Biological Products; Bacterial Vaccines and Toxoids; Implementation of Efficacy Review; Anthrax Vaccine Adsorbed; Final Order, 75180-75198 [05-24223]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 70, Number 242 (Monday, December 19, 2005)]
[Notices]
[Pages 75180-75198]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 05-24223]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 1980N-0208]


Biological Products; Bacterial Vaccines and Toxoids; 
Implementation of Efficacy Review; Anthrax Vaccine Adsorbed; Final 
Order

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) proposed, among other 
things, to classify Anthrax Vaccine Adsorbed (AVA) on the basis of 
findings and recommendations of the Panel on Review of Bacterial 
Vaccines and Toxoids (the Panel) on December 13, 1985. The Panel 
reviewed the safety, efficacy, and labeling of bacterial vaccines and 
toxoids with standards of potency, bacterial antitoxins, and immune 
globulins. After the initial final rule and final order was vacated by 
the United States District Court for the District of Columbia on 
October 27, 2004, FDA published a new proposed rule and proposed order 
on December 29, 2004. The purpose of this final order is to categorize 
AVA according to the evidence of its safety and effectiveness, thereby 
determining if it may remain licensed and on the market; issue a final 
response to recommendations made in the Panel's report, and; respond to 
comments on the previously published proposed order. The final rule and 
final order concerning bacterial vaccines and toxoids other than AVA is 
published elsewhere in this issue of the Federal Register.

DATES: The final order on categorization of AVA is effective December 
19, 2005.

FOR FURTHER INFORMATION CONTACT: Kathleen Swisher, Center for Biologics 
Evaluation and Research (HFM-17), Food and Drug Administration, 1401 
Rockville Pike, Suite 200N, Rockville, MD 20852-1448, 301-827-6210.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction
II. Background
    A. General Description of the ``Efficacy Review'' for Biological 
Products Licensed Before July 1972
    B. The December 1985 Proposal
    C. Additional Proceedings Following the December 1985 Proposal
III. Categorization of Anthrax Vaccine Adsorbed--Final Order
    A. Efficacy of Anthrax Vaccine Adsorbed
    B. Safety of Anthrax Vaccine Adsorbed
    C. The Panel's General Statement: Anthrax Vaccine, Adsorbed, 
Description of Product
    D. The Panel's Specific Product

[[Page 75181]]

Review: Anthrax Vaccine Adsorbed: Efficacy
    E. The Panel's Specific Product Review: Anthrax Vaccine Adsorbed: 
Labeling
IV. Comments on the December 2004 Anthrax Vaccine Adsorbed (AVA) 
Proposed Order and FDA's Responses
    A. Comments Supporting Placing AVA into Category I
    B. Comments on the Evidence of Safety and Effectiveness of AVA
1. Brachman Study
2. CDC Surveillance Data
3. CDC Open Label Safety Study
4. DoD Pilot Study and Safety Data
5. Long-Term Safety Monitoring and Additional Studies
    C. Comments Describing Adverse Events
1. Review of Adverse Event Reports Submitted to the Docket
2. Summary of Adverse Event Reports Submitted to the Docket
    D. Comments on the Vaccine Used in the Studies
    E. Comments about Allegedly Contaminated Vaccine and Inspectional 
Observations
    F. Comments on Labeling
    G. Additional Comments
    H. Comments on Matters Outside the Scope of this Proceeding
V. FDA's Responses to Additional Panel Recommendations
VI. References

I. Introduction

    Biological products licensed before July 1972 are subject to a 
review procedure described in Sec.  601.25 (21 CFR 601.25). AVA was 
licensed before July 1972. The purpose of this document is to: (1) 
Categorize AVA under Sec.  601.25 according to the evidence of its 
safety and effectiveness, thereby determining if it may remain licensed 
and on the market, (2) issue a final response to recommendations made 
in the Panel's report, and (3) respond to comments on the proposed 
order (69 FR 78281, December 29, 2004).

II. Background

A. General Description of the ``Efficacy Review'' for Biological 
Products Licensed Before July 1972

    In 1972, in an effort to assure that regulatory standards for drugs 
and biological products were harmonized, the National Institutes of 
Health (NIH) announced a review of all licensed biological products (37 
FR 5404, March 15, 1972). However, on July 1, 1972, NIH's Division of 
Biologics Standards, which had been charged with administering and 
enforcing the licensing provisions of the Public Health Service Act, 
was transferred to FDA (37 FR 12865, June 29, 1972). FDA then assumed 
responsibility for reviewing the previously licensed biological 
products. In the Federal Register of February 13, 1973 (38 FR 4319), 
FDA issued procedures for the review of the safety, effectiveness, and 
labeling of biological products licensed before July 1, 1972. This 
process was eventually codified in Sec.  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 each 
review of a biological product 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 the initial review of each of the 
six biological product categories to a separate independent advisory 
panel consisting of qualified experts. Each panel was charged with 
preparing for the Commissioner of Food and Drugs an advisory report 
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 I, designating those biological products 
determined by the panel to be safe, effective, and not misbranded.
     Category II, designating those biological products 
determined by the panel to be unsafe, ineffective, or misbranded.
     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 its report, the panel could also include recommendations 
concerning any condition relating to active components, labeling, tests 
appropriate before release of products, product standards, or other 
conditions necessary or appropriate for a biological product's safety 
and effectiveness.
    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.

