Public Health Preparedness
Developing and Acquiring Medical Countermeasures Against Chemical, Biological, Radiological, and Nuclear Agents Gao ID: GAO-11-567T April 13, 2011The anthrax attacks of 2001 and a radiation leak after the recent natural disaster in Japan highlighted concerns that the United States is vulnerable to threats from chemical, biological, radiological, and nuclear (CBRN) agents, which can cause widespread illness and death. Medical countermeasures--such as drugs, vaccines, and diagnostic devices--can prevent or treat the health effects of exposure, but few are currently available for many of these CBRN agents. GAO was asked to testify on the Department of Health and Human Services' (HHS) CBRN medical countermeasure development and acquisition activities. This statement focuses on (1) how HHS determines needed CBRN medical countermeasures and priorities for development and acquisition and (2) selected challenges to medical countermeasure development and acquisition. This statement of preliminary findings is based on ongoing work. To do this work, GAO examined relevant laws and presidential directives, analyzed federal agency documents and reports from advisory boards and expert groups, and interviewed officials from HHS and the Department of Homeland Security (DHS) about the processes for developing and acquiring CBRN medical countermeasures and the challenges related to those efforts. GAO shared the information in this statement with HHS. HHS provided technical comments, which GAO incorporated as appropriate.
HHS coordinates and leads federal efforts to determine CBRN medical countermeasure priorities and develop and acquire CBRN medical countermeasures, primarily through an interagency body that includes other federal agencies with related responsibilities, such as DHS and the Department of Defense. HHS's medical countermeasure acquisition strategy is based on a four-step process: (1) identify and assess the threat of CBRN agents, (2) assess medical and public health consequences of attacks with these agents, (3) establish medical countermeasure requirements, and (4) identify and prioritize near-, mid-, and long-term development and acquisition. Through these processes, HHS determines which countermeasures to buy for specific CBRN agents, including the desired characteristics of these countermeasures--such as how many doses a vaccine requires to confer immunity--the needed quantity of certain medical countermeasures, and the acquisition priorities. While a few CBRN countermeasures can be immediately acquired, most have not yet been developed. Therefore, HHS and the interagency body support and oversee several stages of research and development to try to obtain usable countermeasures. These include basic cellular and biological research to understand the effects of these agents on humans; applied research to validate approaches, such as testing the effectiveness of treatment in animals; early development to assess the safety of potential countermeasures; and advanced development, in which the products are more fully evaluated for safety and effectiveness, including their formulation and manufacturing processes. The federal government faces a variety of challenges in developing and acquiring medical countermeasures, such as the high failure rate in research and development and difficulties meeting regulatory requirements. For example, the failure rate for development and licensure of most drugs, vaccines, and diagnostic devices can be more than 80 percent, depending on the stage of scientific research and development. Given this risk, as well as a lack of a commercial market for most medical countermeasures, attracting large, experienced pharmaceutical firms to research and develop them is challenging. Smaller biotechnology companies are more likely to be developing medical countermeasures, but HHS must provide more guidance to these less experienced small companies than might be typical with larger companies. In addition, several challenges exist related to regulatory processes for evaluating promising medical countermeasures. These challenges include (1) proving a countermeasure's effectiveness using animals as proxies for humans, because humans cannot ethically be used in studies involving CBRN agents; (2) determining appropriate doses of countermeasures for children, who may be more vulnerable to exposure to CBRN agents; and (3) evaluating the safety and effectiveness of medical countermeasures for use in a public health emergency if they have not yet been approved or licensed. Finally, HHS faces the logistical challenge of ongoing replenishment of expiring medical countermeasures in the U.S. Strategic National Stockpile, the national repository of medications, medical supplies, and equipment for public health emergencies.
GAO-11-567T, Public Health Preparedness: Developing and Acquiring Medical Countermeasures Against Chemical, Biological, Radiological, and Nuclear Agents
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United States Government Accountability Office:
GAO:
Testimony:
Before the Subcommittee on Emergency Preparedness, Response, and
Communications, Committee on Homeland Security, House of
Representatives:
For Release on Delivery:
Expected at 2:00 p.m. EDT:
Wednesday, April 13, 2011:
Public Health Preparedness:
Developing and Acquiring Medical Countermeasures Against Chemical,
Biological, Radiological, and Nuclear Agents:
Statement of Cynthia A. Bascetta:
Managing Director, Health Care:
GAO-11-567T:
GAO Highlights:
Highlights of GAO-11-567T, a testimony before the Subcommittee on
Emergency Preparedness, Response, and Communications, Committee on
Homeland Security, House of Representatives.
Why GAO Did This Study:
The anthrax attacks of 2001 and a radiation leak after the recent
natural disaster in Japan highlighted concerns that the United States
is vulnerable to threats from chemical, biological, radiological, and
nuclear (CBRN) agents, which can cause widespread illness and death.
