Anthrax
Federal Agencies Have Taken Some Steps to Validate Sampling Methods and to Develop a Next-Generation Anthrax Vaccine Gao ID: GAO-06-756T May 9, 2006GAO has done many studies over the past 7 years on anthrax vaccine safety and anthrax detection methods. GAO has reported the lack of validated methods for detecting anthrax contamination and has recommended a coordinated approach to improving the overall process for detecting anthrax that included a probability-based sampling strategy. GAO also reported that the vaccine has not been adequately tested on humans; no studies have been done to determine the optimum number of doses; the long-term safety has not been studied and data on short-term reactions are limited; however, women report higher rates of reactions than do men. Given these problems, GAO recommended the development, of a better, alternative vaccine.
The threat of bioterrorism has long been recognized in the United States and abroad. The Department of Defense (DOD) considers inhalation anthrax to be the greatest biological warfare threat to U.S. military forces. The U.S. Army Medical Research Institute of Infectious Diseases has been conducting basic and applied research on biological threats since 1969, in order to develop medical countermeasures--prophylactics, vaccines, medical diagnostics--to protect warfighters. The anthrax incidents in 2001 highlighted major gaps in civilian preparedness to detect and respond to anthrax attacks, leading the federal government to focus on developing new drugs, vaccines, and therapeutics to protect U.S. citizens. As a result, the Department of Health and Human Services (HHS) now has major responsibility to ensure that appropriate medical countermeasures are available for civilians. And the Department of Homeland Security (DHS) assumes major responsibility for coordinating federal responses to national incidents of chemical, biological, radiological, and nuclear release. Despite the many recommendations GAO has made over the past few years regarding problems related to the anthrax vaccine's safety and effectiveness and the reliability of anthrax detection, deficiencies remain. While agencies have taken steps in the right direction, the government still lacks a strategic plan outlining how individual agency efforts would lead to the validation of the overall sampling process, including methods, and the development of a probability-based sampling strategy that accounts for the complexity of indoor environments. In November 2004, HHS awarded a contract for $877.5 million to procure 75 million doses of a new anthrax vaccine--the first contract awarded under Project Bioshield for medical countermeasures procurement. The terms of the award state that the urgency of the current threat requires an accelerated pace of vaccine development, testing, approval, and procurement. While developing vaccine is known to be difficult and highly likely to encounter testing and production issues in the best of circumstances, the contract's milestones leave little room for slippage from established delivery dates. The biotechnology sector is watching to see if government and industry can make this partnership work. Understanding the unique issues in this early phase of the biodefense strategy is important. Problems with this initial Project Bioshield contract could affect the biotechnology industry's response to future government overtures to develop and procure medical countermeasures against the many other biothreat agents still to be addressed.
GAO-06-756T, Anthrax: Federal Agencies Have Taken Some Steps to Validate Sampling Methods and to Develop a Next-Generation Anthrax Vaccine
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United States Government Accountability Office:
GAO:
Testimony before the Subcommittee on National Security, Emerging
Threats and International Relations, Committee on Government Reform,
House of Representatives:
Anthrax:
Federal Agencies Have Taken Some Steps to Validate Sampling Methods and
to Develop a Next-Generation Anthrax Vaccine:
Statement of Keith Rhodes, Chief Technologist, Center for Technology
and Engineering, Applied Research and Methods:
GAO-06-756T:
GAO Highlights:
Highlights of GAO-06-756T, a testimony before the Chairman,
Subcommittee on National Security, Emerging Threats, and International
Relations, House Committee on Government Reform, House of
Representatives.
Why GAO Did This Study:
GAO has done many studies over the past 7 years on anthrax vaccine
safety and anthrax detection methods. GAO has reported the lack of
validated methods for detecting anthrax contamination and has
recommended a coordinated approach to improving the overall process for
detecting anthrax that included a probability-based sampling strategy.
GAO also reported that the vaccine has not been adequately tested on
humans; no studies have been done to determine the optimum number of
doses; the long-term safety has not been studied and data on short-term
reactions are limited; however, women report higher rates of reactions
than do men. Given these problems, GAO recommended the development, of
a better, alternative vaccine.
What GAO Found:
The threat of bioterrorism has long been recognized in the United
States and abroad. The Department of Defense (DOD) considers inhalation
anthrax to be the greatest biological warfare threat to U.S. military
forces. The U.S. Army Medical Research Institute of Infectious
Diseases has been conducting basic and applied research on biological
threats since 1969, in order to develop medical
countermeasures”prophylactics, vaccines, medical diagnostics”to protect
warfighters.
The anthrax incidents in 2001 highlighted major gaps in civilian
preparedness to detect and respond to anthrax attacks, leading the
federal government to focus on developing new drugs, vaccines, and
therapeutics to protect U.S. citizens. As a result, the Department of
Health and Human Services (HHS) now has major responsibility to ensure
that appropriate medical countermeasures are available for civilians.
And the Department of Homeland Security (DHS) assumes major
responsibility for coordinating federal responses to national incidents
of chemical, biological, radiological, and nuclear release.
Despite the many recommendations GAO has made over the past few years
regarding problems related to the anthrax vaccine‘s safety and
effectiveness and the reliability of anthrax detection, deficiencies
remain. While agencies have taken steps in the right direction, the
government still lacks a strategic plan outlining how individual agency
efforts would lead to the validation of the overall sampling process,
including methods, and the development of a probability-based sampling
strategy that accounts for the complexity of indoor environments.
In November 2004, HHS awarded a contract for $877.5 million to procure
75 million doses of a new anthrax vaccine–the first contract awarded
under Project Bioshield for medical countermeasures procurement. The
terms of the award state that the urgency of the current threat
requires an accelerated pace of vaccine development, testing, approval,
and procurement. While developing vaccine is known to be difficult and
highly likely to encounter testing and production issues in the best of
circumstances, the contract‘s milestones leave little room for slippage
from established delivery dates.
The biotechnology sector is watching to see if government and industry
can make this partnership work. Understanding the unique issues in this
early phase of the biodefense strategy is important. Problems with this
initial Project Bioshield contract could affect the biotechnology
industry‘s response to future government overtures to develop and
procure medical countermeasures against the many other biothreat agents
still to be addressed.
What GAO Recommends:
The Secretary of Homeland Security needs to develop a formal strategic
plan, including a roadmap, outlining how individual agency efforts
would lead to the validation of the overall sampling process.
[Hyperlink, www.gao.gov/cgi-bin/getrpt?GAO-06-756T].
To view the full product, click on the link above. For more
information, contact Keith Rhodes at (202) 512-6412 or rhodesk@gao.gov.