B. The December 1985 Proposal

    The Panel was convened in a July 12, 1973, organizational meeting, 
which was followed by multiple working meetings until February 2, 1979. 
The Panel completed its final report in August 1979. In that report, 
the Panel found that AVA, manufactured by Michigan Department of Public 
Health (MDPH, now BioPort), License No. 99,\1\ was safe and effective 
for its intended use and recommended that the vaccine be placed into 
Category I. The Panel based its evaluation of the safety and efficacy 
of AVA on two studies: The Brachman study, a well-controlled field 
study conducted in the 1950s (Ref. 1), 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, 
December 13, 1985). 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, December 13, 1985).
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    \1\On December 17, 1965, the company name was changed from the 
Division of Laboratories, Michigan Department of Health to the 
Bureau of Laboratories, Michigan Department of Public Health. On 
April 10, 1979, the name was changed to the Michigan Department of 
Public Health. On May 14, 1996, the name was changed to the Michigan 
Biologics Products Institute. On November 11, 1998, FDA accepted a 
name change to BioPort Corporation (BioPort) with an accompanying 
license number change to 1260.
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    In the Federal Register of December 13, 1985 (50 FR 51002), FDA 
issued a proposed rule that contained the full Panel report on 
bacterial vaccines and toxoids with standards of potency,

[[Page 75182]]

including the anthrax vaccine,\2\ and FDA's response to the 
recommendations of the Panel (the December 1985 proposal). 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. FDA agreed with 
the Panel's recommendation and proposed to place AVA into Category I.
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    \2\In addition to publication in the Federal Register of 
December 13, 1985 (50 FR 51002), the full Panel report is available 
on FDA's Web site at https://www.fda.gov/ohrms/dockets/default.htm 
(Docket No. 1980N-0208). A copy of the Panel report is also 
available at the Division of Dockets Management, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20852.
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    The public was provided 90 days to submit comments in response to 
the December 1985 proposal. FDA received four letters of comments in 
response to the December 1985 proposal, but none of those comments 
pertained to AVA. We discuss them in a final rule and final order 
concerning bacterial vaccines and toxoids other than AVA published 
elsewhere in this issue of the Federal Register.
    FDA 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)).

C. Additional Proceedings Following the December 1985 Proposal

    On October 12, 2001, a group of individuals filed a citizen 
petition requesting that FDA find AVA, as currently manufactured by 
BioPort, ineffective for its intended use, classify the product as 
Category II, and revoke the license for the vaccine. The petitioners 
complained that the December 1985 proposal that placed AVA into 
Category I had not been finalized. FDA responded separately in a 
written response to the petitioners on August 28, 2002 (Docket No. 
2001P-0471).
    In March 2003, six plaintiffs, known as John and Jane Doe 1 through 
6, filed suit in the U.S. District Court for the District of Columbia 
(the Court) asking the Court to enjoin the Anthrax Vaccine 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 of informed consent (see 
Sec.  50.23 (21 CFR 50.23)). Doe v. Rumsfeld, 297 F.Supp. 2d 119 
(D.D.C. 2003).
    In the Federal Register of January 5, 2004 (69 FR 255), FDA 
published a final rule and final order amending the biologics 
regulations and categorizing certain biological products in response to 
the report and recommendations of the Panel. The final order placed AVA 
into Category I. Following FDA's issuance of the final rule and final 
order, on January 7, 2004, the Court lifted the preliminary injunction 
except as it applied to the six Doe plaintiffs. Doe v. Rumsfeld, 297 
F.Supp. 2d 200 (D.D.C. 2004).
    On October 27, 2004, the Court issued a memorandum opinion vacating 
and remanding the January 2004 final rule and final order to FDA for 
reconsideration, requiring an additional opportunity for comment. Doe 
v. Rumsfeld, 341 F.Supp. 2d 1 (D.D.C. 2004). On December 29, 2004 (69 
FR 78280), FDA published a withdrawal of the January 5, 2004, final 
rule and final order. Concurrently with the withdrawal of the final 
rule and final order, FDA published again a proposed rule and proposed 
order (69 FR 78281) (the December 2004 proposal) to provide notice and 
to give interested persons an opportunity to comment on FDA's proposals 
relating to bacterial vaccines and toxoids classified into Category I, 
Category II, and Category IIIB, including AVA. In the December 2004 
proposal, FDA reopened the comment period for 90 days on the entire 
Bacterial Vaccines and Toxoids efficacy review document.
    Most of the comments received in response to the December 2004 
proposal pertained to the anthrax vaccine (AVA). We provide a response 
to comments about AVA under section IV of this document. A discussion 
of comments to the December 2004 proposal concerning bacterial vaccines 
and toxoids other than AVA is provided in a final rule and final order 
published elsewhere in this issue of the Federal Register.

III. Categorization of Anthrax Vaccine Adsorbed--Final Order

    After review of the comments and finding no additional scientific 
evidence to alter the proposed categorization, FDA accepts the Panel's 
recommendation and adopts Category I as the final category for AVA and 
determines AVA to be safe and effective and not misbranded.
    In this section of this document, we describe the data supporting 
our conclusion that AVA is safe and effective for its labeled 
indication to protect individuals at high risk for anthrax disease. 
Anthrax disease can be fatal despite appropriate antibiotic therapy. We 
also discuss points of disagreement with certain statements in the 
Panel's report.
    In order to provide clarity to the reader, we use the following 
terms to refer to studies relevant to this final order. The versions of 
vaccine used in these studies reflect the optimization of anthrax 
vaccine during product and clinical development.
    1. Brachman study--The Brachman study was an adequate and well-
controlled clinical study conducted from 1954 to 1959 to evaluate the 
effectiveness of the anthrax vaccine. The vaccine used in the Brachman 
study (the DoD vaccine) was supplied by Dr. G. G. Wright and associates 
of the U.S. Army Chemical Corps., Fort Detrick, Frederick, MD.
    2. CDC open label safety study--The CDC open label safety study was 
conducted from 1966 to 1971. Merck Sharp & Dohme (MSD) manufactured 
anthrax vaccine (DoD/MSD vaccine) under contract to DoD in 1960 and 
1961. The Michigan Department of Public Health (MDPH) also manufactured 
anthrax vaccine (DoD/MDPH/AVA) under contract to DoD starting in the 
mid-1960s. CDC used one lot of DoD/MSD vaccine and one lot of DoD/MDPH/
AVA vaccine in the first year of the CDC open label safety study, but 
only DoD/MDPH/AVA vaccine was used for the remainder of that study. The 
vaccine manufactured by MDPH was licensed by the NIH, Bureau of 
Biologics, in November 1970 as AVA. MDPH subsequently underwent a name 
change to Michigan Biologic Products Institute (MBPI) and later, 
BioPort Corporation (BioPort).
    3. DoD pilot study--The DoD pilot study was conducted from 1996 to 
1999. The purpose of the study was to make an initial assessment of the 
effects that alternative immunization schedules and/or an alternative 
route of administration may have on the safety and immunogenicity of 
AVA. The DoD pilot study used the licensed DoD/MDPH/AVA vaccine.