Medical countermeasures”such as drugs, vaccines, and diagnostic
devices”can prevent or treat the health effects of exposure, but few
are currently available for many of these CBRN agents.
GAO was asked to testify on the Department of Health and Human Services‘
(HHS) CBRN medical countermeasure development and acquisition
activities. This statement focuses on (1) how HHS determines needed
CBRN medical countermeasures and priorities for development and
acquisition and (2) selected challenges to medical countermeasure
development and acquisition. This statement of preliminary findings is
based on ongoing work. To do this work, GAO examined relevant laws and
presidential directives, analyzed federal agency documents and reports
from advisory boards and expert groups, and interviewed officials from
HHS and the Department of Homeland Security (DHS) about the processes
for developing and acquiring CBRN medical countermeasures and the
challenges related to those efforts. GAO shared the information in
this statement with HHS. HHS provided technical comments, which GAO
incorporated as appropriate.
What GAO Found:
HHS coordinates and leads federal efforts to determine CBRN medical
countermeasure priorities and develop and acquire CBRN medical
countermeasures, primarily through an interagency body that includes
other federal agencies with related responsibilities, such as DHS and
the Department of Defense. HHS‘s medical countermeasure acquisition
strategy is based on a four-step process: (1) identify and assess the
threat of CBRN agents, (2) assess medical and public health
consequences of attacks with these agents, (3) establish medical
countermeasure requirements, and (4) identify and prioritize near-,
mid-, and long-term development and acquisition. Through these
processes, HHS determines which countermeasures to buy for specific
CBRN agents, including the desired characteristics of these
countermeasures”such as how many doses a vaccine requires to confer
immunity”the needed quantity of certain medical countermeasures, and
the acquisition priorities. While a few CBRN countermeasures can be
immediately acquired, most have not yet been developed. Therefore, HHS
and the interagency body support and oversee several stages of
research and development to try to obtain usable countermeasures.
These include basic cellular and biological research to understand the
effects of these agents on humans; applied research to validate
approaches, such as testing the effectiveness of treatment in animals;
early development to assess the safety of potential countermeasures;
and advanced development, in which the products are more fully
evaluated for safety and effectiveness, including their formulation
and manufacturing processes.
The federal government faces a variety of challenges in developing and
acquiring medical countermeasures, such as the high failure rate in
research and development and difficulties meeting regulatory
requirements. For example, the failure rate for development and
licensure of most drugs, vaccines, and diagnostic devices can be more
than 80 percent, depending on the stage of scientific research and
development. Given this risk, as well as a lack of a commercial market
for most medical countermeasures, attracting large, experienced
pharmaceutical firms to research and develop them is challenging.
Smaller biotechnology companies are more likely to be developing
medical countermeasures, but HHS must provide more guidance to these
less experienced small companies than might be typical with larger
companies. In addition, several challenges exist related to regulatory
processes for evaluating promising medical countermeasures. These
challenges include (1) proving a countermeasure‘s effectiveness using
animals as proxies for humans, because humans cannot ethically be used
in studies involving CBRN agents; (2) determining appropriate doses of
countermeasures for children, who may be more vulnerable to exposure
to CBRN agents; and (3) evaluating the safety and effectiveness of
medical countermeasures for use in a public health emergency if they
have not yet been approved or licensed. Finally, HHS faces the
logistical challenge of ongoing replenishment of expiring medical
countermeasures in the U.S. Strategic National Stockpile, the national
repository of medications, medical supplies, and equipment for public
health emergencies.
View [hyperlink, http://www.gao.gov/products/GAO-11-567T] or key
components. For more information, contact Cynthia A. Bascetta at (202)
512-7114 or bascettac@gao.gov.
[End of section]
Chairman Bilirakis, Ranking Member Richardson, and Members of the
Subcommittee:
I am pleased to be here today to discuss the Department of Health and
Human Services' (HHS) chemical, biological, radiological, and nuclear
(CBRN) medical countermeasure development and acquisition activities
and associated challenges.[Footnote 1] The anthrax attacks of 2001
raised concerns that the United States is vulnerable to intentional
threats from CBRN agents. In addition, the recent earthquake and
resulting tsunami in Japan that caused a nuclear reactor to rupture
highlighted a population's vulnerability to unintentional CBRN
exposure, such as to radiation. CBRN agents have the potential to
cause widespread illness and death, which can be partially mitigated
through the use of medical countermeasures. Medical countermeasures
for CBRN agents include drugs, vaccines, and devices to diagnose,
treat, prevent, or mitigate potential effects of exposure. Members of
Congress, federal commissions, and other experts have noted the need
for the United States to acquire available medical countermeasures and
develop new ones to protect the public from attacks with CBRN agents.
