Influenza Vaccine
Federal Investments in Alternative Technologies and Challenges to Development and Licensure Gao ID: GAO-11-435 June 27, 2011Production delays for the 2009 H1N1 pandemic vaccine using the current egg-based production technology heightened interest in alternative technologies that could expand the supply or accelerate the availability of influenza vaccine. Within the federal government, the Department of Health and Human Services (HHS) and the Department of Defense (DOD) support the development of technologies that can be used in producing influenza vaccines. HHS's Food and Drug Administration (FDA) reviews licensing applications for new vaccine, and the Department of State is the U.S. diplomatic liaison to the international entity that declares worldwide pandemics. GAO was asked to review federal activities for the development of alternative technologies used in producing influenza vaccine. This report examines (1) federal funding from fiscal year 2005 through March 2011 for alternative technologies and the status of manufacturers' efforts, (2) challenges to development and licensure identified by stakeholders, and (3) how HHS is addressing those challenges. GAO reviewed HHS and DOD documents and funding data. GAO also interviewed stakeholders, including manufacturer representatives, industry associations, and other experts on challenges to development and licensure. GAO interviewed HHS officials on how they are addressing those challenges.
From fiscal year 2005 through March 2011, HHS and DOD provided about $2.1 billion in funding for the development of alternative technologies that could potentially expand the supply or accelerate the availability of influenza vaccine. Specifically, HHS and DOD have funded two alternative production technologies--cell-based and recombinant technologies, which produce vaccine in cells instead of eggs--and adjuvants, which can reduce the amount of vaccine needed to stimulate an immune response. HHS's funding supports the development of a new influenza vaccine using alternative technologies with the goal of manufacturers submitting licensing applications to FDA. DOD's funding supports the research and development of a technology that can make various vaccines, including influenza vaccines. HHS awarded $1 billion in contracts to manufacturers to develop cell-based technology, with manufacturers making progress toward licensure. HHS and DOD funded $296.5 million in contracts and $86.9 million in technology investment agreements, respectively, for the development of recombinant technology. HHS also awarded about $152 million in contracts for the development of adjuvanted influenza vaccines. Two manufacturers receiving HHS funds plan to submit licensing applications for their adjuvanted vaccines to FDA within the next 2 years. Some stakeholders said low demand, high research and development costs, and regulatory challenges can hinder the development and licensure of new vaccines using alternative technologies. For example, despite the United States using more seasonal vaccine than any other country, some stakeholders told us that low vaccination rates can decrease incentives for manufacturers to develop new influenza vaccines using alternative technologies because there is not sufficient demand for new products. Some stakeholders said high research and development costs can also decrease manufacturers' incentives; however, HHS noted that increased investments in this area have generated a significant interest in this type of research and development. Some stakeholders also told us that some of FDA's guidance documents are not sufficiently comprehensive. FDA officials told us that their guidance documents cannot cover all possible scenarios; thus, they regularly meet with manufacturers to discuss issues and provide advice. HHS is addressing challenges in the development and licensure of new influenza vaccines using alternative technologies. For example, HHS intends to fund the establishment of specialized facilities that will provide support and expertise to manufacturers. Additionally, through FDA, HHS plans to facilitate the review of licensing applications for new influenza vaccines using alternative technologies and to enhance FDA's staff expertise. HHS, DOD, and the Department of State reviewed a draft of this report. In commenting on a draft of this report, HHS and DOD agreed with GAO on its findings. The Department of State did not provide comments. HHS provided suggestions to clarify the discussion.
GAO-11-435, Influenza Vaccine: Federal Investments in Alternative Technologies and Challenges to Development and Licensure
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United States Government Accountability Office:
GAO:
Report to Congressional Requesters:
June 2011:
Influenza Vaccine:
Federal Investments in Alternative Technologies and Challenges to
Development and Licensure:
GAO-11-435:
GAO Highlights:
Highlights of GAO-11-435, a report to congressional requesters.
Why GAO Did This Study:
Production delays for the 2009 H1N1 pandemic vaccine using the current
egg-based production technology heightened interest in alternative
technologies that could expand the supply or accelerate the
availability of influenza vaccine. Within the federal government, the
Department of Health and Human Services (HHS) and the Department of
Defense (DOD) support the development of technologies that can be used
in producing influenza vaccines. HHS‘s Food and Drug Administration
(FDA) reviews licensing applications for new vaccine, and the
Department of State is the U.S. diplomatic liaison to the
international entity that declares worldwide pandemics.
GAO was asked to review federal activities for the development of
alternative technologies used in producing influenza vaccine. This
report examines (1) federal funding from fiscal year 2005 through
March 2011 for alternative technologies and the status of manufacturers‘
efforts, (2) challenges to development and licensure identified by
stakeholders, and (3) how HHS is addressing those challenges.
GAO reviewed HHS and DOD documents and funding data. GAO also
interviewed stakeholders, including manufacturer representatives,
industry associations, and other experts on challenges to development
and licensure. GAO interviewed HHS officials on how they are
addressing those challenges.
What GAO Found:
From fiscal year 2005 through March 2011, HHS and DOD provided about
$2.1 billion in funding for the development of alternative
technologies that could potentially expand the supply or accelerate
the availability of influenza vaccine. Specifically, HHS and DOD have
funded two alternative production technologies”-cell-based and
recombinant technologies, which produce vaccine in cells instead of
eggs”-and adjuvants, which can reduce the amount of vaccine needed to
stimulate an immune response. HHS‘s funding supports the development
of a new influenza vaccine using alternative technologies with the
goal of manufacturers submitting licensing applications to FDA. DOD‘s
funding supports the research and development of a technology that can
make various vaccines, including influenza vaccines. HHS awarded
$1 billion in contracts to manufacturers to develop cell-based
technology, with manufacturers making progress toward licensure. HHS
and DOD funded $296.5 million in contracts and $86.9 million in
technology investment agreements, respectively, for the development of
recombinant technology. HHS also awarded about $152 million in
contracts for the development of adjuvanted influenza vaccines. Two
manufacturers receiving HHS funds plan to submit licensing
applications for their adjuvanted vaccines to FDA within the next 2
years.
Some stakeholders said low demand, high research and development
costs, and regulatory challenges can hinder the development and
licensure of new vaccines using alternative technologies. For example,
despite the United States using more seasonal vaccine than any other
country, some stakeholders told us that low vaccination rates can
decrease incentives for manufacturers to develop new influenza
vaccines using alternative technologies because there is not
sufficient demand for new products. Some stakeholders said high
research and development costs can also decrease manufacturers‘
incentives; however, HHS noted that increased investments in this area
have generated a significant interest in this type of research and
development. Some stakeholders also told us that some of FDA‘s
guidance documents are not sufficiently comprehensive. FDA officials
told us that their guidance documents cannot cover all possible
scenarios; thus, they regularly meet with manufacturers to discuss
issues and provide advice.
HHS is addressing challenges in the development and licensure of new
influenza vaccines using alternative technologies. For example, HHS
intends to fund the establishment of specialized facilities that will
provide support and expertise to manufacturers. Additionally, through
FDA, HHS plans to facilitate the review of licensing applications for
new influenza vaccines using alternative technologies and to enhance
FDA‘s staff expertise.
HHS, DOD, and the Department of State reviewed a draft of this report.
In commenting on a draft of this report, HHS and DOD agreed with GAO
on its findings. The Department of State did not provide comments. HHS
provided suggestions to clarify the discussion.
View [hyperlink, http://www.gao.gov/products/GAO-11-435] or key
components. For more information, contact Marcia Crosse at (202) 512-
7114 or crossem@gao.gov.
[End of section]
Contents:
Letter:
Background:
The Federal Government Has Provided about $2.1 Billion in Funding for
the Development of Alternative Technologies that Can Be Used in
Producing Influenza Vaccines, and Manufacturers Are Demonstrating
Progress toward Licensure:
Some Stakeholders Identified Challenges to the Development and
Licensure of Influenza Vaccines Using Alternative Technologies:
HHS Is Addressing Challenges in the Development and Licensure of
Influenza Vaccines Using Alternative Technologies:
Agency Comments:
Appendix I: The Research, Development, and Review of Licensing
Applications for New Influenza Vaccine in the United States:
Appendix II: Influenza Vaccine Production Process Using Egg-Based
Technology:
Appendix III: Egg-Based and Alternative Technologies for Use with
Influenza Vaccines:
Appendix IV: Comments from the Department of Health and Human Services:
Appendix V: Comments from the Department of Defense:
Appendix VI: GAO Contact and Staff Acknowledgments:
Related GAO Products:
Tables:
Table 1: Federal Government's Role in the Research and Development of
Alternative Technologies and the Licensure and Regulation of Influenza
Vaccines:
Table 2: Alternative Technologies and Their Potential to Expand the
Supply or Accelerate the Availability of Influenza Vaccine:
Table 3: Department of Health and Human Services (HHS) Contracts
Awarded to Manufacturers for the Research and Development of Cell-
Based Influenza Vaccine, Fiscal Year 2005 through March 2011:
Table 4: Department of Health and Human Services (HHS) Contracts
Awarded to Manufacturers for the Research and Development of
Recombinant Influenza Vaccine, Fiscal Year 2009 through March 2011:
Table 5: Department of Health and Human Services (HHS) Contracts
Awarded to Manufacturers for the Research and Development of an
Adjuvanted Influenza Vaccine, Fiscal Year 2007 through March 2011:
Table 6: Number of U.S.-Licensed Manufacturers of Seasonal Influenza
Vaccine and Number of Doses Produced and Distributed for the 2000-01
through 2010-11 Influenza Seasons:
Table 7: Influenza Vaccine Production Process Using Egg-Based
Technology:
Table 8: Additional Potential Benefits of Adjuvants:
Figure:
Figure 1: Estimated Timeline for the Research, Development, and Review
of Licensing Applications for New Influenza Vaccine for the United
States:
Abbreviations:
CDC: Centers for Disease Control and Prevention:
DOD: Department of Defense:
FDA: Food and Drug Administration:
HHS: Department of Health and Human Services:
NIH: National Institutes of Health:
PCAST: President's Council of Advisors on Science and Technology:
[End of section]
United States Government Accountability Office:
Washington, DC 20548:
June 27, 2011:
The Honorable Fred Upton:
Chairman:
The Honorable Henry A. Waxman:
Ranking Member:
Committee on Energy and Commerce:
House of Representatives:
The Honorable Bennie G. Thompson:
Ranking Member:
Committee on Homeland Security:
House of Representatives:
The Honorable Roy Blunt:
United States Senate:
The Honorable Joe Barton:
House of Representatives:
Influenza, in both its seasonal and pandemic forms, is an ongoing
public health concern. Seasonal influenza may begin as early as August
and generally diminishes by April in the northern hemisphere. It has
been associated with 3,000 to nearly 50,000 deaths each year in the
United States in recent decades, according to the Department of Health
and Human Services's (HHS) Centers for Disease Control and Prevention
(CDC).[Footnote 1] Pandemic influenza, which periodically causes a
global outbreak of serious illness with the potential for many more
deaths than seasonal influenza, has occurred four times in the past
100 years.[Footnote 2] In the late 1990s and early 2000s, detection of
the H5N1 avian influenza (also known as "bird flu") virus in animals
raised concerns among experts that it or another influenza virus might
mutate into a strain that could lead to a human influenza pandemic.
[Footnote 3] The recent 2009 H1N1 influenza pandemic reinforced the
need to be prepared for future influenza pandemics.
The federal government, specifically HHS and the Department of Defense
(DOD), funds the research and development of alternative technologies
that can be used in producing human influenza vaccines as a part of
its pandemic influenza preparedness efforts.[Footnote 4] According to
HHS, HHS's and DOD's funding represents virtually all of the federal
government's investment in this type of research and development.
Vaccines are considered the first line of defense against seasonal and
pandemic influenza, as they can prevent infection and control the
spread of the disease. Furthermore, influenza vaccines are--along with
diagnostic tools and treatments such as antiviral drugs--a type of
medical countermeasure that can be used to protect the population
during public health emergencies.[Footnote 5] In 2005, HHS issued the
HHS Pandemic Influenza Plan (Plan) for responding to an influenza
pandemic.[Footnote 6] One of the goals stated in the Plan is to have
sufficient domestic capacity to produce enough pandemic vaccine to
cover the United States' population within 6 months of a pandemic
declaration.[Footnote 7] These global declarations are made by the
United Nations' World Health Organization, to which the Department of
State is the United States' diplomatic liaison.[Footnote 8] HHS also
laid out its intent to support the development of new influenza
vaccines using alternative technologies that could help achieve this
goal. DOD plays an active role in pandemic influenza preparedness in
order to maintain the military's readiness and ongoing military
operations abroad, such as stockpiling antiviral drugs for use during
a pandemic and developing other countermeasures.[Footnote 9] In
addition to ensuring the military's readiness, DOD's pandemic
preparedness goals include being able to support U.S. government
efforts to save lives, reduce human suffering, and slow the spread of
infection.[Footnote 10]
Challenges in the production of 2009 H1N1 pandemic vaccines caused
fewer doses of vaccine to be available early in the pandemic than
manufacturers had initially estimated; this heightened interest in the
status of vaccine technologies that provide alternatives to egg-based
technology. Egg-based technology is used to make all influenza vaccine
currently licensed for the U.S. market by the Food and Drug
Administration (FDA), the agency within HHS responsible for licensing
and regulating influenza vaccines for the U.S. market. It is a well-
established technology that has been in use for decades; however, it
has demonstrated certain limitations in speed and efficiency in
producing influenza vaccine as evidenced in the delay in producing the
2009 H1N1 pandemic vaccine supply. Given the limitations of egg-based
technology and the vulnerability of chicken flocks to infectious
diseases, the federal government has funded the development of
alternative technologies that can be used to produce new influenza
vaccines. Vaccines produced using these alternative technologies may
be used during the annual influenza season or during a pandemic in
order to respond faster or to create a greater supply than is possible
with the current technology and production capacity. New influenza
vaccines using alternative technologies are being pursued by influenza
vaccine manufacturers that have egg-based influenza vaccines currently
licensed for marketing and distribution in the United States or
internationally, as well as by manufacturers that currently only have
products in development. No influenza vaccines using alternative
technologies have yet been licensed in the United States.