A. Efficacy of Anthrax Vaccine Adsorbed

    The Brachman study was conducted in four textile mills where, prior 
to initiation of the study, the yearly average number of human anthrax 
cases was 1.2 cases per 100 mill employees. These textile mills were 
located in the northeastern United States and processed imported goat 
hair. The study included 1,249 workers from these

[[Page 75183]]

mills. Of these 1,249 workers, 379 received anthrax vaccine, 414 
received placebo, 116 received incomplete inoculations of either 
anthrax 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 DoD vaccine administered subcutaneously 
at 0, 2, and 4 weeks and 6, 12, and 18 months. During the study, 26 
cases of anthrax were reported across the four mills: 5 inhalation and 
21 cutaneous anthrax cases. Of the five inhalation anthrax cases (four 
of which were fatal), two received placebo, three were in the 
observational group, and none received anthrax vaccine. 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'' (emphasis supplied) 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, December 13, 1985). We do not agree with the Panel's 
statement that the protection was limited to cutaneous anthrax cases. 
The Brachman study's comparison between anthrax cases in the placebo 
and vaccine groups included both inhalation and cutaneous anthrax 
cases. Accordingly, the calculated effectiveness of the vaccine to 
prevent both types of anthrax disease combined was 92.5 percent (lower 
95 percent confidence interval = 65 percent) as described in the 
Brachman, et al. report (Ref. 1). We agree that the cases of inhalation 
anthrax reported in the course of the Brachman study, if analyzed 
separately, are too few to support a meaningful statistical conclusion. 
However, the Brachman study's analysis of the effectiveness of the 
vaccine appropriately included all cases of anthrax disease that 
occurred in individuals who received at least three doses of vaccine or 
placebo and were on schedule for the remaining doses of the six-dose 
schedule regardless of the route of exposure or manifestation of 
disease, and was not limited to cutaneous cases. Thus, the study 
supports AVA's indication for active immunization against Bacillus 
anthracis, independent of the route of exposure.
    As stated previously in this document, the Panel also considered 
epidemiological data--which we refer to as the CDC surveillance data--
on the occurrence of anthrax disease in at-risk industrial settings 
collected by the CDC and summarized for the years 1962 to 1974, as 
supportive of the effectiveness of AVA. In that time period, 
individuals received either DoD/MDPH/AVA vaccine or an earlier version 
of anthrax vaccine. The Panel explained,
    Twenty-seven cases of anthrax disease were identified. Three 
cases were not mill employees but worked in or near mills; none of 
these cases had been vaccinated. Twenty-four cases were mill 
employees; three were partially immunized (one with 1 dose, two with 
2 doses); the remainder (89 percent) were unvaccinated. Therefore, 
no cases have occurred in fully vaccinated subjects while the risk 
of infection has continued. These observations lend further support 
to the effectiveness of this product.
(50 FR 51002 at 51058, December 13, 1985).
    In 1998, the DoD initiated the Anthrax Vaccine Immunization 
Program, calling for mandatory vaccination of service members. 
Thereafter, questions about the vaccine caused the U.S. Congress to 
direct DoD to support an independent examination of AVA by the 
Institute of Medicine (IOM).\3\ The IOM committee was charged with 
reviewing data regarding the efficacy and safety of the currently 
licensed anthrax vaccine--Anthrax Vaccine Adsorbed (AVA)--and assessing 
the efforts to resolve manufacturing issues and resume production and 
distribution of vaccine. 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.\4\ 
However, our review of AVA, is independent of the IOM's review. We 
discuss later in this document comments that we received related to the 
IOM review.
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    \3\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.
    \4\For example: The Brachman study (Ref. 1); the CDC 
surveillance data described in the December 1985 proposal; Fellows 
(2001) (Ref. 3); Ivins (1996) (Ref. 4); and Ivins (1998) (Ref. 5).
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B. Safety of Anthrax Vaccine Adsorbed

    CDC conducted the CDC open label safety study under an 
investigational new drug application (IND) between 1966 and 1971 in 
which approximately 7,000 persons, including textile employees, 
laboratory workers, and other at-risk individuals, were vaccinated with 
DoD/MDPH/AVA vaccine\5\ 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 DoD/MDPH/AVA vaccine 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).
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    \5\In addition, one lot of the DoD/MSD vaccine was used during 
the CDC open label safety study.
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    Subsequent to the publication of the Panel's recommendations, from 
1996 to 1999, DoD conducted the DoD pilot study, a small, randomized 
clinical study of AVA, administered by alternative route and schedules, 
compared to the vaccine administered according to the approved 
labeling. Safety data from the group that received the vaccine 
according to the labeling as well as post-licensure adverse event 
surveillance data available from the Vaccine Adverse Event Reporting 
System (VAERS), which FDA regularly reviews, further support the safety 
of AVA. These data provided the basis for labeling revisions approved 
by FDA in January 2002 (Ref. 6) to better describe the types and 
severities of adverse events associated with administration of AVA.

C. The Panel's General Statement: Anthrax Vaccine, Adsorbed, 
Description of Product

    The Panel report states:
    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 description of the anthrax vaccine has an inaccuracy. 
While the B. anthracis strain used in the manufacture of AVA is the 
nonproteolytic, nonencapsulated strain identified in the Panel report, 
it is not a mutant of the Vollum strain but was derived from a B. 
anthracis culture originally isolated from a case of bovine anthrax in 
Florida.