While rapid diagnosis, treatment, and prevention may minimize the
public health impact of a release of these agents, there are currently
few countermeasures available for many CBRN agents, and research and
development to create usable countermeasures is a lengthy and complex
process.
You asked us to provide information about HHS's CBRN medical
countermeasure development and acquisition activities. My statement
today addresses (1) how HHS determines needed CBRN medical
countermeasures and priorities for development and acquisition and (2)
selected challenges to federal CBRN medical countermeasure development
and acquisition.
To develop preliminary findings based on our ongoing work on HHS's
CBRN medical countermeasure development and acquisition activities and
selected challenges of these activities, we reviewed relevant laws and
agency documents and interviewed federal officials. Specifically, to
understand how HHS determines needed CBRN medical countermeasures and
priorities for developing and acquiring them, we examined relevant
laws and reviewed presidential directives that guide HHS's CBRN
medical countermeasure development and acquisition activities. We
obtained and analyzed HHS planning documents for medical
countermeasure development and acquisition, such as public health and
medical consequence modeling reports and strategy and implementation
plans for medical countermeasure development and acquisition
priorities. We interviewed officials from the Department of Homeland
Security (DHS) about their activities related to CBRN agents and
medical countermeasures. We also interviewed officials from HHS
offices and agencies, including the Biomedical Advanced Research and
Development Authority (BARDA) within the Office of the Assistant
Secretary for Preparedness and Response (ASPR), the Centers for
Disease Control and Prevention (CDC), the Food and Drug Administration
(FDA), and the National Institutes of Health (NIH), to obtain
information on their activities related to medical countermeasure
development and acquisition. These officials participate in the Public
Health Emergency Medical Countermeasures Enterprise (PHEMCE), HHS's
interagency decision-making body responsible for providing
recommendations to the Secretary of HHS regarding CBRN medical
countermeasure development and acquisition. To identify selected
challenges that the federal government faces in developing and
acquiring CBRN medical countermeasures, we reviewed reports from
federal agencies, advisory boards, and nongovernmental organizations
and interviewed federal officials from the agencies identified above
and other experts. We included selected challenges that were discussed
in multiple reports published by federal agencies or other expert
groups, such as the Institute of Medicine, or those mentioned to us by
officials from multiple federal agencies or organizations. We did not
include any challenges that related to interagency coordination and
agency investments in medical countermeasure development and
acquisition because we are currently examining these issues for
ongoing audit work. In addition, because it was not the focus of this
hearing, we excluded HHS processes for and challenges in distributing
CBRN medical countermeasures from the scope of this statement. We
shared the information in this statement with HHS. HHS provided
technical comments, which we incorporated as appropriate.
We are conducting this performance audit in accordance with generally
accepted government auditing standards. This statement is based on
work conducted from March 2011 to April 2011. The performance audit
standards require that we plan and perform the audit to obtain
sufficient, appropriate evidence to provide a reasonable basis for our
findings and conclusions based on our audit objectives. We believe
that the evidence obtained provides a reasonable basis for our
findings and conclusions based on our audit objectives.
Background:
Several federal departments and agencies have responsibilities for
assessing the threat of CBRN agents and determining requirements and
priorities for developing and acquiring medical countermeasures for
these agents, as part of their mission and, in some cases, as
specifically required by law.
DHS leads federal interagency coordination and planning for emergency
response to catastrophic CBRN incidents. Under the Project BioShield
Act of 2004, DHS is required, in consultation with HHS, to assess the
threat of CBRN agents.[Footnote 2]
HHS leads the federal medical and public health response to potential
CBRN incidents.
* HHS established PHEMCE in 2006. PHEMCE is a federal interagency
decision-making body responsible for providing recommendations to the
Secretary of HHS on (1) prioritized requirements for CBRN medical
countermeasures, (2) coordination of medical countermeasure
development and acquisition activities to address the requirements,
and (3) strategies for distributing medical countermeasures held in
the U.S. Strategic National Stockpile (SNS), the national repository
of medications, medical supplies, and equipment for use in a public
health emergency. As required by the Pandemic and All-Hazards
Preparedness Act of 2006, PHEMCE also conducts annual reviews of the
SNS, the results of which are used to make necessary additions or
modifications to its contents.[Footnote 3] PHEMCE is composed
primarily of officials from HHS's ASPR, BARDA, CDC, FDA, and NIH,
which also have specific agency responsibilities for countermeasure
development and acquisition. In addition, PHEMCE includes officials
from DHS, the Department of Defense (DOD), the Department of Veterans
Affairs, the Department of Agriculture, and the Executive Office of
the President.
* Within HHS, ASPR is responsible for leading federal government
efforts to research, develop, evaluate, and acquire public health
emergency medical countermeasures to prevent, treat, or mitigate the
potential health effects from exposure to CBRN agents. Under the
Project BioShield Act, HHS is responsible for arranging for the
acquisition of certain medical countermeasures, some of which may not
yet be FDA-approved or licensed.[Footnote 4] These countermeasures
also include those for children and other vulnerable populations, such
as those for the elderly and immunocompromised individuals. The
Project BioShield Act authorized the Special Reserve Fund for
acquisition of these countermeasures.[Footnote 5]
* Within ASPR, BARDA--established by the Pandemic and All-Hazards
Preparedness Act of 2006--is responsible for overseeing and funding
advanced development and acquisition of CBRN medical countermeasures.
[Footnote 6]
* CDC is responsible for maintaining the SNS. CDC also supports state
and local public health departments in their efforts to detect and
respond to public health emergencies such as CBRN incidents, including
providing guidance and recommendations for the mass distribution and
use of medical countermeasures.
* FDA is responsible for assessing the safety and effectiveness of
CBRN medical countermeasures and regulates their development, approval
and licensure, and postmarket surveillance.[Footnote 7] FDA also
provides technical support for the development of tools to support
medical countermeasure development. Under the Project BioShield Act,
as delegated by the HHS Secretary, FDA may temporarily authorize the
emergency use of unapproved or unlicensed medical products in certain
circumstances through emergency use authorizations (EUA).[Footnote 8]
* The National Institutes of Health (NIH) is responsible for
conducting and coordinating basic and applied research to develop new
or enhanced medical countermeasures and related medical tools for CBRN
agents.
* The National Biodefense Science Board (NBSB), established by the
Pandemic and All-Hazards Preparedness Act, provides the HHS Secretary
with expert advice and guidance on scientific and technical matters
related to current and future CBRN agents, including those that occur
naturally.[Footnote 9]
DOD has exclusive responsibility for research, development,
acquisition, and deployment of medical countermeasures to prevent or
mitigate the health effects of CBRN agents and naturally occurring
diseases on Armed Forces personnel. Under the PHEMCE structure, DOD
also coordinates with HHS on the Integrated Portfolio to identify
common medical countermeasure priorities.[Footnote 10]
HHS, Through PHEMCE, Uses a Four-Step Process to Determine Acquisition
Priorities for Medical Countermeasures and Oversees Their Development:
HHS coordinates and leads federal efforts to determine CBRN medical
countermeasure priorities and develop and acquire CBRN medical
countermeasures, primarily through PHEMCE. HHS's medical
countermeasure acquisition strategy is based on a four-step process:
(1) identify and assess the threat of CBRN agents, (2) assess medical
and public health consequences of attacks with these agents, (3)
establish medical countermeasure requirements, and (4) identify and
prioritize near-, mid-, and long-term development and acquisition
programs.[Footnote 11] Because desired CBRN medical countermeasures
may not be immediately available for acquisition, HHS oversees and
supports the various stages of research and development of these
countermeasures, also under PHEMCE. (See figure 1.)
Figure 1: Medical Countermeasures: Process to Prioritize Development
and Acquisition:
[Refer to PDF for image: illustration]
Identify threats: DHS;
Assess medical consequences: PHEMCE;
Establish counter-measure requirements: PHEMCE;
Prioritize development and acquisition: PHEMCE;
Determine if existing products can serve as countermeasures: PHEMCE:
Support basic research: NIH;
Support applied research: NIH;
Support early development: NIH;
Support advanced development: BARDA;
Acquisition & licensure: PHEMCE, BARDA, FDA[A].
Source: GAO analysis of HHS information.
[A] FDA works with researchers throughout the development stages, to
review safety and effectiveness test results, ensure that research
meets FDA's regulatory requirements, and approve successful products
for licensure.
[End of figure]
With input from HHS, DHS leads the first step in the process to
assess, on an ongoing basis, the threat of CBRN agents and determine
which of these agents pose a material threat to national security, as
required by the Project BioShield Act.[Footnote 12] The material
threat assessments (MTA) that DHS issues examine the threat posed by
given CBRN agents or classes of agents for plausible, high-consequence
scenarios and provide estimates of the number of people exposed to
different dose levels of an agent in the scenarios. Since 2004, DHS
has determined that 13 of these CBRN agents pose a material threat,
based on the MTAs.[Footnote 13]
In the second step, HHS and its PHEMCE partners use the data from the
MTA scenarios to assess the public health and medical consequences of
an attack using these agents.[Footnote 14] Public health consequence
modeling estimates the number of individuals who may become ill, be
hospitalized, or die from exposure to and infection with CBRN agents,
with or without medical intervention. To develop these estimates from
the MTA exposure data, HHS consults with experts and uses available
scientific data, such as data on how much of an agent is needed to
cause infection and how long it takes to develop symptoms of disease
after exposure. In addition, HHS assesses the status of current
countermeasure development and availability, including applicable
countermeasures that DOD may be developing. Through consequence
modeling, HHS determines the public health impact on the affected
population in terms of the potential health effects throughout the
course of disease based on different time frames for medical
countermeasure delivery and treatment. According to HHS officials,
consequence modeling allows PHEMCE to consider public health
preparedness needs, such as whether a particular countermeasure is
plausible or feasible for a certain CBRN agent and the amount that
would be needed.
In the third step, PHEMCE uses the consequence modeling results to
determine requirements for needed medical countermeasures, including
the needed quantity and the desired characteristics, such as how they
would be used and stored. HHS officials told us that these
requirements would include the preferred method of administration,
such as oral administration of a medicine that can be stored at room
temperature. PHEMCE partners consult with experts and incorporate
intelligence information and information on state and local response
capabilities to determine ideal countermeasure characteristics. If
countermeasures that meet these characteristics are not immediately
available, HHS may acquire countermeasures that are currently
available and work with manufacturers over time to develop
countermeasures that better meet the ideal characteristics.[Footnote
15]
In the fourth step, the established medical countermeasure
requirements help HHS assess and prioritize its countermeasure
investments, and, according to HHS officials, form the basis for
development and acquisition solicitations and contracts. Based on the
requirements, in 2007, PHEMCE set its medical countermeasure
acquisition priorities to focus on spending the remainder of the
Project BioShield Special Reserve Fund for certain CBRN agents that
DHS determined posed a material threat to national security. In
addition, PHEMCE priorities focus on obtaining medical countermeasures
for postexposure prevention or treatment of disease caused by those
CBRN agents. HHS grouped these priorities in time frames for the near
term (fiscal year 2007 through fiscal year 2008), midterm (fiscal year
2009 through fiscal year 2013), and long term (beyond fiscal year
2013). PHEMCE's stated priorities include acquiring diagnostics for
each biological agent deemed a material threat, smallpox vaccine,
medical countermeasures for Ebola and Marburg viruses, and medications
to treat the acute and delayed effects of radiation. PHEMCE also uses
the results of its annual SNS review to reassess prioritization of
CBRN medical countermeasures, based on any SNS acquisitions made after
the initial 2007 prioritizations.
BARDA oversees the acquisition and delivery of medical countermeasures
into the SNS. If a medical countermeasure is not FDA-approved or
licensed, its acquisition is funded by BARDA using the Project
BioShield Special Reserve Fund. If a medical countermeasure is FDA-
approved or licensed for use in treating the health effects of a CBRN
agent, CDC purchases the countermeasure for the SNS. HHS officials
told us that once FDA approves or licenses a countermeasure acquired
with the Special Reserve Fund, BARDA is still responsible for
overseeing its acquisition through the end of the Project BioShield
contract. BARDA is also responsible for negotiating with the
manufacturer to obtain additional quantities of the countermeasure in
the event of a CBRN attack. CDC officials told us that they develop a
5-year project plan for each countermeasure in the SNS upon
acquisition to evaluate specific needs over time--such as shelf life,
replacement costs of expiring products, and storage and space
requirements--and update the plan every year, or more frequently if
conditions change.
HHS officials told us that of the few available medical
countermeasures for CBRN agents, some are FDA-approved or licensed
specifically for CBRN use. Other countermeasures that HHS has acquired
for CBRN use have been approved or licensed for other uses only. For
example, there are no currently available rapid diagnostic tools for
any of the biological agents that DHS deemed material threats other
than anthrax, nor are there any available medical countermeasures for
postexposure prevention of disease for Ebola and Marburg viruses.
NIH and BARDA oversee and support CBRN medical countermeasure research
and development, which is conducted in several stages.[Footnote 16]
(See figure 1.)
* Early research: Early, or basic, research seeks to better understand
CBRN agents and the response of the host organism to the agents
through the study of the cellular and molecular biology of agents and
hosts, their physiologic processes, and their genome sequences and
structures. According to NIH officials, individual researchers
typically initiate research in this stage. NIH assesses these research
projects and their application for specific CBRN agents.
* Applied research: Applied, or translational, research builds on
basic research by validating and testing concepts in practical
settings to identify potential products. NIH officials told us that
the agency funds applied research to identify scientific or practical
limitations that may affect the potential of a scientific concept to
develop into a medical countermeasure product.
* Early development: NIH moves successful concepts from the applied
research stage into the early development stage, in which it funds
research to demonstrate basic safety, reproducibility, and ability to
be used in humans. In its requests for research proposals for early
development, NIH officials told us that the agency specifies its needs
by product modes and categories, such as therapeutics, diagnostics,
and vaccines; NIH can further specify the characteristics of a medical
countermeasure, and companies agree to the terms of the contract up
front.
* Advanced development: BARDA oversees and funds CBRN advanced
research and development. In this stage, potential medical
countermeasures are further evaluated in animal studies to demonstrate
safety and effectiveness for preventing, diagnosing, or treating
disease in humans. Successful products are then available for
development and acquisition. In addition, in this stage, BARDA
determines that manufacturing, scale-up production, and licensing of
countermeasures can be achieved in a timely and reliable manner. BARDA
also awards contracts using the Project BioShield Special Reserve Fund
to acquire medical countermeasures for the SNS that are reasonably
expected to qualify for FDA approval or licensure within 8 years.
Challenges to Development and Acquisition of Medical Countermeasures
Include High Failure Rates in Research and Difficulties Meeting
Regulatory Requirements:
The federal government faces a variety of challenges in developing and
acquiring medical countermeasures, such as the high failure rate in
research and development and difficulties meeting regulatory
requirements. One scientific challenge is that, as with other medical
products, the failure rate for development of certain CBRN medical
countermeasures can be high, depending on the stage of scientific
research and development. HHS estimates that the failure rate for
development and licensure of most drugs, vaccines, and diagnostic
devices in the early development stage can be more than 80 percent,
with an increasing probability of success as the product moves further
through development. Because most CBRN research does not result in
viable medical countermeasures, HHS officials told us that they try to
fund a larger set of candidates in earlier stages of research in order
to increase the likelihood that at least one candidate countermeasure
may be successful. HHS officials noted that they would ideally prefer
to have at least two successfully developed medical countermeasures
from different manufacturers available for a particular CBRN agent for
several reasons, such as if certain segments of the population are
resistant to one of the countermeasures or if one of the companies
experiences manufacturing problems.
Given the high risk of failure in research, as well as a lack of a
commercial market for most CBRN countermeasures, attracting companies
experienced in meeting the complex requirements necessary to develop a
new product is also challenging. The private sector--especially large
pharmaceutical companies--has little incentive to invest millions of
dollars to develop a potential new medical countermeasure because the
lack of a commercial market makes a return on investment less likely
or less lucrative. The Project BioShield Act facilitates the creation
of a government market by authorizing the government to commit to make
the Special Reserve Fund available to acquire certain medical
countermeasures, including those that are not yet licensed or
approved, provided they meet certain conditions.[Footnote 17] In
addition, the Pandemic and All-Hazards Preparedness Act established
BARDA to support advanced research and development by, for example,
awarding contracts and grants for countermeasure advanced research and
development.[Footnote 18] BARDA provides funding for advanced research
and development for those countermeasures that are not eligible for
the Special Reserve Fund. Nevertheless, despite the Special Reserve
Fund and BARDA support, HHS and others have noted that engaging large
pharmaceutical companies remains a challenge. In addition, smaller
biotechnology companies conducting much of the research and
development for medical countermeasures generally have less experience
with drug development. As a result, FDA officials told us that they
have to provide more regulatory and scientific guidance to these
companies than they might provide to larger pharmaceutical companies,
which generally have more experience with bringing products through
the regulatory process.
There are also several challenges related to the regulatory processes
for evaluating the development of promising medical countermeasures.
For example, researchers face challenges proving the effectiveness of
potential countermeasures because they cannot ethically or feasibly
test the effectiveness of countermeasures on humans due to the dangers
posed by CBRN agents. However, because FDA requires evidence of a
countermeasure's effectiveness for approval or licensure, researchers
can submit evidence of effectiveness obtained from appropriate studies
in animals in accordance with FDA's Animal Rule. The Animal Rule
states that in selected circumstances, when it is neither ethical nor
feasible to conduct human efficacy studies, FDA may grant marketing
approval based on adequate and well-controlled animal studies when the
results of those studies establish that the drug or biological product
is reasonably likely to produce clinical benefit in humans.[Footnote
19] Under this rule, researchers can demonstrate effectiveness of
medical countermeasures if the way a disease occurs in the animal
being studied adequately mimics the way the disease occurs in humans.
However, animals that manifest the disease in the same way as humans
may not always exist for a given CBRN agent. For example, according to
FDA officials, smallpox occurs only in humans, and related viruses
that occur in animals, such as monkey pox, may not be similar enough
to mimic smallpox in humans. Because of the complexities of using
animal studies as models for human reactions to agents and potential
countermeasures, FDA would prefer to meet with researchers earlier and
more frequently, and FDA takes longer to evaluate product applications
for CBRN medical countermeasures than to evaluate other medical
products. In addition, the NBSB and others have reported that
researchers face difficulty in applying FDA's draft guidance on the
Animal Rule, which is currently under revision. According to the
guidance, the agent tested in the animal must be identical to the
agent that causes human disease. However, as discussed above, some
animal studies may not meet that criterion and therefore cannot be
used to demonstrate a countermeasure's effectiveness. To date, FDA has
not approved any newly developed CBRN medical countermeasures based on
animal model testing.[Footnote 20]
Determining appropriate doses of CBRN countermeasures for children,
who may be more vulnerable to the adverse effects of a CBRN agent,
also involves regulatory challenges.[Footnote 21] Most approved or
licensed CBRN medical countermeasures have been approved for use in
adults only and lack pediatric dosing information. In addition,
several candidate medical countermeasures currently in development
lack or have limited pediatric dosing information. Regulations
restrict children's participation in clinical trials when they do not
benefit from them;[Footnote 22] therefore, developing pediatric dosing
information relies on existing adult data or data from animal studies.
There are also challenges in the processes for evaluating the
emergency use of a promising medical countermeasure that has not been
FDA-approved or licensed for treatment or postexposure prevention of
disease for a given CBRN agent. In order for the government to use an
unapproved countermeasure to respond to a CBRN event, FDA must issue
an EUA. FDA can issue EUAs only after the HHS Secretary declares a
public health emergency. In order for FDA to issue an EUA, CDC or
another government or private entity has to submit detailed
information for FDA to evaluate, such as available safety and
effectiveness information, a discussion of risks and benefits of using
the unapproved countermeasure, draft fact sheets for health care
providers and patients, and instructions for using the countermeasure.
While CDC or other entities may submit all available data for FDA
review in advance, such as when CDC acquires a countermeasure for the
SNS, the agency must formally submit the EUA request at the time of
the declared emergency. In the event of an attack with a CBRN agent
that can cause disease within hours or days after exposure, CDC and
FDA would have to process the final documents quickly in order for FDA
to issue EUAs for appropriate medical countermeasures. Further, the
Project BioShield Act precludes the use of data collected during the
emergency use of an unapproved product to constitute a clinical
investigation to support later product approval.[Footnote 23]
Finally, CDC faces the logistical challenge of ongoing replenishment
of expiring medical countermeasures in the SNS. CDC can work with FDA
to extend the expiration date of certain drugs in the stockpile, and
thereby defer the cost of replacing the countermeasure and extend its
availability for use in a potential CBRN event. In such cases,
however, FDA has to conduct studies to ensure stability and quality of
each drug. In addition, CDC faces the cost of relabeling the products
to reflect the new expiration date. If the shelf life of an expiring
countermeasure cannot be extended, CDC must replace it. For some
countermeasures in the SNS, CDC may not face this challenge. For
example, CDC officials told us that anthrax vaccine is moved out of
the SNS before expiration because CDC rotates it out to DOD facilities
for routine use.[Footnote 24] In addition, other countermeasures may
be held for the SNS by private vendors and can be used commercially,
provided that the vendors hold a certain amount for use in the event
of a public health emergency.
Chairman Bilirakis, this concludes my prepared statement. I would be
happy to answer any questions that you, Ranking Member Richardson, or
other Members of the Subcommittee may have.
GAO Contact and Staff Acknowledgments:
For further information about this statement, please contact Cynthia
A. Bascetta at (202) 512-7114 or bascettac@gao.gov. Contact points for
our Offices of Congressional Relations and Public Affairs may be found
on the last page of this statement. Key contributors to this statement
were Marcia Crosse, Director; Sheila K. Avruch, Assistant Director;
Shana R. Deitch; Tracey King; Corissa Kiyan; Carolina Morgan; and
Roseanne Price.
[End of section]
Appendix I: Abbreviations:
ASPR: Office of the Assistant Secretary for Preparedness and Response:
BARDA: Biomedical Advanced Research and Development Authority:
CBRN: chemical, biological, radiological, and nuclear:
CDC: Centers for Disease Control and Prevention:
DHS: Department of Homeland Security:
DOD: Department of Defense:
EUA: emergency use authorization:
FDA: Food and Drug Administration:
HHS: Department of Health and Human Services:
MTA: material threat assessment:
NBSB: National Biodefense Science Board:
NIH: National Institutes of Health:
PHEMCE: Public Health Emergency Medical Countermeasures Enterprise:
SNS: U.S. Strategic National Stockpile:
[End of section]
Footnotes:
[1] See appendix I for a list of abbreviations used in this statement.
[2] 42 U.S.C. § 247d-6b(c)(2)(A).
[3] 42 U.S.C. § 247d-6b(a)(1).
[4] 42 U.S.C. § 247b(c)(7)(C)(i).
