to have a license for Diphtheria             infants and children. Vaccines
      manufacturers.                                          Toxoid, Tetanus Toxoid, and Pertussis                 recommended for adults are not covered
                                                              Vaccines. Because this policy is no                   unless they are routinely recommended
      C. Improvement in the Reporting of                      longer in effect, most licenses are for               for children as well, e.g., Hepatitis B
      Adverse Reactions                                       currently marketed products. In a few                 Vaccine.
        The Panel recommended that actions                    cases, there may be no current demand
      be taken to improve the reporting and                   for a product but, for public health                  F. Public Support for Immunization
      documentation of adverse reactions to                   reasons, a license continues to be held               Programs
      biological products. The Panel                          for the product. There are some vaccines                 The Panel recommended that both
      particularly noted the need to improve                  for which there is little current demand              FDA and the public support widespread
      the surveillance systems to identify                    but continued licensure could expedite                immunization programs for tetanus,
      adverse reactions to pertussis vaccine.                 the manufacture and availability of the               diphtheria, and pertussis.
        Since publication of the Panel’s                      product in the event an outbreak of the                  The National Immunization Program
      report, the Vaccine Adverse Event                       targeted disease should occur. FDA                    is part of CDC and was established to
      Reporting System (VAERS) was created                    believes that the routine inspection of               provide leadership to health agencies in
      as an outgrowth of the National                         licensed facilities adequately assures                planning and implementing
      Childhood Vaccine Injury Act (NCVIA)                    that the information held in product                  immunization programs, to identify
      and is administered by FDA and Centers                  licenses is current and that a routine                unvaccinated populations in the United
      for Disease Control and Prevention                      review of safety and efficacy data is                 States, to assess vaccination levels in
      (CDC). VAERS accepts from health care                   unnecessary and burdensome. The                       state and local areas, and to generally
      providers, manufacturers, and the                       Panel’s recommendation that some new                  promote immunization programs for
      public, reports of adverse events that                  vaccines be provisionally licensed for                children, including vaccination against
      may be associated with U.S.-licensed                    only limited periods of time while                    diphtheria, tetanus, and pertussis. A


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                         Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules                                           78289

