Source: https://regulations.vlex.com/vid/part-v-22712191
Timestamp: 2019-12-12 19:54:39
Document Index: 714113570

Matched Legal Cases: ['arts 201', 'art 201', 'art 201', 'art 620', 'ART 201', 'art 201', 'ART 610', 'art 610']

Part V - December 29, 2004 - Regulations - VLEX 22712191
[Federal Register: December 29, 2004 (Volume 29, Number 249)]
[Page 78281-78293]
[DOCID:fr29de04-32]
21 CFR Parts 201 and 610
[Docket No. 1980N-0208]
ACTION: Proposed rule and proposed order.
SUMMARY: The Food and Drug Administration (FDA) is proposing to amend the biologics regulations in response to the report and recommendations of the Panel on Review of Bacterial Vaccines and Toxoids (the Panel). The Panel reviewed the safety, efficacy, and labeling of bacterial vaccines and toxoids with standards of potency, bacterial antitoxins, and immune globulins. On the basis of the Panel's findings and recommendations, FDA is proposing to classify these products as Category I (safe, effective, and not misbranded), Category II (unsafe, ineffective, or misbranded), or Category IIIB (off the market pending completion of studies permitting a determination of effectiveness). On December 13, 1985, FDA proposed to amend the biologics regulations and proposed to classify the bacterial vaccines and toxoids. After reviewing the Panel's report and comments on the proposal, FDA published a final rule and final order on January 5, 2004. The court vacated the January 5, 2004 (69 FR 255) final rule. Therefore, elsewhere in this issue of the Federal Register, FDA is withdrawing the January 5, 2004, final rule. FDA is issuing this proposed rule and proposed order again to provide notice and to give interested persons an opportunity to comment.
DATES: Submit written or electronic comments on the proposed rule and proposed order by March 29, 2005.
ADDRESSES: You may submit comments, identified by Docket No. 1980N- 0208, by any of the following methods:
Instructions: All submissions received must include the agency name and Docket No. for this proposal. All comments received will be posted without change to http://www.fda.gov/ohrms/dockets/default.htm,
including any personal information provided. For detailed instructions on submitting comments and additional information on the process, see the ``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this document.
and insert the docket number found in brackets in the heading of this document, into the ``Search'' box and follow the prompts and/or go to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Astrid Szeto, Center for Biologics Evaluation and Research (HFM-17), Food and Drug Administration, 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, 301-827-6210.
Categorize those bacterial vaccines and toxoids licensed before July 1972 according to the evidence of their safety and effectiveness, thereby determining whether they may remain licensed and on the market;
Issue a proposed response to recommendations made in the Panel's report.\1\ These recommendations concern conditions relating to active components, labeling, tests required before release of product lots, product standards, or other conditions considered by the Panel to be necessary or appropriate for assuring the safety and effectiveness of the reviewed products;
\1\ The Panel was convened on July 12, 1973, in an organizational meeting, followed by multiple working meetings until February 2, 1979. The Final Report of the Panel was completed in August 1979.
Revise the standard for potency of Tetanus Immune Globulin in Sec. 610.21 (21 CFR 610.21); and
Apply the labeling requirements in Sec. Sec. 201.56 and 201.57 (21 CFR 201.56 and 201.57) to bacterial vaccines and toxoids by amending the implementation dates in Sec. 201.59 (21 CFR 201.59).
In the Federal Register of February 13, 1973 (38 FR 4319), FDA issued procedures for the review by independent advisory review panels of the safety, effectiveness, and labeling of biological products licensed before July 1, 1972. This process was eventually codified in Sec. 601.25 (21 CFR 601.25) (38 FR 32048 at 32052, November 20, 1973). Under the panel assignments published in the Federal Register of June 19, 1974 (39 FR 21176), FDA assigned the biological product review to one of the following groups: (1) Bacterial vaccines and bacterial antigens with ``no U.S. standard of potency,'' (2) bacterial vaccines and toxoids with standards of potency, (3) viral vaccines and rickettsial vaccines, (4) allergenic extracts, (5) skin test antigens, and (6) blood and blood derivatives.
Under Sec. 601.25, FDA assigned responsibility for the initial review of each of the biological product categories to a separate independent advisory panel consisting of qualified experts to ensure objectivity of the review and public confidence in the use of these products. Each panel was charged with preparing an advisory report to the Commissioner of Food and Drugs which was to: (1) Evaluate the safety and effectiveness of the biological products for which a license had been issued, (2) review their labeling, and (3) identify the biological products that are safe, effective, and not misbranded. Each advisory panel report was also to include recommendations classifying the products reviewed into one of three categories.
Category III designating those biological products determined by the panel not to fall within either Category I or Category II on the basis of the panel's conclusion that the available data were insufficient to classify such biological products, and for which further testing was therefore required. Category III products were assigned to one of two subcategories. Category IIIA products were those that would be permitted to remain on the market pending the completion of further studies. Category IIIB products were those for which the panel recommended license revocation on the basis of the
panel's assessment of potential risks and benefits.
In accordance with Sec. 601.25, after reviewing the conclusions and recommendations of the review panels, FDA would publish in the Federal Register a proposed order containing: (1) A statement designating the biological products reviewed into Categories I, II, IIIA, or IIIB, (2) a description of the testing necessary for Category IIIA biological products, and (3) the complete panel report. Under the proposed order, FDA would propose to revoke the licenses of those products designated into Category II and Category IIIB. After reviewing public comments, FDA would publish a final order on the matters covered in the proposed order.