[End of section]
Abbreviations:
AVA: anthrax vaccine adsorbed:
AVRP: Anthrax Vaccine Research Program:
AVST: Anthrax Vaccine Safety Team:
CBER: Center for Biologics Evaluation and Research:
CDC: Centers for Disease Control and Prevention:
DHS: Department of Homeland Security:
DOD: Department of Defense:
EPA: Environmental Protection Agency:
FBI: Federal Bureau of Investigation:
FDA: Food and Drug Administration:
HHS: Department of Health and Human Services:
IND: investigational new drug:
NIAID: National Institute of Allergy and Infectious Diseases:
NIH: National Institutes of Health:
OPHEP: Office for Public Health Emergency Preparedness:
ORDC: Office of Research and Development Coordination:
rPA: recombinant protective antigen:
SDST: Subcommittee of Decontamination Standards Technology:
SNS: Strategic National Stockpile:
USAMRIID: U.S. Army Medical Research Institute of Infectious Diseases:
USPS: United States Postal Service:
Mr. Chairman and Members of the Subcommittee:
We are pleased to be here today to discuss the status of our
recommendations on two bodies of work that we did at your request:
licensed anthrax vaccine and anthrax detection methods.[Footnote 1] As
you know, the threat of bioterrorism had been recognized for a
considerable time in the United States, as well as internationally. The
Department of Defense (DOD) has considered inhalation anthrax in an
aerosolized form to be the greatest biological warfare threat to U.S.
military forces for quite some time. The U.S. Army Medical Research
Institute of Infectious Diseases (USAMRIID) has been conducting basic
and applied research on biological threats since its inception in 1969,
in order to develop medical countermeasures--for example,
prophylactics, vaccines, and medical diagnostics--to protect the
warfighter.
The anthrax incidents in September and October 2001 highlighted major
gaps in our civilian preparedness to detect and respond. It also led
the federal government to focus attention on the importance of
developing new drugs, vaccines, and therapeutics to protect U.S.
citizens.
Consequently, the Department of Health and Human Services (HHS) has the
major responsibility to ensure that appropriate medical countermeasures
are available for the civilian population, while the Department of
Homeland Security (DHS) has assumed the major responsibility for
coordinating federal responses to national incidents of chemical,
biological, radiological, and nuclear material release.
The President's 2006 federal budget includes $1.8 billion allocated to
the National Institutes of Health (NIH) to fund biodefense research and
development activities, which includes the development of new and
improved medical countermeasures. Additionally, under Project
Bioshield, a discretionary reserve fund of $5.6 billion has been
allocated to procure medical countermeasures for the Strategic National
Stockpile (SNS) through fiscal year 2013.[Footnote 2]
To respond to your request, we interviewed officials from federal
agencies--HHS, including the Food and Drug Administration (FDA); the
Centers for Disease Control and Prevention (CDC); the National
Institute of Allergy and Infectious Disease (NIAID); DHS, and DOD. In
addition, we reviewed documents provided by these agencies as well as
those provided by the United States Postal Services (USPS). We visited
and interviewed the officials of the company that is developing the new
anthrax vaccine. Finally, we reviewed scientific literature on this
issue. We conducted our review from March 2006 to April 2006 in
accordance with generally accepted government auditing standards.
In today's testimony, I will specifically report on (1) the problems we
identified with the anthrax detection methods and the licensed anthrax
vaccine, (2) recommendations we made, (3) the extent to which federal
agencies have taken corrective actions, and (4) what remains to be done.
Results in Brief:
With regard to anthrax detection methods, federal agencies responsible
for responding to the 2001 anthrax incidents adopted a targeted
sampling strategy that they based on their best judgment at the time.
When the level of contamination is extremely high and dispersed in a
facility, the method of sampling (for example, using wipes versus
swabs) may not be critical, if the purpose is to find some contaminant.
However, at lower levels, away of interpreting negative results is
needed, and this requirement emphasizes the importance of the
validation of the methods and the need for statistically based sampling
strategies.
Therefore, it is necessary to invest in empirical studies so as to
develop a probability-based sampling strategy that will account for the
complex geometry and surface types of many facilities. Using a
probability-based sampling strategy, together with validated methods
for detecting contamination, would provide a known level of confidence
with which to interpret any negative results and would thus enable
agencies to be more definitive in determining necessary actions.
The lack of validated methods for assessing contamination in postal
facilities in 2001 impeded the agencies in responding to the incidents.
The significance of the lack of validated methods was exemplified in
the case of one postal facility where negative preliminary results were
obtained by field-based methods of analysis, with limitations that
appear to have been not well understood by some agencies.
Given the lack of validated methods for detecting anthrax contamination
in facilities, we recommended that the Secretary of Homeland Security
develop a coordinated approach to (1) improve the overall process for
detecting anthrax and (2) increase confidence in negative test results
generated by that process. This approach would include working with
agencies to ensure that appropriate validation studies of the overall
process of sampling activities, including the methods, are conducted.
Specifically, we recommended that the Secretary:
1. take a lead role in promoting and coordinating the activities of the
various agencies that have the technical expertise related to
environmental testing;
2. ensure that a definition of validation is developed and agreed on;
3. guarantee that the overall process of sampling activities, including
methods, is validated so that performance characteristics, including
limitations, are clearly understood and results can be correctly
interpreted;
4. see that appropriate investments are made in empirical studies to
develop probability-based sampling strategies that take into account
the complexities of indoor environments;
5. ensure that appropriate, prioritized investments are made for all
biothreat agents; and:
6. ensure that agency policies, procedures, and guidelines reflect the
results of such efforts.
When we issued our report, CDC, DHS, and USPS agreed with our
conclusion--that methods for detecting anthrax contamination in
facilities were not validated--and with the thrust of our
recommendations--calling for a coordinated, systematic effort to
validate the methods to be used for such testing, but they (1)
disagreed with or expressed concern about our conclusions or the
recommendation dealing with targeted versus probability sampling, (2)
emphasized that validated testing methods for anthrax were not
available in 2001 and that federal and state organizations did the best
they could under the circumstances, and (3) identified factors or
issues that need to be considered in validating testing methods.
In addition, uncertainty over which agency would take the lead role in
improving the overall process for detecting anthrax, and how studies
were to be funded, continued after the release of our report. DHS
stated that while it has overall responsibility for coordinating the
federal response during future biological attacks, the Environmental
Protection Agency (EPA) had the "primary responsibility for
establishing the strategies, guidelines, and plans for the recovery
from a biological attack" while HHS had the lead role for any related
public health response and guidelines. DHS also stated that it
coordinated regularly with EPA's National Homeland Research Center to
exchange information on research needs and to discuss priorities and
gaps for a wide range of security-related research areas. DHS stated
that it would coordinate with EPA to ensure that appropriate
investments were made to explore improved sampling. Consequently, it
was unclear how DHS could ensure that appropriate prioritized
investments were made for all biothreat agents, with respect to
agencies other than EPA, and how such priorities and gaps would be
addressed.
Although in the past there had been confusion as to which federal
agency would take the lead, as well as the responsibility for ensuring
that our recommendations are addressed, DHS is now accepting
responsibility. On May 3, 2006, DHS told us that DHS recognizes that it
is the principal agency responsible for coordinating the federal
response and would be responsible for ensuring that sampling methods,
including the process, are validated. DHS also would work toward
developing a probability-based sampling strategy.
While actions taken by DHS are steps in the right direction, DHS needs
to develop a formal strategic plan that includes a "roadmap" outlining
how individual agency efforts would lead to (1) validation of the
overall process of sampling activities, including the methods, and (2)
development of a probability-based sampling strategy that takes into
account the complexity of indoor environments.