[[Page 75184]]

D. The Panel's Specific Product Review: Anthrax Vaccine Adsorbed: 
Efficacy

    The Panel report states:
    3. 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, December 13, 1985).
    FDA found that contrary to the Panel's statement, the vaccine used 
in the Brachman study was not manufactured by MSD, but instead this 
vaccine was manufactured by DoD and provided to Dr. Brachman by Dr. G. 
G. Wright of Fort Detrick, U.S. Army, DoD (Ref. 1). The DoD vaccine 
used in the Brachman study was manufactured using an aerobic culture 
method (Ref. 7). Subsequent to the Brachman study, DoD modified the 
vaccine's manufacturing process to, among other things, optimize 
production of a stable and immunogenic formulation of vaccine antigen 
and increase the scale of manufacture. In the early 1960s (after the 
Brachman study), DoD entered into a contract with MSD 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. This DoD-MDPH contract resulted in the 
production of the anthrax vaccine that CDC used in the CDC open label 
safety study and that was licensed in 1970.
    We have reviewed the historical development of AVA and conclude 
that DoD directed the development of the vaccine, including its 
formulation and manufacturing process, from the vaccine used in the 
Brachman study (DoD vaccine) to the vaccine that was ultimately 
licensed and manufactured by BioPort (DoD/MDPH/AVA vaccine). All three 
versions of anthrax vaccine, DoD vaccine, DoD/MSD vaccine, and DoD/
MDPH/AVA vaccine, were tested in animals and demonstrated to protect 
test animals (e.g., guinea pigs, rabbits) against challenge with 
virulent B. anthracis spores. In addition, there are clinical data 
comparing the safety and immunogenicity of DoD/MDPH/AVA vaccine with 
DoD vaccine. These data, while limited in the number of vaccinees and 
samples evaluated, reveal that the serological responses to DoD/MDPH/
AVA vaccine and DoD vaccine were similar with respect to peak antibody 
response and seropositivity.
    Under FDA's long-standing approach to comparability, a manufacturer 
may make manufacturing changes in a product without performing 
additional clinical studies to demonstrate the safety and effectiveness 
of the similar product if data regarding the manufacturing changes 
support the conclusion that the versions are comparable. Put another 
way, after a manufacturing change, a manufacturer may use data gathered 
with a previous version of its product to support the effectiveness of 
a comparable version of the same product. These principles are further 
reflected in FDA's ``Guidance Concerning Demonstration of Comparability 
of Human Biological Products, Including Therapeutic Biotechnology-
derived Products'' (1996) (Ref. 8). As discussed previously in this 
document, DoD vaccine and DoD/MDPH/AVA vaccine are comparable in their 
ability to protect test animals against challenge with virulent strains 
of B. anthracis and to elicit similar immune responses in humans.

E. The Panel's Specific Product Review: Anthrax Vaccine Adsorbed: 
Labeling

    The Panel report states:
    3. 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, December 13, 1985).
    The Panel was concerned with whether the vaccination schedule 
conformed to a standard set out in former Sec.  620.24(a), a rule that 
FDA revoked in 1996 with certain other biologics regulations because 
they were obsolete or no longer necessary (Ref. 9). The dosing schedule 
for AVA has always consisted of three doses of 0.5 mL administered in 
short succession at 0, 2, and 4 weeks, and three additional doses at 6, 
12, and 18 months, with additional doses at 1-year intervals to 
maintain immunity. However, the use of certain terminology has varied 
as discussed in this section of this document. Pre-licensure labeling 
(submitted to the license application with a letter dated January 25, 
1968) described the vaccination schedule as three initial doses, 
followed by three additional doses, and yearly subsequent doses. This 
schedule is consistent with the additional standards of AVA that were 
originally published on October 27, 1970 (35 FR 16631), 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, approved after the 
publication of the Panel's report, described the vaccination schedule 
as a ``primary immunization'' consisting of three doses followed by 
three additional doses (for a total of six doses), followed by annual 
injections. While the labeling has variously used the term ``primary'' 
to describe the AVA vaccination schedule, the licensed schedule itself 
has always consisted of three initial doses administered at 2-week 
intervals, followed by three additional doses at 6, 12, and 18 months, 
with additional annual doses to maintain immunity.

IV. Comments on the December 2004 Anthrax Vaccine Adsorbed (AVA) 
Proposed Order and FDA's Responses

    We received about 350 comments on the December 2004 proposal. Most 
comments related to AVA. To provide clarity to readers, we separated 
the AVA final order from the final rule and final order for other 
bacterial vaccines and toxoids. We are describing and responding to 
comments about AVA in this section of this document. Comments relating 
to other portions of the December 2004 proposal are discussed in a 
final rule and final order concerning bacterial vaccines and toxoids 
other than AVA published elsewhere in this issue of the Federal 
Register.
    We carefully reviewed all comments submitted to the Docket, 
including those attaching copies of articles and other references. 
However, a number of comments submitted to the Docket simply referred 
to articles or other publications, or to Web site materials, without 
providing copies of the materials. FDA regulations governing 
submissions to the Docket expressly provide that ``information referred 
to or relied upon in a submission is to be included in full and may not 
be incorporated by reference unless previously submitted in the same 
proceeding.'' (Sec.  10.20(c) (21 CFR 10.20(c)). Without a copy to 
review, we were unable to review all references cited but not included 
in the comments. We obtained and reviewed readily available recognized 
medical or scientific textbooks (see Sec.  10.20(c)(1)(iv)). The 
provision of Web site addresses, without substantive material, posed an 
additional problem. Since Web sites change continually, we were unable 
to review material at the Web site addresses provided with any

[[Page 75185]]

degree of certainty that the comment intended to incorporate the 
material we found. Also, many Web sites we checked contained irrelevant 
information. It was often difficult to determine a connection between 
the Web site and the comment's submission. FDA regulations require that 
only relevant information is to be submitted (Sec.  10.20(c)(3)) and 
failure to comply with these requirements results in exclusion from 
consideration of any portion of the comment that fails to comply (Sec.  
10.20(c)(6)).
    Many comments agreed with the Panel's recommendation that AVA is 
safe and effective and supported licensure of the vaccine; other 
comments advocated a need for a panel of experts to review in depth the 
data on AVA. Many of the comments did not support placing AVA into 
Category I as recommended by the Panel. Many comments described adverse 
events and suggested a relationship between the administration of AVA 
and the adverse events. Other comments recommended further testing of 
AVA through the conduct of clinical studies or other means. Numerous 
miscellaneous comments were received, some of which are not relevant to 
the proposed order. Many of the comments expressed an opinion about the 
conduct of vaccination administration programs, the need for 
compensation from public funds to individuals suffering injury from 
vaccinations, or other activities that are outside of FDA's 
jurisdiction, authority, and control.
    To make it easier to identify comments and our responses, the word 
``Comment,'' in parentheses, will appear before the description of 
comments, and the word ``Response,'' in parentheses, will appear before 
our response. We numbered the comments to help distinguish between 
different types of comments. The number assigned to a comment is purely 
for organizational purposes and does not signify the comment's value or 
importance or the order in which the comment was received.