In the Federal Register of November 21, 1980 (45 FR 77135), FDA issued a notice of availability of the Panel's final report. In the Federal Register of December 13, 1985 (50 FR 51002), FDA issued a proposed rule that contained the full Panel report\2\ and FDA's response to the recommendations of the Panel (the December 1985 proposal) (Ref. 1). In the December 1985 proposal, FDA proposed regulatory categories (Category I, Category II, or Category IIIB as defined previously in this document) for each bacterial vaccine and toxoid reviewed by the Panel, and responded to other recommendations made by the Panel. The public was offered 90 days to submit comments in response to the December 1985 proposal.
\2\ In addition to publication in the Federal Register of December 13, 1985 (50 FR 51002), FDA is making the full Panel report available on FDA's Website at http://www.fda.gov/ohrms/dockets/default.htm. A copy of the Panel report is also available at the
The definition of Category IIIA as described previously in this document, was applied at the time of the Panel's review and served as the basis for the Panel's recommendations. In the Federal Register of October 5, 1982 (47 FR 44062), FDA revised Sec. 601.25 and codified Sec. 601.26, which established procedures to reclassify those products in Category IIIA into either Category I or Category II based on available evidence of effectiveness. The Panel recommended that a number of biological products be placed into Category IIIA. FDA assigned the review of those products previously classified into Category IIIA to the Vaccines and Related Biological Products Advisory Committee. FDA has addressed the review and reclassification of bacterial vaccines and toxoids classified into Category IIIA through a separate administrative procedure (see the Federal Register of May 15, 2000 (65 FR 31003), and May 29, 2001 (66 FR 29148)). Therefore, FDA does not further identify or discuss in this document any bacterial vaccines and toxoids classified into Category IIIA.
Comments on the December 1985 Proposal
FDA received four letters of comments in response to the December 1985 proposal. One letter from a licensed manufacturer of bacterial vaccine and toxoid products concerned the confidentiality of information it had submitted for the Panel's review. As provided in Sec. 601.25(b)(2), FDA considered the extent to which the information fell within the confidentiality provisions of 18 U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. 331(j), before placing the information in the public docket for the December 1985 proposal. Another comment from a member of the Panel provided an update of important scientific information related to bacterial vaccines and toxoids that had accrued since the time of the Panel's review. The letter did not comment on the December 1985 proposal nor did it contend that the newly available information should result in modification of the Panel's recommendations or FDA's proposed actions. FDA's responses to the comments contained in the remaining two letters follow.
As described previously in this document, FDA is considering those products proposed for Category IIIA in a separate rulemaking process.\3\ This proposal does not propose any action regarding the further classification of those products proposed for Category IIIA, including those proposed for Category IIIA for primary immunization. All manufacturers and others in the general public have been offered additional opportunity to comment on the final categorization of specific Category IIIA products in the above-noted process.
\3\ See the Federal Register of May 15, 2000 (65 FR 31003), containing the proposed order to reclassify Category IIIA products into Category I and Category II based on the review and recommendation of the Vaccines and Related Biological Products Advisory Committee.
(Comment 3) One comment concerned the generic order and wording for product labeling recommended by the Panel and which FDA proposed to adopt in its response to the Panel recommendation. The comment recommended that a labeling section concerning ``Overdose'' be included only when circumstances dictate. The comment stated that because all biological products are prescription products administered by health care providers, the risk of overdose should be greatly reduced.
FDA agrees that, in many cases, a labeling section in part 201 (21 CFR part 201) entitled ``Overdosage'' is not necessary. Section 201.56(d)(3) (21 CFR 201.56(d)(3)) of the labeling regulations provides that the labeling may omit any section or subsection of the labeling format (outlined in Sec. 201.56) if clearly inapplicable. The ``Overdosage'' section, provided for in Sec. 201.57(i) of the regulations, is omitted for many bacterial vaccine and toxoid products.
FDA is not considering comments on the Panel's report in this proposed rule
and proposed order. The Panel's recommendations are not binding but represent the scientific opinions of a panel of experts. FDA believes that the agency should not modify the statements and recommendations of the Panel as provided in its report, including through public comment. The purpose of the opportunity for comment is to allow comment on FDA's responses to the Panel's report and not on the Panel's report directly.
III. Proposed Categorization of Products--Proposed Order
Category I. Licensed biological products determined to be safe and effective and not misbranded. Table 1 of this document is a list of those products proposed in December 1985 by FDA for Category I. Under the ``Comments'' column, FDA notes those products for which FDA's proposed category differs from that recommended by the Panel. Products for which the licenses were revoked before the December 1985 proposal and that were already identified in the December 1985 proposal are not listed in the tables below. Products for which the licenses were revoked after the December 1985 proposal are identified in the ``Comments'' column. FDA proposes to adopt Category I as the final category for the following products.