With regard to the licensed anthrax vaccine, we identified a number of
problems, including, among others, greater understanding of:
1. the need for a six-shot regimen and annual booster shots;
2. the long-term and short-term safety of the vaccine, including gender
differences; and:
3. the vaccine's efficacy.
In addition, we provided information on the disadvantages of the
licensed anthrax vaccine and the status of federal efforts to develop
an improved vaccine. Given these problems, and taking into account
promising early DOD research into an alternative, recombinant
protective antigen (rPA) vaccine for anthrax, we recommended the
development of a second-generation vaccine, based on this technology.
In September 2002 and September 2003, NIAID awarded contracts to
develop a new rPA vaccine against inhalation anthrax. These contracts
to develop and test candidate rPA vaccines included the requirement to
evaluate safety, efficacy, and a potential provider's manufacturing
capability to achieve eventual licensing from FDA.
The objectives in these two NIAID contracts addressed some of the
problems we identified with the licensed vaccine, including requiring a
recombinant vaccine to address issues of purity, potency, and
manufacturing consistency; the need for fewer doses for the civilian
population; and the capability for postexposure use. However, studies
on gender differences and long-term safety were not explicitly required.
In November 2004, in the first contract under Project Bioshield, HHS
awarded a contract for $877.5 million for the manufacture and delivery
of 75 million doses of rPA anthrax vaccine for SNS. In the production
contract's RFP, HHS stated that the urgent nature of the current threat
required an accelerated pace of development, testing, approval, and
procurement of the vaccine. While developing vaccine is known to be
difficult and highly likely to encounter testing and production issues,
even in the best of circumstances, early development work to ensure
safety of the vaccine and a solid large-scale manufacturing capability
had not been completed before awarding the full procurement contract.
Additionally, the contract milestones leave little to no provision for
slippage and, being a fixed-price contract, if there is an unexpected
slip in schedule, the financial burden will be fully on the contractor.
While the government should not pay out money to a contractor unless
and until it has met the terms of its contract, contractors that do not
have the resources to assume such risk will not be able to meet the
contract requirements, thus limiting the pool of companies that are
capable of meeting the nation's needs.
While the government should be a tough negotiator when contracting for
major procurements, it is important to understand the unique issues at
stake in this early phase of implementing the U.S. biodefense strategy.
Failure of this initial Project Bioshield contract could have an impact
on how the biotechnology industry responds to government overtures in
the future for the development and procurement of medical
countermeasures for the many biothreat agents still to be addressed.
Background:
The History and Nature of Anthrax and the Anthrax Vaccine:
Anthrax is an acute infectious disease caused by the spore-forming
bacterium Bacillus anthracis. It can infect humans but occurs most
commonly in warm-blooded animals (herbivores) in the agricultural
regions of the countries that have less standardized and less effective
public health programs. Human anthrax occurs only rarely in the United
States from natural causes. However, the anthrax attacks in October
2001 through contaminated mail resulted in the death of five persons.
Human infection normally results from an occupational exposure to
infected animals or animal products. For example, workers may be
exposed to dead animals or to products such as wool, hides, leather, or
hair products (especially goat hair). Since there have been no reports,
even now, of the disease spreading from person to person, anthrax is
most likely not spread in humans directly.
Anthrax infection can occur in three forms: (1) cutaneous, usually
through a cut or an abrasion; (2) gastrointestinal, by ingesting
contaminated meat; and (3) inhalation, by breathing anthrax spores into
the lungs. Symptoms depend on how the disease is contracted but usually
appear within 7 days. The disease can be treated with antibiotics:
tetracycline and doxycycline are preferred, but penicillin,
erythromycin, chloramphenicol, or ciprofloxacin can also be used. To be
effective, treatment should be started early.
The original anthrax vaccine in the United States was developed by
George Wright and others in the 1950s and was first produced on a large
scale by the pharmaceutical manufacturer Merck Sharp & Dohme.[Footnote
3] A 1962 clinical study that evaluated the safety and effectiveness of
the Merck vaccine in mill workers formed the basis for the subsequent
licensing of a modified vaccine in 1970.[Footnote 4] The Division of
Biologics of the National Institutes of Health issued the original
license for anthrax vaccine to the Michigan Department of Public
Health.[Footnote 5] In 1995, the facility changed its name to Michigan
Biologic Products Institute. In 1998, the facility was sold, and its
name was changed to BioPort Corporation.
Anthrax Vaccine and the Federal Role:
As the lead agency for public health and medical response to manmade or
natural disasters, HHS has the responsibility for developing,
licensing, procuring, and storing medical countermeasures, which
includes vaccines, for SNS. In 2002, HHS established the Office for
Public Health Emergency Preparedness (OPHEP) with responsibility for
implementing HHS's strategy for protecting civilians from bioterrorism
and other public health emergencies. OPHEP coordinates transitions
between NIH medical countermeasures development, FDA approval and
licensing, and CDC storage and maintenance within SNS.
Within NIH, NIAID is the lead agency for early candidate research and
development for medical countermeasures for biodefense. NIAID issues
grants and contracts for research on medical countermeasures
exploration and early development but has no responsibility in taking
research forward into marketable products. Within OPHEP, the Office of
Research and Development Coordination (ORDC) has the primary
responsibility for contracting with industry for the large-scale
manufacturing of licensable products, including vaccines, for delivery
into SNS. Distinct from development contracts, ORDC production
contracts typically require the submission of a formal request for FDA
product licensing, license supplements, long-term maintenance of the
stockpiled products, and a long-term manufacturing base to continue
replenishing the stockpile as product expires.
Through the Center for Biologics Evaluation and Research (CBER), FDA
licenses biological products, which include vaccines, and the
facilities they are produced in. Manufacturers are required to comply
with current good manufacturing practices regulations, which regulate
personnel, buildings, equipment, production controls, records, and
other aspects of the vaccine manufacturing process.[Footnote 6]
The Characteristics and Development of Vaccines:
Vaccines have three distinguishing features that contrast with those of
chemical drugs. First, either they have no clearly chemically defined
composition or simple chemical analysis is insufficient for their
effective characterization. Second, they are properly evaluated,
qualitatively or quantitatively, usually by measuring their effects in
the living organism. Third, quality can be guaranteed not from final
tests on random samples but only from a combination of in-process
tests, end-product tests, and strict controls of the entire
manufacturing process.
The quality of a vaccine is closely linked to its manufacturing
process, which must be rigorously controlled to ensure that batches of
vaccines produced at different times are reproducible and consistent in
quality. In general, quality is achieved by applying the current good
manufacturing practice. This process is not static but involves
manufacturers and regulators in continuing assessment and upgrades as
scientific progress, technical development, and experience help
identify deficiencies and make improvements possible. Such principles
also apply to the manufacturing facilities and equipment. Accordingly,
vaccine production is very highly regulated to ensure that the products
are consistent in quality and safe and effective for the purposes for
which regulatory approval was granted.