You asked us to review the federal government's actions regarding the
research and development of alternative technologies that can be used
in producing new influenza vaccines. In this report, we examine (1)
federal funding from fiscal year 2005 through March 2011 in
alternative technologies that can be used in producing influenza
vaccines and the status of manufacturers' efforts, (2) the challenges
identified by stakeholders to the development and licensure of
influenza vaccines using alternative technologies, and (3) how HHS is
addressing challenges to the development and licensure of influenza
vaccines using alternative technologies.
To examine federal funding from fiscal year 2005 through March 2011 in
alternative technologies that can be used in producing influenza
vaccines and the status of manufacturers' efforts, we reviewed
documents pertaining to HHS's and DOD's funding for this purpose.
According to HHS, HHS's and DOD's funding represents virtually all of
the federal government's investment in this type of research and
development. We reviewed documents from HHS on its funding from fiscal
year 2005 through March 2011. These documents included semiannual
reports prepared by HHS that were submitted to Congress on the
department's contracts to develop influenza vaccines using alternative
technologies. We also interviewed HHS officials who oversee contracts
with manufacturers to assist with the research and development of
influenza vaccine for the federal government. We reviewed HHS's
proposals for funding the research and development of these
technologies and interviewed HHS budget officials to discuss and
clarify the department's efforts. Additionally, we reviewed
information from DOD on its technology investment agreements from
fiscal year 2005 through fiscal year 2010. We interviewed DOD
officials on the department's support of alternative technologies and
the status of these development efforts. To assess the reliability of
HHS's contracting data, we reviewed published data across multiple
years to ensure relative consistency and interviewed knowledgeable
officials to clarify questions regarding the department's funding. For
DOD, we compared data on its funding provided by different sources
within the department. We also asked officials about its data sources
and how the department validates its data. Although we did not
independently verify the information provided by HHS or DOD, based on
our reviews of the data and interviews with federal officials, we
concluded that these data were sufficiently reliable for the purposes
of our work. Additionally, to better understand these technologies we
conducted site visits to three influenza vaccine manufacturing
facilities, each utilizing a different production technology, and
attended national conferences on influenza vaccine research and
development.
To examine challenges to the development and licensure of influenza
vaccines using alternative technologies, we interviewed a judgmental
sample of stakeholders, which included representatives from industry
associations and manufacturers and other experts. Specifically, we
interviewed 15 representatives of the vaccine industry, including
those from three associations that represent pharmaceutical
manufacturers--the Biotechnology Industry Organization, the
International Federation of Pharmaceutical Manufacturers &
Associations, and the Pharmaceutical Research and Manufacturers of
America. We also interviewed officials representing 12 vaccine
manufacturers--which included those manufacturers pursuing the
research and development of influenza vaccines using alternative
technologies, as well as those that have chosen to forgo such research
and development--about the factors influencing their decisions. Of
these 12 manufacturers, 8 have received funding from HHS to pursue the
research and development of influenza vaccines using alternative
technologies, and 1 received funds from DOD. Additionally, we
interviewed a judgmental sample of 12 other experts in vaccine
technology on challenges to research and development and licensure. We
selected these other experts, in part, based on recommendations from
an initial round of interviews with members of associations
representing researchers and scientists, such as the American Society
for Microbiology and the Infectious Disease Society of America. Other
experts we interviewed included those from provider groups--
specifically the American Academy of Pediatrics, the American Congress
of Obstetricians and Gynecologists, and the American Medical
Association. We interviewed representatives from these provider groups
about the public's and providers' concerns about influenza vaccine
safety and their understanding of alternative technologies. We also
reviewed peer-reviewed journal articles and federal reports on
challenges to the development and licensure of influenza vaccines
using alternative technologies, including HHS's medical countermeasure
review and the President's Council of Advisors on Science and
Technology's (PCAST) report on influenza vaccine production.[Footnote
11] We also interviewed officials representing manufacturers with
influenza vaccines licensed for use in other countries and officials
from the Department of State, the diplomatic liaison to the United
Nations' World Health Organization--the international body that
declares worldwide pandemics.
To examine how HHS is addressing challenges to the development and
licensure of influenza vaccines using alternative technologies, we
interviewed HHS officials on their assessments of challenges to
research, development, and licensure identified by stakeholders. We
also interviewed HHS officials on their efforts to address these
challenges, including plans to use funds available for this purpose.
Additionally, we reviewed federal documents, such as a report by FDA
on its plans to improve its oversight of new products, including
influenza vaccines using alternative technologies.[Footnote 12]
We conducted this performance audit from March 2010 through June 2011
in accordance with generally accepted government auditing standards.
Those standards require that we plan and perform the audit to obtain
sufficient, appropriate evidence to provide a reasonable basis for our
findings based on our audit objectives. We believe that the evidence
obtained provides a reasonable basis for our findings based on our
audit objectives.
Background:
Influenza is a contagious respiratory illness caused by a number of
different influenza virus strains and can range in severity from mild
to lethal.[Footnote 13] Symptoms can include cough, muscle or body
aches, and fatigue. Vaccination is the primary method for preventing
infection with strains of the influenza virus and controlling the
disease.[Footnote 14] In order for a vaccine to be most effective, it
needs enough well-matched antigen to stimulate a protective immune
response, antigen being the active substance in a vaccine that
provides immunity by causing the body to produce protective antibodies
to fight off a particular influenza strain.[Footnote 15] The vaccine's
antigen needs to be derived from a strain that is well-matched to a
specific influenza strain--in wide circulation in humans--so that the
antibodies formed in response to the vaccine protect against infection
from that strain. Because multiple influenza strains are in constant
circulation, seasonal vaccine is produced and administered annually to
protect against the three influenza strains expected to be most
prevalent that year (i.e., a trivalent vaccine). In contrast, the 2009
H1N1 pandemic vaccine was formulated to match the single pandemic-
causing strain (i.e., a monovalent vaccine).
Federal Government's Role in the Research and Development of
Alternative Technologies and the Licensure and Regulation of Influenza
Vaccines:
Within the federal government, HHS is the department responsible for
leading and coordinating preparedness and medical response activities
to public health emergencies, per the 2006 Pandemic and All-Hazards
Preparedness Act.[Footnote 16] Additionally, as the principal
department for protecting the public's health, HHS is the primary
department funding the research and development of influenza vaccines.
HHS enters into contracts with manufacturers for the development of
new influenza vaccines using alternative technologies.[Footnote 17]
DOD also makes some investments through its technology investment
agreements for the research and development of alternative
technologies that can be used in producing influenza vaccine as part
of its preparedness efforts in order to maintain the military's
readiness.[Footnote 18] Manufacturers with which these agencies have
entered into contracts or technology investment agreements include
large-scale influenza vaccine manufacturers that have vaccines
licensed for use in the United States and internationally as well as
manufacturers that currently only have vaccines in research and
development. Influenza vaccines--both seasonal and pandemic--are
biological products. Within HHS, FDA is the federal agency responsible
for the licensure and regulation of biological products for use in the
U.S. market (see app. I for additional information on the research and
development and review of licensing applications for new influenza
vaccines in the United States). These responsibilities include issuing
guidance for existing and new vaccines and consulting with
manufacturers on the development of their new vaccines, such as on how
manufacturers conduct clinical trials required for licensure of new
vaccines.[Footnote 19] Until FDA has approved its licensing
application, no manufacturer can market its biological product in the
United States.[Footnote 20] Table 1 summarizes the federal
government's role in the research and development of alternative
technologies and the licensure and regulation of influenza vaccines.
Table 1: Federal Government's Role in the Research and Development of
Alternative Technologies and the Licensure and Regulation of Influenza
Vaccines:
Department: Department of Health and Human Services (HHS);
Agency:
* The Biomedical Advanced Research and Development Authority within
the Office of the Assistant Secretary for Preparedness and Response
contracts with manufacturers for influenza vaccine research and
development with the goal of manufacturers submitting licensing
applications to the Food and Drug Administration (FDA) for new
vaccines and establishing domestic production capacity for these new
vaccines;
* The National Institutes of Health supports the research and
development of vaccines using alternative technologies through various
activities, including conducting basic and clinical research;
* FDA is responsible for the licensure and regulation of influenza
vaccine--including the approval of facilities in which influenza
vaccine is produced--for the U.S. market. Its responsibilities include
issuing guidance for new and existing vaccines and consulting with
manufacturers on the development of their new vaccines. Until FDA has
approved its licensing application, no manufacturer can market its
influenza vaccine in the United States.[A] Once FDA issues a license
for an influenza vaccine, it continues to regulate the vaccine's
production and use. For example, FDA must review and approve the
seasonal vaccine annually because the influenza strains included in it
frequently change from one year to the next.[B]
Department: Department of Defense (DOD);
Agency:
* The Defense Advanced Research Projects Agency within DOD funds
programs focused on unique and innovative research and development
efforts--including the early stage research and development of
alternative technologies that can be used in producing influenza
vaccines--and that accelerate the discovery and research and
development of medical countermeasures, in part, through the use of
novel technologies.[C]
Source: GAO analysis of HHS and DOD documents.
[A] After the HHS Secretary declares a public health emergency and
under certain circumstances, FDA, as delegated by the HHS Secretary,
may authorize the emergency use of licensed pharmaceutical products,
such as vaccines, for unapproved uses or the emergency use of
unlicensed pharmaceutical products through emergency use
authorizations. See 21 U.S.C. § 360bbb-3.
[B] Each manufacturer of a U.S.-licensed influenza vaccine annually
submits a supplement to its initial licensing application, noting the
new influenza strains selected for a given influenza season. This same
process of submitting a supplement to an existing, approved licensing
application was used in the licensure of vaccine for use in the United
States for the 2009 H1N1 pandemic.
[C] Medical countermeasures are drugs, biological products, or devices
that treat, identify, or prevent harm from a biological or other agent
that may cause a public health emergency. Medical countermeasures for
use during an influenza pandemic may include vaccine, antiviral drugs,
personal respirators, and influenza diagnostic tests. Antiviral drugs
are medications that can prevent or reduce the severity of a viral
infection, such as influenza. This report focuses on influenza vaccine.
[End of table]
HHS Efforts to Enhance Domestic Production Capacity to Expand the
Supply or Accelerate the Availability of Influenza Vaccine:
Given its responsibilities for national seasonal influenza and
pandemic preparedness and response, HHS has an interest in enhancing
domestic production capacity--that is, enhancing the nation's overall
infrastructure for influenza vaccine production--and expanding the
supply or accelerating the availability of influenza vaccine. HHS
began awarding contracts to enhance domestic production capacity for
the current egg-based technology as early as fiscal year 2005.
[Footnote 21] Since fiscal year 2005, HHS has supported a program to
ensure a year-round, secure, domestic egg supply; prior to this
funding, manufacturers maintained a 9-month supply of eggs--enough for
production only during the influenza season without any additional
capacity for emergencies, such as an influenza pandemic.
Despite HHS's initial efforts to maintain a year-round egg supply,
other events have occurred that highlighted the need for HHS to
increase domestic production capacity for influenza vaccine and to
support the introduction of influenza vaccines produced using
alternative technologies. First was the unexpected loss of almost half
of the influenza vaccine supply because of potential contamination
during the 2004-05 season and the reliance on two domestic influenza
vaccine manufacturers to supply enough vaccine for that year.[Footnote
22] Second was the recognition by HHS that one of the greatest
challenges to preparing for an influenza pandemic and implementing its
strategy for using vaccines was the lack of production capacity within
the United States. As we noted in prior work, the lack of U.S.
production capacity is cause for concern among experts because it is
possible that countries without domestic production capacity will not
have access to influenza vaccine in the event of a pandemic if
countries where vaccine is produced prohibit the export of the
pandemic vaccine until their own needs are met.[Footnote 23] As a
result, HHS continued its funding of egg-based technology for the
production of influenza vaccine to enhance domestic production
capacity using this technology. For example, in fiscal year 2007, HHS
entered into contracts with two manufacturers for the retrofitting of
existing domestic egg-based production facilities for the production
of pandemic influenza vaccine. Some of the completed facilities were
used in the 2009 H1N1 pandemic, and according to HHS, when all the
retrofitting is complete, one of these facility's production capacity
will double and the other will triple. Third, concerns about strains
of the H5N1 virus that had reemerged in the early 2000s, and continues
to cause severe infection in humans, further prompted interest in
alternative technologies to egg-based technology for producing
influenza vaccine.[Footnote 24] Strains of the H5N1 virus have
infected chicken flocks and other poultry, resulting in the culling of
these flocks, raising concern that the egg supply for influenza
vaccine was at risk. Thus, HHS began a more concerted effort to fund
the research and development of influenza vaccines using three
alternative technologies. Specifically, HHS has funded the development
of vaccines using two alternative production technologies--cell-based
and recombinant technologies--and vaccines using a third alternative
technology--antigen-sparing technology (adjuvants).