A. Comments Supporting Placing AVA into Category I

    (Comment 1) We received a number of comments expressing support for 
the safety and effectiveness of AVA, and for FDA's proposal to accept 
the Panel's recommendation to place AVA into Category I. Some of these 
comments were specific in their support of the Brachman study as 
evidence of effectiveness against anthrax regardless of route of 
exposure; others discussed or described results of animal studies that 
they regarded as providing additional supporting evidence that AVA is 
effective in preventing inhalation anthrax. Some were from vaccine 
recipients and medical personnel who expressed support for the DoD 
vaccination program in its effort to protect military personnel from 
anthrax used as a biological weapon. Others were supportive of the work 
conducted by DoD to document and evaluate adverse events experienced by 
military personnel enrolled in the vaccination program.
    One comment was from a former director of the Division of 
Biological Standards (DBS) of the NIH and subsequently within the FDA, 
who stated his recollection that AVA had been subject to a careful 
review by DBS staff prior to approval in 1970. He stated that there 
have been three detailed, unbiased, and scientifically sound reviews, 
including the initial review by DBS, the expert Panel review in the 
1970s (published in the December 1985 Proposal), and the IOM review 
more recently; and all three reviews concluded that the vaccine is safe 
and effective. Two comments were submitted by scientists who had been 
clinical investigators in the Brachman study. One stated that during 
the study he was blinded to group assignment when evaluating the 
reactions; i.e., he did not know whether the subject had received the 
placebo or the vaccine. He also stated that the pathophysiology of 
human anthrax, regardless of where the organism gains entrance to the 
body, is a result of the toxin released by the organism. Thus, it is 
appropriate to combine inhalation and cutaneous disease in the 
analysis. The other scientist stated that the vaccine has demonstrated 
effectiveness in animal and human studies, as described in published 
scientific literature articles.
    We received comments from Army research scientists in support of 
placing AVA into Category I. One of these included tables of data from 
anthrax spore inhalation challenge studies in non-human primates and 
rabbits evaluating the effectiveness of AVA in prevention of death from 
disease. The comment noted that a high degree of protection was 
observed in these animals following only one or two doses of AVA, and 
that the IOM committee concluded that these animal models are 
representative of the human form of inhalation anthrax. Another 
research scientist also noted that, in addition to the Brachman study, 
inhalation anthrax challenge studies in non-human primates provide 
evidence of AVA's effectiveness in preventing disease caused by anthrax 
spores. Further, he noted that current knowledge of the pathogenesis of 
anthrax would indicate that, regardless of the route by which spores 
enter the body, toxins produced after those spores germinate into 
growing bacilli are essential for the anthrax organism to cause 
disease. Current scientific understanding of how the toxins work 
indicates that antibodies induced by AVA block the activities of 
anthrax toxins such that they would be effective in preventing any form 
of the disease regardless of the route of exposure to B. anthracis 
spores. Another researcher discussed further and in more detail how the 
pathology of cutaneous and inhalation anthrax at the cellular level is 
fundamentally the same, i.e., dependent upon the actions of anthrax 
toxin, such that cytotoxic activities are blocked by antibodies 
produced in response to AVA in the same manner despite the route of 
exposure.
    Military personnel involved in the vaccine's administration under 
the DoD vaccination program also filed comments in support of 
classifying AVA into Category I, reasoning that the vaccine is 
important for soldiers entering potentially dangerous areas; however, 
one comment stated that long-term use of the vaccine should be studied 
further. Another comment was submitted by a physician who thought that 
there was evidence that AVA protects against inhalation anthrax and 
that the side effects of vaccination were comparable to other adult 
vaccines. Comments supportive of placing AVA into Category I were also 
submitted by a representative of the Armed Forces Epidemiological Board 
(AFEB), a civilian advisory body to the Assistant Secretary of Defense 
for Health Affairs and the military Surgeons General. This comment 
described the AFEB deliberations on the use of anthrax vaccine by the 
military and the recommendations made by the AFEB to the DoD supporting 
use of AVA as an appropriate force protection measure. A representative 
of the Partnership for Anthrax Vaccine Education, a coalition of public 
and private organizations, also submitted comments reflecting that 
organization's support for placing AVA into Category I.
    (Response) We agree with those comments that provided support for 
placing AVA into Category I.

B. Comments on the Evidence of Safety and Effectiveness of AVA

    (Comment 2) Some comments were concerned about the safety of AVA.
    (Response) With regard to safety, FDA finds that AVA is safe for 
its indicated use as noted in the 2002 package insert:

[[Page 75186]]