The development of a vaccine is similar to the development of drugs and
other immunizing agents. A sponsor who has developed a candidate
vaccine and wishes to begin clinical trials with human subjects must
submit an investigational new drug (IND) application to FDA.[Footnote
7] This starts an official oversight process of formal studies,
regulated by CBER within FDA, typically composed of three phases of
clinical trials involving an increasing number of human
subjects.[Footnote 8] Phase 1 trials are safety and immunogenicity
studies performed in 20 to 100 healthy, volunteer subjects. Phase 2
studies, which may involve hundreds of subjects, take an in-depth look
at the effectiveness of the drug and may include analysis of dose
ranges and dose regimens. Finally, Phase 3 trials typically involve
thousands of individuals and provide the documentation of effectiveness
and important additional safety data required for licensing. At any
stage of the clinical or animal studies, if the data raise significant
concerns about either safety or effectiveness, FDA may request
additional information or studies or may halt ongoing clinical studies.
Clinical trials typically last 6 years.
After successful completion of all three phases, the sponsor submits a
biologics license application for FDA's review and approval. The
proposed manufacturing facility is inspected during this stage, and
production of the vaccine as it is in progress is examined in detail.
This FDA review process can take several years, depending on the
product.
To ensure continuing safety, FDA oversees the manufacturing process for
as long as the manufacturer holds a license for the product. According
to industry sources, the challenge in scaling up vaccine production
from a research laboratory to a large manufacturing environment while
still maintaining quality requires much skill, sophisticated
facilities, and a great deal of experience.
Anthrax Detection in Postal Facilities and the Federal Role:
The federal agencies involved in the response in the postal facilities
had differing responsibilities. CDC and state and local health
departments primarily provided public health advice and assistance to
USPS. CDC has had primary responsibility for national surveillance of
specific diseases, including anthrax; it has also conducted
epidemiologic investigations to determine, among other things, the
source of the disease. The Federal Bureau of Investigation (FBI) has
been responsible for criminal investigations involving interstate
commerce and the mail and crimes committed on federal property. EPA has
been the nation's lead agency for responding to a release of hazardous
substances into the environment.
Responding to health emergencies, including bioterrorist attacks, is
generally a local responsibility, but localities could and did request
CDC's assistance in fall 2001. CDC performed the tests needed to
confirm cases of anthrax and analyzed the substances in the two
contaminated letters recovered in New York City. The Agency for Toxic
Substances and Disease Registry and the National Institute for
Occupational Safety and Health within CDC helped USPS conduct
environmental tests of some of its facilities and advised USPS on its
facilities' decontamination.
USAMRIID has conducted basic and applied research in the diagnosis,
treatment, and prevention of hazardous infectious diseases for the
military. It analyzed some environmental samples from postal
facilities. It also performed detailed analyses, for the FBI, of
anthrax spores in the letters addressed to Senators Tom Daschle and
Patrick Leahy. The Occupational Safety and Health Administration,
responsible for employee health and safety issues, provided technical
assistance and guidance to USPS on the decontamination of postal
facilities.
The response to the incident in the American Media Incorporated
building in Florida in September 2001 led to the identification of mail
as the potential source of contamination; eventually, it led to the
sampling of the postal facilities. The agencies began sampling on
October 12, 2001, in Florida and stopped on April 21, 2002, when the
Wallingford, Connecticut, facility was sampled for the last time.
On October 8, 2001, the President created the Office of Homeland
Security to develop and coordinate a comprehensive national strategy
for dealing with domestic terrorist threats or attacks. The office,
which had limited involvement in the 2001 response, was superseded by
the Homeland Security Act of 2002, which transferred many of its
functions to DHS. DHS, which became operational in 2003, was created by
combining many previously separate agencies. It is assigned the lead
role in coordinating the efforts of federal agencies that respond to
acts of terrorism in the United States.
Agency Sampling Detection Methods Were Not Validated:
As you know, the agencies that sampled postal facilities in 2001--USPS,
CDC, and EPA--did not use validated sample collection and analysis
methods to perform their tests. According to these agencies, validated
methods were not available at that time. They conducted several
interdependent activities, including sample strategy development,
followed by sample collection, transportation, and analysis of the
samples to detect anthrax. Neither these activities nor the overall
process had been validated for anthrax testing.
Validation is a formal, empirical process in which an authority
determines and certifies the performance characteristics of a given
method. Therefore, investments are also needed to validate these
methods, as well as the overall anthrax detection process. Validating
the overall process is important because operational and health-related
decisions are made on the basis of testing results that the process
generates.
CDC and USPS officials said that they used targeted sampling; that is,
they collected samples from specific areas considered--based on
agencies' technical judgments--more likely to be contaminated. Such
judgments can be effective in some situations, for example, in
determining the source of contamination in a disease outbreak
investigation, provided results are positive. However, if the results
are negative, the basic question--Is this building contaminated?--
cannot be answered with statistical confidence.
When the level of contamination is extremely high and dispersed in a
facility, the method of sampling (for example, wipes versus swabs) may
not be as critical if the purpose is to find some contaminant. However,
at lower levels, a way of interpreting negative results is needed, and
this requirement emphasizes the importance of the validation of the
methods and the need for statistically based sampling strategies. This
emphasizes the need for methods that have been validated and sampling
strategies that are likely to find contamination at low levels.
Probability-based sampling does allow conclusions at specific levels of
confidence about testing results.
Using a probability-based sampling strategy, together with validated
methods for detecting contamination, would provide a known level of
confidence with which to interpret any negative results. This would
allow agencies to be more definitive in determining necessary actions.
Figure 1 shows how lack of validation could affect individual
activities--which include the sampling strategy--as well as the results
generated by the overall process.
Figure 1: Lack of Validation Can Affect Individual Activities and the
Overall Process:
[See PDF for image]
Source: GAO analysis of CDC, EPA, and USPS data.
[End of figure]
The lack of validated methods for assessing contamination in postal
facilities impeded the agencies in responding to the incidents. The
significance of the lack of validated methods was exemplified in the
case of the one postal facility, where negative preliminary results
were obtained by field-based methods of analysis, with limitations that
appear to have been not well understood by some agencies. Negative
results do not necessarily mean a facility is free from contamination.
As we reported, results can be negative if (1) samples were not
collected from places where anthrax was present, (2) the detection
limit of the method was greater than the actual contamination level,
(3) not enough samples were recovered from the sample material, (5)
analysis of the sample extract did not detect spores, or (6) anthrax
was not present in the facility.
Given the lack of validated methods for detecting anthrax contamination
in facilities, we recommended that the Secretary of Homeland Security
develop a coordinated approach to (1) improve the overall process for
detecting anthrax and (2) increase confidence in negative test results
generated by that process. This approach would include working with
agencies to ensure that appropriate validation studies of the overall
process of sampling activities, including the methods, are conducted.
Specifically, we recommended that the Secretary:
1. take a lead role in promoting and coordinating the activities of the
various agencies that have the technical expertise related to
environmental testing;
2. ensure that a definition of validation is developed and agreed on;
3. guarantee that the overall process of sampling activities, including
methods, is validated so that performance characteristics, including
limitations, are clearly understood and results can be correctly
interpreted;
4. see that appropriate investments are made in empirical studies to
develop probability-based sampling strategies that take into account
the complexities of indoor environments.