Each of these three alternative technologies has the potential to
expand the supply or accelerate the availability of both seasonal and
pandemic influenza vaccines (see app. II for a description of the
production process for influenza vaccine using the current, egg-based
technology). Expanding the supply or accelerating the availability of
influenza vaccine is particularly important when there is a perceived
shortage of seasonal vaccine--when vaccine is not available and demand
is highest--or during a pandemic when demand increases because of
increased risk of disease and death. Expanding the supply or
accelerating the availability of influenza vaccine can be done in two
ways. The first is to increase the overall amount of vaccine available
at the end of the production process; the second is to speed up the
production process itself by, for example, reducing or eliminating
step(s) in the process. Table 2 describes these three alternative
technologies and their potential to expand the supply or accelerate
the availability of influenza vaccines (see app. III for more
information on these alternative technologies).
Table 2: Alternative Technologies and Their Potential to Expand the
Supply or Accelerate the Availability of Influenza Vaccine:
Alternative technologies: Cell-based technology;
Description of technology: An alternative production technology, cell-
based technology involves a production process similar to egg-based
technology. For example, as with egg-based technology, the vaccine's
antigen--that is, the active substance of the vaccine that stimulates
a protective immune response--is produced from the influenza virus.
However, rather than using fertilized eggs as the medium for producing
the influenza vaccine, cell-based technology typically uses cells
infected with the influenza virus for the production of vaccine. This
technology for influenza vaccines typically relies on the use of well-
established cell lines, such as those originally derived from the
kidney cells of monkeys or canines;
Potential expansion of the supply or acceleration of the availability
of influenza vaccine: Increase the overall amount of vaccine
available: [Check];
Potential expansion of the supply or acceleration of the availability
of influenza vaccine: Speed up the production process: [Empty].
Alternative technologies: Recombinant technology[A];
Description of technology: A second type of alternative production
technology, recombinant technology uses specific protein(s) or genes
from the influenza virus instead of the entire virus, as used in egg-
based and cell-based technologies, as the antigen for the vaccine.
This technology can use cells from mammals as the medium for producing
the influenza vaccine as well as cells from other sources, such as
from bacteria, yeast, insects, or plants;
Potential expansion of the supply or acceleration of the availability
of influenza vaccine: Increase the overall amount of vaccine
available: [Check];
Potential expansion of the supply or acceleration of the availability
of influenza vaccine: Speed up the production process: [Check].
Alternative technologies: Adjuvants[B];
Description of technology: A type of antigen-sparing technology,
adjuvants are substances that may be added to an influenza vaccine to
enhance the immune response, resulting in a dose-sparing capability
because less antigen is needed per dose to stimulate a protective
immune response. This technology can be included with influenza
vaccines made using different production technologies, such as egg-
based, cell-based, or recombinant technology;
Potential expansion of the supply or acceleration of the availability
of influenza vaccine: Increase the overall amount of vaccine
available: [Check];
Potential expansion of the supply or acceleration of the availability
of influenza vaccine: Speed up the production process: [Empty].
Source: GAO analysis of President's Council of Advisors on Science and
Technology report.
[A] The Department of Health and Human Services (HHS) refers to this
technology as recombinant/molecular technology. According to HHS, this
technology is also used for researching and developing a universal
influenza vaccine. The National Institutes of Health, which is
conducting research on a universal vaccine, defines it as a vaccine
that would theoretically provide protection against any strain of
influenza without needing to be updated or administered every year to
protect against newly emerging annual or pandemic strains.
[B] In this report, we are referring to adjuvants made using a
combination of oil and water; there are different types of adjuvants
that can be used with vaccines.
[End of table]
HHS Funding for the Development of Influenza Vaccines Using
Alternative Technologies:
In fiscal year 2005, with funds available from that year's
appropriation, HHS funded the research and development of an influenza
vaccine produced using cell-based technology.[Footnote 25] Following
the release of the Plan, numerous additional appropriations became
available for the acquisition and development of pharmaceutical
interventions for pandemic-related purposes, including approximately
$3.2 billion dedicated for vaccines.[Footnote 26] HHS has since used
these funds, as well as funds available from previous appropriations,
for multiyear contracts for the development of influenza vaccine using
cell-based technology, recombinant technology, and adjuvants. In
response to the 2009 H1N1 pandemic, Congress provided HHS with a
supplemental appropriation to prepare for and respond to an influenza
pandemic.[Footnote 27] In addition to making $1.85 billion immediately
available to HHS, the 2009 supplemental appropriation made $5.8
billion available contingent upon one or more presidential
notifications to Congress.[Footnote 28] In August 2010, after the 2009
H1N1 pandemic had ended, HHS notified Congress of its plan to direct
some of the remaining funds toward pandemic and related preparedness
activities. Specifically, HHS proposed spending $1.98 billion in a
variety of vaccine-related activities, including the development of
alternative technologies, such as recombinant technology.[Footnote 29]
According to HHS, it also uses funding available from annual
appropriations, such as its fiscal year appropriations for 2009 and
2010, for pandemic-related activities.[Footnote 30]
The Federal Government Has Provided about $2.1 Billion in Funding for
the Development of Alternative Technologies that Can Be Used in
Producing Influenza Vaccines, and Manufacturers Are Demonstrating
Progress Toward Licensure:
From fiscal year 2005 through March 2011, the federal government
awarded approximately $2.1 billion in contracts and technology
investment agreements for the research and development of cell-based
and recombinant technologies and adjuvants, which can be used in
producing influenza vaccines. Manufacturers are demonstrating progress
toward licensure.
HHS Has Primarily Funded the Development of Cell-Based Technology,
with Two Manufacturers Completing Clinical Trials and One Manufacturer
Constructing a Domestic Facility:
In fiscal year 2005, HHS awarded the most funding through contracts to
manufacturers to develop cell-based technology.[Footnote 31] With
these funds, two manufacturers are demonstrating progress toward
licensure of a vaccine by completing clinical trials required to file
for licensure with FDA, and one of these two manufacturers has also
constructed a domestic cell-based influenza vaccine facility. HHS
awarded contracts to six manufacturers--one manufacturer in fiscal
year 2005 and five manufacturers in fiscal year 2006--worth a total of
approximately $1 billion for the development of an influenza vaccine
produced using cell-based technology (see table 3). According to HHS,
it awarded multiple contracts because it expected some attrition by
manufacturers as the development of new influenza vaccines progressed.
Cell-based technology has the potential to increase the overall amount
of vaccine available at the end of the production process. As of March
2011, two of the manufacturers to which HHS had awarded contracts--
DynPort Vaccine Company LLC (with Baxter International Inc.) (DynPort/
Baxter)[Footnote 32] and Novartis Vaccines and Diagnostics Inc.
(Novartis Vaccines)--have completed clinical trials required to file
for licensure with FDA. While Novartis Vaccines anticipates submitting
a licensing application for its seasonal influenza vaccine using cell-
based technology to FDA in 2011, DynPort/Baxter anticipates submitting
its licensing application to FDA in 2012. Additionally,
GlaxoSmithKline plc (GlaxoSmithKline) is currently conducting clinical
trials with its adjuvanted cell-based pandemic influenza vaccine, and
MedImmune, LLC is conducting preclinical studies in animals on its
cell-based pandemic influenza vaccine. The remaining two contracts
with sanofi pasteur[Footnote 33] and Solvay Pharmaceuticals were
terminated by HHS.
Table 3: Department of Health and Human Services (HHS) Contracts
Awarded to Manufacturers for the Research and Development of Cell-
Based Influenza Vaccine, Fiscal Year 2005 through March 2011:
Manufacturer: sanofi pasteur[B];
Fiscal year of award: 2005;
Total obligations[A]: $77.0 million[C];
Development status as of March 2011: The manufacturer concluded that
cell-based technology was not more advantageous than egg-based
technology, lacked a clear path for further development, and thus
chose to forgo pursuit of cell-based technology. According to HHS, it
terminated this contract for the development of a cell-based influenza
vaccine.
Manufacturer: GlaxoSmithKline;
Fiscal year of award: 2006;
Total obligations[A]: $274.8 million;
Development status as of March 2011: The manufacturer completed early-
stage clinical trials of its cell-based seasonal influenza vaccine in
2009 and is currently conducting early-stage clinical trials of its
cell-based, adjuvanted pandemic influenza vaccine.
Manufacturer: Novartis Vaccines;
Fiscal year of award: 2006;
Total obligations[A]: $220.5 million;
Development status as of March 2011: The manufacturer completed
clinical trials required to file for licensure and anticipates
resubmitting a licensing application for its cell-based seasonal
influenza vaccine to the Food and Drug Administration (FDA) in 2011.[D]
Manufacturer: DynPort/Baxter[E];
Fiscal year of award: 2006;
Total obligations[A]: $242.3 million[F];
Development status as of March 2011: The manufacturer completed
clinical trials required to file for licensure and anticipates
submitting a licensing application for its cell-based seasonal
influenza vaccine to FDA in 2012.
Manufacturer: MedImmune, LLC;
Fiscal year of award: 2006;
Total obligations[A]: $169.5 million;
Development status as of March 2011: As directed by HHS, the
manufacturer halted development of its cell-based seasonal and
pandemic influenza vaccine in March 2009. The manufacturer resumed
development of its cell-based pandemic influenza vaccine in June 2010
and is conducting preclinical studies in animals.
Manufacturer: Solvay Pharmaceuticals[G];
Fiscal year of award: 2006;
Total obligations[A]: $48.6 million[H];
Development status as of March 2011: The manufacturer discontinued
plans for the construction of a cell-based influenza vaccine
production facility in the United States because of lack of commercial
viability. HHS terminated the contract for the development of a cell-
based influenza vaccine in June 2009.
Manufacturer: Total;
Total obligations[A]: $1.033 billion.
Source: GAO analysis of HHS and manufacturer data.
[A] Obligations are definite commitments that establish the legal
liability of a federal agency to make payments for goods or services
ordered or received, immediately or in the future. Because payments
are typically made as goods or services are received, the funds listed
may not have been expended. Upon termination of a contract, unexpended
funds may be deobligated and, depending on the terms of their
appropriation, may remain available to the agency.
[B] The policy of sanofi pasteur is to spell its name without capital
letters.
[C] This amount reflects a $20 million deobligation in fiscal year
2009. A deobligation refers to the cancellation or downward adjustment
of previously incurred obligations.
[D] According to Novartis Vaccines, it submitted a licensing
application for its cell-based seasonal influenza vaccine to FDA in
April 2009. However, in agreement with FDA, Novartis Vaccines
subsequently withdrew the application in order to incorporate efficacy
data at FDA's request.
[E] HHS contracted with DynPort Vaccine Company LLC (DynPort), which
collaborated with Baxter International Inc., (Baxter) to develop a
seasonal and a pandemic influenza vaccine using cell-based technology.
Baxter oversaw the development of the vaccine, including supporting
licensure efforts for the seasonal vaccine. Baxter also oversaw the
completion of clinical trials for the pandemic vaccine. DynPort
managed the overall project as well as clinical trials. For the
purposes of this report, we refer to this contract as DynPort/Baxter
because of the collaboration between the two manufacturers.
[F] This amount includes a modification of $201.3 million made in
fiscal year 2007 to the existing contract. The original contract was
awarded for $41 million.
[G] Abbott Laboratories purchased Solvay Pharmaceuticals in February
2010.
[H] This amount reflects a $250 million deobligation in fiscal year
2009.
[End of table]
In addition to the six contracts awarded for the research and
development of cell-based influenza vaccine, HHS also entered into a
$486.6 million contract with Novartis Vaccines in fiscal year 2009 for
the construction of a cell-based influenza vaccine production facility
in the United States to enhance domestic production capacity.[Footnote
34] According to HHS, Novartis Vaccines completed construction of this
facility in November 2009 and will have qualified the facility for
producing pandemic vaccine using cell-based technology, if needed, by
the end of 2011. HHS expects the new facility to provide at least 25
percent of the needed domestic production capacity for pandemic
vaccine. This facility also has the capacity to produce seasonal and
adjuvanted influenza vaccine as well as other biological products that
use this technology for other infectious diseases.
HHS and DOD Have Funded the Research and Development of Recombinant
Technology, and One Manufacturer Has Submitted a Licensing Application
to FDA:
In fiscal year 2009, HHS awarded contracts to manufacturers for the
research and development of recombinant technology. Recombinant
technology has the potential to increase the overall amount of vaccine
available at the end of the production process and speed up the
production process itself, in part, because unlike egg-based and cell-
based technologies, it does not depend on the replication of the
influenza virus for production. In fiscal year 2009, HHS entered into
a $34.5 million contract with Protein Sciences Corporation (Protein
Sciences) for the continued development of recombinant technology for
use in producing an influenza vaccine. According to HHS, if Protein
Sciences' recombinant, seasonal influenza vaccine is shown to be safe
and effective through clinical trials, the contract requires the
company to establish enough domestic manufacturing capacity to provide
finished vaccine within 12 weeks of the beginning of a pandemic and to
produce at least 50 million doses of pandemic vaccine within 6 months
of the beginning of a pandemic.[Footnote 35] In May 2011, HHS extended
its contract with Protein Sciences for 2 years with $46.8 million of
additional funding.
In February 2011, HHS awarded two additional contracts for the
research and development of pandemic influenza vaccines using
recombinant technology. HHS awarded contracts to Novavax, Inc.
(Novavax) for $97.3 million and VaxInnate, Inc. (VaxInnate) for $117.9
million each for a 3-year period. According to HHS, if the
manufacturer and department mutually agree, each respective contract
may be extended for an additional 2-year period, resulting in contract
amounts totaling $179.1 million for Novavax and $196.6 million for
VaxInnate (see table 4).
Table 4: Department of Health and Human Services (HHS) Contracts
Awarded to Manufacturers for the Research and Development of
Recombinant Influenza Vaccine, Fiscal Year 2009 through March 2011:
Manufacturer: Protein Sciences;
Fiscal year of award: 2009, 2011;
Total obligations[A]: $81.3 million;
Development status as of March 2011: According to HHS, the contract
requires Protein Sciences to establish enough domestic manufacturing
capacity to provide finished vaccine within 12 weeks of the beginning
of a pandemic and to produce at least 50 million doses of pandemic
vaccine within 6 months of the beginning of a pandemic.