      recent survey shows that nearly 95                      bioengineered vaccines, acellular                     purity in the United States, CBER has
      percent of children 19 to 35 months of                  vaccines, and the diversity of                        generally required a purity specification
      age have received three or more doses                   populations in which the vaccine may                  of at least 1,000 Lf/mg of nondialyzable
      of any vaccine that contained diphtheria                be studied, it is difficult to develop                nitrogen for tetanus toxoids.
      and tetanus toxoids (i.e., diphtheria and               guidance that would apply to more than
                                                                                                                    K. Immunogenic Superiority of
      tetanus toxoids and pertussis vaccines                  one or two studies. FDA routinely meets
                                                                                                                    Adsorbed Toxoids Over Fluid Toxoids
      (DTP), diphtheria and tetanus toxoids                   with manufacturers before the initiation
      and acellular pertussis vaccines (DTaP)                 of clinical studies to discuss the study                 The Panel recommended that the
      or diphtheria and tetanus toxoids                       and will comment on proposed                          immunogenic superiority of the
      vaccines (DT)) (Ref. 12).                               protocols for efficacy studies. FDA                   adsorbed DTs over the fluid (plain)
                                                              proposes to continue to allow flexibility             preparations be strongly emphasized in
      G. Assuring Adequate Supplies of                                                                              product labeling, especially with regard
                                                              in selecting appropriate tests,
      Bacterial Vaccines and Toxoids;                                                                               to the duration of protection.
                                                              procedures, and study populations for a
      Establishment of a National Vaccine                                                                              Tetanus Toxoid fluid, manufactured
                                                              clinical study while assuring that the
      Commission                                                                                                    by Aventis Pasteur, Inc., is the only
                                                              necessary data are generated to fulfill
        The Panel recommended that FDA                        the intended objectives of the study.                 fluid toxoid product that remains
      work closely with CDC and other groups                                                                        licensed in the United States in 2004.
      to assure that adequate supplies of                     I. The Effect of Regulations Protecting               This product is licensed for booster use
      vaccines and passive immunization                       and Informing Human Study Subjects                    only in persons over 7 years of age. The
      products continue to be available. The                  on the Ability to Conduct Clinical Trials             current package insert for this product
      Panel recommended establishment of a                       The Panel expressed concern that the               states that, although the rates of
      national vaccine commission to address                  regulations governing informed consent                seroconversion are essentially
      such issues.                                            and the protection of human subjects                  equivalent with either type of tetanus
        Since the publication of the December                 involved in clinical investigations                   toxoid, the adsorbed toxoids induce
      1985 proposal, the National Vaccine                     should not establish unnecessary                      more persistent antitoxin titers than
      Program was created by Congress                         impediments to the goal of obtaining                  fluid products.
      (Public Law 99–660) with the National                   adequate evidence for the safety and
                                                                                                                    L. Laboratory Testing Systems for
      Vaccine Program Office (NVPO) within                    effectiveness of a product.
      HHS designated to provide leadership                       FDA believes that the regulations and              Determining Potency of Tetanus and
      and coordination among Federal                          policies applying to informed consent                 Diphtheria Toxoids
      agencies as they work together to carry                 and the protection of human subjects do                  The Panel noted a need for further
      out the goals of the National Vaccine                   not inhibit the adequate clinical study               studies with tetanus toxoids in a World
      Plan. The National Vaccine Plan                         of a product. FDA notes that whenever                 Health Organization (WHO) sponsored