When we issued our report, CDC, DHS, and USPS agreed with our
conclusion--that methods for detecting anthrax contamination in
facilities were not validated--and with the thrust of our
recommendations--calling for a coordinated, systematic effort to
validate the methods to be used for such testing, but they (1)
disagreed with or expressed concern about our conclusions or the
recommendation dealing with targeted versus probability sampling, (2)
emphasized that validated testing methods for anthrax were not
available in 2001 and that federal and state organizations did the best
they could under the circumstances, and (3) identified factors or
issues that need to be considered in validating testing methods.
Also, at that time, uncertainty over which agency would take the lead
role in improving the overall process for detecting anthrax, and how
studies were to be funded, continued after our report was released. DHS
stated that while it has overall responsibility for coordinating the
federal response during future biological attacks, EPA had the "primary
responsibility for establishing the strategies, guidelines, and plans
for the recovery from a biological attack" while HHS had the lead role
for any related public health response and guidelines. DHS also stated
that it coordinated regularly with EPA's National Homeland Research
Center to exchange information on research needs and to discuss
priorities and gaps for a wide range of security-related research
areas. DHS stated that it would coordinate with EPA to ensure that
appropriate investments were made to explore improved sampling.
Consequently, it was unclear how DHS could ensure that appropriate
prioritized investments were made for all biothreat agents, with
respect to agencies other than EPA, and how such priorities and gaps
would be addressed.
DHS Has Taken Some Actions to Implement Our Recommendations on the
Validation of Sampling Methods and Strategies:
Concerning our recommendation about probability-based sampling
strategies, DHS said that it first wanted to develop sampling
requirements and then evaluate both targeted and probability-based
sampling against those requirements. While CDC and USPS stated that
they agreed with the importance of using validated testing methods,
they raised various concerns about our discussion of targeted versus
probability-based sampling.
DHS formally responded to our recommendations on September 19, 2005,
stating that it agreed with them and was taking several actions to
address them. These actions included working with agencies through
interagency memorandums of understanding, interagency committees,
working groups, and collaborations, with various federal agencies such
as HHS and EPA. In particular, a memorandum of understanding for
coordinating and monitoring biological threat agents among DHS, DOD,
HHS, USPS, and the Department of Justice was signed on May 9, 2005.
Another involved several agencies--DOD, EPA, HHS, Justice, and the
Department of Agriculture, to name a few--and was to establish an
integrated consortium of laboratory networks. Also, in fiscal year
2005, DHS said it was to standardize and validate the method by which
hazardous materials technicians (for example, first responders)
collect, transport, and store suspicious powder samples.
In preparation for this testimony, we asked USPS, CDC, DHS, and EPA for
comments regarding actions they have taken to implement our
recommendations. EPA did not provide us comments. Comments from USPS,
CDC, and DHS are summarized below.
USPS, on April 24, 2006, reported to us that it has been assisting DHS
to implement our recommendations. DHS has asked USPS to become part of
a subject matter expert team as a result of the real-world experience
gained during the 2001 anthrax attacks and the subsequent response,
clean-up, and remediation efforts at a number of mail processing
facilities and post offices. (For more on USPS's actions, see app. I).
CDC, on May 5, 2006, told us it is taking steps we believe are in the
right direction. CDC officials told us that CDC has not changed its
position on using targeted sampling as its primary strategy for initial
response sampling but is exploring probability-based sampling to
augment this approach. CDC officials told us that CDC has also
developed a program to expand its microbiology objectives; the
program's focus areas include plans for evaluating priority biothreat
agents, including anthrax, in a variety of media. Further, CDC told us
it has completed or has ongoing studies on the recovery of Bacillus
anthracis spores from various types of surfaces. (More on CDC's actions
is in app. II).
On May 3, 2006, DHS stated that it:
"concurs with the GAO that use of stratified and probabilistic sampling
strategies, together with validated methods for detecting
contamination, would provide a known level of confidence with which to
interpret any negative results and would thus enable agencies to be
more definitive in determining necessary actions."
DHS reported to us several actions it had taken toward implementing the
recommendations. (For more on DHS's actions, see app. III).
While we believe that DHS's individual actions are in the right
direction, DHS needs to develop a formal strategic plan that includes a
"roadmap" outlining how individual agencies' efforts would lead to (1)
the validation of the overall process of sampling activities, including
methods, and (2) the development of a probability-based sampling
strategy that takes into account the complexities of indoor
environments. Such a plan would assist DHS in monitoring progress and
measuring agency performance toward improving the detection of anthrax
and other prioritized threat agents.
The Licensed Anthrax Vaccine Had Several Limitations:
Starting in 1999, we identified a number of problems with the licensed
anthrax vaccine. These included, among others, (1) the need for a six-
shot regimen and annual booster shots; (2) questions about the long-
term and short-term safety of the vaccine, including how safety is
affected by gender differences; and (3) uncertainty about the vaccine's
efficacy. In addition, we provided information on the disadvantages of
the licensed vaccine and the status of federal efforts to develop an
improved anthrax vaccine.
The dosing regimen, or protocol, for the licensed anthrax vaccine calls
for a series of six shots over 18 months. An initial series of three
shots is given at 2-week intervals, followed by a series of three shots
at 6-month intervals. Annual boosters are required thereafter. The
required six-dose schedule and annual boosters complicate the logistics
and increase the cost of vaccination. At the time of our earlier
reports, no studies had been done on the optimum dosing regimen.
Recently, however, CDC has begun conducting studies to determine the
feasibility of a three-dose schedule. FDA would have to review and
approve any change in product labeling.[Footnote 9]
The long-term safety of the licensed vaccine has not been studied. Data
on the prevalence and duration of short-term reactions to the vaccine
are limited but suggest that women experience a higher rate of adverse
reactions, both local and systemic, than men do.
Before the vaccine was licensed, a study on the efficacy of the
original vaccine concluded that it provided protection to humans
against cutaneous anthrax. In the 1980s, DOD began testing the efficacy
of the licensed vaccine on animals, focusing on its protection against
inhalation anthrax. DOD's studies, while showing some positive results,
may not be extrapolated to humans until serologic correlates of
immunity in an animal model that can be applied to humans are
established.
According to researchers and the Institute of Medicine of the National
Academy of Sciences, the licensed anthrax vaccine has several
additional disadvantages.[Footnote 10] The amount of protective antigen
in the vaccine varies from lot to lot, because the manufacturing
process cannot precisely quantify the antigen.[Footnote 11] Also, there
is some evidence that the current anthrax vaccine may have diminished
efficacy against certain virulent strains of anthrax.
The licensed vaccine has been given primarily to military personnel.
DOD, however, has a unique set of requirements, as it has a narrow,
relatively young, healthy, and homogenous, target population. This
reduces many problems, although not all, as in the case of
reactogenicity by gender. DOD requirements also assume a continuous
threat for which they require preexposure immunization. Civilian
populations, in contrast, are much more diverse than military
populations, and immunization of civilians would likely be difficult to
justify, based on the available bio-threat assessments.