Manufacturer: Novavax;
Fiscal year of award: 2011;
Total obligations[A]: $97.3 million;
Development status as of March 2011: According to HHS, the
manufacturer is currently designing the clinical trials for its
recombinant pandemic influenza vaccine.
Manufacturer: VaxInnate;
Fiscal year of award: 2011;
Total obligations[A]: $117.9 million;
Development status as of March 2011: According to HHS, the
manufacturer is currently designing the clinical trials for its
recombinant, pandemic influenza vaccine.
Manufacturer: Total;
Total obligations[A]: $296.5 million.
Source: GAO analysis of HHS data.
[A] Obligations are definite commitments that establish the legal
liability of a federal agency to make payments for goods or services
ordered or received, immediately or in the future. Because payments
are typically made as goods or services are received, the funds listed
may not have been expended. Upon termination of a contract, unexpended
funds may be deobligated and, depending on the terms of their
appropriation, may remain available to the agency.
[End of table]
In contrast to HHS's contract awards specifically designated for
influenza vaccine described above, DOD's funding efforts have been
more generally targeted toward the research and development of
technologies that could be used in producing these vaccines. For
example, in fiscal year 2010, DOD entered into technology investment
agreements with manufacturers and research institutes--totaling
approximately $86.9 million--for the research and development of
recombinant technology through a DOD initiative called Blue Angel. The
Blue Angel initiative is intended to accelerate ongoing programs that
would potentially assist the federal government in providing a
governmentwide response to an influenza pandemic.[Footnote 36] Under
the Blue Angel initiative, DOD supported the initial testing of a
production process using recombinant technology to produce antigen--
the active substance in a vaccine that stimulates the production of
protective antibodies--using the 2009 H1N1 pandemic strain.[Footnote
37] According to DOD, although the initiative did not result in a
finished vaccine, the first batch of antigen was produced within 30
days of receiving information on the pandemic-causing strain.
HHS and DOD Have Also Funded the Research and Development of
Adjuvanted Influenza Vaccines, and Two Manufacturers Are Demonstrating
Progress toward Licensure:
Since fiscal year 2007, HHS has also awarded contracts for the
research and development of an adjuvanted influenza vaccine. Adjuvants
have the potential to increase the overall amount of vaccine available
at the end of the production process by enhancing the immune response,
thereby reducing the amount of antigen needed per vaccine dose. Two
manufacturers have demonstrated progress toward licensure of their
vaccines by completing clinical trials. HHS awarded three contracts
totaling $152 million to GlaxoSmithKline, Novartis Vaccines, and
Intercell AG for the research and development of an adjuvanted
influenza vaccine (see table 5).[Footnote 38] Of the three
manufacturers awarded contracts, GlaxoSmithKline anticipates
submitting a licensing application for its adjuvanted egg-based
pandemic influenza vaccine to FDA for review in 2011, while Novartis
Vaccines anticipates submitting a licensing application for its
adjuvanted egg-based seasonal influenza vaccine to FDA for review in
2012. According to HHS, Intercell AG's clinical trials did not achieve
the desired result and were ended.
Table 5: Department of Health and Human Services (HHS) Contracts
Awarded to Manufacturers for the Research and Development of an
Adjuvanted Influenza Vaccine, Fiscal Year 2007 through March 2011:
Manufacturer: GlaxoSmithKline[B];
Fiscal year of award: 2007, 2011;
Total obligations[A]: $70.2 million;
Development Status as of March 2011: The manufacturer completed
clinical trials and anticipates submitting a licensing application to
the Food and Drug Administration (FDA) for its adjuvanted egg-based
pandemic influenza vaccine in 2011.
Manufacturer: Novartis Vaccines[B];
Fiscal year of award: 2007;
Total obligations[A]: $54.8 million;
Development Status as of March 2011: The manufacturer completed
clinical trials and anticipates submitting a licensing application to
FDA for its adjuvanted egg-based seasonal influenza vaccine in 2012.
Manufacturer: Intercell AG[C];
Fiscal year of award: 2007;
Total obligations[A]: $27 million;
Development Status as of March 2011: According to HHS, the
manufacturer's clinical trials did not achieve the desired result and
were ended.
Manufacturer: Total;
Total obligations[A]: $152 million.
Source: GAO analysis of HHS and manufacturer data.
[A] Obligations are definite commitments that establish the legal
liability of a federal agency to make payments for goods or services
ordered or received, immediately or in the future. Because payments
are typically made as goods or services are received, the funds listed
may not have been expended. Upon termination of a contract, unexpended
funds may be deobligated and, depending on the terms of their
appropriation, may remain available to the agency.
[B] These manufacturers also have an adjuvanted cell-based pandemic
influenza vaccine under development.
[C] HHS originally awarded the contract for adjuvant research and
development to IOMAI Corporation. Because Intercell AG acquired IOMAI
Corporation in August 2008, we refer to Intercell AG.
[End of table]
In addition to its awards through contracts with manufacturers, HHS
also provided $4 million in funding to the National Institutes of
Health (NIH)--an agency within HHS--for H5N1 "mix-and-match" studies
starting in March 2008.[Footnote 39] According to HHS, these studies
are designed to determine whether the adjuvant from one manufacturer
can be safely and effectively combined with the antigen from another
manufacturer in the case of a public health emergency, such as an
influenza pandemic.[Footnote 40] The ability to combine the antigen
from one manufacturer with the adjuvant from another manufacturer
could increase the overall vaccine supply during a pandemic. The
preliminary preclinical studies in animals with a H5N1 vaccine were
completed in early 2009 in preparation for clinical testing by NIH.
However, NIH delayed its work on the H5N1 vaccine to conduct clinical
trials testing the unadjuvanted and mix-and-match 2009 H1N1 pandemic
vaccine as part of HHS's response to the pandemic. According to NIH
officials we spoke with, NIH resumed work on the H5N1 mix-and-match
studies in May 2011; officials anticipate completing clinical trials
for these studies in 2012.
DOD has also funded the development of adjuvants for use with
influenza vaccine. In fiscal year 2009, DOD entered into a technology
investment agreement for $3.3 million with the Infectious Disease
Research Institute. According to DOD, the department is currently
awaiting the results of completed animal studies using an adjuvanted
vaccine.
Some Stakeholders Identified Challenges to the Development and
Licensure of Influenza Vaccines Using Alternative Technologies:
Some stakeholders and federal reports identified three primary
challenges to the development and licensure of influenza vaccines
using alternative technologies: low demand, high research and
development costs, and regulatory challenges.
Some Stakeholders Said Low Demand Hinders the Development of Influenza
Vaccines Using Alternative Technologies:
Some stakeholders told us that low demand because of low vaccination
rates hinders manufacturers' willingness to develop seasonal influenza
vaccines using alternative technologies.[Footnote 41] According to
CDC, during the 2009-10 influenza season, national vaccination rates
reached an estimated 41 percent of the population aged 6 months or
older for the seasonal vaccine, and an estimated 27 percent for the
separate 2009 H1N1 pandemic vaccine.[Footnote 42] Each influenza
season more vaccine is produced than is actually used, even in years
where there has been a perceived shortage of influenza vaccine because
of challenges in the production process. Data from CDC, FDA, and the
American Medical Association confirm that--despite an increase in the
total amount of influenza vaccine produced and distributed since at
least 2001--more doses of seasonal vaccine are produced than
distributed each year, including in years when there were few licensed
manufacturers or a perceived vaccine shortage (see table 6). This
excess vaccine expires and is destroyed at the season's end as it will
not be useful for the next influenza season, when a new vaccine will
need to be formulated using the three influenza strains expected to be
most prevalent that year. Additionally, despite the increase in
influenza vaccine production and distribution and the United States
using more seasonal vaccine than any other country, 5 of 12
manufacturer representatives, 1 of 3 industry association
representatives, and 2 of 12 other experts we interviewed said that
this low demand decreases incentives for manufacturers to develop new
seasonal influenza vaccines using alternative technologies.
Table 6: Number of U.S.-Licensed Manufacturers of Seasonal Influenza
Vaccine and Number of Doses Produced and Distributed for the 2000-01
through 2010-11 Influenza Seasons:
Influenza season: 2000-01;
Number of licensed manufacturers: 3;
Total number of doses produced: 78 million;
Total number of doses distributed: 70 million.
Influenza season: 2001-02;
Number of licensed manufacturers: 3;
Total number of doses produced: 88 million;
Total number of doses distributed: 78 million.
Influenza season: 2002-03;
Number of licensed manufacturers: 3;
Total number of doses produced: 95 million;
Total number of doses distributed: 83 million.
Influenza season: 2003-04;
Number of licensed manufacturers: 3;
Total number of doses produced: 87 million;
Total number of doses distributed: 83 million.
Influenza season: 2004-05;
Number of licensed manufacturers: 3[A];
Total number of doses produced: 61 million;
Total number of doses distributed: 57 million.
Influenza season: 2005-06;
Number of licensed manufacturers: 4;
Total number of doses produced: 92 million;
Total number of doses distributed: 82 million.
Influenza season: 2006-07;
Number of licensed manufacturers: 5;
Total number of doses produced: 121 million;
Total number of doses distributed: 104 million.
Influenza season: 2007-08;
Number of licensed manufacturers: 6;
Total number of doses produced: 141 million;
Total number of doses distributed: 113 million.
Influenza season: 2008-09;
Number of licensed manufacturers: 6;
Total number of doses produced: 143-146 million;
Total number of doses distributed: 111 million.
Influenza season: 2009-10[B];
Number of licensed manufacturers: 6;
Total number of doses produced: 114-115 million;
Total number of doses distributed: 114 million.
Influenza season: 2010-11 (est.);
Number of licensed manufacturers: 6[C];
Total number of doses produced: 160-165 million;
Total number of doses distributed: 163 million.
Source: GAO analysis of Centers for Disease Control and Prevention,
Food and Drug Administration, and American Medical Association data.
Note: Table includes the number of doses produced by manufacturers and
distributed to customers, such as medical supply distributors,
physicians, or other types of providers.
[A] Of the three manufacturers of seasonal influenza vaccine for the
2004-05 influenza season, two produced and distributed vaccine and one
ceased production and did not distribute any vaccine for the U.S.
market after its license was suspended by the United Kingdom in
October 2004. In addition to these three manufacturers, two foreign
manufacturers' vaccines were purchased by the Department of Health and
Human Services for potential use in the United States under an
investigational new drug protocol; however, none of these doses were
distributed.
[B] In the 2009-10 season, U.S.-licensed manufacturers also produced
the 2009 H1N1 pandemic vaccine, which was purchased exclusively by the
federal government for distribution in the United States. According to
the Centers for Disease Control Prevention, approximately 147 million
doses were available for states to order, and about 119 million were
shipped to state-designated locations.
[C] The manufacturers of vaccine licensed for the 2010-11 season and
their vaccines (in parentheses) were CSL Biotherapies (Afluria),
GlaxoSmithKline plc (Fluarix), ID Biomedical Corporation (FluLaval),
MedImmune, LLC (FluMist), Novartis Vaccines and Diagnostics, Inc.
(Fluvirin and Agriflu), and sanofi pasteur (Fluzone and Fluzone High-
Dose).
[End of table]
Stakeholders told us that there are a number of reasons why demand for
seasonal influenza vaccine is low. For example, two experts stated
that patients commonly do not view seasonal influenza as a serious
disease, and another expert and an industry association representative
stated there is a need for more patient education on the safety of
influenza vaccine to overcome patient and provider hesitancy.
Researchers have also found that patients and providers have concerns
about influenza vaccine.[Footnote 43] One manufacturer representative
also noted that the current influenza vaccine is less effective for
certain populations, such as the elderly, which also decreases demand.
We have previously reported that according to CDC, a recommendation
from a physician or other health care provider is the most important
factor in an individual's decision to get vaccinated.[Footnote 44]
Additionally, a recent review of survey data found that health care
professionals were cited as one of three most important sources of
information in making decisions about children's vaccines by 85
percent of parents surveyed.[Footnote 45] CDC has made efforts to
encourage providers to recommend vaccination to their patients.
However, despite these efforts, available data suggest that getting
providers to recommend vaccination for their patients has been
difficult.[Footnote 46] CDC told us that it is working closely with
numerous partners to implement an influenza vaccine communication plan
utilizing multiple forms of media to reach the general public as well
as specific target populations.
HHS officials acknowledged the challenge of low demand for seasonal
influenza vaccine; however, they said manufacturers remain interested
in pursuing the development of new influenza vaccines using
alternative technologies. For example, according to department
officials, manufacturers have more than two dozen influenza vaccines
in development, and many of these manufacturers have received funds
from HHS.
Some Stakeholders Said High Research and Development Costs Decrease
Incentives for Developing Influenza Vaccines Using Alternative
Technologies:
Some stakeholders said that high research and development costs
required for the development of influenza vaccines can decrease
manufacturers' incentives to pursue new influenza vaccines using
alternative technologies. Six of the manufacturer representatives we
spoke with said that research and development costs are high.