Table 1.--Category I
Alpha Therapeutic Tetanus Immune
Although the Panel Corp., License No. Globulin (Human)
recommended that Tetanus 744
Immune Globulin (Human), manufactured by Alpha Therapeutic Corp., be placed in Category IIIB, FDA proposed that it be placed in Category I\1\
Advance Biofactures Collagenase
......................... Corp., License No. 383
Armour Pharmaceutical Tetanus Immune
Manufacturer's licensed Co., License No. 149 Globulin (Human)
name is now Centeon L. L. C. On July 26, 1999, FDA revoked the license for Tetanus Immune Globulin (Human) at the request of the manufacturer
Diphtheria and Tetanus On December 9, 1999, a Laboratories, Inc., Toxoids and Pertussis name change to Aventis License No. 711
Vaccine Adsorbed, and Pasteur, Inc. with an Diphtheria Antitoxin accompanying license number 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
BCG Vaccine, Botulism On February 24, 2000, a Laboratories, Ltd., Antitoxin (Types A, name change to Aventis License No. 73
B, and E), Botulism Pasteur, Ltd. with an Antitoxin (Type E), accompanying license Tetanus Toxoid
number change to 1280 was granted. On December 21, 2000, FDA revoked the license for Tetanus Toxoid at the request of the manufacturer
Cutter Laboratories, Plague Vaccine,
On October 5, 1994, the Inc., License No. 8 Tetanus Immune
manufacturing facilities Globulin (Human)
and 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 previous 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., Diphtheria and Tetanus On December 2, 1985, FDA License No. 56
Toxoids and Pertussis revoked the license for Vaccine Adsorbed
Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed at the request of the manufacturer
Glaxo Laboratories, BCG Vaccine
On July 17, 1990, FDA Ltd., License No.
revoked the license for 337
BCG Vaccine at the request of the manufacturer
Diphtheria Antitoxin, On July 17, 1990, FDA Sieroterapico
Diphtheria Toxoid revoked the license for Vaccinogeno Toscano Adsorbed, Tetanus Diphtheria Antitoxin at Sclavo, License No. Toxoid Adsorbed
the request of the 238
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, Cholera Vaccine,
On December 23, 1992, FDA Division American Tetanus Immune
revoked the license for Cyanamid Co.,
Tetanus Immune Globulin License No. 17
(Human) at the request of the manufacturer. On October 23, 1996, FDA revoked the license for Cholera Vaccine at the request of the manufacturer
Massachusetts Public Diphtheria and Tetanus Although the Panel Health Biologic
Toxoids Adsorbed, recommended that Tetanus Laboratories,
Antitoxin be placed in License No. 64
Tetanus Toxoids and Category IIIB, FDA Pertussis Vaccine proposed in the December Adsorbed, Tetanus and 1985 proposal that it be Diphtheria Toxoids placed in Category I. On Adsorbed (For Adult October 26, 1988, FDA Use), Tetanus
revoked the license for Antitoxin, Tetanus Typhoid Vaccine at the Immune Globulin
request of the (Human), Tetanus
manufacturer. On January Toxoid Adsorbed,
10, 1994, FDA revoked Typhoid Vaccine
the license for Tetanus Antitoxin at the request 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, Tetanus Immune
The manufacturer is now Division of Merck & Globulin (Human)
known as Merck & Co., Co., Inc, License
Inc. On January 31, No. 2
1986, FDA revoked the license for Tetanus Immune Globulin (Human) at the request of the manufacturer
Michigan Department Anthrax Vaccine
On November 11, 1998, a of Public Health, Adsorbed, Diphtheria name change to BioPort License No. 99
and Tetanus Toxoids Corporation (BioPort) and Pertussis Vaccine with an accompanying Adsorbed, Pertussis license number change to Vaccine Adsorbed, 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 November 20, 2000. The license for Pertussis Vaccine Adsorbed was revoked at the request of the manufacturer (BioPort) on April 22, 2003
Parke-Davis, Division Tetanus Immune
On November 19, 1983, FDA of Warner-Lambert Globulin (Human)
revoked the license for Co., License No. 1
Tetanus Immune Globulin (Human) at the request of the manufacturer
Swiss Serum and
Tetanus Antitoxin Although the Panel Vaccine Institute
recommended that Tetanus Berne, License No.
Antitoxin be placed in 21
Category IIIB, FDA proposes that it be placed in Category I. On March 13, 1980, FDA revoked the license for Tetanus Antitoxin at the request of the manufacturer
Tetanus Immune
The manufacturer is now Laboratories, Inc., Globulin (Human)
known as Baxter Hyland Therapeutics
Healthcare Corporation. Division, License
On July 27, 1995, FDA No. 140
revoked the license for Tetanus Immune Globulin (Human) at the request of the manufacturer
On May 29, 1987, FDA Illinois, License
revoked the license for No. 188
Wyeth Laboratories, Cholera Vaccine,
On December 23, 1992, FDA Inc, License No. 3 Tetanus Immune
revoked the license for Globulin (Human), Tetanus Immune Globulin Typhoid Vaccine
(Human) at the request (acetone
of the manufacturer. On inactivated), Typhoid September 11, 2001, FDA Vaccine (heat-phenol revoked the licenses for inactivated)
Cholera Vaccine and Typhoid Vaccine (both forms) at the request 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 commerce. In the December 1985 proposal, the agency disagreed with the Panel's recommendation as the product was manufactured only as a partially 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 IIIB. Biological products for which available data are insufficient to classify their safety and effectiveness and should not continue in interstate commerce. Table 2 of this document is a list of those products proposed by FDA for Category IIIB. We have not listed products for which FDA revoked the licenses before the December 1985 proposal but we identified them in the proposal. Products for which FDA revoked the licenses after the December 1985 proposal are identified in the ``Comments'' column.