HHS Has Taken Steps to Fund the Development of a Second-Generation
Anthrax Vaccine:
In the late 1980s, DOD research identified a second-generation
recombinant protective antigen (rPA) anthrax vaccine, created with a
process that is fully defined, quantified, and controlled in terms of
protective antigen; that can be developed; and that requires fewer
doses.[Footnote 12] DOD research also showed that an rPA anthrax
vaccine could be created with modern techniques to produce highly
purified protective antigen. This process not only would remove
unwanted bacterial proteins but would also enable precise amounts of
the purified protective antigen to be incorporated into the vaccine. A
further potential benefit was that compared to the current vaccine, the
protective antigen could be produced in a nonspore-forming organism. As
a result, according to DOD officials, manufacturers could use their
buildings and equipment to produce the anthrax vaccine as well as other
vaccines.
In 1995, the USAMRIID developed a pilot lot of a new rPA vaccine
against anthrax. It has been tested successfully in experiments using
animals but has not been tested on humans. USAMRIID officials stated
that this testing would take about 3 years; FDA approval of the
manufacturing could take years longer. In 1999, DOD considered further
development of this vaccine an unfunded requirement. In response to the
perceived threat of bioterrorism, HHS's NIAID formed a working group to
develop and test a second-generation anthrax vaccine and, accordingly,
funded several active research grants.
In September 2002 and September 2003, NIAID awarded contracts to
develop a new rPA vaccine effective against inhalation
anthrax.[Footnote 13] The contracts were for developing and testing
candidate vaccines, with a requirement for evaluating safety, efficacy,
and a potential provider's capability for manufacturing the vaccine and
achieving FDA licensing. The contracts--for $13.6 million in 2002 and
$80.3 million in 2003--were awarded to VaxGen Inc., a California-based
biopharmaceutical company.[Footnote 14]
The 2002 RFP called for developing, manufacturing, characterizing, and
evaluating pilot lots of an rPA anthrax vaccine developed under
conditions necessary to support the product's use as an investigational
new drug. The 2003 RFP built on the 2002 work and was to further
develop a vaccine candidate suitable for commercial-scale manufacturing
that demonstrated safety and immunogenicity in clinical and animal
studies.
The stated objectives in these two RFPs addressed some of the problems
we identified with the licensed vaccine, including our recommendation.
First, they required the development of a recombinant vaccine. As
noted, DOD research showed that modern recombinant techniques could
produce a vaccine that would contain highly purified and precise
amounts of protective antigen, thereby reducing lot-to-lot variation,
whose disadvantage was noted with the licensed anthrax vaccine.
Second, as we reported, the six-dose, 18-month immunization regimen,
followed by annual booster shots, was problematic. In the 2002 RFP,
NIAID required that the rPA candidate vaccines be administered in not
more than three doses.
We also reported that the long-term safety of the licensed vaccine had
not been studied and that data on short-term reactions, although
limited, suggested that women experience a higher rate of adverse
reactions, both local and systemic, than men do. NIAID requirements in
the two development RFPs included Phase I and Phase II clinical trials
to evaluate short-term safety, but neither RFP included analysis of
gender differences. In discussions with company officials, however,
VaxGen has stated that it included both male and female subjects in its
clinical trials and is examining this issue.
An issue that remains outstanding, however, is that long-term safety
studies have not been conducted or required before making awards for
full procurement.
We also found that because terrorist events would be likely to occur
with little or no warning, postexposure immunization capability would
be beneficial. A stated objective in the 2002 RFP was to investigate
candidate vaccines that would provide protection when administered both
before exposure and in a postexposure immunization regimen, when
combined with antibiotics.
NIAID has taken steps to anticipate downstream, large-scale
manufacturing issues by requiring a feasibility plan for the
manufacture and delivery of 25 million doses in the 2002 contract and,
in the 2003 contract, the actual delivery of 3 million to 5 million
doses of rPA anthrax vaccine from at least three consistency lots,
following good manufacturing practices. The 2003 RFP also included
objectives to develop and validate product release and characterization
criteria to support eventual submission to FDA for licensing.
HHS's Procurement Strategy Is Very Aggressive:
In November 2004, in the first contract under Project Bioshield, ORDC
awarded VaxGen a contract for $877.5 million for the manufacture and
delivery of 75 million doses of rPA anthrax vaccine in prefilled
syringes for SNS. Among other things, the contract requires VaxGen to
obtain FDA licensure for both preexposure use and postexposure use with
antibiotics, and the initiation and completion of special population
clinical trials, including pediatric and geriatric populations.
In the RFP for the contract, ORDC stated that the urgent nature of the
current threat required an accelerated pace of development, testing,
approval, and procurement of the vaccine and anticipated that it would
have to be administered under a "contingency use"
IND protocol, held by CDC, if needed, prior to licensure by FDA.
However, the RFP also specified that all vaccine manufactured and
acquired under the contract must meet the regulatory deliverables as
required for licensure.
The normal schedule for taking a vaccine from preclinical studies to
licensure varies, depending on what is known about both the specific
nature of the infectious disease and the planned application of the
vaccine in terms of when and on whom the vaccine is to be used. These
factors can prolong the development of a vaccine as long as 15 years
(for civilian use) or as short as 8 years (for military use). Because
of the U.S. government's stated need for a vaccine that can counter a
domestic biothreat against civilian populations, HHS has undertaken an
aggressive procurement of a vaccine on a very short schedule.
The NIAID development and test contracts, whose purpose was presumably
to aid in making the best procurement award decision, are not yet
completed and, in fact, overlap to a great degree with the procurement
contract. At the time the full procurement contract was awarded in
November 2004, the initial 2002 development contract to study the basic
safety and immunogenicity of candidate vaccines was still ongoing, and
the 2003 contract was only part way through Phase II clinical trials.
In fact, today, neither the 2002 nor the 2003 contract--intended to
ensure a candidate vaccine with appropriate characteristics and a
provider's manufacturing capability sufficient for licensing and
successful delivery--has yet been completed, only 6 months before first
delivery of 25 million doses of SNS-ready product is required. HHS
officials acknowledge that the procurement contract's milestones are
very aggressive and agree that the contract contains little to no
provision for slippage. Additionally, the procurement contract is fixed-
price and specifies that no payment will be made before delivery. The
financial burden is fully on the contractor should additional costs
arise because of an unexpected slip in schedule.
In conclusion, a contract schedule with no margin for error, especially
for vaccine development, which is known to be risky, is not conducive
to building confidence that a vaccine will be available for use within
the arbitrarily defined time period. While the government should not
pay out money to a contractor unless and until it has met the terms of
its contract, contractors that do not have the resources to assume such
risk will not be able to meet the contract requirements, thus limiting
the pool of companies that are capable of meeting the nation's needs.
While the government should be a tough negotiator when contracting for
major procurements, it is important to understand the unique issues at
stake in this early phase of implementation of the biodefense strategy.
The rest of the biotechnology sector will be watching to see whether
the industry and the U.S. government can make this partnership work.
Issues with this contract might have an effect beyond just this
individual vaccine procurement. They could have an impact on how the
biotechnology industry responds to government overtures in the future
for the development and procurement of medical countermeasures for the
many biothreat agents still to be addressed.