Furthermore, five manufacturer representatives we spoke with noted
that clinical trials in particular contributed to high research and
development costs. For example, a representative for one manufacturer
we spoke with noted the significant costs associated with the research
and development of its currently licensed egg-based influenza vaccine,
estimating that his company has spent $400 million alone on clinical
trials. One small-scale manufacturer conducting clinical trials for a
new influenza vaccine using an alternative technology estimated that
it spends $150,000 per day on these trials and other expenses as it
moves toward applying for licensure. In addition, PCAST--a
presidential advisory council--found in a recent report on influenza
vaccine research and development that constructing a cell-based
influenza vaccine production facility could cost more than $1 billion
and it could take over 30 years to recover the investment.[Footnote 47]
Access to capital is important to manufacturers because of these high
research and development costs. A manufacturer representative and an
industry association representative that we spoke with told us that
manufacturers' difficulties in raising capital to finance research and
development costs deterred or slowed the development of new influenza
vaccines produced using alternative technologies. One manufacturer
representative told us that in the current economic market it has been
challenging for his firm to find investors. Three other manufacturer
representatives noted that their decision making is also influenced by
perceptions of whether the benefits of a new influenza vaccine will
offset these high research and development costs by increasing
production efficiency or supporting higher prices for the new product
compared to the current vaccine.[Footnote 48] HHS told us that it has
worked to address this issue through its funding for influenza
vaccines using alternative technologies and that its support of
manufacturers' efforts has helped to change the return on investment
such that manufacturers have more incentive to pursue the development
of new influenza vaccines using alternative technologies.
Additionally, HHS noted that increased investments in this area have
generated a significant interest in this type of research and
development.
Some Stakeholders Identified Regulatory Challenges That Hinder the
Development of Influenza Vaccines Using Alternative Technologies:
Some stakeholders identified two regulatory challenges to the
development of influenza vaccines using alternative technologies.
First, some stakeholders and recent federal reports identified
weaknesses in FDA's "regulatory science" capacity--that is, its
ability to utilize resources, such as staff expertise, to develop new
tests and measures to assess the safety, efficacy, quality, and
performance of FDA-regulated products, such as influenza vaccines.
[Footnote 49],[Footnote 50] Three manufacturer representatives, one
industry association representative, and three experts told us that
regulatory science weaknesses at FDA create challenges in the review
of new product licensing applications, including those for new
influenza vaccines. In particular, stakeholders told us that FDA's
staff expertise in alternative technologies affects its ability to
work with manufacturers developing new influenza vaccines using these
technologies, and that limited staff expertise is a challenge to
efficient communication. A manufacturer representative told us that
FDA's ability to conduct its own research is important in
understanding the science manufacturers present in licensing
applications, but noted that some of FDA's research programs have been
cut in recent years thereby hindering its ability to gain needed
experience. An industry association representative told us that
manufacturers pursuing the development of some influenza vaccines
using alternative technologies sometimes find it difficult to find FDA
staff who can answer their questions. One expert said that many
experienced senior leaders in FDA's biologics division--where
licensing applications for new vaccines are reviewed--have left the
agency in recent years; therefore, reviewers are less familiar with
these alternative technologies. This expert said this lack of
familiarity can make it more difficult for manufacturers to work with
reviewers to explain the technology to them.
Some recent federal reports have echoed stakeholders' concerns about
FDA's regulatory science capacity. According to a recent HHS report,
FDA needs to be able to conduct applied research in order to better
incorporate advances in life sciences research and knowledge into the
regulatory process. In order to make that possible, the report states
that FDA needs greater staff expertise and infrastructure.[Footnote
51] In addition, a 2007 report prepared for the FDA Science Board--an
FDA advisory group--found that the development of products based on
new science cannot be adequately regulated by FDA because of a lack of
capacity to review new technologies.[Footnote 52] However, FDA
officials told us that they are not aware of actual examples of lack
of expertise within the agency and that their staff consists of highly
qualified scientists. Furthermore, FDA officials noted the continuing
education that staff members engage in to maintain their proficiency
in technological advances as well as the quality of FDA's research
programs. The agency said it has the scientific and regulatory
experience to adequately assess the safety and effectiveness of
vaccines for use in the United States, but as noted later in this
report, it continues to fund improvements in regulatory science
capacity and staff expertise.
Some stakeholders also identified a second challenge, namely that
FDA's written guidance and consultation with manufacturers on some of
the requirements for licensure of new influenza vaccines using
alternative technologies is not sufficiently comprehensive.[Footnote
53] They noted that FDA's guidance documents do not include all of the
various scenarios manufacturers may encounter. Additionally, one
manufacturer representative said it can take months to arrange a
formal meeting with FDA officials. Another manufacturer representative
noted that FDA often conducts its discussions with manufacturers in
stages, which can limit their ability to plan for long-term issues.
According to stakeholders, this lack of detail and incremental
approach can hinder manufacturers' abilities to plan their research
and development efforts, including those for new influenza vaccines,
because they are uncertain as to what requirements they must meet in
order to obtain licensure. For example, two manufacturer
representatives said that it is unclear what size clinical trials will
be required for influenza vaccines using alternative technologies
because the guidance documents available are not specific enough in
laying out these requirements. In addition, PCAST found in a recent
report on influenza vaccine research and development that there is
currently uncertainty about the regulatory pathway for recombinant
influenza vaccines and recommended that guidance be developed on areas
including criteria for formulation, safety, immunogenicity, and
efficacy.[Footnote 54] Also, one manufacturer representative told us
that his company was repeating clinical trials for an adjuvanted
vaccine that had already been performed in Europe because the company
had been unaware of certain FDA requirements for data that are not
typically required for similar vaccines or by regulatory authorities
in other countries. The manufacturer representative noted that this
situation could have been avoided if FDA had provided a more complete
explanation of the requirements in this regard.
FDA officials acknowledged that its guidance documents are high level,
explaining that specific instructions are unique to the product as
guidance documents cannot cover all possible scenarios. In its
comments, HHS officials noted that FDA's guidance is intended to
provide a regulatory framework, adding that guidance cannot be
specific to individual manufacturing processes because these processes
are trade secrets. Because of their inability to be very specific in
guidance documents, FDA officials told us that they regularly meet
with manufacturers developing vaccines using alternative technologies
to discuss various issues and provide advice. They also noted that the
agency has a good record of achieving its goals on meeting with
manufacturers within a specific time frame, adding that officials
often consult with manufacturers in other ways, such as participating
in teleconferences. Additionally, FDA officials said that it is
necessary to consult with manufacturers in stages because their review
is an iterative process. They explained that it is not always apparent
what requirements may be necessary for a late phase of clinical trials
because such decisions are based, in part, on results from earlier
trials the manufacturer has completed. Furthermore, FDA noted that it
has approved many vaccines for other diseases that used alterative
technologies, such as adjuvants, and these manufacturers were able to
successfully develop and license their products using FDA's guidance.
Finally, FDA has published guidance on criteria for the formulation,
safety, immunogenicity, and efficacy for vaccines using recombinant
technology, and one manufacturer has submitted a licensing application
for its influenza vaccine using this technology.[Footnote 55]
According to HHS, part of this guidance, which is available on FDA's
Web site, is related to clinical trials and is specific to clinical
data needed to support the licensure of pandemic influenza vaccines.
HHS Is Addressing Challenges in the Development and Licensure of
Influenza Vaccines Using Alternative Technologies:
HHS has expanded its recommendations for seasonal vaccination to a
larger population and has released a 10-year strategic plan to address
national immunizations. HHS also plans to assist manufacturers with
high research and development costs by funding the establishment of
specialized facilities. In addition, HHS plans to fund the enhancement
of regulatory science capacity and FDA's staff expertise to address
challenges that may hinder the licensure of new influenza vaccines
using alternative technologies.
HHS Has Expanded Its Vaccination Recommendations for Seasonal
Influenza to a Larger Population and Has Released Its Strategy for
National Immunization, Which It Expects Could Eventually Increase
Demand for Vaccine:
HHS has expanded its recommendations for seasonal influenza
vaccination to a larger population and has released its 10-year
strategy to enhance immunization rates in the United States, which it
expects could eventually increase demand for influenza vaccine. In
August 2010, HHS announced that it was expanding its vaccination
recommendations for the 2010-11 influenza season from specific target
groups based on personal risk from the disease to all persons aged 6
months and older. According to HHS, its expanded recommendations
simplify the public health message to providers and to the public on
who should be vaccinated against seasonal influenza. Because the 2010-
11 influenza season is the first for which the recommendations are in
place and the first influenza season after the 2009 H1N1 pandemic, HHS
is also evaluating vaccination rates from this season for changes from
previous years. For example, preliminary data from CDC suggest an
increase in vaccination rates against seasonal influenza among
children aged 6 months to 17 years. According to CDC, vaccination
rates for this population increased by 6.7 percentage points, or from
42.3 percent during the 2009-10 influenza season to 49 percent, as of
February 2011.[Footnote 56] Officials noted that currently, only about
40 percent of Americans are vaccinated against seasonal influenza. HHS
added that eventually demand for seasonal vaccine could increase by
approximately 32 percent--or 100 million people--as a result of the
expanded recommendations. Additionally, a rise in immunization rates
for seasonal influenza vaccine could result in an increase in the
market for this vaccine of approximately $3 billion annually,
according to HHS.
In February 2011, HHS released its updated national immunization
strategy, which outlines, in part, the department's efforts to address
low vaccination rates for influenza.[Footnote 57] This strategy,
called the National Vaccine Plan, lays out HHS's efforts to enhance
aspects of vaccines and vaccination rates against infectious diseases
and provides a comprehensive plan for U.S. vaccine and immunization
efforts from childhood to adulthood.[Footnote 58] As we have noted
above, several stakeholders we spoke with cited a lack of provider and
public education and concerns regarding the safety of vaccines as
factors affecting the demand for influenza vaccine. The National
Vaccine Plan has been updated to reflect experiences from the 2009
H1N1 pandemic and describes various goals, such as enhancing provider
and public education on vaccines and vaccine safety and assisting
providers and the public with making informed decisions regarding
vaccination. HHS also plans to develop a corresponding implementation
plan that will include measurable indicators so the department can
assess its progress in achieving the goals of the National Vaccine
Plan; HHS anticipates releasing this implementation plan later in
2011. Additionally, HHS launched a new Web site, [hyperlink,
http://www.vaccines.gov] in the spring of 2011 as another way of
educating providers and the public on vaccines and vaccine safety.
HHS Plans to Assist Manufacturers with High Research and Development
Costs by Funding the Establishment of Specialized Facilities to
Provide Support and Expertise:
HHS plans to assist manufacturers with high research and development
costs by supporting the establishment of two or three privately owned
facilities called Centers for Innovation in Advanced Development and
Manufacturing that will provide support and expertise to
manufacturers. HHS indicated that it intends to enter into contracts
to partially fund the construction of new facilities or the
retrofitting of existing facilities using approximately $478 million
available from various appropriations.[Footnote 59],[Footnote 60]
Although not the primary purpose of these facilities, according to
HHS, one benefit of these specialized facilities is that they could
reduce smaller, less-experienced manufacturers' research and
development costs by providing needed resources and knowledge about
manufacturing, and reduce the technical risks of researching and
developing medical countermeasures, such as influenza vaccine produced
using alternative technologies. These facilities are primarily
intended to provide, on a routine basis, core services that include
the advanced development and manufacturing of chemical, biological,
radiological, and nuclear medical countermeasures. These specialized
facilities may also be used in an emergency to make pandemic influenza
vaccine produced using alternative technologies, such as recombinant
technology.[Footnote 61] HHS noted that smaller, less-experienced
manufacturers often lack the staff and other resources to address
technical issues--such as those related to production, quality
control, and licensure--resulting in delays and higher costs, which
could cause an effort to fail. These specialized facilities would have
the resources to provide manufacturers with the necessary staff,
technical resources, and expertise to address these delays that can
result in higher costs or effort failures.
According to HHS, these facilities might also reduce the total cost of
the federal government's contracts with manufacturers. By using these
specialized facilities for vaccine production, the costs associated
with producing these initial vaccine doses, such as those for use in
clinical trials, could be included in the facilities' operating
budgets rather than in manufacturers' research and development
contracts, thereby reducing the total amount of these contracts.
According to HHS, the enhanced production capacity from these
facilities could also help manufacturers with which HHS has contracts
avoid production delays. These specialized facilities could also allow
smaller, less-experienced manufacturers to focus more on developing
new influenza vaccines using alternative technologies rather than on
production and licensure issues. HHS anticipates awarding competitive
contracts to establish these facilities in 2011 or 2012.
HHS Intends to Enhance Regulatory Science at FDA to Facilitate the
Review of Licensing Applications for Influenza Vaccines Produced Using
Alternative Technologies:
HHS has announced plans to spend $170 million available from its
fiscal year 2009 and fiscal year 2010 annual appropriations, in part,
to facilitate FDA's review of licensing applications for influenza
vaccines produced using alternative technologies and for other medical
countermeasures.[Footnote 62] Specifically, HHS intends to enhance
regulatory science at FDA, that is, the development of new tests and
methods to assess the safety, efficacy, quality, and performance of
FDA-regulated products, such as influenza vaccines. According to HHS's
report, The Public Health Emergency Medical Countermeasures Enterprise
Review, improvements in regulatory science at FDA will help strengthen
the agency's review of licensing applications.[Footnote 63] In October
2010, FDA released a report outlining a proposed framework for
advancing regulatory science using the funding intended by HHS for
this purpose. According to FDA, improvements in regulatory science
would focus on transitioning products more efficiently through review
from initial concepts to licensed products. In its report, FDA
identified areas in which it would focus that would potentially assist
it in reviewing licensing applications for products more quickly,
including during an influenza pandemic or other public health
emergency.[Footnote 64]
In its October 2010 report, FDA proposes additional efforts that could
enhance staff expertise in reviewing licensing applications for new
vaccines using alternative technologies.[Footnote 65] For example, FDA
intends to initiate a program to help recruit experts in emerging
technologies to work as researchers and reviewers throughout the
agency. FDA is also initiating the creation and support of Centers of
Excellence in Regulatory Science to conduct applied regulatory science
research both independently and in collaboration with the agency.