    BioThrax [the Tradename for AVA] is indicated for the active 
immunization against Bacillus anthracis of individuals between 18 
and 65 years of age who come in contact with animal products such as 
hides, hair or bones that come from anthrax endemic areas, and that 
may be contaminated with Bacillus anthracis spores. BioThrax is also 
indicated for individuals at high risk of exposure to Bacillus 
anthracis spores such as veterinarians, laboratory workers and 
others whose occupation may involve handling potentially infected 
animals or other contaminated materials. (Ref. 6)
    The adverse reactions observed after administration of AVA in 
clinical study settings are described in the product labeling approved 
in 2002. At that time, FDA conducted an extensive review of the 
clinical study data from the DoD pilot study, reports from DoD safety 
surveys conducted as part of their Anthrax Vaccine Immunization 
Program, and reports submitted to the Vaccine Adverse Event Reporting 
System (VAERS). Since approval of the revised labeling in 2002, FDA has 
conducted periodic evaluations of the reports in the VAERS database, 
and, as discussed elsewhere in this document, continues to find AVA to 
be safe for its intended use: To protect individuals at high risk for 
anthrax disease. Anthrax disease can be fatal despite appropriate 
antibiotic therapy.
1. Brachman Study
    (Comment 3) Some comments expressed criticisms of the design and 
conduct of the Brachman study (Ref. 1).
    (Response) The Brachman study was an adequate and well-controlled 
clinical study that involved workers in four textile mills that 
processed imported goat hair in the northeastern United States. This 
selected population was at risk because the mill workers routinely 
handled anthrax-infected animal materials. Prior to vaccination, the 
yearly average number of human anthrax infections among workers in 
these mills was 1.2 cases per every 100 employees.
    The Brachman study design permitted a valid comparison of the 
vaccine group with the placebo control group to provide a quantitative 
assessment of effectiveness. For this study, employees with no known 
history of anthrax disease were assigned to one of two groups, 
treatment and placebo. The groups were balanced with regard to the 
individual's age, length of employment, department and job; both men 
and women were enrolled into the study. Voluntary cooperation was 
solicited and those who refused did not receive inoculations but were 
monitored for anthrax disease as part of the observational group. The 
subjects who chose to receive inoculations were not told whether they 
received anthrax vaccine or placebo. The published report of the 
Brachman study (Ref. 1) described all anthrax cases that occurred in 
the study, including ones in the vaccine, placebo, and observational 
groups. The Brachman study's efficacy analysis included only the cases 
that occurred in the treatment and placebo groups in completely 
vaccinated subjects (i.e., those receiving at least three inoculations 
and on schedule to receive the remaining three doses of the six-dose 
series), an approach that remains typical of vaccine analyses to date. 
We determine that the original statistical analysis presented in the 
report from the Brachman study was correct in its estimation of vaccine 
effectiveness. Some of the specific criticisms of the Brachman study 
included in the submitted comments claimed that the sample size was too 
small and that it was inappropriate to combine data from all four mills 
in the efficacy analysis.
    Clinical studies are designed with a sample size sufficient to 
assure with high probability that, if there is a true effect of the 
intervention under study, that effect will be ``detected;'' that is, a 
comparison of outcomes in the treatment and control groups will show a 
``statistically significant'' difference. To obtain the required sample 
size, investigators often have to implement the study at multiple sites 
(i.e., a multicenter study). The number of patients enrolled at any 
given site may be small, relative to the total number, and may not 
afford a high probability of achieving statistical significance at each 
individual site independently. Thus, when analyzing a multicenter 
clinical study, it is not reasonable to expect a statistically 
significant result at each site. Instead, consistent effects among 
individual study sites are the standard for multicenter studies (Ref. 
10).
    The Brachman study, a multicenter study, was based on an adequate 
sample size and appropriately combined the data from all mills in its 
analysis of vaccine efficacy. The site-specific data for the Brachman 
study are quite consistent in that at all sites, the vaccine group had 
fewer cases of anthrax than the placebo group. The strength of the 
overall finding of vaccine efficacy is such that, even with small 
numbers at each site, differences in outcome between the treatment and 
control groups are clearly statistically significant in one site and 
marginally significant in another. Thus, the site-specific data are 
fully supportive of the overall result, which showed a large reduction 
in risk of anthrax among those receiving vaccine.
    (Comment 4) One comment noted that a 1960 publication by Brachman 
et al. stated ``The efficacy of the anthrax cell-free antigen as a 
vaccine was not fairly tested in this epidemic. Although none of the 9 
cutaneous plus inhalation cases occurred in vaccinated individuals, 
only approximately one fourth of the employees had received the 
vaccine. There was an apparent difference in attack rates between 
workers who received placebo inoculations and those who received 
vaccine, but analysis of their job categories suggested that the 
vaccinated group was not at as high a risk as the placebo or 
uninoculated control groups.'' The comment makes several critical 
statements, based upon this 1960 publication, about FDA's reliance upon 
the Brachman study as evidence of vaccine effectiveness, claiming that 
the placebo group was at a greater risk of anthrax disease than the 
vaccine group.
    (Response) Prior to publication of the complete study report in 
1962, Brachman et al. published two papers (Refs. 11 and 12) describing 
the clinical features and epidemiology of an outbreak of inhalation and 
cutaneous anthrax cases that occurred in the Manchester, New Hampshire 
mill, one of the four mills included in the field study. The 
publication describing the epidemiology of that outbreak does include 
the statement quoted previously; however, the statement is specifically 
in reference to one study site and not to the field study as a whole, 
across the four woolen mills. The subsequent 1962 publication (Ref. 1) 
of the complete study across all four sites includes a table depicting 
participation of employees from all four mills included in the study. 
The table shows whether employees worked in high or low risk work areas 
and whether they received vaccine, placebo, or refused to participate 
in the study (Ref. 1 at Table 2). Of note, the totals for recipients of 
vaccine, placebo, incomplete inoculation and refusals in high risk work 
areas were 209, 226, 65 and 89, respectively. The same totals in low 
risk work areas were 170, 188, 51 and 251, respectively.
    The distribution of vaccine recipients, placebo recipients, and 
incompletely inoculated subjects was similar for both the high and low 
risk work areas, which means that the vaccine and placebo groups were 
balanced with regard to the exposure risk factor. A larger number of 
persons who did not participate in the study (observation group) were 
in the low risk work areas than in the high risk areas, but the 
efficacy analysis did not

[[Page 75187]]