Table 2.--Category IIIB
Diphtheria Toxoid On July 27, 1993, FDA Sieroterapico
revoked the license for Vaccinogeno Toscano
Diphtheria Toxoid at the Sclavo, License No.
request of the 238
Diphtheria Toxoid, On June 21, 1994, FDA Laboratories, Inc., Pertussis Vaccine revoked the license for License 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 Tetanus Toxoid
On October 11, 1989, FDA Health Biologic
revoked the license for Laboratories,
Tetanus Toxoid at the License No. 64
request of the manufacturer
Merck Sharpe & Dohme, Cholera Vaccine,
The manufacturer is now Division of Merke & Diphtheria and
known as Merck & Co., Co., Inc., License Tetanus Toxoids and Inc. On January 31, No. 2
Pertussis Vaccine 1986, FDA revoked the Adsorbed, Tetanus and licenses for all the Diphtheria Toxoids listed products at the Adsorbed (For Adult request of the Use), Tetanus Toxoid, manufacturer Typhoid Vaccine
Michigan Department Diphtheria Toxoid On November 12, 1998, the of Public Health, Adsorbed
name of the manufacturer License No. 99
was changed to BioPort, and the license number was changed to 1260. On November 20, 2000, FDA revoked the license for Diphtheria Toxoid Adsorbed at the request of the manufacturer
Wyeth Laboratories, Diphtheria Toxoid, On May 19, 1987, FDA Inc., License No.3 Diphtheria Toxoid revoked the licenses for Adsorbed, Pertussis all listed products at Vaccine
the request of the manufacturer
IV. Anthrax Vaccine Adsorbed--Proposed Order
The Panel Recommendation that Anthrax Vaccine Adsorbed be Placed in Category I (Safe, Effective, and Not Misbranded)
The Panel based its evaluation of the safety and efficacy of AVA on two studies: A well-controlled field study conducted in the 1950s, ``the Brachman study'' (Ref. 1a) and an open-label safety study conducted by the National Center for Disease Control (CDC, now the Centers for Disease Control and Prevention) (50 FR 51002 at 51058). The Panel also considered surveillance data on the occurrence of anthrax disease in the United States in at-risk industrial settings as supportive of the effectiveness of the vaccine (50 FR 51002 at 51059). In its proposed determination that the data support the safety and efficacy of AVA, FDA has identified points of disagreement with statements in the Panel report. However, FDA proposes that the data do support the safety and efficacy of the vaccine and, thus, FDA continues to accept the Panel's recommendation and proposes to place AVA in Category I.\4\
\4\ In October 2000, the Institute of Medicine (IOM) convened the Committee to Assess the Safety and Efficacy of the Anthrax Vaccine. In March 2002, the Committee issued its report: The Anthrax Vaccine: Is It Safe? Does It Work? (Ref. 2). The report concluded that the vaccine is acceptably safe and effective in protecting humans against anthrax.
In March 2003, six plaintiffs, known as John and Jane Doe 1 through 6, filed suit in the United States District Court for the District of Columbia (the Court) seeking the Court to enjoin the Anthrax Vaccination Immunization Program (AVIP) of the Department of Defense (DoD), and to declare AVA an investigational drug when used for protection against inhalation anthrax. On December 22, 2003, the Court issued a preliminary injunction enjoining inoculations under the AVIP in the absence of informed consent or a Presidential waiver.
Efficacy of Anthrax Vaccine Adsorbed
The Brachman study included 1,249 workers in four textile mills in the northeastern United States that processed imported goat hair. Of these 1,249 workers, 379 received anthrax vaccine, 414 received placebo, 116 received incomplete inoculations of
[[Page 78286]]
either vaccine or placebo, and 340 received no treatment but were monitored for the occurrence of anthrax disease as an observational group. The Brachman study used an earlier version of the protective antigen-based anthrax vaccine administered subcutaneously at 0, 2, and 4 weeks and 6, 12, and 18 months. During the trial, 26 cases of anthrax were reported across the four mills: 5 inhalation and 21 cutaneous anthrax cases. Prior to vaccination, the yearly average number of human anthrax cases was 1.2 cases per 100 employees in these mills. Of the five inhalation anthrax cases (four of which were fatal), two received placebo and three were in the observational group. Of the 21 cutaneous anthrax cases, 15 received placebo, 3 were in the observational group, and 3 received anthrax vaccine. Of the three cases in the vaccine group, one case occurred just prior to administration of the third dose, one case occurred 13 months after the individual received the third of the six doses (but no subsequent doses), and one case occurred prior to receiving the fourth dose of vaccine.
In its report, the Panel stated that the Brachman study results demonstrate ``a 93 percent (lower 95 percent confidence limit = 65 percent) protection against cutaneous anthrax'' and that ``inhalation anthrax occurred too infrequently to assess the protective effect of vaccine against this form of the disease.'' (50 FR 51002 at 51058). On the latter point, FDA does not agree with the Panel report. Because the Brachman comparison of anthrax cases between the placebo and vaccine groups included both inhalation and cutaneous cases, FDA has determined that the calculated efficacy of the vaccine to prevent all types of anthrax disease combined was, in fact, 92.5 percent (lower 95 percent confidence interval = 65 percent). The efficacy analysis in the Brachman study includes all cases of anthrax disease regardless of the route of exposure or manifestation of disease. FDA agrees that the five cases of inhalation anthrax reported in the course of the Brachman study are too few to support an independent statistical analysis. However, of these cases, two occurred in the placebo group, three occurred in the observational group, and no cases occurred in the vaccine group. Therefore, we propose the indication section of the labeling for AVA not specify the route of exposure, and the vaccine be indicated for active immunization against Bacillus anthracis, independent of the route of exposure.\5\
\5\ The Panel noted that it would be very difficult, if not impossible, to clinically study the efficacy of any anthrax vaccine (50 FR 51058). Further study raises ethical considerations, and the low incidence and sporadic occurrence of anthrax disease also makes further adequate and well-controlled clinical studies of effectiveness not possible.