According to FDA, this additional research will enhance staff
expertise with emerging technologies.
FDA has issued guidance to the industry on various aspects of vaccine
production, such as on the selection of cells as a medium for
producing vaccines and the clinical data needed for licensure of
pandemic influenza vaccines.[Footnote 66] FDA officials noted that
developing guidance relies on experience, which takes time to acquire,
adding that they plan to continue to make themselves available to
manufacturers to consult with and advise them on various aspects of
the vaccine development process, including on conducting clinical
trials and safety assessments.
Agency Comments:
HHS, DOD, and the Department of State reviewed a draft of this report.
HHS and DOD provided written comments, which we have reprinted in
appendixes IV and V, respectively. The Department of State did not
provide comments. HHS also provided technical comments, which we have
incorporated as appropriate.
In its comments, HHS stated that it agreed on the importance of
expertise and research to the development of influenza vaccines
produced using alternative technologies--cell-based and recombinant
technologies and adjuvants. HHS also noted that the department has
made significant contributions to advancing such expertise and
research, as reflected in the collaboration within the department as
well as with influenza vaccine manufacturers during the 2009 H1N1
pandemic. For example, HHS described how the Biomedical Advanced
Research and Development Authority, FDA, and NIH worked with
manufacturers producing both the seasonal and pandemic influenza
vaccine. After approving seasonal vaccines from six manufacturers
during the summer of 2009, FDA approved pandemic vaccines from four
manufacturers in September 2009, and a pandemic vaccine from a fifth
manufacturer in November 2009. HHS also described work done that
allowed for influenza vaccine to be produced more rapidly. For
example, FDA developed a technique to assess the sterility of vaccine,
reducing the time for testing from 14 days to 5 days.
HHS's written comments also noted the department's concern that our
description of challenges identified by stakeholders could be
construed as an endorsement of them. However, as stated in our
objectives, scope, and methodology, we examined challenges identified
by stakeholders to the development and licensure of influenza vaccines
produced using alternative technologies, and we believe our report
clearly attributes these statements to the stakeholders. In response
to industry concerns, HHS stated that FDA has an excellent record of
responding to industry within agreed-upon time frames under applicable
law and that FDA's guidance documents cannot be specific to individual
manufacturing processes because these processes are trade secrets. HHS
also stated that FDA provides clear guidance to manufacturers
regarding the size of clinical trials and meets with sponsors of new
vaccines at key stages of the product development process to provide
further guidance that is informed by earlier trials.
In its comments, DOD agreed with the contents of the draft and noted
that it had no substantive or administrative issues with the draft
report.
We are sending copies of this report to the Secretaries of HHS, DOD,
and State and to interested congressional committees. The report also
is available at no charge on the GAO Web site at [hyperlink,
http://www.gao.gov.]
If you or your staff have any questions about this report, please
contact me at (202) 512-7114 or crossem@gao.gov. Contact points for
our Offices of Congressional Relations and Public Affairs may be found
on the last page of this report. GAO staff who made major
contributions to this report are listed in appendix VI.
Signed by:
Marcia Crosse:
Director, Health Care:
[End of section]
Appendix I: The Research, Development, and Review of Licensing
Applications for New Influenza Vaccine in the United States:
The research, development, and review of licensing applications for
new influenza vaccine for the U.S. market involve several stages.
Manufacturers producing a biological product, of which influenza
vaccines are one type, must submit a licensing application for review
by the Food and Drug Administration (FDA) in order to market their
vaccine in the United States. If FDA approves the application, the
vaccine will be licensed for use in the United States. As shown in
figure 1, this process can take, on average, a little over 10 years to
complete.
Figure 1: Estimated Timeline for the Research, Development, and Review
of Licensing Applications for New Influenza Vaccine for the United
States:
[Refer to PDF for image: illustrated table]
Preclinical development:
* Sponsor prepares and submits an investigational new drug application
to the Food and Drug Administration (FDA), which includes information
on how a new influenza vaccine will be produced and about its
safety[A];
Estimated timeline for completion (approximated): 3-4 years.
Clinical trials[B]:
* Vaccine clinical trials test potential treatments in volunteers and
are typically done in three phases:
Estimated timeline for completion (approximated): 5-8 years;
- Phase 1 trials focus on safety and immune response studies performed
in a small number of closely monitored volunteers;
Estimated timeline for completion (approximated): 2 years;
- Phase 2 trials determine the appropriate dose of vaccine and may
involve hundreds of volunteers;
Estimated timeline for completion (approximated): 2 years.
- Phase 3 trials provide the documentation of efficacy and additional
safety data required for licensing and may involve thousands of
volunteers;
Estimated timeline for completion (approximated): 2 years;
Review of licensing applications and facility inspection:
* A licensing application is submitted to FDA for review. This
application must include safety and efficacy data associated with the
new influenza vaccine as well as information on the vaccine‘s
labeling. FDA may obtain advice from the Vaccines and Related
Biological Products Advisory Committee ” one of its advisory
committees comprised of outside experts[C];
Estimated timeline for completion (approximated): 6-10 months;
* During this stage, FDA also conducts an inspection of the proposed
production facility in which the vaccine is made.
Source: GAO analysis of FDA data.
[A] A sponsor may only begin clinical trials in humans after FDA has
reviewed and approved its investigational new drug application.
[B] At any time during a clinical trial, if data raise significant
concerns about either safety or efficacy, FDA may request additional
information or studies or may halt ongoing clinical trials.
[C] FDA's review of a licensing application generally occurs at either
6 months or 10 months after submission of a priority or a standard
application, respectively.
[End of figure]
[End of section]
Appendix II: Influenza Vaccine Production Process Using Egg-Based
Technology:
Both seasonal and pandemic influenza vaccines for the U.S. market are
produced using egg-based technology--a complex process that involves
growing seed strains in millions of fertilized chicken eggs. As shown
in table 7, this process involves a sequence of steps that can take
approximately 4 to 5 months to complete.
Table 7: Influenza Vaccine Production Process Using Egg-Based
Technology:
Step of production process: Identification and selection of most
prevalent strain(s)[A];
Description:
* Entities such as the United Nations' World Health Organization, the
Centers for Disease Control and Prevention, and the Department of
Defense conduct surveillance to identify the circulating influenza
virus strain(s) expected to be most prevalent;
* The Food and Drug Administration (FDA) decides which strain(s) U.S.
manufacturers must include in the influenza vaccine.[B]
Step of production process: Development of modified strain;
Description:
* One of three laboratories develops a modified strain that has the
characteristics of the circulating strain(s) and grows well in
eggs.[C] This step takes approximately 3 weeks to complete;
* The modified strain undergoes additional testing in one of the
collaborating centers associated with the United Nations' World Health
Organization before being distributed to manufacturers.[D] This
testing also takes approximately 3 weeks to complete.
Step of production process: Development, growth, and purification of
seed strain;
Description:
* After receiving the modified strain, manufacturers inject it into
batches of fertilized chicken eggs to produce a seed strain that can
be used for large-scale vaccine production. The modified strain is now
called a seed strain. This process takes approximately 3 weeks to
complete;
* The virus seed strain is injected into millions of fertilized eggs
and incubated so the strain can grow. Incubation takes approximately 2
to 3 days;
* The virus is collected from the eggs and then inactivated so it is
no longer infectious and is unable to cause disease.[E];
* The virus is then purified and used to produce a concentrated batch
of antigen--the active substance of the vaccine that stimulates the
protective immune response;
* Producing one batch of antigen takes approximately 2 weeks; a new
batch can be started every few days.
Step of production process: Testing, filling, and packaging of
influenza vaccine;
Description:
* Manufacturers and FDA test the vaccine using reagents produced and
supplied by FDA to determine the potency, purity, and yield of the
vaccine and that the potency of the antigen is sufficient to produce
protective antibodies--molecules produced by a person's immune system
that help fight infection.[F] This testing takes approximately 2 weeks;
* Manufacturers then fill vaccine doses into vials or syringes. Labels
are applied to include information such as the expiration date. This
step takes approximately 2 weeks;
* FDA releases all lots of influenza vaccine and may conduct
additional testing of the vaccine before officially releasing it for
distribution. This additional testing occurs concurrently with the
manufacturer's testing of the bulk vaccine. This testing can take up
to 1 week.
Source: GAO analysis of FDA and United Nations' World Health
Organization documents.
Notes: The seasonal influenza vaccine is called a trivalent vaccine
because it contains three strains of the influenza virus. A pandemic
vaccine, which follows the same basic production process as a seasonal
vaccine, is called a monovalent vaccine because it includes only the
one pandemic-causing strain.
[A] The number of influenza strains used varies depending on the type
of influenza vaccine being developed. Because multiple influenza
strains are in constant circulation, seasonal vaccine is produced
annually to protect against the three influenza strains expected to be
most prevalent that year (i.e., a trivalent vaccine). In contrast, the
2009 H1N1 pandemic vaccine was formulated to match the single pandemic-
causing strain (i.e., a monovalent vaccine).
[B] FDA conducts this strain selection process in consultation with
its Vaccines and Related Biological Products Advisory Committee.
[C] These three laboratories are located at CSL Biotherapies in
Australia, the National Institute for Biological Standards and Control
in the United Kingdom, and New York Medical College in the United
States. Also, for a seasonal vaccine a modified strain is developed
for each of the three influenza strains selected.
[D] This network of laboratories includes five collaborating centers
associated with the United Nations' World Health Organization located
in Australia, China, Japan, the United Kingdom, and the United States.
The Centers for Disease Control and Prevention is the collaborating
center in the United States.
[E] At this stage in the process, the virus seed strain is referred to
as a virus. Additionally, unlike the injectable influenza vaccine, the
live attenuated vaccine is administered as a nasal spray and does not
require inactivation because of the weakened nature of the virus in
the vaccine.
[F] FDA is one of the four United Nations' World Health Organization
essential regulatory laboratories responsible for producing and
distributing referencing agents for vaccine testing. Reagents are
substances used to, for example, measure or detect components during
product development. Potency tests are a measure of the vaccine's
ability to stimulate an immune response. Sterility tests are intended
to determine purity by detecting and identifying vaccine contaminants.
Also, antibodies are molecules produced by the immune system that help
fight infections.
[End of table]
[End of section]
Appendix III: Egg-Based and Alternative Technologies for Use with
Influenza Vaccines:
Both seasonal and pandemic influenza vaccines for the U.S. market are
produced using egg-based technology--a complex process that involves
growing seed strains in millions of fertilized chicken eggs.[Footnote
67] The antigen for an egg-based influenza vaccine--the active
substance in a vaccine that provides immunity by causing the body to
produce protective antibodies to fight off a particular influenza
strain--is derived from strains well matched to the strains in wide
circulation. In order for a vaccine to be most effective, it needs to
contain enough antigen to stimulate a protective immune response.
[Footnote 68]
Egg-Based Technology:
Egg-based technology has been used to produce influenza vaccine for
several decades. Department of Health and Human Services (HHS)
officials we spoke with described it as a "tried and true" production
technology with which regulators and manufacturers are familiar. This
technology utilizes fertilized eggs as the medium for producing the
vaccine.[Footnote 69] Additionally, several decades of safety and
efficacy data on the influenza vaccine produced using egg-based
technology are available.
However, the timeliness of vaccine production is hindered, in part, by
egg-based technology's reliance on seed strain development and growth.
Another factor affecting the production timeline is the amount of
antigen produced per egg. For example, during the 2009 H1N1 pandemic,
vaccine delivery was delayed, in part, because of poorer yields of
antigen per egg than expected. Also, the amount of influenza vaccine
that can be produced depends on the manufacturer's egg supply. It
generally takes 12 to 18 months to establish an egg supply large
enough to meet the demands of either seasonal or pandemic influenza.
Some experts we spoke with expressed concern that despite keeping
chicken flocks producing the eggs in secure conditions to prevent
contamination, these flocks are at risk of infection by, for example,
the H5N1 avian influenza virus (also known as "bird flu").
Alternative Technologies for Use with Influenza Vaccines:
Alternative technologies that can be used in producing influenza
vaccines include alternative production technologies--such as cell-
based and recombinant technologies--as well as the use of adjuvants.
[Footnote 70] While various alternative technologies are in
development, in this report we focus on these three because these are
the alternative technologies the federal government has primarily
funded.
These three technologies have the potential to expand the supply or
accelerate the availability of both seasonal and pandemic influenza
vaccines. Expanding the supply or accelerating the availability of
influenza vaccine is particularly important during times of a
perceived seasonal vaccine shortage--when vaccine is not available and
demand is highest--or during a pandemic when demand increases because
of increased risk of disease and death. Expanding the supply or
accelerating the availability of influenza vaccine can be done in two
ways. The first is to increase the overall amount of vaccine available
at the end of the production process; the second is to speed up the
production process itself by, for example, reducing or eliminating
step(s) in the process.
Cell-Based Technology:
The key potential benefit to cell-based technology is the ability to
increase the overall amount of vaccine available at the end of the
production process. This technology for influenza vaccines typically
relies on the use of well-established cell lines, such as those
originally derived from the kidney cells of monkeys or canines. These
cells can exponentially increase in number, allowing for the rapid
expansion of the medium used for influenza vaccine production.
Additionally, cells can be stored in freezers and prepared for use
within days or weeks for large-scale production demands. Vaccines
using cell-based technology are licensed for use in the United States
for use against other infectious diseases, such as polio. Both
seasonal and pandemic vaccines using such technology are also licensed
in other countries, such as those in the European Union, including
Germany and Spain. Cell-based seasonal and pandemic vaccines are also
licensed for use in Iceland and Norway.