[5] 42 U.S.C. § 247d-6b(c)(1)(A). The Department of Homeland Security
Appropriations Act of 2004 appropriated over $5.5 billion to the
Special Reserve Fund to be available for obligation from fiscal year
2004 through fiscal year 2013. Pub. L. No. 108-90, 117 Stat. 1137,
1148 (2003). The Project BioShield Act also authorizes the federal
government to use specific contracting authorities to procure certain
medical countermeasures for these agents and requires HHS to report on
these contracting authorities and procurements using the Special
Reserve Fund, among other information. 42 U.S.C. §§ 247d-6b, 247d-6c.
[6] 42 U.S.C. § 247d-7e. The act also gave BARDA the authority to make
advance and milestone-based payments to vendors prior to product
delivery to the SNS. 42 U.S.C. § 247d-7e(c)(5)(C), (D).
[7] In FDA regulations, drugs are "approved," vaccines and other
biologics are "licensed," and devices may either be "approved" or
"cleared." For this statement, we use the term "approve" to refer to
both approval and clearance.
[8] 21 U.S.C. § 360bbb-3. FDA can issue EUAs only after the HHS
Secretary declares a public health emergency and under certain
circumstances. For example, FDA can issue EUAs in declared emergencies
only if the agent specified in the emergency declaration can cause a
serious or life-threatening disease or condition; the known and
potential benefits outweigh the known and potential risks of the
countermeasure to diagnose, prevent, or treat the condition; and there
is no adequate, approved, and available alternative to the product,
among other requirements. FDA has issued 19 EUAs since 2004. In 2005,
FDA issued an EUA for an anthrax vaccine to allow vaccination of DOD
personnel. FDA has also issued several EUAs for medical
countermeasures to diagnose and treat pandemic strains of influenza.
The only currently active EUA is for anthrax antibiotics in home kits
for postal workers to be used in the event of an anthrax attack.
[9] 42 U.S.C. § 247d-7f.
[10] The Integrated Portfolio is intended to reduce duplication of
effort and provide a mechanism for HHS and DOD to share information
and resources for common CBRN medical countermeasure priorities.
[11] PHEMCE's near-term development and acquisition period is fiscal
years 2007 and 2008; the midterm period is fiscal year 2009 through
fiscal year 2013, and the long-term period is beyond fiscal year 2013.
PHEMCE established these development and acquisition periods to
correspond with appropriations for the Special Reserve Fund. The
Department of Homeland Security Appropriations Act appropriated over
$5.5 billion for the Special Reserve Fund to be available for
obligation through fiscal year 2013 but provided that no more than
$3.4 billion may be obligated through fiscal year 2008.
[12] Pub. L. No. 108-276, § 3(a), 118 Stat. 835, 842 (2004) (codified
as amended at 42 U.S.C. § 247d-6b(c)(2)(A)(B)).
[13] The 13 agents that DHS determined pose a material threat to
national security and public health are Bacillus anthracis (anthrax),
Burkholderia mallei (glanders), Burkholderia pseudomallei
(melioidosis), Clostridium botulinum (botulism toxin), Ebola virus
(hemorrhagic fever), Francisella tularensis (tularemia), Junin virus
(hemorrhagic fever), Marburg virus (hemorrhagic fever), multidrug-
resistant Bacillus anthracis (MDR anthrax), Rickettsia prowazekii
(typhus), Variola major (smallpox), Yersinia pestis (plague), and
radiological and nuclear materials.
[14] To date, DHS has not issued determinations that any of the
assessed chemical agents pose a material threat to the United States.
Nevertheless, HHS has assessed the public health consequences of
chemical agents for which DHS has developed MTAs.
[15] For example, HHS officials said that they would like to acquire
an anthrax vaccine that confers immunity in a single dose, but because
no such vaccine was available when HHS set the requirements, the
department initially acquired a vaccine that could provide immunity in
six doses. Through further research, HHS was able to determine that
this vaccine could be administered in fewer doses.
[16] FDA works with researchers throughout the development stages, to
review safety and effectiveness test results, ensure that research
meets FDA's regulatory requirements, and approve successful products
for licensure.
[17] 42 U.S.C. § 247d-6b(c)(4)(A).
[18] 42 U.S.C. § 247d-7e(c)(4)(B).
[19] 21 C.F.R. §§ 314.600-.650; 601.90-.95.
[20] Under the Animal Rule, FDA has approved existing products for
CBRN use, such as drugs to treat the effects of nerve gas and cyanide
exposure.
[21] See National Commission on Children and Disasters, 2010 Report to
the President and Congress (Rockville, Md.: October 2010). According
to the report, in a CBRN incident children may be more vulnerable to
exposure than adults because children inhale more air and consume more
water in comparison to their body weight than adults.
[22] 21 C.F.R. §§ 50.50-.56.
[23] 21 U.S.C. § 360bbb-3(k).
[24] CDC and DOD have an agreement to share anthrax vaccine, which CDC
holds in the SNS for DOD use.
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