As stated previously in this document, the Panel also considered epidemiological data--sometimes called surveillance data--on the occurrence of anthrax disease in at-risk industrial settings collected by the CDC and summarized for the years 1962-1974 as supportive of the effectiveness of AVA. In that time period, individuals received either vaccine produced by MDPH, now BioPort, or an earlier version of anthrax vaccine. Twenty-seven cases of anthrax disease were identified. Three cases were not mill employees but people who worked in or near mills; none of these cases had been vaccinated. Twenty-four cases were mill employees; three were partially immunized (one with one dose, two with two doses); the remainder (89 percent) were unvaccinated (50 FR 51002 at 51058). These data provide confirmation that the risk of disease still existed for those persons who were not vaccinated and that those persons who had not received the full vaccination series (six doses) were susceptible to anthrax infection, while no cases occurred in those who had received the full vaccination series.
In 1998, the DoD initiated the Anthrax Vaccination Program, calling for mandatory vaccination of service members. Thereafter, concerns about the vaccine caused the U.S. Congress to direct DoD to support an independent examination of AVA by the IOM. The IOM committee reviewed all available data, both published and unpublished, heard from Federal agencies, the manufacturer, and researchers. The committee in its published report concluded that AVA, as licensed, is an effective vaccine to protect humans against anthrax, including inhalation anthrax (Ref. 2). FDA agrees with the report's finding that certain studies in humans and animal models support the conclusion that AVA is effective against B. anthracis strains that are dependent upon the anthrax toxin as a mechanism of virulence, regardless of the route of exposure.\6\
\6\ For example: The Brachman study (Ref. 1a); the CDC epidemiological data described in the December 1985 proposal; Fellows (2001) (Ref. 3); Ivins (1996) (Ref. 4); Ivins (1998) (Ref. 5).
Safety of Anthrax Vaccine Adsorbed
CDC conducted an open-label study under an investigational new drug application (IND) between 1967 and 1971 in which approximately 7,000 persons, including textile employees, laboratory workers, and other at- risk individuals, were vaccinated with anthrax vaccine and monitored for adverse reactions to vaccination. The vaccine was administered in 0.5-mL doses according to a 0-, 2-, and 4-week initial dose schedule followed by additional doses at 6, 12, and 18 months with annual boosters thereafter. Several lots, approximately 15,000 doses, of AVA manufactured by MDPH were used in this study period. In its report, the Panel found that the CDC data ``suggests that this product is fairly well tolerated with the majority of reactions consisting of local erythema and edema. Severe local reactions and systemic reactions are relatively rare'' (50 FR 51002 at 51059).
The Panel's General Statement: Anthrax Vaccine, Adsorbed, Description of Product
``Anthrax vaccine is an aluminum hydroxide adsorbed, protective, proteinaceous, antigenic fraction prepared from a nonproteolytic, nonencapsulated mutant of the Vollum strain of Bacillus anthracis'' (50 FR 51002 at 51058).
The Panel's Specific Product Review: Anthrax Vaccine Adsorbed: Efficacy
Analysis--a. Efficacy--(2) Human. The vaccine manufactured by the Michigan Department of Public Health has not been employed in a controlled field trial. A similar vaccine prepared by Merck Sharp & Dohme for Fort Detrick was employed by Brachman * * * in a placebo- controlled field trial in
mills processing imported goat hair * * *. The Michigan Department of Public Health vaccine is patterned after that of Merck Sharp & Dohme with various minor production changes. (50 FR 51002 at 51059).
FDA has found that contrary to the Panel's statement, the vaccine used in the Brachman study was not manufactured by Merck Sharp & Dohme, but instead this initial version was provided to Dr. Brachman by Dr. G. Wright of Fort Detrick, U.S. Army, DoD (Ref. 1a). The DoD version of the anthrax vaccine used in the Brachman study was manufactured using an aerobic culture method (Ref. 8). Subsequent to the Brachman trial, DoD modified the vaccine's manufacturing process to, among other things, optimize production of a stable and immunogenic formulation of vaccine antigen and to increase the scale of manufacture. In the early 1960s, DoD entered into a contract with Merck Sharp & Dohme to standardize the manufacturing process for large-scale production of the anthrax vaccine and to produce anthrax vaccine using an anaerobic method. Thereafter, in the 1960s, DoD entered into a similar contract with MDPH to further standardize the manufacturing process and to scale up production for further clinical testing and immunization of persons at risk of exposure to anthrax spores. This DoD-MDPH contract resulted in the production of the anthrax vaccine that CDC used in the open- label safety study and that was licensed in 1970.
The Panel's Specific Product Review: Anthrax Vaccine Adsorbed: Labeling
Analysis--d. Labeling: The labeling seems generally adequate. There is a conflict, however, with additional standards for anthrax vaccine. Section 620.24 (a) (21 CFR 620.24(a)) defines a total primary immunizing dose as 3 single doses of 0.5 mL. The labeling defines primary immunization as 6 doses (0, 2, and 4 weeks plus 6, 12, and 18 months). (50 FR 51002 at 51059).
The dosing schedule for AVA has always consisted of six doses, a 0.5-mL dose at 0, 2, and 4 weeks, and then at 6, 12, and 18 months, followed by a subsequent 0.5-mL dose at 1 year intervals to maintain immunity. Prelicensure labels described the vaccination schedule as three initial doses, followed by three additional doses, and yearly subsequent doses, which is consistent with the additional standards of AVA that were originally published in October 1970, immediately before the licensure of AVA. The 1979 labeling referred to ``primary immunization'' as consisting of six injections, with recommended yearly subsequent injections. The 1987 labeling of AVA, subsequent to the Panel's report, described the vaccination schedule as ``primary immunization'' consisting of three doses followed by three additional doses for a total of six doses followed by annual injections. The labeling is not inconsistent with Sec. 620.24(a) (21 CFR 620.24(a)) before it was revoked by FDA in 1996 as part of a final rule that revoked 21 CFR part 620 and other biologics regulations because they were obsolete or no longer necessary (Ref. 9). Thus while use of the term ``primary'' has varied over time in reference to the AVA vaccination schedule, the licensed schedule itself has always consisted of six doses of 0.5 mL administered at 0, 2, and 4 weeks and 6, 12, and 18 months, followed by additional doses on an annual basis to maintain immunity.
Generic Order and Wording of Labeling; Amendment of Sec. 201.59
In the December 1985 proposal, FDA proposed that 6 months after publication of a final rule, manufacturers of products subject to this Panel review submit, for FDA's review and approval, draft labeling revised in conformance with the Panel's report and with the regulations. FDA proposed to require that the revised labeling accompany all products initially introduced or initially delivered for introduction into interstate commerce 30 months after the date of publication of the final rule. The proposed labeling review schedule was consistent with the scheduling provided in Sec. 201.59 of the regulations.
Since the time of the Panel's recommendation, FDA has made a number of changes to the labeling regulations and related regulatory policies. FDA has added or revised the requirements in Sec. 201.57 for including in the labeling, in standardized language, the information concerning use during pregnancy, pediatric use, and geriatric use. Section 201.57 requires a specific order and content for drug product labeling. A number of labeling sections included in Sec. 201.57 were not included in the Panel's recommended ordering and wording of the labeling but are now required to help ensure clarity in the labeling. FDA has also provided guidance regarding the wording of sections in which the agency believes complete and consistent language is important. Because FDA regularly monitors labeling for the products subject to this Panel review to determine if the labeling is consistent with applicable labeling requirements, FDA does not believe that a labeling review is necessary at this time. Accordingly, FDA proposes to amend the table in Sec. 201.59 by providing that the labeling requirements in Sec. Sec. 201.56, 201.57, and 201.100(d)(3) (21 CFR 201.100(d)(3)) become effective on the date 30 months after the date of publication of the final rule. Because FDA regularly monitors the labeling of all products on an ad hoc basis, FDA also proposes to explain in a footnote to the table in Sec. 201.59(a)(3) that specification of a date for submission of
revised product labeling under Sec. 201.59 is unnecessary.
Section 314 of the National Childhood Vaccine Injury Act (NCVIA) of 1986 required FDA to review the warnings, use instructions, and precautionary information that are distributed with each vaccine listed in section 2114 of the Public Health Service Act and to determine whether this information was adequate to warn health care providers of the nature and extent of the dangers posed by such vaccine. Since the December 1985 proposal, FDA has completed this review and labeling has been revised accordingly. FDA is also taking this opportunity to propose updating the table in Sec. 201.59(a)(3) to include the current mail codes for the review of labeling for various biological products.
Periodic Review of Product Labeling
Improvement in the Reporting of Adverse Reactions
Periodic Review of Product Licenses
Compensation for Individuals Suffering Injury From Vaccination
A compensation program has been implemented consistent with the Panel's recommendation. The NCVIA established the National Vaccine Injury Compensation Program (NVICP) designed to compensate individuals, or families of individuals, who have been injured by childhood vaccines, whether administered in the private or public sector. The NVICP, administered by the Health Resources and Services Administration, Department of Health and Human Services (HHS), is a no- fault alternative to the tort system for resolving claims resulting from adverse reactions to routinely recommended childhood vaccines. The specific vaccines and injuries covered by NVICP are identified in a Vaccine Injury Table that may periodically be revised as new vaccines come into use or new types of potential injuries are identified. The NVICP has resulted in a reduction in the amount of litigation related to injury from childhood vaccines while assuring adequate liability coverage and protection. The NVICP applies only to vaccines routinely recommended for infants and children. Vaccines recommended for adults are not covered unless they are routinely recommended for children as well, e.g., Hepatitis B Vaccine.
Public Support for Immunization Programs
The National Immunization Program is part of CDC and was established to provide leadership to health agencies in planning and implementing immunization programs, to identify unvaccinated populations in the United States, to assess vaccination levels in state and local areas, and to generally promote immunization programs for children, including vaccination against diphtheria, tetanus, and pertussis. A
recent survey shows that nearly 95 percent of children 19 to 35 months of age have received three or more doses of any vaccine that contained diphtheria and tetanus toxoids (i.e., diphtheria and tetanus toxoids and pertussis vaccines (DTP), diphtheria and tetanus toxoids and acellular pertussis vaccines (DTaP) or diphtheria and tetanus toxoids vaccines (DT)) (Ref. 12).