Despite the potential benefits of cell-based technology, there are
challenges associated with its use. Similar to egg-based technology,
cell-based technology relies on seed strain development and growth to
obtain the influenza vaccine's antigen. For example, during the 2009
H1N1 pandemic, manufacturers had low production yields in both eggs
and cells when they started vaccine production, which resulted in
limited supplies for delivery to the public. Also, cell-based
technology has not yet been licensed for use with influenza vaccine
for the U.S. market. Additionally, few manufacturers have established
domestic production capacity for influenza vaccine using this
technology, and construction costs for cell-based facilities are high.
For example, the construction costs for Novartis Vaccine and
Diagnostics Inc.'s cell-based facility in Holly Springs, North
Carolina, were over $1 billion, of which HHS funded approximately 40
percent and the manufacturer funded the remaining 60 percent.
Recombinant Technology:
Recombinant technology potentially increases the overall amount of
vaccine available at the end of the production process and speeds up
the production process itself. First, this technology can also utilize
specialized cells--from mammals or from other sources, such as from
bacteria, yeast, insects, or plants--that can exponentially increase
in number as the medium for influenza vaccine production, allowing for
the rapid expansion of the medium used for influenza vaccine
production. Recombinant technology also has the potential to speed up
the production process because it does not rely on the development and
growth of a seed strain to obtain the influenza vaccine's antigen.
Instead, antigen is derived from the protein(s) on the surface of the
influenza virus or from the virus's genes. Recombinant technology is
currently used in U.S.-marketed vaccines against other diseases, such
as hepatitis B and the human papillomavirus, so FDA has experience
reviewing licensing applications for vaccines produced using this
technology.
However, influenza vaccine using recombinant technology has not yet
been licensed for use in the United States. Although some influenza
vaccine has been produced for use and is currently being used in
clinical trials, influenza vaccine has not yet been produced on a
large scale using this production technology. One manufacturer,
Protein Sciences Corporation, has submitted a licensing application to
FDA for a recombinant seasonal influenza vaccine, but some experts we
spoke with said it is unlikely we will know the benefits of this
technology in producing influenza vaccine for several years.
Adjuvants:
Adjuvants' antigen-sparing capability has the potential to increase
the amount of vaccine available at the end of the production process.
Adjuvants--which can be used with influenza vaccines produced using
egg-based, cell-based, or recombinant technologies--can enhance the
immune response, thereby reducing the amount of antigen needed per
vaccine dose. By reducing the amount of antigen needed per vaccine
dose, adjuvants could increase the overall influenza vaccine supply.
Adjuvants have other benefits beyond potentially accelerating the
delivery of influenza vaccine (see table 8).
Table 8: Additional Potential Benefits of Adjuvants:
Potential benefit: Enhance immune response in certain populations;
Description: Adjuvants can help enhance the immune response in certain
populations that tend to respond poorly to vaccination, such as the
elderly or those with underlying health conditions.
Potential benefit: Enhance immune response;
Description: Adjuvants have the potential to enhance the immune
response to protect against influenza for multiple years.
Potential benefit: Cross protection against multiple influenza viral
strains;
Description: Adjuvants, in some cases, have been found to elicit an
antibody response that may be protective against similar strains of
influenza viruses, thereby enhancing the potential efficacy of
influenza vaccine.[A] For example, some research has shown that an
adjuvanted influenza vaccine against the H5N3 strain provides
protection against the H5N1 strain.[B]
Source: GAO summary of President's Council of Advisors on Science and
Technology data and peer-reviewed data.
[A] An antibody is a molecule produced by the immune system that helps
fight infections.
[B] See Iain Stephenson, Roberto Bugarini, Karl G. Nicholson, Audino
Podda, John M. Wood, Maria C. Zambon, and Jacqueline M. Katz, "Cross-
reactivity to Highly Pathogenic Avian Influenza H5N1 Viruses after
Vaccination with Non-Adjuvanted and MF-59-Adjuvanted Influenza A/Duck/
Singapore97 (H5N3) Vaccine: A Potential Priming Strategy," Journal of
Infectious Diseases, no. 191 (2005): 1210-5.
[End of table]
Seasonal influenza vaccines administered with adjuvants are licensed
for use in other countries for targeted populations, such as the
elderly. Adjuvants are licensed for use with seasonal influenza
vaccine in other countries, such as those in the European Union,
including Belgium and Italy. Adjuvanted seasonal influenza vaccines
are also licensed for use in Argentina, Columbia, Hong Kong, Mexico,
the Republic of South Africa, New Zealand, and Thailand. Adjuvants
were also used with the 2009 H1N1 pandemic vaccine in other countries.
These other countries include Canada and Malyasia.
Although adjuvants have been used in other vaccines licensed for the
U.S. market--such as in vaccine against tetanus--FDA has not approved
a licensing application for a seasonal influenza vaccine using this
technology in the United States; adjuvants were also not used in the
U.S. supply of 2009 H1N1 pandemic vaccine. Some experts have noted
potential concerns regarding the safety of repeated, annual
administration of adjuvants in healthy populations--such as young
adults--in a seasonal influenza vaccine.
[End of section]
Appendix IV: Comments from the Department of Health and Human Services:
Department of Health & Human Services:
Office of The Secretary:
Assistant Secretary for Legislation:
Washington, DC 20201:
June 6, 2011:
Marcia Crosse:
Director, Health Care:
U.S. Government Accountability Office:
441 G Street N.W.
Washington, DC 20548:
Dear Ms. Crosse:
Attached are comments on the U.S. Government Accountability Office's
(GAO) draft report entitled, "Influenza Vaccine: Federal Investments
in Alternative Technologies and Challenges to Development and
Licensure" (GA0-11-435).
The Department appreciates the opportunity to review this report prior
to publication.
Sincerely,
Signed by:
Jim R. Esquea:
Assistant Secretary for Legislation:
Attachment:
[End of letter]
General Comments Of The Department Of Health And Human Services (HHS)
On The Government Accountability Office's (GAO) Draft Report Entitled.
"Influenza Vaccine: Federal Investments In Alternative Technologies
And Challenges To Development And Licensure" (GA0-11-435):
The Department appreciates the opportunity to review and comment on
this draft report.
Regulatory Capacity and Expertise:
The Department agrees with GAO that expertise and in-house state-of-
the-art research is important and critical, and we believe that we
have made significant contributions to advancing such expertise and
research, as described below.
The 2009-2010 influenza season was very unusual. A new and very
different viral strain of influenza (2009 H1N1), was not identified as
being in circulation until production of the seasonal influenza
vaccines had already been initiated, and therefore, was not included
in the seasonal vaccine. In response to the need, components of HHS,
including the Food and Drug Administration (FDA) the Biomedical
Advanced Research and Development Authority (BARDA), and the National
Institutes of Health (NIH) worked collaboratively with industry, which
produced both the pandemic influenza vaccine and the seasonal vaccine,
to protect the public from influenza. After approving six seasonal
vaccines during the summer of 2009, FDA was able to approve pandemic
influenza vaccines from four manufacturers on September 15, 2009 and
from a fifth manufacturer on November 10, 2009. The pandemic vaccine
was a good match to the circulating pandemic virus. These outcomes
reflected extensive communication and cooperation between the
influenza vaccine industry and the Department.
In 2009-2011, we conducted cutting-edge scientific work that
significantly improved the ability to produce influenza vaccine more
rapidly. First, FDA developed a technique to assess vaccine sterility
that cut the duration of the test from 14 to 5 days. Second, FDA
scientists developed a more rapid way to make one of the key materials
needed to test the potency of influenza vaccine. Scientists throughout
HHS are currently working to develop new potency tests that would make
both seasonal and pandemic influenza vaccines available more quickly.
Additionally, multiple HHS agencies are advancing research on
universal influenza vaccines. For example, researchers at FDA and the
Centers for Disease Control and Prevention (CDC) developed and tested
in mice a candidate "universal," off-the-shelf vaccine designed to
reduce illness and slow the spread of disease caused by new influenza
A viruses that emerge suddenly, spread quickly, and for which there is
no specific vaccine available. A single dose of the vaccine reduced
illness and virus levels in mice later infected with highly virulent
H1N1 and H3N2 (seasonal influenza), and H5N1 (bird flu).[Footnote 1]
In addition, scientists at the NIH Vaccine Research Center used DNA
vaccine technology in a two-step immunization approach that was
effective against a diverse array of influenza virus strains in mice,
ferrets, and monkeys.[Footnote 2] These types of vaccine approaches,
if effective in humans, could be stockpiled and then used to reduce
deaths and severe illness in the event of delayed production of
traditional vaccine against a newly emergent influenza virus.
All of these activities required working very closely with industry,
foreign regulators, and other domestic public health agencies. FDA
consistently provided one-on-one detailed guidance specific to issues
related to each manufacturer, and to industry in general during this
process. In addition, HHS increased active surveillance to monitor the
safety of these vaccines as they were deployed to the public.
Responsiveness to Industry:
We note that GAO includes a finding that stakeholders GAO interviewed
identified regulatory challenges that hinder the development of
influenza vaccines using alternative technologies. GAO cites as the
sources of this finding meetings attended, journal articles reviewed,
and various stakeholders interviewed, including manufacturers pursuing
alternative technologies.
Although HHS understands that GAO is simply describing the views that
the stakeholders provided, with no intention of endorsing such views,
restating such claims may be construed as an endorsement of them. HHS
believes that it is important that GAO clarify that their intent is
not to substantiate nor endorse the stakeholder views.
Some of the challenges associated with the development of influenza
vaccine technologies are documented on FDA's website, including
transcripts of Vaccine and Related Biological Products Advisory
Committee Meetings (VRBPAC), where topics included in the GAO draft
report were discussed.
* [hyperlink,
http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVa
ccinesandOtherBiologicsNaccinesandRelatedBiologicalProductsAdvisoryCommi
ttee/ucm129568.htm]
* [hyperlink,
http://www.fda.gov/downloads/AdvisorvCommittees/CommitteesMeetingMateria
ls/BloodVaccinesandOtherBiologicsNaceinesandRelatedBiologicalProductsAdv
isoryCommittee/UCM197912.pdf]
* [hyperlink,
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMateria
ls/BloodVaccinesandOtherBiologicsNaccinesandRelatedBiologicalProductsAdv
isoryCommittee/UCM167162.pdf]
* [hyperlink,
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMateria
ls/BloodVaccinesandOtherBiologics/VaccinesandRelatedBiologicalProductsAd
visoryCommittee/UCM215266.pdf]
* [hyperlink,
http://www.fda.gov/ohnns/dockets/ac/08/transcripts/2008-4384T11.htm]
* [hyperlink,
http://www.fda.gov/ohrms/dockets/ac/08/transcripts/2008-4384T12.htm]
* [hyperlink,
http://www.fda.gov/ohnns/dockets/ac/08/transcripts/2008-4384T-add.htm]
* [hyperlink,
http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVa
ccinesandOtherBiologicsNaccinesandRelatedBiologicalProductsAdvisorvCommi
ttee/default.htm]
FDA has actively used these meetings to explore many of the challenges
and issues associated with developing these new technologies.
In response to comments by representatives of regulated industry
regarding the timeliness of agency responsiveness, the Department
would also like to note that FDA adheres to timelines agreed upon with
industry during the Prescription Drug User Fee Act (PDUFA)
negotiations for scheduling meetings and responding to submissions.
FDA regulations describe key meetings that are helpful in resolving
questions and issues raised during the course of clinical
development.[Footnote 3] FDA has an excellent record of responding to
such meeting requests.
To assist industry and when appropriate, FDA develops guidance to
clarify the requirements under a given regulation. The intent of FDA's
guidance documents is to provide a regulatory framework. Guidance
cannot be specific to individual manufacturing processes, as these
very processes are trade secrets. Therefore, FDA strongly encourages
manufacturers, especially vaccine manufacturers, to meet with the
agency to discuss the scientific options appropriate for their
specific needs.
Regarding the clarity of requirements for clinical trials, FDA
provides clear guidance to manufacturers regarding the size of
clinical trials. FDA meets with the sponsors regularly as they develop
their products, starting with the pre-investigational new drug (IND)
phase. FDA also strongly encourages sponsors to meet with the agency
at the end of phase II, which is a critical milestone in product
development. The size of clinical trials will be informed by the
efficacy and safety endpoints, which will depend upon the product, the
clinical indication, and information gleaned during product
development. In addition, FDA has issued two guidance documents that
describe endpoints used for clinical trials, including one specific to
clinical data needed to support the licensure of pandemic influenza
vaccines. They can be found on FDA's website.[Footnote 4]
Appendix IV Footnotes:
[1] "Single-dose Mucosal Immunization with a Candidate Universal
influenza Vaccine Provides Rapid Protection from Virulent H5N I, H3N2
and H1N1 Viruses," PLoS 2010; 5(10) October 4; [hyperlink,
http://dx.plosorg/10.1371/journal.pone.0013162].
[2] C-J Wei, et at. Induction of broadly neutralizing H1N1 influenza
antibodies by vaccination. Science DOI: 10.1126/science. 1192517
(2010).
[3] (I) pre-IND meetings (21 CFR 312.82), (2) certain end of Phase I
meetings (21 CFR 312.82), (3) end of Phase 2/pre-Phase 3 meetings (21
CFR 312.47), and (4) pre-NDA/BLA meetings (21 CFR 312.47).
[4] [hyperlink,
http://www.fda.gov/BiologicsBloodVaccines/GuidaneeComolianceResulatorvIn
formation/Guidances/Vaceinesucm074786.htm];
[hyperlink,
http://www.fda.mv/BiologicsBloodVaccines/GuidanceConmlianeeReaulatorvInf
omttion/Guidances/Vaccinesttem074794.htm].