      provides a framework, including goals,                  the regulations or guidance documents                 quantitative potency test in animals to
      objectives, and strategies, for pursuing                related to these subjects are modified or             establish the conditions under which
      the prevention of infectious diseases                   amended, FDA offers an opportunity for                the test results are reproducible, and to
      through immunizations. The National                     public comment on the revisions. FDA                  relate these results more closely to those
      Vaccine Program brings together all of                  particularly welcomes comments on                     obtained in the immunization of
      the groups that have key roles in                       how appropriate informed consent and                  humans. The Panel also recommended
      immunizations, and coordinates the                      protection of human subjects can be                   the development of an animal or
      vaccine-related activities, including                   maintained while assuring that the                    laboratory testing system for diphtheria
      addressing adequate production and                      development and study of useful                       toxoid that correlates consistently, and
      supply issues. Despite efforts to assure                products is not inhibited.                            with acceptable precision, with primary
      vaccine availability, shortages may                                                                           immunogenicity in humans.
                                                              J. Standards for Determining the Purity                  DT-containing vaccines are tested
      occur (Ref. 13) for a variety of reasons.
                                                              of Diphtheria and Tetanus Toxoids                     during the licensing process for their
      FDA proposes to continue to work with
                                                              (DTs)                                                 ability to induce acceptable levels of
      the NVPO, the National Institutes of
      Health, CDC, and vaccine manufacturers                     The Panel recommended that                         protective antibodies in clinical trials in
      to help facilitate continued vaccine                    standards should be established for                   the target populations. Properties of
      availability making the establishment of                purity of both DTs in terms of limits of              vaccines used in these clinical trials,
      a national vaccine commission                           flocculation (Lf) content per milligram               including potency, also are determined
      unnecessary.                                            (mg) of nitrogen.                                     during licensing. The acceptance
                                                                 In the December 1985 proposal, FDA                 criteria for commercial lots of these
      H. Consistency of Efficacy Protocols                    agreed that standards should be set.                  vaccines are set at licensing on the basis
        The Panel recommended that the                        FDA has since determined that this                    of the properties of the vaccines that
      protocols for efficacy studies be                       approach is overly restrictive; does not              induced acceptable quantitative/
      reasonably consistent throughout the                    allow FDA to keep pace with advances                  qualitative levels of antibodies. The
      industry for any generic product. To                    in manufacturing and technology; and,                 establishment of a correlation between a
      achieve this goal, the Panel                            proposes that standards for determining               specific antibody response and a given
      recommended the development of                          the purity of DTs not be established.                 assay would require an efficacy trial
      industry guidelines that provide                        The Center for Biologics Evaluation and               designed specifically to establish this
      standardized methodology for adducing                   Research (CBER) establishes the release               correlation. This may call for
      required information.                                   specifications for the purity of DTs                  vaccination of humans with sub-optimal
        FDA believes that the standardization                 during the review of a Biologics License              doses of vaccine. Such an efficacy study
      of clinical testing methodology for a                   Application (BLA). The purity of                      is not feasible for ethical reasons.
      group of vaccines is often not practical                diphtheria toxoids in currently licensed                 The animal potency tests currently
      or useful. Because of the variety of                    vaccines is usually at least 1,500 Lf/mg              required by the WHO, the European
      possible vaccine types, e.g., live                      nondialyzable nitrogen. While there are               Pharmacopoeia (EP), and FDA differ.
      vaccines, killed vaccines, toxoids,                     no general standards for tetanus toxoid               Despite these differences, the potency