include cases that occurred in the observational group. The 
effectiveness calculation described in the 1962 publication included 
the anthrax cases that occurred in participants who received at least 
three doses of either vaccine or placebo and remained on schedule for 
the remainder of the six doses for all four mills, not just the 
Manchester, New Hampshire mill described in the 1960 publications. 
Thus, FDA's consideration of the Brachman study as evidence of 
effectiveness is based upon the complete analysis across all four study 
sites.
    (Comment 5) One comment stated that it was inappropriate for the 
Brachman study to include both cutaneous and inhalation cases in the 
efficacy analysis.
    (Response) The efficacy analysis presented in the Brachman study 
includes both cutaneous and inhalation anthrax cases that occurred in 
individuals who received at least three doses of vaccine or placebo and 
were on schedule for the remaining doses of the six-dose schedule. It 
did not include cases that occurred in the observation group. Based on 
this analysis, the calculated effectiveness level against all reported 
cases of anthrax combined in those subjects was 92.5 percent (lower 95 
percent confidence interval = 65 percent). The efficacy analysis 
included the combined outcome of cutaneous and inhalation anthrax cases 
and thus included anthrax cases regardless of the route of exposure or 
manifestation of the disease.
    The inclusion of both cutaneous and inhalation cases of anthrax in 
the analysis of the Brachman study was appropriate because it was not 
possible to predict the route of exposure (cutaneous versus inhalation) 
that would occur within the environmental setting of the woolen mills. 
With regard to the known pathophysiology of anthrax, the signs and 
symptoms of disease arise due to the production of toxins by anthrax 
bacteria growing within the infected individual. The toxins produced by 
anthrax bacteria do not vary based on the route of exposure. The 
antibodies produced in response to vaccination contribute to the 
protection of the vaccinated individual by neutralizing the activities 
of those toxins. Thus, AVA elicits an antibody response to disrupt the 
cytotoxic effects of toxins produced by anthrax bacteria, regardless of 
the route of infection.
    (Comment 6) One comment stated that any decision by FDA to license 
AVA must provide a scientifically valid explanation of how FDA has 
assessed this vaccine's effectiveness against anthrax infection by 
inhalation in humans in the absence of an adequate and well-controlled 
clinical study specifically studying its effectiveness against anthrax 
infection by inhalation. The comment contends that in the absence of 
such data, or unless FDA uses the ``animal efficacy rule,'' FDA should 
not license AVA as a Category I biological product.
    (Response) AVA has been licensed since 1970. The Panel, as 
reflected in its report published in the December 1985 proposal, and 
the FDA, as reflected in this final order, have determined that AVA is 
safe and effective for its labeled indication, decisions based in part 
on the Brachman study, which was an adequate and well-controlled study. 
Even if the referenced ``animal efficacy rule''\6\ had been in effect 
at the time of AVA licensure, it would not have been applicable because 
there are sufficient data from adequate, well-controlled clinical 
studies to assess the safety and effectiveness of AVA as a vaccine 
against anthrax infection regardless of route of exposure. The ``animal 
efficacy rule'' does not apply to products that can be approved based 
on efficacy standards described in other regulations (Sec.  601.90 (21 
CFR 601.90)).
---------------------------------------------------------------------------

    \6\New Drug and Biological Drug Products; Evidence Needed to 
Demonstrate Effectiveness of New Drugs When Human Efficacy Studies 
Are Not Ethical or Feasible; Final Rule (21 CFR 601.90 through 
601.95) (67 FR 37988, May 31, 2002).
---------------------------------------------------------------------------

    (Comment 7) One comment pointed out that the route of exposure to 
an infectious agent can be a critical factor influencing vaccine 
effectiveness.
    (Response) We agree that the route of exposure to an infectious 
agent may potentially have an impact on the effectiveness of a vaccine. 
The impact likely depends on the nature of the infectious agent in 
terms of its mechanism of virulence and the pathophysiology of 
infection and disease, and the mechanism of protection afforded by the 
vaccine. The Brachman study showed the anthrax vaccine to be effective 
in preventing anthrax disease regardless of route of exposure (Ref. 1). 
This finding is consistent with our current knowledge of the critical 
role played by anthrax toxins in the pathophysiology of cutaneous and 
inhalation anthrax and how antibodies generated in response to 
vaccination with AVA disrupt cytotoxic activities of those toxins. 
Furthermore, aerosolized anthrax spore challenge studies in both 
rabbits and nonhuman primates do demonstrate the ability of AVA to 
protect the test animals against inhalation anthrax (Refs. 3, 4, and 
5).
    (Comment 8) One comment proposed that a vaccine would have to be 
inhaled in order to protect against inhalation anthrax, noting that the 
lungs are susceptible to anthrax.
    (Response) Vaccines generally do not need to be administered by the 
same route of exposure as the infectious agent uses to infect humans. 
In fact, there are numerous examples to the contrary. For example, 
vaccines against pertussis, pneumococcus, Hemophilus influenzae type b, 
meningococcus, measles, varicella, and influenza are administered by 
injection, although the infectious agents gain entry into humans by the 
respiratory route. The inactivated poliovirus vaccine is administered 
by injection, although the poliovirus infects humans by way of the 
intestinal tract. Although these vaccines are administered by a route 
that differs from the route of exposure, clinical trials have 
demonstrated their effectiveness against the targeted infectious 
disease. The same is true of anthrax vaccine. The vaccine is 
administered by injection, but has been shown to be effective against 
anthrax in a study that included both cutaneous and inhalation cases 
(Ref. 1). Furthermore, animal studies in which injected AVA protected 
animals from inhalation anthrax challenge are consistent with the 
finding of effectiveness in the clinical study. (Refs. 3, 4, and 5)
    (Comment 9) One comment stated that FDA has deviated from the 1985 
Panel recommendations (i.e., ``No meaningful assessment of its value 
against inhalation anthrax is possible due to its low incidence.'' 50 
FR 51002 at 51059) and that FDA should not dispute its advisory 
committee's analysis of the safety and effectiveness data.
    (Response) A critical component of the efficacy review process is 
FDA's consideration of the Panel's recommendations (Sec.  601.25(f)). 
Such consideration, by necessity, provides for the possibility that FDA 
might disagree with the Panel's recommendations. Indeed, in the 
preamble to Sec.  601.25, FDA stated that ``the report of each panel is 
advisory to the Commissioner, who has the final authority either to 
accept or to reject the conclusions and recommendations of the panel.'' 
(38 FR 4319 at 4321, February 13, 1973). As noted in section III.A of 
this document, and as stated in the December 2004 proposal, we do not 
agree with the Panel's assessment that the vaccine is 93 percent 
efficacious against cutaneous anthrax only. In fact, the calculation of 
effectiveness presented in the published report of the Brachman study 
pertains to both cutaneous and inhalation anthrax. The Brachman study 
included in the effectiveness calculation both the

[[Page 75188]]

