VIEWS: 17 PAGES: 13 POSTED ON: 7/27/2011
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: firstname.lastname@example.org. 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 VerDate jul<14>2003 19:00 Dec 28, 2004 Jkt 205001 PO 00000 Frm 00001 Fmt 4701 Sfmt 4702 E:\FR\FM\29DEP2.SGM 29DEP2 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 VerDate jul<14>2003 19:00 Dec 28, 2004 Jkt 205001 PO 00000 Frm 00002 Fmt 4701 Sfmt 4702 E:\FR\FM\29DEP2.SGM 29DEP2 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 VerDate jul<14>2003 19:00 Dec 28, 2004 Jkt 205001 PO 00000 Frm 00003 Fmt 4701 Sfmt 4702 E:\FR\FM\29DEP2.SGM 29DEP2 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. VerDate jul<14>2003 19:00 Dec 28, 2004 Jkt 205001 PO 00000 Frm 00004 Fmt 4701 Sfmt 4702 E:\FR\FM\29DEP2.SGM 29DEP2 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 VerDate jul<14>2003 19:00 Dec 28, 2004 Jkt 205001 PO 00000 Frm 00005 Fmt 4701 Sfmt 4702 E:\FR\FM\29DEP2.SGM 29DEP2 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 VerDate jul<14>2003 19:00 Dec 28, 2004 Jkt 205001 PO 00000 Frm 00006 Fmt 4701 Sfmt 4702 E:\FR\FM\29DEP2.SGM 29DEP2 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 VerDate jul<14>2003 19:00 Dec 28, 2004 Jkt 205001 PO 00000 Frm 00007 Fmt 4701 Sfmt 4702 E:\FR\FM\29DEP2.SGM 29DEP2 78288 Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules 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 VerDate jul<14>2003 19:00 Dec 28, 2004 Jkt 205001 PO 00000 Frm 00008 Fmt 4701 Sfmt 4702 E:\FR\FM\29DEP2.SGM 29DEP2 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 VerDate jul<14>2003 19:00 Dec 28, 2004 Jkt 205001 PO 00000 Frm 00009 Fmt 4701 Sfmt 4702 E:\FR\FM\29DEP2.SGM 29DEP2 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. VerDate jul<14>2003 19:00 Dec 28, 2004 Jkt 205001 PO 00000 Frm 00010 Fmt 4701 Sfmt 4702 E:\FR\FM\29DEP2.SGM 29DEP2 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 VerDate jul<14>2003 19:00 Dec 28, 2004 Jkt 205001 PO 00000 Frm 00011 Fmt 4701 Sfmt 4702 E:\FR\FM\29DEP2.SGM 29DEP2 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: VerDate jul<14>2003 19:00 Dec 28, 2004 Jkt 205001 PO 00000 Frm 00012 Fmt 4701 Sfmt 4702 E:\FR\FM\29DEP2.SGM 29DEP2 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 VerDate jul<14>2003 19:00 Dec 28, 2004 Jkt 205001 PO 00000 Frm 00013 Fmt 4701 Sfmt 4702 E:\FR\FM\29DEP2.SGM 29DEP2
"Federal Register Vol No Wednesday December"