Assuring Adequate Supplies of Bacterial Vaccines and Toxoids; Establishment of a National Vaccine Commission
Consistency of Efficacy Protocols
Standards for Determining the Purity of Diphtheria and Tetanus Toxoids (DTs)
Immunogenic Superiority of Adsorbed Toxoids Over Fluid Toxoids
The animal potency tests currently required by the WHO, the European Pharmacopoeia (EP), and FDA differ. Despite these differences, the potency
tests have been adequate to ensure sufficient immunogenic activity of the vaccines to induce protective immunity in target populations. However, international efforts to harmonize the diphtheria and tetanus potency tests under development are based on immunogenicity in animals. CBER is currently participating in these international harmonization efforts.
Potency Testing of DTs for Pediatric Use
Potency Requirements for Pertussis Vaccine
Weight-Gain Test in Mice for Pertussis Vaccine
At the time of the Panel's deliberations, only DTP vaccines containing a whole-cell pertussis component were licensed in the United States. The mouse weight-gain test was a toxicity test used for whole- cell pertussis vaccines. Whole-cell pertussis vaccines are no longer licensed in the United States for human use, thus the mouse weight-gain test is no longer in use. Currently, only DTP vaccines containing an acellular pertussis component (DTaP) are licensed in the United States. These vaccines are tested specifically for residual pertussis toxin activity.
Agglutination Test to Determine Pertussis Vaccine Response in Humans
Warnings in Labeling for Pertussis Vaccine
Field Testing of Fractionated Pertussis Vaccines
Use of Same Seed Lot Strain in Manufacturing Bacillus Calmette- Guerin (BCG) Vaccine
Development of an Improved Cholera Vaccine
Plague Vaccine Immunization Schedule
A primary series of 3 intramuscular (IM) injections (1 mL, 0.2 mL, and 0.2 mL), 1 and 6 months apart, respectively;
Booster IM injections of 0.2 mL at 12, 18, and 24 months; and,
For persons achieving a titer of 1:128 after the third and fifth inoculations, booster doses when the passive agglutination titer falls below 1:32 and empirically every 2 years when the patient cannot be tested serologically.
Because of limited resources, FDA also supports the leveraging of resources to create effective collaborations in the advancement of science. FDA has issued a ``Guidance for FDA Staff: The Leveraging Handbook, an Agency Resource for Effective Collaborations.'' (Ref. 19). Through cooperation with international, other Federal, and State health care agencies and the industry and academia, the agency intends that its research resources will reap the benefits of a wide range of experience, expertise, and energy from the greater scientific community while the agency maintains its legal and regulatory obligations. FDA invites comment at any time on ways it may improve its research program and set its objectives.
In the December 1985 proposal, FDA proposed to amend Sec. 610.21 (21 CFR 610.21), limits of potency, by revising the potency requirements for Tetanus Immune Globulin (Human) (TIG). FDA proposed to amend the regulations to require a minimum potency of 250 units of tetanus antitoxin per container for TIG. FDA advises that in this discussion and in the proposed regulation, ``per container'' means that amount of the contents of the container deliverable to the patient in normal use. The current regulation provides for a minimum potency of 50 units of tetanus antitoxin per milliliter of fluid. FDA proposes the change because the concentration of antitoxin per milliliter has varied widely in the past without any apparent effect on the performance of the product. TIG is routinely manufactured consistently at a concentration of 170 units per milliliter. However, there was no evidence upon which to establish a revised minimum potency on a per milliliter basis. Because the evidence of efficacy for TIG was based on use of product administered consistently at doses of 250 units or larger and the varying concentration of the product without any apparent adverse effect, FDA proposes that it is more appropriate to regulate the potency on a per vial basis, rather than by units per milliliter. The current licensed product continues to be marketed at a potency no less than the minimum dose (250 units), which historically has been shown to be clinically effective.
FDA received no comments opposing the proposed revision to Sec. 610.21 and therefore proposes to amend the regulations to require a minimum potency of 250 units of tetanus antitoxin per container for TIG.
Review Under Executive Order 12866, the Regulatory Flexibility Act, and the Unfunded Mandates Act of 1995
The agency believes that this proposed rule is consistent with the
regulatory philosophy and principles identified in the Executive Order. In addition, this proposed rule is not a significant regulatory action as defined by the Executive Order and so is not subject to review under the Executive Order. Because this proposed rule does not impose new requirements on any entity it has no associated compliance costs, and the agency certifies that the proposed rule will not have a significant economic impact on a substantial number of small entities. Therefore, under the Regulatory Flexibility Act, no further analysis is required. Because this proposed rule does not impose mandates on State, local, or tribal governments, in the aggregate, or the private sector, that will result in an expenditure in any one year of $100 million or more, FDA is not required to perform a cost benefit analysis under the Unfunded Mandates Reform Act. The current inflation adjusted statutory threshold is approximately $110 million.
The full Panel Report was incorporated into the ``Biological Products; Bacterial Vaccines and Toxoids; Implementation of Efficacy Review,'' proposed rule, published in the Federal Register of December 13, 1985 (50 FR 51002).
1a. Brachman, P. S.; H. Gold; S. Plotkin; F. R. Fekety; M. Werrin; and N. R. Ingraham, ``Field Evaluation of a Human Anthrax Vaccine,'' American Journal of Public Health, 52:632-645, 1962.