Mr. Chairman, this concludes my prepared remarks. I would be happy to
respond to any questions that you or other members of the subcommittee
may have at this time.
Contacts and Acknowledgments:
For further information regarding this statement, please contact Keith
Rhodes at (202) 512-6412, or rhodesk@gao.gov, or Sushil K. Sharma,
Ph.D., Dr.PH,, at (202) 512-3460, or sharmas@gao.gov. Contact points
for our Offices of Congressional Relations and Public Affairs may be
found on the last page of this statement. Hazel Bailey, William
Carrigg, Barbara Chapman, Crystal Jones, Penny Pickett, and Elaine
Vaurio made key contributions to this statement.
[End of section]
Appendix I: United States Postal Service Initiatives:
U.S. Postal Service (USPS) officials reported to us these activities in
responding to our recommendations:
On the recommendation addressed to the Department of Homeland Security
(DHS) to develop appropriate validation studies of various activities
in detecting anthrax:
* USPS has been helping DHS implement that recommendation. It has been
working with its federal partners to further examine existing
biological coordination and protocol efforts, within the National
Capital Region.
* USPS is also working with state and local public health departments
by participating in several biological working groups chartered to help
clarify and reduce variance in procedures and protocols and, per GAO's
recommendations, to develop validation procedures to help ensure that
biothreat test results are reliable and can be clearly understood and
correctly interpreted.
* DHS has asked USPS to become part of a subject matter expert team as
a result of the real-world experience USPS gained in the 2001 anthrax
attacks, its response, and its cleanup and remediation efforts at a
number of mail processing facilities and post offices.
* USPS was asked to help develop and implement the guidance as part of
the National Capital Region BioWatch Advisory Council.
[End of section]
Appendix II: Centers for Disease Control and Prevention Initiatives:
Centers for Disease Control and Prevention (CDC) officials reported
information on their work on anthrax detection and anthrax vaccine.
With respect to anthrax detection, CDC said it is developing a
probabilistic sampling approach. This project will augment the targeted
sampling approach that it uses for initial response sampling. CDC
officials told us that CDC is "exploring the need for probability
sampling in those instances when statistical inferences are necessary."
CDC has also developed a program that will expand its environmental
microbiology objectives. This program has several focus areas. One is
identifying priority agents, through sampling strategy development,
sample collection, sample transportation, and sample analysis. Another
is risk reduction activities, such as determining the risk of infection
and evaluating techniques and procedures for reducing risk, including
improving decontamination methods.
Further, CDC has completed studies and has studies in progress on the
recovery of Bacillus anthracis spores from various types of surfaces
using different collection methods, including macrofoam swabs, wipes,
and HEPA vacuum. It also plans to study the survival rates of other
biothreat agents on nonporous surfaces and to evaluate HEPA-vacuum
samples for microbial analysis.
The National Immunization Program and the National Center for
Infectious Diseases components of the proposed National Center for
Immunization and Respiratory Diseases appreciated the opportunity to
share information about the status of CDC's Anthrax Vaccine Research
Program.
In 1999, CDC received funding to conduct studies of the safety and
efficacy of the U.S. licensed anthrax vaccine--anthrax vaccine adsorbed
(AVA). CDC's Anthrax Vaccine Research Program (AVRP) consists of a
human clinical vaccine trial with quantitative primary serological
endpoints, corroborative antibody functional analyses, and an
immunological correlates of protection study in rhesus macaques.
The focus of AVRP is a large-scale, multicenter, Phase III human
clinical trial with 1,564 participants. The study's objective is to
optimize the use of AVA, the only licensed anthrax vaccine in the
United States.[Footnote 15] The study evaluates the potential for
changing the route of administration, reducing the number of primary
series vaccinations for the licensed vaccine, and improving the profile
of side effects. A successful conclusion to the study will double the
availability of AVA, increase vaccine acceptance and uptake because of
a reduction in side effects, and provide animal study data
demonstrating long-term protection against inhalation anthrax afforded
by a priming series of three intramuscular injections.
Analysis of the human clinical trial serological and reactogenicity
data at an intermediate stage in the study showed that it is possible
to drop the dose at week two, change the route of administration to
intramuscular, and reduce side effects without making an impact on
antibody responses to a priming series of three injections. The interim
report was submitted to the Food and Drug Administration (FDA) in
February 2005, and subsequently the vaccine manufacturer filed a
supplement to its biologics license application to add this new regimen.
The AVRP's remaining research goals are to confirm that two additional
doses can be dropped from the priming series at 12 months and 18
months, thus moving to a three-injection intramuscular regimen; to
adopt biennial rather than annual boosters; and to establish in
nonhuman primate models the onset and duration of the protection of the
three-dose intramuscular regimen (the "correlates of protection" study).
CDC's Anthrax Vaccine Safety Team (AVST) is conducting a wide range of
anthrax vaccine safety research activities critical to accomplishing
the objectives in CDC's 1999 congressional mandate. These activities'
goals are to (1) address important anthrax vaccine safety questions,
(2) build an infrastructure to ensure the anthrax vaccine's safety, (3)
build a system to address concerns regarding vaccine safety and aid in
resolving potential liability questions, and (4) optimize the
vaccination schedule and the vaccine's administration to ensure its
efficacy while minimizing the number of doses required, reducing the
occurrence of adverse events, and maximizing the availability of the
only licensed anthrax vaccine in the United States.
In collaboration with the Army Medical Surveillance Activity of the
Department of Defense (DOD) and FDA, CDC established the Vaccine
Analytic Unit in 2003 on the Walter Reed Army Medical Center Campus. It
uses data from the Defense Medical Surveillance System to assess
whether specific longer-term adverse events are associated with AVA and
other biodefense vaccines; this system is a unique source of active
surveillance data containing medical, vaccination, and deployment
histories for U.S. military personnel. The Vaccine Analytic Unit's
research agenda for investigating potential AVA adverse events and an
AVA study on optic neuritis are in press, and a multiple near-
concurrent immunization study has been completed. Funded studies
include evaluations of AVA and Stevens Johnson Syndrome/Toxic Epidermal
Necrolysis, connective tissues diseases, diabetes mellitus, Guillain-
Barré Syndrome, and atrial fibrillation.
Studies to assess the possible effects of AVA on health-related quality
of life and the role of hormones as the basis for adverse AVA events
occurring more frequently in women are ongoing in participants of CDC's
AVRP, begun in 2002 for administering AVA to workers occupationally at
high risk for exposure to Bacillus anthracis. Also, AVST has ongoing
collaborative research studies with CDC's Immunization Safety Office,
FDA, and DOD to enhance AVA adverse event surveillance and improve AVA
acceptability.
[End of section]
Appendix III: Department of Homeland Security Initiatives:
Department of Homeland Security (DHS) officials reported the following
activities to us in addressing our recommendations:
DHS has taken a lead role in promoting and coordinating the activities
of various agencies that have technical expertise related to
environmental testing. DHS:
* led the formulation of a memorandum of understanding among DHS, DOD,
the Department of Health and Human Services (HHS), and USPS on
coordinated monitoring of biological threat agents and is leading the
execution of the memorandum;
* is leading an effort to establish an Integrated Consortium on
Laboratory Networks;
* has established a Federal Postal and Shipping Integrated Project Team;
* is co-chairing the Subcommittee of Decontamination Standards
Technology (SDST);
* is co-sponsoring the Second (and First) National Conference on
Environmental Sampling for Bio-Threat Agents.