cutaneous and inhalation cases that occurred in vaccine and placebo 
recipients who received at least three doses and remained on schedule 
to receive the rest of the six-dose series.
2. CDC Surveillance Data
    (Comment 10) One comment stated that the CDC surveillance data do 
not provide a reliable basis for an assessment of effectiveness 
because: (1) They represent the use of at least two earlier versions of 
anthrax vaccine, which are not the same vaccine currently produced by 
BioPort; (2) they are not statistically significant; and (3) these data 
may not be accurate and complete. Other comments asked why the CDC 
surveillance data for the years 1962 to 1974 are not regarded as 
supportive of safety of anthrax vaccine.
    (Response) During the time these surveillance data were collected 
by CDC, both DoD/MSD vaccine and DoD/MDPH/AVA vaccine were available 
for use. The DoD/MDPH/AVA vaccine was licensed in 1970 and is the same 
vaccine currently manufactured and distributed by BioPort. An 
additional response to comments regarding different versions of the 
anthrax vaccine is addressed later in this document.
    Although we do not consider the CDC surveillance data to be 
statistically significant, we regard the data as indicative that, 
during this time period, workers continued to be at risk of exposure, 
because anthrax cases were identified in unvaccinated and partially 
vaccinated individuals employed at woolen mills. The data are 
supportive of the effectiveness evidenced by the Brachman study, in 
that no anthrax cases were reported in fully vaccinated individuals 
during that time period. We do not regard the CDC surveillance data as 
contributing to an assessment of safety because the data do not 
describe adverse events occurring after vaccination.
    The comment provides no support for the conclusion that the CDC 
surveillance data were unreliable. The comment described an anecdotal 
report of an additional anthrax case that occurred in an unspecified 
year and apparently was not included in the CDC surveillance data. We 
recognize that there is a potential for underreporting in disease 
surveillance systems. However, this one report does not provide a basis 
for concluding that the CDC surveillance data were unreliable for the 
purposes of supporting the effectiveness of the vaccine.
3. CDC Open Label Safety Study
    (Comment 11) Some of the comments questioned the reliability of the 
CDC open label safety study, alleging that the open label safety study 
conducted by CDC ``made no attempt to identify, quantify or follow 
systemic adverse vaccine reactions'' and thus would be of no value in 
establishing vaccine safety, or that the study did not use consistent 
standards to identify and grade adverse events occurring at different 
study sites.
    (Response) As described previously in this document, FDA believes 
that there are adequate data to demonstrate the safety and 
effectiveness of AVA. Moreover, the CDC open label safety study 
appropriately collected and analyzed adverse event reports. The IND 
protocol for the CDC open label safety study included specific criteria 
to be used to categorize mild, moderate and severe local reactions 
reported in the course of the study. In addition, the annual study 
reports submitted to the IND included information regarding systemic 
reactions reported during the respective reporting periods, and those 
data are described in the current product labeling for AVA: ``In the 
same open label safety study, four cases of systemic reactions were 
reported during a five-year reporting period (<0.06% of doses 
administered). These reactions, which were reported to have been 
transient, included fever, chills, nausea and general body aches.'' 
(Ref. 6)
    (Comment 12) One comment claimed that one annual safety report for 
the CDC open label safety study might have underreported adverse 
reaction rates for that period, alleging that arithmetic 
miscalculations caused underreporting in one May 1967 reactogenicity 
table.
    (Response) The commenter refers to the May 1967 table included in 
an appendix to one of the annual reports to the CDC trial; the appendix 
describes a protocol and the results of a small safety and 
immunogenicity study comparing DoD vaccine and DoD/MDPH/AVA vaccine. 
The safety data from this small study were reported separately from the 
CDC open label safety study due to differences in protocol design, such 
as the administration of one-half volume booster doses to some subjects 
instead of the full 0.5 mL human dose. Inclusion of safety data from 
the small ancillary safety study with a different protocol design does 
not support the inference that the annual safety report for the CDC 
open label safety study might have underreported adverse reaction rates 
for that period.
    (Comment 13) One comment stated that in the course of the CDC open 
label safety study, Ft. Detrick and mill employees were required to be 
vaccinated as a condition of employment and therefore, they may have 
underreported adverse reactions to the vaccine from fear of losing 
their jobs. The comment also states that the employees did not provide 
free informed consent to participate in the study because they were 
compelled to be vaccinated, and no informed consent documents were 
signed by Ft. Detrick employees. Thus, the study did not comply with 
FDA requirements for informed consent.
    (Response) The comment provides no support for the assumption that 
subjects in the CDC open label safety study may have underreported 
adverse reactions to the vaccine. With regard to the statements that 
mill workers in the CDC open label safety study were compelled to be 
vaccinated, and therefore did not provide informed consent, and that 
the Ft. Detrick subjects in the study did not sign informed consent 
documents, we note that the CDC open label safety study was conducted 
under IND 180 from 1966 through 1971. The NIH was responsible for 
reviewing IND 180 and the subsequent marketing application for AVA 
under the regulations then in effect. Significantly, the NIH did not 
reject the study, or place it on hold. Moreover, the comment does not 
identify a legal basis for requiring FDA to reject the study for this 
reason.
    FDA is committed to assuring the protection of human subjects in 
clinical trials, as evidenced by the comprehensive regulations now in 
place (see FDA's current informed consent regulations, 21 CFR part 50, 
in effect since 1981, and IND regulations, 21 CFR part 312, in effect 
since 1987). Other data and studies, such as the DoD pilot study, 
conducted subsequent to the CDC open label safety study and under 
current informed consent regulations, provide additional safety 
evidence that corroborate the CDC open label safety study findings. We 
decline to reject the findings of the CDC open label safety study and 
we continue to view them as supportive of safety.
4. DoD Pilot Study and Safety Data
    (Comment 14) One comment inquired whether the results of the DoD 
pilot study relating to the vaccine's safety required changes to AVA 
labeling in 2002, and whether additional data were considered in 
support of the new labeling. Other comments asked whether the DoD pilot 
study was also regarded as supportive of effectiveness.
    (Response) BioPort voluntarily submitted to FDA proposed revised 
labeling for AVA for review and comment as part of an ongoing process 
of updating product and manufacturing information. In the course of 
FDA's review, revisions were made to the proposed labeling. Following 
our

[[Page 75189]]

review, in 2002 we approved revised product labeling that incorporated 
more recently acquired safety information from the DoD pilot study and 
FDA's ongoing review of reports to VAERS. The DoD pilot study was not 
intended to assess effectiveness; rather its purpose was to make an 
initial assessment of the effects that alternative immunization 
schedules and/or an alternative route of administration may have on the 
safety and immunogenicity of AVA.
    (Comment 15) One comment claimed that the 1996 to 1999 DoD pilot 
study as reported is entirely inadequate to determine the safety of 
AVA, noting that the study was ``uncontrolled'' and that a quarantined 
lot was used in the study.
    (Response) As discussed previously in this document, the CDC open 
label safety study, involving approximately 7,000 subjects who received 
DoD/MDPH/AVA vaccine,\7\ demonstrated the safety of AVA. The DoD pilot 
study, which included 28 subjects randomized to receive the licensed 
vaccin