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      78290              Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules

      tests have been adequate to ensure                      mouse weight-gain test is no longer in                   FDA agrees with the recommendation
      sufficient immunogenic activity of the                  use. Currently, only DTP vaccines                     except that such information should be
      vaccines to induce protective immunity                  containing an acellular pertussis                     included in product labeling, i.e., the
      in target populations. However,                         component (DTaP) are licensed in the                  package insert, rather than the product
      international efforts to harmonize the                  United States. These vaccines are tested              label. Labeling applicable to the whole-
      diphtheria and tetanus potency tests                    specifically for residual pertussis toxin             cell pertussis vaccine conformed to this
      under development are based on                          activity.                                             recommendation. Because the acellular
      immunogenicity in animals. CBER is                         Although not currently licensed in the             form of pertussis vaccine has a different
      currently participating in these                        United States, vaccines containing a
                                                                                                                    profile of potential adverse events and
      international harmonization efforts.                    whole-cell pertussis component are still
                                                                                                                    contraindications, the product labeling
                                                              in use in other countries. CBER
      M. Potency Testing of DTs for Pediatric                 continues to participate in international             is worded consistent with available
      Use                                                     efforts to improve the tests used to                  data.
        The Panel recommended that the                        assess toxicity of whole-cell pertussis               R. Field Testing of Fractionated
      agency require potency testing after                    vaccines, including the mouse weight-                 Pertussis Vaccines
      combination of the individual toxoid                    gain test. CBER is represented on WHO
      components in DTs for pediatric use.                    committees and working groups with                       The Panel recommended that any
        FDA agrees with the recommendation.                   the goal of improving regulation and                  fractionated pertussis vaccine that
      All manufacturers and the FDA testing                   testing of whole-cell pertussis vaccines.             differs from the original whole cell
      laboratory follow this procedure on                                                                           vaccine be field tested until better
                                                              P. Agglutination Test to Determine
      products submitted to the agency for                                                                          laboratory methods for evaluating
                                                              Pertussis Vaccine Response in Humans
      release.                                                                                                      immunogenicity are developed. The
                                                                 The Panel recommended that the
      N. Potency Requirements for Pertussis                                                                         Panel recommended that the field-
                                                              agglutination test used to determine
      Vaccine                                                                                                       testing include agglutination testing
                                                              pertussis vaccine response in humans
         The Panel recommended that the                       be standardized and that a reference                  and, if possible, evaluation of clinical
      regulations concerning the maximum                      serum be used for comparison. It also                 effectiveness.
      pertussis vaccine dose should be                        recommended that a reference                             The currently approved vaccines
      updated to reflect current                              laboratory be available at FDA.                       containing an acellular pertussis
      recommendations and practices. At the                      As stated previously in this                       component were studied in the United
      time of the Panel review, whole cell                    document, at the time of the Panel’s                  States and abroad in human populations
      pertussis vaccines were in use.                         deliberations, only whole-cell pertussis              with the antibody response being
      Specifically, the Panel recommended                     vaccines were licensed in the United                  measured and clinical effectiveness
      that pertussis vaccine have a potency of                States. The agglutination test was used               evaluated.
      four protective units per single human                  for the clinical evaluation of DTP
      dose with the upper estimate of a single                vaccines. Under the Panel’s                           S. Use of Same Seed Lot Strain in
      human dose not to exceed eight                          recommendations, FDA (CBER)                           Manufacturing Bacillus Calmette-Guerin
      protective units. The Panel also                        developed and distributed reference                   (BCG) Vaccine
      recommended that the total immunizing                   materials for the agglutination assay and
                                                              served as a reference laboratory.                        The Panel recommended that all BCG
      dose be defined as four doses of four
      units each, compared to the three doses                 Currently, only DTaP vaccines are                     vaccines be prepared from the same
      of four units each defined at the time of               licensed in the United States. For the                seed lot strain with demonstrated
      the recommendation in the regulations.                  clinical evaluation of DTaP vaccines,                 efficacy, if available data justify such
         FDA has removed the additional                       the agglutination test was replaced by                action.
      standard regulations applicable to                      antigen-specific immunoassays,                           BCG vaccines are not recommended
      pertussis vaccine (Ref. 9). As whole cell               specifically enzyme-linked                            for routine immunization in the United
      pertussis vaccines are no longer                        immunosorbent assays (ELISAs). As had                 States. The two currently U.S.-licensed
      licensed for human use in the United                    been done with the agglutination assay,               BCG vaccines are produced using
      States, this recommendation no longer                   CBER took an active role in                           different seed strains. Most BCG
      applies to products available in the                    standardization of the ELISAs used to                 vaccines produced globally are
      United States.                                          measure the specific antibody to the                  manufactured using seed strains with a
                                                              pertussis components of DTaP vaccines.                unique history. Recent evidence
      O. Weight-Gain Test in Mice for                         Specifically, CBER distributes reference
      Pertussis Vaccine                                                                                             suggests that these different BCG strains
                                                              and control materials for the antigen-                do differ genetically and have slightly
         The Panel recommended that the                       specific pertussis ELISA and has served               varying phenotypes. However, a meta
      weight-gain test in mice used to                        as a reference laboratory.
      determine toxicity of pertussis vaccines                                                                      analysis of the current human BCG
      be revised to include a reference                       Q. Warnings in Labeling for Pertussis                 vaccination data performed in 1994 by
      standard and specifications regarding                   Vaccine                                               Harvard University concluded that no
      mouse strains to be used.                                 The Panel recommended that the                      strain-to-strain differences in protection
         At the time of the Panel’s                           pertussis vaccine label warn that if                  could be detected. Although there have
      deliberations, only DTP vaccines                        shock, encephalopathic symptoms,                      been differences in immunogencity
      containing a whole-cell pertussis                       convulsions, or thrombocytopenia                      among strains demonstrated in animal
      component were licensed in the United                   follow a vaccine injection, no additional             models, no significant differences have
      States. The mouse weight-gain test was                  injections with pertussis vaccine should              been seen in human clinical trials (Ref.
      a toxicity test used for whole-cell                     be given. The Panel also recommended                  14). Thus, FDA does not find that
      pertussis vaccines. Whole-cell pertussis                that the label include a cautionary                   available human data justify
      vaccines are no longer licensed in the                  statement about fever, excessive                      requirement of a single BCG vaccine
      United States for human use, thus the                   screaming, and somnolence.                            strain.


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                         Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules                                           78291

      T. Development of an Improved Cholera                   new concerns require a continual                      change because the concentration of
      Vaccine                                                 reevaluation of research priorities and               antitoxin per milliliter has varied
        The Panel recommended public                          objectives to assure their relevance to               widely in the past without any apparent
      support for development of an improved                  current concerns.                                     effect on the performance of the
      cholera vaccine because unsatisfactory                     FDA recognizes the Panel’s desire to               product. TIG is routinely manufactured
      sanitary conditions in many countries                   have FDA’s research program evolve                    consistently at a concentration of 170
      make it clear that control of the disease               with the significant issues and findings              units per milliliter. However, there was
      by sanitation alone cannot be realized in               of medical science. In order to assure                no evidence upon which to establish a
      the foreseeable future.                                 the continued relevance of its research               revised minimum potency on a per
        Cholera is not an endemic disease in                  program, CBER’s research program for                  milliliter basis. Because the evidence of
      the United States. However, there is risk               vaccines, including bacterial vaccines                efficacy for TIG was based on use of
      to U.S. travelers to certain countries                  and related biological products, is                   product administered consistently at
      where the disease is endemic. FDA                       subject to peer review by the Panel’s                 doses of 250 units or larger and the
      continues to cooperate with                             successor, the Vaccines and Related                   varying concentration of the product
      international health agencies in efforts                Biological Products Advisory                          without any apparent adverse effect,
      to evaluate new types of vaccines and to                Committee (see, for example, the                      FDA proposes that it is more
      study the pathogenesis of the disease.                  transcripts from the meetings of June 11              appropriate to regulate the potency on a
      CBER personnel have chaired and                         (Ref. 15) and November 29, 2001 (Refs.                per vial basis, rather than by units per
      participated in the WHO Cholera                         16 and 17), and March 6, 2002 (Ref. 18)).             milliliter. The current licensed product
      Vaccine Standardization Committee and                   In addition, CBER has defined as part of              continues to be marketed at a potency
      have participated in drafting new WHO                   its mission statement a strategic goal of             no less than the minimum dose (250
      guidelines for immune measurement of                    assuring a high quality research program              units), which historically has been
      protection from cholera.                                that contributes directly to its regulatory           shown to be clinically effective.
                                                              mission. This goal includes a plan to                    FDA received no comments opposing
      U. Plague Vaccine Immunization                          assure that CBER’s research program                   the proposed revision to § 610.21 and
      Schedule                                                continues to support the regulatory                   therefore proposes to amend the
        The Panel recommended that the                        review of products and timely                         regulations to require a minimum
      following plague vaccine immunization                   development of regulatory policy, and                 potency of 250 units of tetanus antitoxin
      schedule be considered:                                 to have a significant impact on the                   per container for TIG.
         1. A primary series of 3 intramuscular (IM)          evaluation of biological products for
      injections (1 mL, 0.2 mL, and 0.2 mL), 1 and            safety and efficacy.                                  VIII. Analysis of Impacts
      6 months apart, respectively;                              Because of limited resources, FDA
         2. Booster IM injections of 0.2 mL at 12,
                                                                                                                    A. Review Under Executive Order
                                                              also supports the leveraging of resources             12866, the Regulatory Flexibility Act,
      18, and 24 months; and,                                 to create effective collaborations in the
         3. For persons achieving a titer of 1:128                                                                  and the Unfunded Mandates Act of
                                                              advancement of science. FDA has issued                1995
      after the third and fifth inoculations, booster
      doses when the passive agglutination titer              a ‘‘Guidance for FDA Staff: The
                                                              Leveraging Handbook, an Agency                           FDA has examined the impacts of this
      falls below 1:32 and empirically every 2
      years when the patient cannot be tested                 Resource for Effective Collaborations.’’              proposed rule under Executive Order
      serologically.                                          (Ref. 19). Through cooperation with                   12866, the Regulatory Flexibility Act (5
        FDA agrees with the recommendation,                   international, other Federal, and State               U.S.C 601–612), and the Unfunded
      and the currently licensed vaccine is                   health care agencies and the industry                 Mandates Reform Act of 1995 (Public
      labeled consistent with the                             and academia, the agency intends that                 Law 104–4). Executive Order 12866
      recommendation.                                         its research resources will reap the                  directs agencies to assess all costs and
                                                              benefits of a wide range of experience,               benefits of available regulatory
      VI. FDA’s Response to General                                                                                 alternatives and, when regulation is
                                                              expertise, and energy from the greater
      Research Recommendations                                                                                      necessary, to select regulatory
                                                              scientific community while the agency
         In its report, the Panel identified                  maintains its legal and regulatory                    approaches that maximize net benefits
      many areas in which there should be                     obligations. FDA invites comment at                   (including potential economic,
      further investigation to improve existing               any time on ways it may improve its                   environmental, public health and safety
      products, develop new products,                         research program and set its objectives.              and other advantages; distributive
      develop new testing methodologies, and                                                                        impacts; and equity). The Regulatory
      monitor the population for its immune                   VII. Proposed Amendment to the                        Flexibility Act requires agencies to
      status against bacterial disease. In the                Regulations                                           analyze whether a rule may have a
      December 1985 proposal, FDA                               In the December 1985 proposal, FDA                  significant economic impact on a
      responded to these recommendations in                   proposed to amend § 610.21 (21 CFR                    substantial number of small entities
      the responses identified as items 11, 17                610.21), limits of potency, by revising               and, if it does, to analyze regulatory
      (in part), 21, 25, and 27. As discussed                 the potency requirements for Tetanus                  options that would minimize the impact
      in the December 1985 proposal, FDA                      Immune Globulin (Human) (TIG). FDA                    on small entities. The Unfunded
      considered the Panel’s                                  proposed to amend the regulations to                  Mandates Reform Act requires that
      recommendations in defining its                         require a minimum potency of 250 units                agencies prepare a written statement
      research priorities at the time the                     of tetanus antitoxin per container for                under section 202(a) of anticipated costs
      recommendations were made. Because a                    TIG. FDA advises that in this discussion              and benefits before proposing any rule
      considerable amount of time has                         and in the proposed regulation, ‘‘per                 that may result in an expenditure by
      elapsed since these recommendations                     container’’ means that amount of the                  State, local, or tribal governments, in the
      were made and FDA initially responded                   contents of the container deliverable to              aggregate, or by the private sector, of
      to the recommendations, FDA is not                      the patient in normal use. The current                $100 million (adjusted annually for
      providing specific responses to each                    regulation provides for a minimum                     inflation) in any one year.
      recommendation. As in any area of                       potency of 50 units of tetanus antitoxin                 The agency believes that this
      scientific research, new discoveries and                per milliliter of fluid. FDA proposes the             proposed rule is consistent with the


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      78292              Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules

      regulatory philosophy and principles                    comments or two paper copies of any                   Precipitated Protective Antigen,’’ Journal of
      identified in the Executive Order. In                   mailed comments, except that                          Immunology, 73:387–391, 1954.
      addition, this proposed rule is not a                   individuals may submit one paper copy.                   9. 61 FR 40153, August 1, 1996.
      significant regulatory action as defined                Comments are to be identified with the                   10. ‘‘Table of Reportable Events Following
                                                                                                                    Vaccination,’’ http://www.vaers.org/
      by the Executive Order and so is not                    docket number found in brackets in the                reportable.htm. (FDA has verified the Web
      subject to review under the Executive                   heading of this document. Received                    site address, but we are not responsible for
      Order. Because this proposed rule does                  comments may be seen in the Division                  subsequent changes to the Web site after this
      not impose new requirements on any                      of Dockets Management between 9 a.m.                  document publishes in the Federal Register).
      entity it has no associated compliance                  and 4 p.m., Monday through Friday.                       11. ‘‘Guidance for Industry: How to
      costs, and the agency certifies that the                                                                      Complete the Vaccine Adverse Event
                                                              X. References                                         Reporting System Form (VAERS–1),’’
      proposed rule will not have a significant
      economic impact on a substantial                          The following references have been                  September 1998, http://www.fda.gov/cber/
      number of small entities. Therefore,                    placed on display in the Division of                  gdlns/vaers–1.pdf. (FDA has verified the Web
                                                              Dockets Management (HFA–305), Food                    site address, but we are not responsible for
      under the Regulatory Flexibility Act, no                                                                      subsequent changes to the Web site after this
      further analysis is required. Because this              and Drug Administration, 5630 Fishers
                                                                                                                    document publishes in the Federal Register).
      proposed rule does not impose                           Lane, rm.1061, Rockville, MD 20852,                      12. ‘‘Estimated Vaccination Coverage With
      mandates on State, local, or tribal                     and may be seen by interested persons                 3+DTP Among Children 19–35 Months of
      governments, in the aggregate, or the                   between 9 a.m. and 4 p.m., Monday                     Age by Race/Ethnicity, and by State and
      private sector, that will result in an                  through Friday.                                       Immunization Action Plan Area—U.S.,
      expenditure in any one year of $100                        1. The full Panel Report was incorporated          National Immunization Survey, Q3/2000 -
                                                              into the ‘‘Biological Products; Bacterial             Q2/2001’’, http://www.cdc.gov/nip/coverage/
      million or more, FDA is not required to
                                                              Vaccines and Toxoids; Implementation of               NIS/00–01/tab19–3dptlraceliap.htm. (FDA
      perform a cost benefit analysis under                   Efficacy Review,’’ proposed rule, published           has verified the Web site address, but we are
      the Unfunded Mandates Reform Act.                       in the Federal Register of December 13, 1985          not responsible for subsequent changes to the
      The current inflation adjusted statutory                (50 FR 51002).                                        Web site after this document publishes in the
      threshold is approximately $110                            1a. Brachman, P. S.; H. Gold; S. Plotkin; F.       Federal Register).
      million.                                                R. Fekety; M. Werrin; and N. R. Ingraham,                13. Protecting Our Kids: What Is Causing
                                                              ‘‘Field Evaluation of a Human Anthrax                 the Current Shortage in Childhood
      B. Environmental Impact                                 Vaccine,’’ American Journal of Public Health,         Vaccines?—Testimony Before the Committee
         The agency has determined, under 21                  52:632–645, 1962.                                     on Governmental Affairs, United States
      CFR 25.31(h), that this action is of a                     2. Joellenbeck, Lois M.; Lee L. Zwanziger;         Senate, June 12, 2002, http://www.cdc.gov/
      type that does not individually or                      Zane S. Durch; and Brian L. Strom; Editors,           nip/news/testimonies/vac-shortages-walt–6–
                                                              Committee to Assess the Safety and Efficacy           12–2002.htm. (FDA has verified the Web site
      cumulatively have a significant effect on               of the Anthrax Vaccine, Medical Follow-Up
      the human environment. Therefore,                                                                             address, but we are not responsible for
                                                              Agency, The National Academies Press,                 subsequent changes to the Web site after this
      neither an environmental assessment                     Washington, DC, April 2002, http://                   document publishes in the Federal Register).
      nor an environmental impact statement                   www.nap.edu/catalog/10310.html (FDA has                  14. Colditz, et al., ‘‘Efficacy of BCG Vaccine
      is required.                                            verified the Web site address, but we are not         in the Prevention of Tuberculosis: Meta
                                                              responsible for subsequent changes to the             Analysis of the Published Literature’’,
      C. Paperwork Reduction Act of 1995                      Web site after this document publishes in the         Journal of the American Medical Association,
        This proposed rule contains no                        Federal Register).                                    271:698–702, 1994.
      collections of information. Therefore,                     3. Fellows, P. F.; M. K. Linscott; B. E. Ivins;       15.http://www.fda.gov/ohrms/dockets/ac/
      clearance by the Office of Management                   M. L. M. Pitt; C. A. Rossi; P. H. Gibbs and           01/transcripts/3755t1.pdf
      and Budget under the Paperwork                          A. M. Friedlander, ‘‘Efficacy of a Human                 16.http://www.fda.gov/ohrms/dockets/ac/
                                                              Anthrax Vaccine in Guinea Pigs, Rabbits, and          01/transcripts/3805t2l01.pdf
      Reduction Act of 1995 is not required.                  Rhesus Macaques Against Challenge by                     17.http://www.fda.gov/ohrms/dockets/ac/
      D. Federalism                                           Bacillus Anthracis Isolates of Diverse                01/transcripts/3805t2l02.pdf
                                                              Geographical Origin,’’ Vaccine 19(23/                    18.http://www.fda.gov/ohrms//dockets/ac/
         FDA has analyzed this proposed rule                  24):3241–3247, 2001.                                  02/transcripts/3842t1.pdf
      in accordance with the principles set                      4. Ivins, B. E.; P. F. Fellows; M. L. M. Pitt;        19.http://www.fda.gov/cber/gdlns/
      forth in Executive Order 13132. FDA                     J. E. Estep; S. L. Welkos; P. L.Worsham and           leverhnbk.pdf
      has determined that the proposed rule                   A. M. Friedlander, ‘‘Efficacy of a Standard
      does not contain policies that have                     Human Anthrax Vaccine Against Bacillus                List of Subjects
      substantial direct effects on the States,               Anthracis Aerosol Spore Challenge in Rhesus
                                                              Monkeys,’’ Salisbury Medical Bulletin                 21 CFR Part 201
      on the relationship between National
      Government and the States, or on the                    87(Suppl.):125–126, 1996.                               Drugs, Labeling, Reporting and
                                                                 5. Ivins, B. E.; M. L. M. Pitt; P. F. Fellows;     recordkeeping requirements.
      distribution of power and                               J. W. Farchaus; G. E. Benner; D. M. Waag; S.
      responsibilities among the various                      F. Little; G. W. Anderson, Jr.; P. H. Gibbs; and      21 CFR Part 610
      levels of government. Accordingly, the                  A. M. Friedlander, ‘‘Comparative Efficacy of            Biologics, Labeling, Reporting and
      agency has concluded that the proposed                  Experimental Anthrax Vaccine Candidates
                                                                                                                    recordkeeping requirements.
      rule does not contain policies that have                Against Inhalation Anthrax in Rhesus
                                                              Macaques,’’ Vaccine, 16(11/12):1141–1148,
                                                                                                                      Therefore, under the Federal Food,
      federalism implications as defined in
                                                              1998.                                                 Drug, and Cosmetic Act, the Public
      the Executive Order and, consequently,
                                                                 6. Anthrax Vaccine Adsorbed (BIOTHRAX)             Health Service Act, and under authority
      a federalism summary impact statement
                                                              Package Insert (January 31, 2002).                    delegated by the Commissioner of Food
      is not required.
                                                                 7. Reports and evaluation of reports of            and Drugs, it is proposed that 21 CFR
      IX. Request for Comments                                adverse events following administration of            parts 201 and 610 be amended as
                                                              anthrax vaccine received by the Federal               follows:
        Interested persons may submit to the                  Vaccine Adverse Event Reporting System
      Division of Dockets Management (see                     (VAERS) through November 2004.                        PART 201—LABELING
      ADDRESSES) written or electronic                           8. Wright, G. G.; T. W. Green; and R. G.
      comments regarding this document.                       Kanode, Jr., ‘‘Studies on Immunity in                   1. The authority citation for 21 CFR
      Submit a single copy of electronic                      Anthrax: V. Immunizing Activity of Alum-              part 201 continues to read as follows:


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                          Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules                                                78293

        Authority: 21 U.S.C. 321, 331, 351, 352,              ‘‘HFM–99’’ in the BIOLOGICS section of                 BIOLOGICS section of the table to read
      353, 355, 358, 360, 360b, 360gg–360ss, 371,             the table, under ‘‘Mail Routing Code’’;                as follows.
      374, 379e; 42 U.S.C 216, 241, 262, 264.
         2. Section 201.59 is amended in the                     b. Revising the entries for the drug                § 201.59 Effective date of §§ 201.56, 201.57,
      table in paragraph (a)(3) by:                           classes ‘‘Bacterial vaccines and toxoids               201.100(d)(3), and 201.100(e).
         a. Removing ‘‘HFB–240’’ everywhere                   with standards of potency’’ and ‘‘Viral                   (a) * * *
      it appears and adding in its place                      and rickettsial vaccines’’ in the                         (3) * * *

                 Effective                       Revised labeling due                                 Drug class                         Mail routing code

                                                                                   Biologics

      [Insert date 30 months after date         See footnote3                              Bacterial vaccines and toxoids with stand-         HFM–99
         of publication in the Federal                                                       ards of potency
         Register]
                    *              *                 *                    *                *                       *                           *
      Nov. 1, 19821                             Nov 1, 19802                               Viral and rickettsial vaccines                     HFM–99
                    *              *                 *                    *                *                       *                           *
         1 Except the effective date for all biological products reviewed generically by the advisory panel is 30 months after a final order is published
      under § 601.25(g) of this chapter.
         2 Except the due date for all biological products reviewed generically by the advisory panel is 6 months after a final order is published under
      § 601.25(g) of this chapter.
         3 FDA has determined that a review of product labeling under this section is unnecessary.




      *      *        *      *     *                            4. Section 610.21 is amended by                        Tetanus Immune Globulin (Human),
                                                              revising the entry ‘‘Tetanus Immune                    250 units of tetanus antitoxin per
      PART 610—GENERAL BIOLOGICAL                             Globulin (Human), 50 units of tetanus                  container.
      PRODUCTS STANDARDS                                      antitoxin per milliliter’’ under the                   *    *     *     *     *
                                                              heading ‘‘ANTIBODIES’’ to read as
        3. The authority citation for 21 CFR                                                                           Dated: December 21, 2004.
                                                              follows:
      part 610 continues to read as follows:                                                                         Jeffrey Shuren,
                                                              § 610.21    Limits of potency.                         Assistant Commissioner for Policy.
        Authority: 21 U.S.C. 321, 331, 351, 352,
      353, 355, 360, 360c, 360d, 360h, 360i, 371,             *   *   *             *      *                         [FR Doc. 04–28322 Filed 12–23–04; 11:16
      372, 374, 381; 42 U.S.C. 216, 262, 263, 263a,           ANTIBODIES                                             am]
      264.                                                    *   *   *             *      *                         BILLING CODE 4160–01–S




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