DHS has adopted the International Quality Management Standard
definition of validation.
DHS has developed a process to standardize and validate methods; it:
* has validated a method for sampling suspicious powders and:
* is developing a method for the validation of public health actionable
assays.
DHS has invested in both targeted and probabilistic sampling strategies
and in methodologies that are appropriate for monitoring facilities and
that apply to wide-area and facility restoration. Its research and
development efforts include:
* performance characterization of three sampling methods on varied
surfaces;
* developing the Building Restoration Operations Optimization Model;
* sponsoring the Visual Sample Module;
* developing Annotated Characterization and Clearance Sampling Plan
Templates for preplanning the response to a biological facility attack;
* developing BioWatch Preparedness and Response Guidance, which
includes Part III: BioWatch Environmental Sampling;
* developing native air sample collection strategies and protocols
associated with transportation facilities.
DHS has prioritized investments for high-risk biological agents through
internal and interagency coordination, to include:
* SDST research and development investment strategy;
* agency-to-agency discussions on leveraging research and development
opportunities;
* internal strategic planning and requirements generation.
(460580):
[End of section]
FOOTNOTES:
[1] For our work on anthrax detection methods, see GAO, Anthrax
Detection: Agencies Need to Validate Sampling Activities in Order to
Increase Confidence in Negative Results, GAO-05-251 (Washington, D.C.:
Mar. 31, 2005), and GAO, U.S. Postal Service: Issues Associated with
Anthrax Testing at the Wallingford Facility, GAO-03-787T (Washington
D.C.: May 19, 2003). For our work on anthrax vaccine, see Gulf War
Illnesses: Questions about the Presence of Squalene Antibodies in
Veterans Can Be Resolved, GAO/NSIAD-99-5 (Washington, D.C.: Mar. 29,
1999); Medical Readiness: Safety and Efficacy of the Anthrax Vaccine,
GAO/T-NSIAD-99-148 (Washington, D.C.: Apr. 29, 1999); Contract
Management: Observations on DOD‘s Financial Relationship with the
Anthrax Vaccine Manufacturer, GAO/T-NSIAD-99-214 (Washington, D.C.:
June 30, 1999); Medical Readiness: Issues Concerning the Anthrax
Vaccine, GAO/T-NSIAD-99-226 (Washington, D.C.: July 21, 1999); Anthrax
Vaccine: Safety and Efficacy Issues, GAO/T-NSIAD-00-48 (Washington,
D.C.: Oct. 12, 1999); Medical Readiness: DOD Faces Challenges in
Implementing Its Anthrax Vaccine Immunization Program, GAO/NSIAD-00-36
(Washington, D.C.: Oct. 22, 1999); Medical Readiness: DOD Continues to
Face Challenges in Implementing Its Anthrax Vaccine Immunization
Program, GAO/T-NSIAD-00-157 (Washington, D.C.: Apr. 13, 2000); State
Department: Serious Problems in the Anthrax Vaccine Immunization
Program, GAO-01-21, (Washington, D.C.: Dec. 13, 2000); Anthrax Vaccine:
Changes to the Manufacturing Process, GAO-02-181T (Washington, D.C.:
Oct. 23, 2001); Anthrax Vaccine: GAO‘s Survey of Guard and Reserve
Pilots and Aircrew, GAO-02-445 (Washington, D.C.: Sept. 20, 2002).
[2] The SNS is a national repository of medical countermeasures, such
as antibiotics and vaccines. It is designed to supplement and resupply
state and local public health agencies in the event of a national
emergency anywhere and anytime within the United States or its
territories.
[3] Merck Sharp & Dhome is a subsidiary of Merck & Co., Inc.
[4] Anthrax infection has occurred most commonly in settings like wool
mills, where workers may be exposed to infected animal products.
[5] Before FDA was established as the licensing authority for vaccines,
NIH performed that function.
[6] The regulations embody a set of scientifically sound methods,
practices, or principles that are implemented and documented during
development and production to ensure the consistent manufacture of
safe, pure, and potent products. Such principles apply to the
manufacturing process as well as to the facilities products are
manufactured in. (21 C.F.R., parts 600 through 680.)
[7] An IND application is a request for authorization from FDA to
administer an investigational drug or biological product to humans.
[8] In May 2002, FDA published Approval of Biological Products When
Human Efficacy Studies Are Not Ethical or Feasible (21 C.F.R. 601,
Subpart H, as well as 21 C.F.R. 314, Subpart I for New Drugs). This
rule, known as the "Animal Rule," permits the substitution of animal
studies for human trials where human efficacy studies are not ethical
and field trials are not feasible, provided a scientifically valid
animal model for the disease exists. This rule does not obviate the
need for safety data, which must still be established.
[9] CDC is conducting a wide range of anthrax vaccine research
activities, including ensuring the vaccine's safety while minimizing
the number of doses.
[10] P. S. Brachman and A. Friedlander, "Anthrax," in Vaccines, eds. S.
A. Plotkin and E. A. Mortimer Jr. (Philadelphia: W. B. Saunders
Company, 1994), p. 737, and Institute of Medicine, Chemical and
Biological Terrorism: Research and Development to Improve Civilian
Medical Response (Washington, D.C.: National Academy Press, 1999), p.
135.
[11] Institute of Medicine, Chemical and Biological Terrorism, p. 135.
[12] B. Ivins and others, "Immunization Studies with Attenuated Strains
of Bacillus anthracis," Journal of Infection and Immunity 52 (1986):
454-58; B. E. Ivins, "The Search for a New-Generation Human Anthrax
Vaccine," Clinical Immunology Newsletter 9 (1988): 30-32; and Y. Singh
and others, "Study of Immunization against Anthrax with the Purified
Recombinant Protective Antigen of Bacillus anthracis," Journal of
Infection and Immunity 66 (1998): 3447-48.
[13] The RFP for the 2002 contract was NIH-NIAID-DMID-02-26; for the
2003 contract, NIH-NIAID-DMID-03-29.
[14] For the 2002 RFP, two awards totaling $22.5 million were given--
$13.6 million to VaxGen and $8.9 million to Avecia Ltd. of Manchester,
England.
[15] AVA, or BioThrax, is licensed to BioPort Corporation, Lansing,
Michigan.
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Web site: www.gao.gov/fraudnet/fraudnet.htm E-mail: fraudnet@gao.gov
Automated answering system: (800) 424-5454 or (202) 512-7470:
Congressional Relations:
Gloria Jarmon, Managing Director, JarmonG@gao.gov (202) 512-4400 U.S.
Government Accountability Office, 441 G Street NW, Room 7125
Washington, D.C. 20548:
Public Affairs:
Paul Anderson, Managing Director, AndersonP1@gao.gov (202) 512-4800
U.S. Government Accountability Office, 441 G Street NW, Room 7149
Washington, D.C. 20548:
