[Federal Register: December 19, 2005 (Volume 70, Number 242)]
[Notices]
[Page 75180-75198]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr19de05-59]
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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 http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://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
vaccine according to the labeling, was conducted subsequent to
licensure and provided additional data in support of the safety of AVA.
The DoD pilot study was a controlled clinical study; the group
receiving AVA according to the licensed schedule and route of
administration served as the control group for the other groups
receiving the vaccine under alternative vaccination schedules and/or
route of administration. The purpose of the DoD pilot 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 alternative schedules were
alterations of the 0-2-4 week initial series of the licensed six-dose
schedule (i.e., 0-4 weeks, 0-2 weeks). These alternative schedules were
administered intramuscularly and subcutaneously. However, because one
of the arms of the study included individuals vaccinated according to
the labeling, we appropriately took such information into account as we
continued to assess the safety of AVA. In this arm of the study,
volunteers received subcutaneous doses of AVA according to the licensed
schedule. Each volunteer was scheduled for follow-up evaluations at 1
to 3 days, 1 week, and 1 month after vaccination, and reactions were
reported up to 30 days after each dose. For subjects who received the
vaccine according to the licensed route and schedule, the latest
follow-up occurred 30 days after the 18-month dose (Ref. 13).
---------------------------------------------------------------------------
\7\In addition, one lot of the DoD/MSD vaccine was used during
the CDC open label safety study.
---------------------------------------------------------------------------
In the December 2004 proposal, FDA discussed the safety data
collected under this study for subjects receiving the vaccine according
to the labeling. Similarly, descriptive information regarding adverse
reactions reported in individuals receiving the vaccine according to
the licensed schedule under this study was included in the 2002
labeling. Thus, the December 2004 proposal and the 2002 labeling
reported this recently acquired safety information, which had been
collected in a planned and prospective manner.
In addition, we believe no subjects in the study received
quarantined doses of lot FAV 016, the lot mentioned in the comment. We
understand that some subjects received lot FAV 032 while the voluntary
quarantine of that lot was being implemented. However, this information
does not provide an adequate basis for us to refuse to consider the
data derived from the study. It is important to note that one of the
chief uses of the study was as one of the bases for the expanded
description of adverse events included in the 2002 labeling. Thus, the
study results provided additional information for individuals
administering and receiving AVA. We believe that this limited use of
lot FAV 032 did not cause the results of the entire study to be
unreliable, particularly in light of the purposes for which we use the
data derived from this arm of the study. We will continue to monitor
all available sources of information relating to the safety of AVA.
(Comment 16) One comment was critical of the fact that the results
of the DoD pilot study were included in the 2002 labeling when the data
were not peer reviewed or available to the public.
(Response) FDA performs its own review of data that are submitted
in support of labeling changes. There is no requirement for peer review
of data submitted to FDA in support of a labeling change. The DoD pilot
study was intended to serve as a pilot study of alternative vaccination
schedules and an alternative route of administration (intramuscular) to
provide information for the design of a larger, more statistically
robust study of promising alternative vaccination schedules and route
of administration. The investigators published their report of this
study in a peer-reviewed journal (Ref. 13).
5. Long-Term Safety Monitoring and Additional Studies
(Comment 17) A number of comments discussed the absence of a long-
term safety study using AVA and the absence of studies of the potential
effects of vaccination on vaccine recipients' children.
(Response) The pre-licensure safety evaluation of a new vaccine may
include clinical studies that extend several months to several years
after administration of the first dose. For example, the CDC open label
safety study spanned from 1966 through 1971. Pre-licensure safety
studies focus on those adverse reactions closely associated with the
time of vaccine administration such as local injection site reactions
and systemic reactions such as fever, malaise and allergic reactions.
However, all serious adverse events that are reported during the
conduct of the study are evaluated regardless of when they occur
relative to vaccination. Longer-term controlled clinical trials (i.e.,
those extending more than several years after vaccination) are not
generally conducted prior to approval of any medical product, including
vaccine products.
The attribution to a vaccine or other drug product of adverse
events or health conditions that develop long after administration is
difficult to make with confidence because other factors such as
environmental exposures, general health, genetic predisposition, etc.,
may also contribute to the development of health problems, symptoms or
diseases. Elsewhere in this document, we provide a more detailed
discussion of FDA's approach to post-licensure safety monitoring of
AVA.
With regard to the potential effects of vaccination on offspring,
the current approved labeling for AVA addresses administration of AVA
to pregnant women. The labeling describes a preliminary assessment of
the possibility that an increase in the rate of birth defects may be
associated with AVA vaccination during pregnancy. Based upon the
limited information available, the vaccine was assigned a Pregnancy
Category D designation. The labeling states that ``Although these data
are unconfirmed, pregnant women should not be vaccinated against
anthrax unless the potential benefits of vaccination have been
determined to outweigh the potential risk to the fetus.'' (Ref. 6)
DoD has undertaken to verify these preliminary results. We will
review those results, when available, and we will continue to review
adverse events.
(Comment 18) Many comments expressed concern about FDA's process of
monitoring the safety of AVA.
(Response) For any drug or biological product, rare adverse events
not observed during pre-licensure clinical studies may occur post-
licensure. The
[[Page 75190]]
need to understand the relationship between vaccination and adverse
events that occur after licensure, and the limitations of clinical
trials, have led to the use of other methods to detect and evaluate the
link between vaccination and rare events. Post-marketing monitoring of
vaccine safety involves the identification of possible adverse effects
of vaccination, followed in some cases by evaluation of these
``signals'' for a possible causal link to the vaccine.
The most common method of signal generation is through the
evaluation of spontaneous reports of cases of adverse events reported
to manufacturers or government-sponsored systems such as the Vaccine
Adverse Event Reporting System (VAERS). The identification of
``signals'' and their prioritization for evaluation involves
qualitative and quantitative aspects, along with medical and
epidemiological judgment. Evaluation of signals can involve literature
review and clinical, laboratory, and epidemiological studies.
Surveillance for adverse events after vaccination is undertaken
using VAERS, which is jointly managed by FDA and CDC. Uses of VAERS
include detecting unrecognized adverse events, monitoring known
reactions, identifying possible risk factors, and vaccine lot
surveillance. Established in 1990, VAERS receives approximately 15,000
adverse event reports annually. Reports are submitted by vaccine
manufacturers, vaccine providers, other health care givers, vaccine
recipients and their relatives, attorneys, and other interested
parties. While vaccine manufacturers are responsible for investigating
and evaluating reports made to them, FDA and CDC also follow up reports
from other parties of deaths and adverse events resulting in life-
threatening illness, hospitalization, prolongation of hospitalization,
persistent or significant disability, or congenital anomaly/birth
defect, by telephone to obtain additional information about the event
and the patient's prior medical history.
Passive surveillance systems such as VAERS are subject to
limitations. Vaccine-associated adverse events will inevitably be
underreported to an unknown extent. Moreover, adverse events reported
in association with vaccination may or may not be caused by
vaccination. For example, some adverse events might be expected to
occur by coincidence after vaccination. Temporal associations often are
reported with little data to evaluate whether any causal connection
with the vaccine exists. Given these limitations, while safety signals
may be detected, incidence rates cannot be determined from VAERS data.
A particularly important limitation on the usefulness of VAERS reports
as a means of investigating the possible causal relationship between an
event and a vaccination generally is the lack of a direct, concurrent
and unbiased comparison group from which to determine the incidence of
the same type of adverse events among people who have not been
vaccinated.
Another important limitation is the lack of standardization of
diagnoses in VAERS reports. Reporting of unconfirmed diagnoses is
common with VAERS reports. On follow-up, initially reported diagnoses
are sometimes found to be inaccurate. Reports are coded by non-
physicians, without the benefit of standardized case definitions, using
the Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) to
describe the adverse event in a computerized database. Report coding
depends on the reporter's use of certain words or phrases. This results
in the use of the same COSTART term for reports with different degrees
of diagnostic precision. For example, a report may simply say, ``I
developed arthritis after I received the vaccine,'' without any other
supporting medical information. Such a report would likely be coded as
``arthritis,'' as would a report that included a complete medical
record in which a physician documents joint swelling and tenderness. As
a result, coding terms must be interpreted very cautiously.
Because of the limitations of passive surveillance data, it is
usually not possible to assess whether a vaccine caused the reported
adverse event, except for conditions such as injection site reactions,
some hypersensitivity conditions (e.g., anaphylaxis occurring shortly
after vaccination), and illnesses consistent with the naturally
occurring disease where vaccine components can be recovered from tissue
specimens (e.g., recovery of live attenuated vaccine virus from
vaccine-associated paralytic polio).
Analysis of VAERS data focuses on describing clinical and
demographic characteristics of reports and looking for patterns to
detect ``signals'' of adverse events plausibly linked to a vaccine. In
FDA's guidance document on ``Good Pharmacovigilance Practices and
Pharmacoepidemiologic Assessment'' (Ref. 14), we define a safety signal
as a concern about an excess of adverse events compared to what would
be expected to be associated with a product's use. This guidance
document also details approaches for signal evaluation. Evidence of a
signal in case reports and in case series of spontaneous reports
includes unexpected patterns in clinical conditions by such factors as
age, gender, time to onset, and dose. Three reports of an event can be
used as the minimum number for case series analysis of rare conditions.
Positive rechallenge is defined as the same event occurring after more
than one dose of the same vaccine in the same subject and may also be
considered evidence of a signal. Signals detected through analysis of
VAERS data do not necessarily represent a causal relationship with the
vaccine and almost always require confirmation through additional
study.
In addition to the approach combining descriptive epidemiology with
medical judgment, described above, several quantitative approaches,
sometimes referred to as ``data mining'' methods, have been proposed. A
common feature of data mining methods is that they identify patterns in
the data that consist of a condition or group of conditions that are
reported as a higher proportion of all adverse events after a
particular vaccine or combination of vaccines than after other
vaccines.
Calculations of reporting rates (number of adverse events reported/
number of doses of vaccine distributed) and reporting rate ratios
(ratio of reporting rate in the vaccine of interest to the reporting
rate in the comparison vaccine(s)) of adverse events have been used to
generate signals. Comparison of reporting rates with background
incidence rates for an adverse event is also sometimes advocated.
Biases in reporting, inadequate denominator data, uncertainty of the
risk interval (the interval after vaccination during which a person
might be at risk for the adverse event under study) and lack of
background incidence rates from an appropriate comparison population
for some conditions limit the utility of the reporting rate approach.
Regardless of the method used, interpretation of vaccine-adverse
event combinations that are identified as possible signals with any
quantitative method must use medical knowledge about the disorders and
take into account biases in reporting, misclassification of reports
that occur with adverse event coding systems, and other limitations of
passive surveillance systems previously discussed. Signals generated
through such quantitative analysis need to be subject to the same
clinical, descriptive epidemiological, and other analysis as for case
reports and case series of spontaneous reports. Elevated reporting rate
ratios or proportional reporting ratios or similar scores from data
mining should not by themselves be interpreted as
[[Page 75191]]
establishing a causal relationship between an adverse event and a
vaccine, but almost always require independent confirmation through
additional study.
In spite of these limitations, use of VAERS data has provided
initial reports that upon further evaluation have raised suspicions,
later confirmed, about rare reactions to vaccines (e.g.,
intussusception after rotavirus vaccine). VAERS data also have
suggested the need for further study of other adverse events (e.g.,
myopericarditis after smallpox vaccine).
Many possible signals\8\ can be generated with these methods and
prioritization for further evaluation is required. Because information
submitted to VAERS is often incomplete, it is sometimes necessary to do
enhanced follow-up of reports to systematically collect information as
the first stage in the signal evaluation process. Objective factors
such as seriousness and ``newness'' of the adverse event, size of the
population potentially affected, ability to prevent the adverse event,
and ability to study the question, influence priority for further
evaluation.
---------------------------------------------------------------------------
\8\Safety signals that may warrant further investigation may
include, but are not limited to, the following: (1) new unlabeled
adverse events, especially if serious; (2) an apparent increase in
the severity of a labeled event; (3) occurrence of serious events
thought to be extremely rare in the general population; (4) new
product-product, product-device, product-food, or product-dietary
supplement interactions; (5) identification of a previously
unrecognized at-risk population (e.g., populations with specific
racial or genetic predispositions or co-morbidities); (6) confusion
about a product's name, labeling, packaging, or use; (7) concerns
arising from the way a product is used (e.g., adverse events seen at
higher than labeled doses or in populations not recommended for
treatment); (8) concerns arising from potential inadequacies of a
currently implemented risk minimization action plan (e.g., reports
of serious adverse events that appear to reflect failure of a risk
minimization action plan goal); and (9) other concerns identified by
the sponsor or FDA. (``Guidance for Industry: Good Pharmacovigilance
Practices and Pharmacoepidemiologic Assessment,'' March 2005.)
---------------------------------------------------------------------------
VAERS reports are not the only source of information used to
evaluate the safety of a vaccine. Evaluation of signals usually
requires a literature review followed by epidemiological studies,
sometimes combined with clinical and laboratory analysis. To evaluate
specific hypotheses it is sometimes necessary to conduct cohort,
population-based case series, case-control or other epidemiological
studies using large administrative databases with medical record
review.
If a clinical trial with sufficient statistical power to evaluate
the adverse event of interest has not been conducted, assessing the
potential causal link between a vaccine and an adverse event often
requires integration of different types and quality of information
(e.g., laboratory studies, case reports, epidemiological studies, and
clinical studies). Causal inference criteria, patterned after those
proposed by A. Bradford Hill in 1965 and adapted by others, and formal
risk assessment have been applied to vaccine safety assessments. In a
study of pertussis and rubella vaccines in the early 1990s, the IOM
used the strength of association, the nature of the dose-response
relation, the existence of a temporally correct association,
consistency of association, specificity of the association, and the
biological plausibility of the association for assessing whether
evidence indicates a causal relationship between an adverse event and
vaccine exposure (Ref. 15). These criteria were also used in other more
recent vaccine safety reviews performed by the IOM in 2001 through 2004
(Ref. 16).
(Comment 19) Many comments questioned the role of VAERS.
(Response) Data from VAERS cannot generally be used to determine if
a vaccine causes an adverse event, but VAERS data can be useful for
hypothesis generation. As noted in the AVA labeling, a report of an
adverse event is not proof that the vaccine caused the event.
From 1990 through March 31, 2005, approximately 1.3 million
military personnel received 5.3 million doses of AVA. We evaluated the
4,370 VAERS reports of adverse events following administration of AVA
submitted to VAERS from 1990 through August 15, 2005, (4,279 through
March 31, 2005) using a combination of the techniques described
previously in this section of this document (e.g., pattern assessment
using frequency calculations, identification and descriptive analysis
of case series, assessment of reporting rates for certain clinical
conditions in the context of available information about background
incidence rates and risk intervals, and data mining). Based on our
review, we cannot conclude that there is a causal relationship between
serious adverse events (other than some injection site reactions and
some reports of allergic reactions) or deaths and AVA (Ref. 17).
However, as with any medical product, FDA cannot rule out that some
rare adverse events could be caused by AVA. As described in our
response to Comment 21, VAERS data were used, along with other data, to
develop a list of certain adverse events that were considered for
further study by the Vaccine Analytic Unit. The Vaccine Analytic Unit
has selected five topics for initial study to determine whether AVA has
a causal role in certain serious adverse events. FDA continues to
perform surveillance and periodic evaluations of adverse event reports,
and will review post-marketing data from any studies that become
available to FDA.
(Comment 20) Some comments on the December 2004 proposal seemed to
interpret the spontaneously reported adverse events that are listed in
the AVA labeling as being caused by the vaccine.
(Response) To make physicians and others aware of what is being
reported, adverse events are sometimes included in the vaccine labeling
even though it has not been shown that the vaccine actually caused the
adverse event. Thus, for AVA, that section of the labeling is preceded
by the statement, ``The following four paragraphs describe spontaneous
reports of adverse events, without regard to causality'' to indicate
that the relationship to the vaccine cannot be determined from the
information provided in the reports for those events.
(Comment 21) One comment asked if FDA has required BioPort or DoD
to conduct focused studies of any safety signals.
(Response) We encourage and support the expeditious conduct of
well-designed studies evaluating the relationship between AVA and
adverse events. The Vaccine Analytic Unit (VAU) was formed as a
collaboration between DoD and CDC to conduct vaccine post-marketing
surveillance investigations of AVA and other vaccines using data
collected by the Defense Medical Surveillance System, which holds
information on vaccinations, hospitalizations, outpatient visits,
occupational variables, and demographics for all U.S. military
personnel. FDA worked with the VAU to develop a list of adverse events
for further study based on VAERS and other data sources. In 2004, VAU
participants and a workgroup of the National Vaccine Advisory Committee
(NVAC) agreed that the VAU's research agenda would include five topics
for initial study: Systemic lupus erythematosus, optic neuritis,
arthritis, erythema multiforme, and multiple, near-concurrent
vaccinations.\9\
---------------------------------------------------------------------------
\9\Description of the VAU and the topic selection process are
available at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.cdc.gov/nip/webutil/about/annual-rpts/ar2005/2005annual-rpt.htm#online
(click on ``Leadership in Vaccine
Safety'') and http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://cdc.confex.com/cdc/nic2004/techprogram/session_787.htm
.
---------------------------------------------------------------------------
(Comment 22) Some comments suggested that new clinical studies be
conducted using anthrax spores milled to a fine powder or using all 60
strains of anthrax. Others asked why it would
[[Page 75192]]
be unethical to conduct additional human efficacy studies.
(Response) It is generally accepted that due to the significant
health risks associated with exposure to anthrax spores, it would not
be ethical to actively expose human study subjects to B. anthracis
spores in order to assess the effectiveness of an anthrax vaccine in a
controlled clinical trial. Furthermore, naturally occurring anthrax is
now so rare that a field study of vaccine effectiveness is no longer
feasible in the United States. For any future effectiveness studies, it
is likely that the efficacy studies will need to be conducted in well-
characterized animal models with an appropriate bridge to human
immunogenicity data as described under the ``animal efficacy rule''\10\
where human efficacy studies are not feasible or ethical (Sec. Sec.
601.90 and 601.91(a)).
---------------------------------------------------------------------------
\10\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).
---------------------------------------------------------------------------
C. Comments Describing Adverse Events
1. Review of Adverse Event Reports Submitted to the Docket\11\
---------------------------------------------------------------------------
\11\Docket Number 1980N-0208.
---------------------------------------------------------------------------
(Comment 23) Many comments to the docket described adverse events
stated to have occurred following administration of AVA. For
approximately 111 individuals, information was provided to the docket
about specific adverse events experienced by the person filing the
comment, a family member, or another person. Several comments indicated
that a report about the adverse event had been submitted previously to
VAERS. However, most of these comments did not mention whether a report
to VAERS had been submitted.
(Response) The comments submitted to the docket for the December
2004 proposal described adverse events after administration of AVA in
approximately 111 individuals. Multiple submissions were received for
some individuals. To facilitate analysis of this information and to
compare the comment reports with other VAERS reports, we entered into
VAERS the adverse events reported in comments to the extent possible
based on the information provided. Comments to the docket that reported
only non-specific adverse events such as became ``ill'' or had a ``bad
reaction'' were not entered into VAERS because of the lack of adequate
specificity. Also, submissions that described groups of persons,
adverse event statistics, or otherwise lacked key individual-level
details used in VAERS, were not entered into VAERS, but were reviewed
and considered.
More than one source (e.g., health care provider, patient, and
manufacturer) might submit to VAERS information concerning a single
individual's adverse events following a particular vaccination date,
resulting in multiple reports. Routine report processing in VAERS
includes steps aimed at identifying and linking such related reports.
Using these processes, we found that 48 (43 percent) of the individuals
described in adverse event reports submitted in comments to the docket
were the subjects of reports previously entered into VAERS.
We categorized 106 of the 111 reports as serious, including 6
deaths. Most described one or more chronic symptoms or illnesses,
though the duration was not always evident. VAERS reports had
previously been received for two of the persons who died.
2. Summary of Adverse Event Reports Submitted to the Docket
The adverse event reports submitted to the docket did not provide
substantially different information about possible new safety signals
than the previous reports to VAERS. The previous reports to VAERS,
together with the reports to the docket, do not establish a causal
relationship between death or serious adverse events (other than some
injection site reactions and some reports of allergic reactions) and
AVA (Ref. 17). We entered into the VAERS database the conditions
described in comments to the docket. These conditions will be
considered along with all other adverse event reports received through
continuing surveillance and incorporated into the periodic evaluations
of these reports.
D. Comments on the Vaccine Used in the Studies
(Comment 24) Several comments raised issues about the versions of
vaccine used in the Brachman study, the CDC open label safety study,
and the vaccine made by MDPH at the time of licensure.
(Response) While the December 2004 proposal discussed the
historical development of AVA, in light of the comments received, we
believe that additional clarification of the historical development is
warranted. In the 1950s, Brachman, et al., conducted a well-controlled
field study in four woolen mills in the United States using DoD vaccine
provided by Dr. G. G. Wright of Fort Detrick, U.S. Army (Ref. 1). This
vaccine was produced from the growth of a nonencapsulated,
nonproteolytic mutant (R1-NP) of the Vollum strain of B. anthracis
using an aerobic culture method and evaluated for potency (i.e.,
ability to protect test animals against challenge with virulent B.
anthracis spores) (Ref. 7).
In the early 1960s, subsequent to completion of the Brachman study,
DoD modified the vaccine manufacturing process to, among other things,
optimize production of a stable and immunogenic formulation of vaccine
antigen and to increase the scale of production. These changes included
a change in the mutant B. anthracis strain (V770-NP1-R) used to produce
the vaccine and use of an anaerobic culture method (Refs. 18 and 19).
These changes coincided with initiation of a contractual agreement
between DoD and Merck Sharp & Dohme (MSD) to standardize the
manufacturing process for large-scale production of anthrax vaccine and
to produce anthrax vaccine using an anaerobic method. Vaccine lots
manufactured by MSD under this contract were evaluated for potency
(i.e., ability to protect test animals against challenge with virulent
B. anthracis spores). One lot of vaccine manufactured by MSD (Merck-9)
was also used during the first year of the CDC open label safety study.
In the mid-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/AVA vaccine was made
using the same strain of B. anthracis as that used under the DoD
contract with MSD (DoD/MSD vaccine) and similar culture conditions.
Vaccine lots manufactured by MDPH under this contract with DoD were
evaluated for potency (i.e., ability to protect test animals against
challenge with virulent B. anthracis spores). DoD/MDPH/AVA vaccine lots
were used in the CDC open label safety study. Under the contract with
DoD, MDPH pursued pre-market approval of the vaccine. The DoD-MDPH
contract resulted in the production of AVA, which the NIH Bureau of
Biologics licensed in 1970, FDA now regulates, and BioPort presently
manufactures.
The safety and immunogenicity of the three generations of the
anthrax vaccine were evaluated in three groups of vaccinees, one
receiving DoD vaccine, another receiving DoD/MSD vaccine, and the third
group receiving DoD/MDPH/AVA vaccine. Vaccine recipients were monitored
for local and systemic adverse events. Antibody responses, expressed as
Geometric Mean Titers and
[[Page 75193]]
percent seropositives, were measured in blood samples collected at
regular intervals following administration of the third vaccine dose
utilizing an agar-gel precipitin-inhibition (AGPI) test. 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 percent
seropositives and support our conclusion that data generated by
administration of DoD and DoD/MSD generations of the vaccines support
licensure of DoD/MDPH/AVA vaccine.
(Comment 25) Some comments mentioned that, in the 1985 report, the
Panel noted that DoD/MDPH/AVA vaccine had not been employed in a
controlled field study.
(Response) Although the Panel Report included the statement
described in Comment 25, the Panel immediately followed with a
statement that a ``similar'' vaccine was employed in a placebo-
controlled field trial. The Panel then concluded that DoD/MDPH/AVA
vaccine was ``patterned after'' the vaccine used in that trial (which
the Panel mistakenly referred to as DoD/MSD vaccine, rather than DoD
vaccine) ``with various minor production changes.'' (50 FR 51002 at
51059, December 13, 1985). Thus, the Panel concluded that the Brachman
study, which used DoD vaccine, supported a finding of safety and
effectiveness of DoD/MDPH/AVA vaccine. It is common practice for a
product to undergo manufacturing changes as it moves from initial
development to product approval. If an earlier generation is
comparable, then studies using that earlier-produced product are
relevant to the later product. As we discuss elsewhere in this section
of this document, the controlled field study using DoD vaccine was
relevant to DoD/MDPH/AVA vaccine, since the two vaccines were
comparable in terms of their ability to protect test animals against
challenge with B. anthracis and to elicit an immune response in humans.
(Comment 26) One comment stated that FDA is using potency data
``that it knows are unreliable to assert comparability of two different
anthrax vaccines [DoD and DoD/MDPH/AVA vaccines]'' and if reliable
``would only establish comparable animal efficacy for the two vaccines,
and fail to establish human efficacy, human safety and the
comparability of the vaccines for humans.''
(Response) We note here that the comment did not provide evidence
to support the statement that the potency data are ``unreliable.'' The
potency data described in the response to Comment 24 demonstrated that
the products are comparable. In addition, the clinical data described
in response to Comment 30 demonstrated clinical comparability between
the vaccines with regard to Geometric Mean Titer and seropositivity
rates.
(Comment 27) One comment inquired about whether the differences in
the versions of AVA resulted in differences in their safety.
(Response) There are ample clinical data and information from the
CDC open label safety study, conducted under IND in the 1960s, which
demonstrate that the DoD/MDPH/AVA vaccine is safe.
FDA's assessment of vaccine safety considered the data collected
under the CDC open label safety study (1966 through 1971). During the
first year of this study, CDC used one lot of DoD/MSD vaccine and one
lot of DoD/MDPH/AVA vaccine, but only DoD/MDPH/AVA vaccine was used
during the remainder of the safety study. Thus, the majority of the
safety data accumulated in that study was from the use of vaccine
manufactured by MDPH. Information pertaining to the incidence and
severity of adverse reactions associated with administration of DoD/
MDPH/AVA vaccine was collected for approximately 7,000 individuals
participating in the CDC open label safety study. In addition, the
safety of the vaccine is evaluated on an ongoing basis through review
of new studies, such as the DoD pilot study, and periodic assessments
of VAERS data.
(Comment 28) One comment stated that the differences in reported
systemic reaction rates for the Brachman study and the later DoD pilot
study indicate that DoD vaccine and DoD/MDPH/AVA vaccine are distinctly
different such that the effectiveness associated with DoD vaccine
cannot be regarded as evidence of effectiveness of DoD/MDPH/AVA
vaccine.
(Response) We agree that the rates of reported systemic reactions
associated with administration of anthrax vaccine in the Brachman study
are lower than the rates reported in the DoD pilot study. However, we
believe that the Brachman study provided evidence of effectiveness of
the licensed vaccine. Differences between the Brachman study and the
DoD pilot study in reported systemic reactions are attributable to a
number of factors. The latter study was specifically designed to
closely monitor and solicit subjects' information pertaining to adverse
reactions associated with administration of the vaccine in accordance
with the licensed schedule and route of administration so that
comparisons of adverse reaction rates could be made between the
licensed schedule and route and the alternative schedules and route
also under investigation in that study. Differences in methodologies
and design as well as a heightened awareness and sensitivity toward
adverse reactions on the part of both study investigators and study
subjects has resulted in a more comprehensive description of adverse
reactions experienced in association with vaccination in the more
recent DoD pilot study.
As discussed more fully previously in this document, DoD/MDPH/AVA
vaccine was used in the CDC open label safety study; the production
strain and culture methods were the same as those currently used by
BioPort. To provide a more current picture of the types and severities
of reactions associated with DoD/MDPH/AVA vaccine, the product labeling
now includes descriptions of adverse events reported in association
with administration of AVA in the DoD pilot study. Although the
reporting rates for certain reactions are greater in the DoD pilot
study, we continue to regard 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.
(Comment 29) One comment stated that the anthrax vaccine produced
in Michigan has undergone a series of manufacturing changes since it
was licensed, resulting in a materially altered product that is much
more concentrated than the original MDPH vaccine.
(Response) We note that the comment did not provide evidence to
support the claim that DoD/MDPH/AVA vaccine is ``more concentrated''
now than when originally licensed. The DoD/MDPH/AVA vaccine currently
manufactured by BioPort was licensed in 1970. Since then, the strain of
B. anthracis used to produce the vaccine has not changed and the
vaccine formulation has not changed. Changes in the manufacturing
process (including equipment changes) have been reviewed and approved
by FDA. Each lot of final vaccine product must pass certain criteria,
including potency testing, as described subsequently in this document
in the response to Comment 33.
(Comment 30) Some comments inquired about whether the change in
vaccine during the 1962 to 1974 surveillance period altered the
vaccine's effectiveness. One comment was critical of FDA's assessment
that both the DoD generation and the DoD/MDPH/AVA
[[Page 75194]]
generation of the vaccine stimulated similar peak antibody responses
and seropositivity rates since there was not an ELISA assay available
at the time the antibody responses were measured. The comment argued
that antibody levels cannot be used as a surrogate marker for
effectiveness.
(Response) The antibody responses were measured by agar-gel
precipitin-inhibition test, which was an acceptable assay. The
immunogenicity data resulting from this testing showed that the DoD and
the DoD/MDPH/AVA generations of the vaccine were both immunogenic.
After the third dose, the peak Geometric Mean Titer for antibodies to
anthrax was 1.30 (60 percent seropositivity of samples tested) for DoD/
MDPH/AVA vaccine, and 1.4 (60 percent seropositivity of samples tested)
for DoD vaccine. Thus, while limited in the number of vaccinees and the
number of samples analyzed, the results do indicate comparable immune
responses with regards to seropositivity rates and peak antibody titer
levels (GMT). Rather than representing a surrogate for effectiveness,
these results are a means of bridging the immunogenicity of these
generations of the vaccine. In any event, the CDC surveillance data,
which were gathered when the DoD/MDPH/AVA and DoD/MSD generations of
the vaccine were in use, corroborate the efficacy data provided by the
Brachman study.
(Comment 31) Some comments inquired whether the DoD pilot study or
a larger ongoing CDC study are intended to provide data to reduce the
vaccine dose level. Another comment asked how FDA has validated the
current dose and inoculation schedule.
(Response) The DoD pilot study was followed by a larger, more
statistically robust and significant CDC study in order to obtain
safety and immunogenicity data to support a reduction in the total
number of doses to be administered in a complete vaccination schedule.
The new CDC study is a double-blind, randomized, placebo controlled
trial conducted under IND to compare the licensed AVA schedule and
route of administration (subcutaneous) to regimens with a different
route of administration (intramuscular) and/or reduced number of doses.
Safety and immunogenicity are assessed. The study started in May 2002
and is currently ongoing. The clinical studies referenced in the
comment were not intended to seek a change in the amount of vaccine
administered with each dose. The current dosage for AVA is 0.5 mL per
inoculation and has been used for anthrax vaccine since before the
Brachman study was conducted in the 1950s. The current 0.5 mL dosage
and 6-dose regimen and schedule are based on the dosage, regimen, and
schedule used in the Brachman study.
(Comment 32) One comment noted that there would have been no need
to continue to develop newer and different anthrax vaccines had
Brachman's vaccine produced acceptable safety and efficacy.
(Response) On the contrary, DoD (in particular, the Army, Dr. G. G.
Wright and his colleagues) pursued improvements in the manufacturing
process, formulation, and other aspects of anthrax vaccine precisely
because it had been shown to be safe and effective in the Brachman
study. The changes implemented with the transfer of production to MSD
and then to MDPH were with the intent of increasing ease of production
and yield to support further study and ultimately licensure of the
vaccine. FDA encourages license holders to embrace continuous
improvement.
E. Comments about Allegedly Contaminated Vaccine and Inspectional
Observations
(Comment 33) Some comments asserted that AVA is contaminated or
adulterated, citing FDA inspections of the Michigan Biologic Products
Institute (MBPI, and then BioPort) facility. Some comments expressed
concerns about particular lots of AVA received by soldiers in the U.S.
military, stating that they were not made under current good
manufacturing practice (cGMP) or were contaminated.
(Response) FDA has a lot release program to determine whether lots
of the AVA licensed vaccine meet criteria for release, which include
sterility, general safety, potency, and specified levels of
benzethonium chloride, aluminum, and formaldehyde. All lots released
from the manufacturer for administration to military personnel and
other individuals met these criteria.
Additionally, FDA performs inspections of all biological product
license holders biennially and at additional times when FDA deems that
more regulatory oversight is warranted. On the basis of such
inspections, FDA issued to AVA's manufacturer a Warning Letter in 1995,
and a Notice of Intent to Revoke the license to manufacture all
products, including AVA, in 1997. FDA did not initiate license
revocation proceedings because BioPort committed to and implemented
appropriate corrective and preventive actions to address the issues
identified by FDA and demonstrated over time its commitment to comply
with all applicable FDA requirements. BioPort did this by, among other
things, renovating its AVA manufacturing facility, discontinuing the
manufacture and distribution of all non-AVA products, closing its
aseptic filling facility, and moving the AVA filling operations to a
contract manufacturer. We believe that the manufacture of AVA is
currently in compliance with regulatory requirements. We continue to
evaluate the production of AVA to assure compliance with applicable
federal standards and regulations.
(Comment 34) A number of comments alleged that squalene had been
added to AVA and questioned how AVA could be approved when it contains
squalene. Others claimed that health problems reported by some
recipients of AVA were caused by squalene. Another comment noted the
finding of small amounts of squalene in samples of AVA tested by FDA
and advocated the testing of all lots of AVA for the presence of
squalene. One comment claims that squalene ``overcharges'' the immune
system when injected into the body even in tiny amounts.
(Response) Squalene is a naturally occurring biodegradable oil
found in plants, animals, and humans. Squalene is an intermediate in
the cholesterol biosynthetic pathway and is a natural constituent of
dietary products including both vegetable and fish oils. Squalene is
synthesized in the liver and circulates in the bloodstream and is
present in human serum at 250 parts per billion (250 nanograms per
milliliter) (Ref. 20). Antibodies to squalene occur naturally in
humans, have an increased prevalence in females, are not correlated
with vaccination with AVA, and appear to increase in prevalence with
age (Ref. 21). Squalene is not used in the AVA manufacturing process
and is not a component of the vaccine.
In 1999, FDA performed testing to determine whether squalene was
added to AVA as an adjuvant. FDA believes that the testing was adequate
for the intended purpose of determining whether squalene had been added
to AVA as an adjuvant, and demonstrated that this was not the case. The
values reported from FDA's testing of certain lots were minute (10 to
83 parts per billion, which is below the low levels normally detected
in human serum (Ref. 20)) and at the low end of the analytical
sensitivity of the test method. Given the extremely low level detected,
more extensive testing and validation would be needed to ascertain
whether any squalene was actually present.
At DoD's request, Stanford Research International (SRI) conducted
testing designed to detect low levels of impurities (including
squalene), in a
[[Page 75195]]
quantitative manner. SRI detected squalene at up to 9 parts per billion
in 1 lot only of the 33 lots of AVA tested. This value can be
contrasted with the amount of squalene added as a component of MF59
adjuvant included in FLUAD, an influenza vaccine which is marketed in
many European countries and whose safety has been evaluated by European
regulatory authorities. (The current version of this adjuvant is
technically named MF59C.1.) According to the ``Summary of Product
Characteristics,'' the amount of squalene contained in FLUAD is 9.75 mg
per dose of 0.5 mL (about 2 parts per hundred or 20 million parts per
billion), which is greater than 2 million times more than that detected
by SRI in one lot of AVA.
We do not believe that additional testing of AVA is warranted
because squalene is not used in the manufacturing process and is not a
component of the vaccine. Moreover, at this time, we reviewed the
evidence and conclude that such minuscule amounts of squalene, if even
present in AVA, would not alter our view of the safety of AVA. The
comment claiming that squalene overcharges the immune system did not
provide any data in support of this assertion.
(Comment 35) Some comments noted that AVA contains formaldehyde.
(Response) The comments are correct in that formaldehyde, at a
concentration of 100 microgram/mL, is included in AVA as a
preservative. We note that formaldehyde has been used in the
manufacture and formulation of AVA since MDPH started manufacturing AVA
in the 1960s. Formaldehyde was present in the vaccine lots used in the
CDC open label safety study and, in similarly small amounts, is a
component of numerous other injectable products. The presence of
formaldehyde in these small amounts does not alter our view of the
safety of AVA.
(Comment 36) One comment was critical of the CDC open label safety
study claiming that activities described in a program report for work
conducted under contract with DoD indicated that some lots of anthrax
vaccine used in the CDC open label safety study were adulterated with
formaldehyde because additional formaldehyde was added.
(Response) The report referenced by this comment was written by
Merck Sharp & Dohme (MSD). It noted that additional formaldehyde was
added to DoD/MSD vaccine Lots 5 and 7, which were not used in the CDC
open label safety study. One lot of DoD/MSD vaccine (Lot 9) was used in
that study. It was used during the first year of the CDC open label
safety study, along with one lot of DoD/MDPH/AVA vaccine; thereafter,
only DoD/MDPH/AVA vaccine lots were used. Accordingly, the CDC open
label safety study was unaffected by the lots that the comment cites.
F. Comments on Labeling
(Comment 37) Some comments noted the Panel statement regarding an
apparent discrepancy between the labeling and a now rescinded section
of the Code of Federal Regulations with regards to the number of doses
to be administered.
(Response) We addressed this issue in section III.E of this
document. The dosing schedule for AVA, from the time of the Brachman
study to the present, has always consisted of six doses; a 0.5 mL dose
at 0, 2, 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. In any
event, perceived variances to a rescinded regulation are not relevant
to this final order under Sec. 601.25, where we determine that AVA is
appropriately placed into Category I, as a vaccine that is safe,
effective, and not misbranded.
(Comment 38) One comment questioned the need for a six-dose
immunization schedule referencing studies in animals where two doses of
vaccine administered 2 weeks apart protected non-human primates from
inhalation challenge with anthrax spores up to 104 weeks later.
(Response) The current immunization schedule described in the AVA
labeling was demonstrated to be effective in the Brachman study. That
schedule consists of a total of six doses of 0.5 mL administered
subcutaneously at 0, 2, 4 weeks, 6, 12 and 18 months with annual
boosters thereafter to maintain immunity. Changes to this vaccination
schedule may be reviewed and considered for approval by FDA based upon
the submission of scientific data to support changes to the product
labeling.
G. Additional Comments
(Comment 39) Several comments were critical of FDA for ``relying''
upon the IOM report as the scientific basis for placing AVA into
Category I and were critical of the IOM report with respect to its
consideration of studies conducted by DoD as supportive of vaccine
safety or its consideration of animal studies as evidence of
effectiveness against inhalation anthrax. However, other comments
stated that FDA was ``somewhat indirect'' regarding the IOM report and
suggested that FDA ``accord the IOM report significant weight as expert
scientific judgment.''
(Response) In the December 2004 proposal, we agreed with the IOM
committee's general conclusion that AVA, as licensed, is an effective
vaccine for protection of humans against anthrax infection, including
inhalation anthrax and that certain studies in humans and animals
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. In response to the
comments submitted regarding the IOM committee report, we wish to
clarify that the general conclusions of the report are consistent with
FDA's own independent assessment of the available data regarding the
safety and effectiveness of AVA.
In response to public concerns expressed about the use of AVA in
the DoD's Anthrax Vaccine Immunization Program, Congress called for DoD
to support an independent examination of AVA by the IOM. The IOM
committee was charged with reviewing data regarding the effectiveness
and safety of the currently licensed anthrax vaccine and assessing the
manufacturer's efforts to resolve manufacturing issues and resume
production and distribution of vaccine.
While the IOM committee did invite FDA scientists to participate in
their open meetings and comment on portions of the draft report, FDA
was not a participant in their closed review sessions, nor did FDA
participate in the writing or finalization of the IOM report.
Similarly, FDA has conducted its review under Sec. 601.25, culminating
in this final order, independently of the activities of the IOM
committee. FDA did not actively seek input or comment from the IOM
committee during its review process.
(Comment 40) Some comments questioned the utility of animal data
with one comment stating that animal testing is ``absolutely not at all
relevant to the study of safety for humans.'' Another comment noted
that AVA provided protection in guinea pigs against spores of some
strains of B. anthracis but not others.
(Response) We wish to clarify that animal studies have not been
relied upon for a determination of the safety of AVA for human use. The
safety database is comprised of data from the CDC open label safety
study in the late 1960s to early 1970s during which approximately
15,000 doses manufactured at MDPH were administered to approximately
7,000 subjects. In addition, safety data from the DoD pilot study (Ref.
13) and adverse reactions reported to VAERS as associated with
administration of AVA were considered as part of FDA's continual
process for assessing the
[[Page 75196]]
safety of AVA. In 2002, information from the DoD pilot study and VAERS
were included in the sections of the labeling describing safety and
adverse reactions. We continue to perform periodic evaluations of
adverse events reported to VAERS.
With regard to data suggesting that the vaccine protected guinea
pigs against spores from some strains of B. anthracis but not others,
we note that different animal species may exhibit different levels of
susceptibility to an infectious organism. The course of infection and
disease may depend greatly upon the strain of the infectious organism
for some species but not so much for other species (Refs. 3, 4, and 5).
Thus, based on the strain used or other factors, studies in some animal
species are likely to produce different results than studies in other
species.
(Comment 41) One comment suggested that AVA had been administered
to military personnel during Desert Storm/Desert Shield under an IND.
(Response) NIH's Division of Biologics Standards originally
licensed AVA under the Public Health Service Act in 1970.
Administration of AVA, an approved product, to military personnel by
DoD during Desert Storm/Desert Shield was not under an IND.
(Comment 42) Many comments claimed that AVA was not properly
licensed.
(Response) We disagree. AVA has been legally licensed since
November 1970.
The purpose of the biologics efficacy review procedures is to
determine whether biological products licensed before July 1, 1972, are
safe and effective and not misbranded. In 1972, the Department of
Health, Education, and Welfare redelegated from the NIH to FDA
authority and responsibility to regulate biological products. FDA
initiated a comprehensive review of the safety, effectiveness, and
labeling of all licensed biologics, including AVA, shortly after the
redelegation of authority. In keeping with Sec. 601.25, independent
advisory panels made up of scientific experts from outside the Federal
Government, reviewed biological products licensed prior to July 1,
1972, in order to recommend to FDA how the agency should classify the
products. One panel reviewed the safety, effectiveness, and labeling of
AVA and recommended that FDA place the vaccine into Category I--safe,
effective, and not misbranded. This recommendation was based on a
review of the available data from the Brachman study and the CDC open
label safety study, and the CDC surveillance data, as described
elsewhere in this document. FDA followed the requirements of Sec.
601.25(f), requiring publication of a proposed order for
classification, and published a proposed rule in the Federal Register
on December 13, 1985 (50 FR 51002). Since the publication of the
December 1985 proposal, FDA has focused on removing Category II
products-unsafe, ineffective, or misbranded, from the market and
completing the final classification of the Category III products-
products with insufficient information to allow classification and
further testing is required. The purpose of this final order, and the
final rule and final order published elsewhere in this issue of the
Federal Register, is to complete FDA's categorization of bacterial
vaccines and toxoids licensed prior to July 1, 1972. As stated in
section III of this document, FDA concludes that AVA is safe,
effective, and not misbranded.
(Comment 43) Some comments questioned why FDA did not reconvene an
advisory review panel when it reopened the comment period in response
to the Court order of October 27, 2004. The comments claim that FDA has
attempted to avoid the normal approval process or circumvented its own
rules by not convening an advisory review panel to review new data
generated by DoD.
(Response) Neither the applicable FDA regulation, Sec. 601.25, nor
the Court's order of October 27, 2004, requires that an advisory review
panel be convened at this time. FDA regulations at Sec. 601.25
explicitly detail the procedures to be used to determine that
biological products licensed prior to July 1, 1972, are safe,
effective, and not misbranded. These regulations require FDA to submit
a product to an advisory review panel at the initiation of the review.
The panel then submits to the Commissioner of Food and Drugs a report
containing the panel's conclusions and recommendations with respect to
the biological product. The Commissioner, after reviewing the
conclusions and recommendations, then publishes a proposed order
categorizing the product as safe and effective (Category I), unsafe or
ineffective (Category II), or determining that the available data are
insufficient to classify such biological product (Category III).
Thereafter, any interested person may within 90 days after publication
of the proposed order, file written comments. After review of the
comments, the Commissioner of Food and Drugs publishes a final order on
the classification.
In Doe v. Rumsfeld, 341 F.Supp.2d 1 (D.D.C. 2004), the Court
examined the step in the process involving the opportunity for public
comment on the agency's proposed order. The court noted that FDA had
published the Panel report in its entirety as a proposed order.
However, the Court concluded that the proposed order did not provide
public notice that FDA considered the vaccine to be indicated for use
against inhalation anthrax, a conclusion that FDA made in its January
2004 final order. Accordingly, the Court remedied what it considered to
be an Administrative Procedure Act violation, by vacating the January
2004 final order, and remanding it to FDA to reconsider following an
additional opportunity for comment. The Court did not find fault with
the Panel report. FDA believes that, with the requirements of Sec.
601.25 satisfied with respect to the advisory review panel report, it
is not necessary to consult another advisory panel on these issues. In
drafting this final order, FDA has been able to review and consider
extensive comments on the December 2004 proposed order.
(Comment 44) Some comments expressed concern that certain Panel
members were also involved in developing AVA. They suggest that the
members were biased, and their role in the review process self-serving.
One comment specifically complained of the bias of Dr. Stanley Plotkin,
who was a co-author on the Brachman study (Ref. 1).
(Response) As provided in Sec. 601.25, the Commissioner appointed
qualified experts to serve on the advisory review panel and the Panel
included persons from lists submitted by organizations representing
professional, consumer, and industry interests. A review of the Panel
members appointed to review the data and information and to prepare a
report on the safety, effectiveness, and labeling of bacterial
vaccines, toxoids, related antitoxins, and immune globulins reveals
that the list did not include the name of Dr. Stanley Plotkin or any
other scientist who worked directly with the development of AVA. (50 FR
51002 at 51003 (December 13, 1985)).
(Comment 45) One comment alleged that FDA and DoD had a conflict of
interest and that the agencies were working together to promote
vaccinations.
(Response) FDA is charged with implementing the Federal Food, Drug,
and Cosmetic Act, as well as certain provisions of the Public Health
Service Act. Under these authorities and applicable regulations,
including Sec. 601.25, FDA is responsible for reviewing the safety and
effectiveness of vaccines. In issuing this order, FDA is
[[Page 75197]]
fulfilling this responsibility, and is not working to promote, or
discourage, vaccination for members of the armed forces. Rather, as
described in this order, FDA has evaluated AVA and concluded that the
product is safe, effective, and not misbranded.
(Comment 46) Other comments expressed concern that FDA had not
considered alternatives to vaccination such as the use of detection
devices and antibiotics to protect individuals from anthrax infection,
or expressed the opinion that antibiotics are a better means of
protection against anthrax.
(Response) Detection devices, if effective, would not prevent
infections, but would simply detect the presence of anthrax spores in
the environment. Moreover, a device would provide this information only
for the particular location under observation by the device and only if
the device was in use and functioning properly at the time.
Moreover, although antibiotic therapies are safe and effective in
the treatment of anthrax disease and in the prevention of anthrax
disease when administered as part of a post-exposure prophylaxis
regimen, the safety and effectiveness of long term use of such
therapies in individuals at high risk for anthrax disease, potentially
for a period of years, has not been studied. Moreover, the early stages
of inhalation anthrax present with flu-like symptoms, and diagnosis may
be delayed. The initiation of antibiotic therapy only after a
definitive diagnosis of inhalation anthrax has a diminished success
rate. Anthrax disease can be fatal despite the use of antibiotics. The
fatality rate for inhalation anthrax in the United States is estimated
to be approximately 45 percent to 90 percent. From 1900 to October
2001, there were 18 identified cases of inhalation anthrax in the
United States, the latest of which was reported in 1976, with an 89
percent (16/18) mortality rate. Most of these exposures occurred in
industrial settings, i.e., textile mills. From October 4, 2001, to
December 5, 2001, a total of 11 cases of inhalation anthrax linked to
intentional dissemination of B. anthracis spores were identified in the
United States. Five of these cases were fatal (Ref. 6). These
fatalities occurred despite aggressive medical care, including
antibiotic therapy (Refs. 22 and 23).
Thus, we have considered possible alternatives to AVA, and continue
to conclude that AVA is safe, effective, and not misbranded.
H. Comments on Matters Outside the Scope of this Proceeding
(Comment 47) We received numerous comments on the December 2004
proposal that, although they relate to significant issues, are not
relevant to the proposed order for placing AVA into Category I. These
comments concerned: (1) The need for compensation programs for
individuals injured by AVA, (2) statements that the vaccine should be
optional for members of the armed forces, (3) statements that antidotes
to anthrax should be developed, (4) concerns about DoD responsibilities
and recordkeeping, and (5) requests for an investigation of BioPort
stock ownership.
(Response) These comments are on matters outside the scope of this
final order and FDA's jurisdiction, authority, and control.
Accordingly, we do not respond to them.
V. FDA's Responses to Additional Panel Recommendations
In the December 1985 proposal, FDA responded to the Panel's general
recommendations regarding the products under review and to the
procedures involved in their manufacture and regulation, and to the
Panel's general research recommendations. Published elsewhere in this
issue of the Federal Register in a final rule and final order
concerning bacterial vaccines and toxoids other than AVA, FDA responds
in final to the Panel's general recommendations.
VI. References
The following references have been placed on display in the
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, rm.1061, Rockville, MD 20852, and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
(FDA has verified the Web site address, but we note subsequent changes
to the Web site might have occurred after this document publishes in
the Federal Register).
1. Brachman, P. S., H. Gold, S. A. 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.
2. Institute of Medicine, ``The Anthrax Vaccine, Is It Safe?
Does It Work?'' Committee to Assess the Safety and Efficacy of the
Anthrax Vaccine, Medical Follow-Up Agency, Washington, DC: National
Academy Press, 2002, http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.nap.edu/catalog/10310.html.
3. 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.
4. 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.
5. 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.
6. Anthrax Vaccine Adsorbed (BIOTHRAX) Package Insert (January
31, 2002).
7. 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.
8. ``FDA Guidance Concerning Demonstration of Comparability of
Human Biological Products, Including Therapeutic Biotechnology-
derived Products,'' April 1996, http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/gdlns/comptest.pdf
.
9. ``Revocation of Certain Regulations; Biological Products,''
Final Rule; 61 FR 40153, August 1, 1996.
10. ``International Conference on Harmonisation; Guidance on
Statistical Principles for Clinical Trials,'' Notice of
Availability; 63 FR 49583, September 16, 1998.
11. Plotkin, S. A., P.S. Brachman, M. Utell, F. H. Bumford, and
M. M. Atchinson, ``An Epidemic of Inhalation Anthrax, the First in
the Twentieth Century, I. Clinical Features.'' American Journal of
Medicine, 29:992-1001, 1960.
12. Brachman, P.S., S. A. Plotkin, F. H. Bumford, and M. M.
Atchinson, ``An Epidemic of Inhalation Anthrax: The First in the
Twentieth Century, II. Epidemiology.'' American Journal of Hygiene;
72:6-23, 1960.
13. Pittman, P. R., G. Kim-Ahn, D. Y. Pifat, K. Coonan, P.
Gibbs, S. Little, J. G. Pace-Templeton, R. Myers, G. W. Parker, and
A. M. Friedlander, ``Anthrax Vaccine: Immunogenicity and Safety of a
Dose-Reduction, Route-Change Comparison Study in Humans,'' Vaccine;
20(9-10):1412-1420, 2002.
14. ``Guidance for Industry: Good Pharmacovigilance Practices
and Pharmacoepidemiologic Assessment,'' March 2005, http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/gdlns/pharmacovig.htm
.
15. Institute of Medicine, ``Adverse Effects of Pertussis and
Rubella Vaccines,'' A Report of the Committee to Review the Adverse
Consequences of Pertussis and Rubella Vaccines. Washington, DC,
National Academy Press, 1991.
16. Institute of Medicine. ``Immunization Safety Review.''
http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.iom.edu/project.asp?id=4705.
[[Page 75198]]
17. Review of VAERS Anthrax Vaccine Reports Received Through 8/
15/05, and Adverse Event Reports Submitted to Docket No. 1980N-0208;
dated December 2005.
18. Puziss, M., L. C. Manning, J. W. Lynch, E. Barclay, I.
Abelow, and G. G. Wright, ``Large-Scale Production of Protective
Antigen of Bacillus anthracis in Anaerobic Cultures,'' Applied
Microbiology, 11(4):330-334, 1963.
19. Wright, G. G., M. Puziss, and W. B. Neely, ``Studies on
Immunity in Anthrax, IX. Effect of Variations in Cultural Conditions
on Elaboration of Protective Antigen by Strains of Bacillus
anthracis,'' Journal of Bacteriology, 83:515-522, 1962.
20. Nikkila K., K. H[ouml]ckerstedt, and T. A. Miettinen,
``Serum and Hepatic Cholestanol, Squalene and Noncholesterol Sterols
in Man: A Study on Liver Transplantation,'' Hepatology, 15:863-70,
1992.
21. Matyas, G. R., M. Rao, P. R. Pittman, R. Burge, I. E.
Robbins, N. M. Wassef, B. Thivierge, and C. R. Alving, ``Detection
of Antibodies to Squalene III. Naturally Occurring Antibodies to
Squalene in Humans and Mice,'' Journal of Immunological Methods,
286: 47-67, 2004.
22. Jernigan, J. A., et al., ``Bioterrorism-Related Inhalational
Anthrax: The First 10 Cases Reported in the United States,''
Emerging Infectious Diseases, 7(6):933-944, 2001.
23. Barakat, L. A., et al., ``Fatal Inhalational Anthrax in a
94-Year-Old Connecticut Woman,'' Journal of the American Medical
Association, 287(7):863-868, 2002.
Dated: December 12, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-24223 Filed 12-15-05; 8:45 am]
BILLING CODE 4160-01-S