Joellenbeck, Lois M.; Lee L. Zwanziger; Zane S. Durch; and Brian L. Strom; Editors, Committee to Assess the Safety and Efficacy of the Anthrax Vaccine, Medical Follow-Up Agency, The National Academies Press, Washington, DC, April 2002, http://www.nap.edu/catalog/10310.html (FDA has verified the Web site address, but we
are not responsible for subsequent changes to the Web site after this document publishes in the Federal Register).
Fellows, P. F.; M. K. Linscott; B. E. Ivins; M. L. M. Pitt; C. A. Rossi; P. H. Gibbs and A. M. Friedlander, ``Efficacy of a Human Anthrax Vaccine in Guinea Pigs, Rabbits, and Rhesus Macaques Against Challenge by Bacillus Anthracis Isolates of Diverse Geographical Origin,'' Vaccine 19(23/24):3241-3247, 2001.
Ivins, B. E.; P. F. Fellows; M. L. M. Pitt; J. E. Estep; S. L. Welkos; P. L.Worsham and A. M. Friedlander, ``Efficacy of a Standard Human Anthrax Vaccine Against Bacillus Anthracis Aerosol Spore Challenge in Rhesus Monkeys,'' Salisbury Medical Bulletin 87(Suppl.):125-126, 1996.
Ivins, B. E.; M. L. M. Pitt; P. F. Fellows; J. W. Farchaus; G. E. Benner; D. M. Waag; S. F. Little; G. W. Anderson, Jr.; P. H. Gibbs; and A. M. Friedlander, ``Comparative Efficacy of Experimental Anthrax Vaccine Candidates Against Inhalation Anthrax in Rhesus Macaques,'' Vaccine, 16(11/12):1141-1148, 1998.
Anthrax Vaccine Adsorbed (BIOTHRAX) Package Insert (January 31, 2002).
Reports and evaluation of reports of adverse events following administration of anthrax vaccine received by the Federal Vaccine Adverse Event Reporting System (VAERS) through November 2004.
Wright, G. G.; T. W. Green; and R. G. Kanode, Jr., ``Studies on Immunity in Anthrax: V. Immunizing Activity of Alum-Precipitated Protective Antigen,'' Journal of Immunology, 73:387-391, 1954.
61 FR 40153, August 1, 1996.
``Table of Reportable Events Following Vaccination,'' http://www.vaers.org/reportable.htm. (FDA has verified the Web site
address, but we are not responsible for subsequent changes to the Web site after this document publishes in the Federal Register).
``Guidance for Industry: How to Complete the Vaccine Adverse Event Reporting System Form (VAERS-1),'' September 1998, http://www.fda.gov/cber/gdlns/vaers-1.pdf. (FDA has verified the Web site
``Estimated Vaccination Coverage With 3+DTP Among Children 19-35 Months of Age by Race/Ethnicity, and by State and Immunization Action Plan Area--U.S., National Immunization Survey, Q3/2000 - Q2/ 2001'', http://www.cdc.gov/nip/coverage/NIS/00-01/tab19-3dpt_race_iap.htm. (FDA has verified the Web site address, but we are not
responsible for subsequent changes to the Web site after this document publishes in the Federal Register).
Protecting Our Kids: What Is Causing the Current Shortage in Childhood Vaccines?--Testimony Before the Committee on Governmental Affairs, United States Senate, June 12, 2002, http://www.cdc.gov/nip/news/testimonies/vac-shortages-walt-6-12-2002.htm. (FDA has
verified the Web site address, but we are not responsible for subsequent changes to the Web site after this document publishes in the Federal Register).
Colditz, et al., ``Efficacy of BCG Vaccine in the Prevention of Tuberculosis: Meta Analysis of the Published Literature'', Journal of the American Medical Association, 271:698-702, 1994.
http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3755t1.pdf 16.http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3805t2_01.pdf
http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3805t2--
http://www.fda.gov/ohrms//dockets/ac/02/transcripts/3842t1.pdf
http://www.fda.gov/cber/gdlns/leverhnbk.pdf
PART 201--LABELING
The authority citation for 21 CFR part 201 continues to read as follows:
Section 201.59 is amended in the table in paragraph (a)(3) by:
Removing ``HFB-240'' everywhere it appears and adding in its place ``HFM-99'' in the BIOLOGICS section of the table, under ``Mail Routing Code'';
Revising the entries for the drug classes ``Bacterial vaccines and toxoids with standards of potency'' and ``Viral and rickettsial vaccines'' in the BIOLOGICS section of the table to read as follows.
Sec. 201.59 Effective date of Sec. Sec. 201.56, 201.57, 201.100(d)(3), and 201.100(e).
[Insert date 30 See footnote\3\ Bacterial vaccines HFM-99 months after
and toxoids with date of
standards of publication in
potency the Federal Register]
* Nov. 1, 1982\1\ Nov 1, 1980\2\ Viral and
HFM-99 rickettsial vaccines * *
\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 Sec. 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 Sec. 601.25(g) of this chapter. \3\ FDA has determined that a review of product labeling under this section is unnecessary.
PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS
The authority citation for 21 CFR part 610 continues to read as follows:
Section 610.21 is amended by revising the entry ``Tetanus Immune Globulin (Human), 50 units of tetanus antitoxin per milliliter'' under the heading ``ANTIBODIES'' to read as follows:
* * * * * ANTIBODIES * * * * *
Tetanus Immune Globulin (Human), 250 units of tetanus antitoxin per container. * * * * *
Dated: December 21, 2004. Jeffrey Shuren, Assistant Commissioner for Policy.