[End of section]
Appendix V: Comments from the Department of Defense:
The Assistant Secretary of Defense:
Health Affairs:
1200 Defense Pentagon:
Washington, DC 20301-1200:
June 3, 2011:
Ms. Marcia Crosse:
Director, Health Care:
U.S. Government Accountability Office:
441 G Street, NW:
Washington, DC 20548:
Dear Ms. Crosse:
This is the Department of Defense's (DoD's) response to the Government
Accountability Office (GAO) Draft Report, GA0-11-435, "Influenza
Vaccine: Federal Investments in Alternative Technologies and
Challenges to Development and Licensure," dated May 19, 2011, (GAO
Code 290847). Thank you for the opportunity to review and comment.
Though the draft report does not contain any recommendations for our
action, the report does contain information that adds to the DoD's
knowledge base on influenza. We found no substantive or administrative
issues with the draft report. If you require additional information,
the points of contact on this issue are COL James Boles (Functional)
and Mr. Gunther Zimmerman (Audit Liaison). COL Boles may be reached at
(703) 578-8444, or James.Boles@ha.osd.mil. Mr. Zimmerman may be
reached at (703) 681-4360, or Gunther.Zimmerman@tma.osd.mil.
Sincerely,
Signed by:
Illegible, for:
Jonathan Woodson, M.D.
[End of section]
Appendix VI: GAO Contact and Staff Acknowledgments:
GAO Contact:
Marcia Crosse, (202) 512-7114 or crossem@gao.gov:
Staff Acknowledgments:
In addition to the contact named above, Thomas Conahan, Assistant
Director; George Bogart; Cathleen Hamann; Mariel Lifshitz; Gay Hee
Lee; John Rancourt; and Kristal Vardaman made key contributions to
this report.
[End of section]
Related GAO Products:
Influenza Pandemic: Monitoring and Assessing the Status of the
National Pandemic Implementation Plan Needs Improvement. [hyperlink,
http://www.gao.gov/products/GAO-10-73]. Washington, D.C.: November 24,
2009.
Influenza Pandemic: Gaps in Pandemic Planning and Preparedness Need to
Be Addressed. [hyperlink, http://www.gao.gov/products/GAO-09-909T].
Washington, D.C.: July 29, 2009.
Influenza Pandemic: Continued Focus on the Nation's Planning and
Preparedness Efforts Remains Essential. [hyperlink,
http://www.gao.gov/products/GAO-09-760T]. Washington, D.C.: June 3,
2009.
Influenza Pandemic: Sustaining Focus on the Nation's Planning and
Preparedness Efforts. [hyperlink,
http://www.gao.gov/products/GAO-09-334]. Washington, D.C.: February
26, 2009.
Influenza Pandemic: HHS Needs to Continue Its Actions and Finalize
Guidance for Pharmaceutical Interventions. [hyperlink,
http://www.gao.gov/products/GAO-08-671]. Washington, D.C.: September
30, 2008.
Influenza Pandemic: Efforts Under Way to Address Constraints on Using
Antivirals and Vaccines to Forestall a Pandemic. [hyperlink,
http://www.gao.gov/products/GAO-08-92]. Washington, D.C.: December 21,
2007.
Influenza Vaccine: Issues Related to Production, Distribution, and
Public Health Messages. [hyperlink,
http://www.gao.gov/products/GAO-08-27]. Washington, D.C.: October 31,
2007.
Influenza Pandemic: Further Efforts Are Needed to Ensure Clearer
Federal Leadership Roles and an Effective National Strategy.
[hyperlink, http://www.gao.gov/products/GAO-07-781]. Washington, D.C.:
August 14, 2007.
Influenza Pandemic: Efforts to Forestall Onset Are Under Way;
Identifying Countries at Greatest Risk Entails Challenges. [hyperlink,
http://www.gao.gov/products/GAO-07-604]. Washington, D.C.: June 20,
2007.
Influenza Pandemic: DOD Combatant Commands' Preparedness Efforts Could
Benefit from More Clearly Defined Roles, Resources, and Risk
Mitigation. [hyperlink, http://www.gao.gov/products/GAO-07-696].
Washington, D.C.: June 20, 2007.
Avian Influenza: USDA Has Taken Important Steps to Prepare for
Outbreaks, but Better Planning Could Improve Response. [hyperlink,
http://www.gao.gov/products/GAO-07-652]. Washington, D.C.: June 11,
2007.
Influenza Pandemic: Applying Lessons Learned from the 2004-05
Influenza Vaccine Shortage. [hyperlink,
http://www.gao.gov/products/GAO-06-221T]. Washington, D.C.: November
4, 2005.
Influenza Vaccine: Shortages in 2004-05 Season Underscore Need for
Better Preparation. [hyperlink,
http://www.gao.gov/products/GAO-05-984]. Washington, D.C.: September
30, 2005.
Influenza Pandemic: Challenges in Preparedness and Response.
[hyperlink, http://www.gao.gov/products/GAO-05-863T]. Washington,
D.C.: June 30, 2005.
Influenza Pandemic: Challenges Remain in Preparedness. [hyperlink,
http://www.gao.gov/products/GAO-05-760T]. Washington, D.C.: May 26,
2005.
[End of section]
Footnotes:
[1] CDC, "Estimates of Deaths Associated with Seasonal Influenza--
United States, 1976-2007," Morbidity and Mortality Weekly Report, vol.
59, no. 33 (2010): 1057-1062.
[2] These pandemics include the "Spanish flu" of 1918, which killed an
estimated 675,000 people in the United States; the "Asian flu" of
1957, which caused approximately 70,000 deaths in the United States;
the "Hong Kong flu" of 1968, which caused an estimated 34,000 deaths
in the United States; and the recent 2009 H1N1 pandemic, which caused
from 8,870 to 18,300 deaths in the United States. Influenza pandemics
can have successive "waves" of disease and last for up to 3 years.
[3] According to the United Nations' World Health Organization, since
2003, 553 cases of human H5N1 influenza have appeared in 15 countries,
resulting in a total of 323 deaths as of May 13, 2011.
[4] Alternative technologies for influenza vaccines can also be
referred to as non-egg based technologies or next generation
technologies. However, for this report, we use alternative
technologies. Examples of these technologies include cell-based
technology or adjuvants, described later in this report. Other
examples include quadravalent vaccine, that is, a vaccine made using
four strains of influenza virus.
[5] Medical countermeasures are drugs, biological products, or devices
that treat, identify, or prevent harm from a biological and other
agent that may cause a public health emergency. Medical
countermeasures for use during an influenza pandemic may include
vaccine, antiviral drugs, personal respirators, and influenza
diagnostic tests. Antiviral drugs are medications that can prevent or
reduce the severity of a viral infection, such as influenza. This
report focuses on influenza vaccine.
[6] HHS, HHS Pandemic Influenza Plan (Washington, D.C., 2005), 24.
HHS's Plan is only part of the federal government's planning efforts
for responding to a pandemic. The President of the United States
released two documents for a broader response: (1) the National
Strategy for Pandemic Influenza, which provides a framework for future
planning efforts for how the country will prepare for, detect, and
respond to a pandemic, and (2) the National Strategy for Pandemic
Influenza Implementation Plan (Implementation Plan), which further
clarifies the roles and responsibilities of governmental and
nongovernmental entities and provides preparedness guidance for all
segments of society. This Implementation Plan includes 324 action
items, some of which are related to enhancing domestic production
capacity and supporting the development of alternative technologies
for use in producing influenza vaccine.
[7] According to HHS, there was an overabundance of 2009 H1N1 pandemic
vaccine available 6 months after the declaration of the 2009 H1N1
pandemic. However, some experts we spoke with noted that the egg-based
technology currently used to make influenza vaccine and the limited
U.S. production capacity hindered the delivery of the 2009 H1N1
pandemic vaccine during the pandemic's peak--the time when it was most
needed and in greatest demand. According to CDC, the first wave of the
2009 H1N1 pandemic peaked in the United States in May and June, with a
second wave peaking in October 2009. Additionally, one federal report
on influenza vaccine research and development from a presidential
advisory committee noted that the pandemic vaccine continued to be
unavailable in sufficient quantities during the second wave of the
pandemic that began in August 2009. In fact, first doses of the 2009
H1N1 pandemic vaccine did not become available until early October
2009.
[8] As part of its overall mission to protect public health, the
United Nations' World Health Organization is the international entity
that monitors global influenza outbreaks and declares pandemics based
on the pattern of outbreaks in its regions. The National Strategy for
Pandemic Influenza assigned the lead for the U.S. government's
diplomatic role in international efforts to address a pandemic
influenza to the Department of State.
[9] The vulnerability of the U.S. armed forces to an influenza
pandemic was demonstrated during World War I when at least 43,000 U.S.
servicemembers died--about half of all the deaths of U.S.
servicemembers during World War I--because of influenza or influenza-
related complications, and another 1 million servicemembers were
hospitalized.
[10] DOD, Office of the Assistant Secretary of Defense, Department of
Defense Implementation Plan for Pandemic Influenza (Washington, D.C.,
2006).
[11] HHS, The Public Health Emergency Medical Countermeasures
Enterprise Review (Washington, D.C., 2010), and PCAST, Report to the
President on Reengineering the Influenza Vaccine Production Enterprise
to Meet the Challenges of Pandemic Influenza (Washington, D.C., 2010).
[12] FDA, A Framework for FDA's Regulatory Science Initiative:
Advancing Regulatory Science for Public Health (Washington, D.C.,
2010).
[13] There are three types of influenza viruses: A, B, and C. However,
only influenza A viruses cause pandemics. Influenza A viruses are
further categorized into subtypes according to differences in the
outer surfaces of the virus. These influenza A subtypes are further
characterized into strains, which can mutate, or change genetically,
over time. Small mutations result in seasonal or common influenza;
more substantial changes can result in a pandemic.
[14] Vaccination is one part of a multilayered prevention strategy
against influenza that also includes treatment with antiviral drugs
and nonpharmaceutical countermeasures, such as regular hand washing
and social distancing actions.
[15] Antibodies are molecules produced by the immune system that help
fight infections.
[16] Pub. L. No. 109-417, § 101, 120 Stat. 2831, 2832. Public health
emergencies may include influenza pandemics.
[17] According to HHS, the National Institutes of Health (NIH) has a
history of supporting the research and development of alternative
technologies for use in producing influenza vaccine. For example, as
early as 2000, NIH awarded $4.93 million in grants to three
manufacturers for the research and development of influenza vaccines
using alternative technologies. In addition to supporting the testing
of influenza vaccines using alternative technologies in preclinical
studies in animals and clinical trials, NIH has supported many
collaborative projects with academia and industry. These projects have
an emphasis on applied research and early stage assessment of new and
improved technologies for influenza vaccines, such as the use of
adjuvants, and evaluating alternative vaccine technologies, such as
recombinant technology. According to NIH officials, the agency's
efforts are intended to further scientific knowledge and to provide
services and expertise to enable the translation of new technological
ideas into products which benefit public health.
[18] The Defense Advanced Research Projects Agency within DOD enters
into and funds these technology investment agreements. A technology
investment agreement is a type of financial assistance instrument
meant to increase the involvement of commercial firms in the
department's research, development, and demonstration programs.
Technology investment agreements are not considered contracts,
cooperative agreements, or grants. See 10 U.S.C. § 2371(a).
[19] Clinical trials are used to test the safety and efficacy of
potential treatments in human volunteers. They occur in multiple
phases, which vary based on the size and objective of the study.
Studies range in size from a small number of closely monitored
volunteers to thousands of volunteers. In most cases, before clinical
trials can be conducted in human volunteers, researchers conduct
preclinical studies in animals.
[20] However, after the HHS Secretary declares a public health
emergency and under certain circumstances, FDA, as delegated by the
HHS Secretary, may authorize the emergency use of licensed
pharmaceutical products, such as vaccines, for unapproved uses or the
emergency use of unlicensed pharmaceutical products through emergency
use authorizations. See 21 U.S.C. § 360bbb-3.
[21] Egg-based technology is a complex process that involves growing
seed strains in millions of fertilized chicken eggs. This process
involves a sequence of steps that can take approximately 4 to 5 months
to complete. Egg-based technology is used to produce both seasonal and
pandemic influenza vaccines for the U.S. market.
[22] GAO, Influenza Vaccine: Shortages in 2004-05 Season Underscore
Need for Better Preparation, [hyperlink,
http://www.gao.gov/products/GAO-05-984] (Washington, D.C.: Sept. 30,
2005), 1.
[23] GAO, Influenza Pandemic: Efforts Under Way to Address Constraints
on Using Antivirals and Vaccines to Forestall a Pandemic, GAO-08-92
(Washington, D.C.: Dec. 21, 2007), 26. This situation occurred during
the 2009 H1N1 pandemic when CSL Biotherapies in Australia and
GlaxoSmithKline, plc in Canada were required to fulfill their domestic
orders for the pandemic vaccine prior to releasing vaccine to the
United States.
[24] Human infections from strains of the H5N1 virus first occurred in
1997 in Hong Kong, Special Administrative Region.
[25] See Consolidated Appropriations Act, 2005, Pub. L. No. 108-447,
118 Stat. 2809, 3112, 3138. During this fiscal year, other
appropriations were also available for the acquisition and development
of pharmaceutical interventions for pandemic-related purposes,
including vaccines. See Consolidated Appropriations Act, 2004, Pub. L.
No. 108-199, 118 Stat. 3, 251, and Emergency Supplemental
Appropriations Act for Defense, the Global War on Terror, and Tsunami
Relief 2005, Pub. L. No. 109-13, 119 Stat. 231, 276, 280. Many of
these appropriations are available without fiscal year limitation.
[26] See Departments of Labor, Health and Human Services, and
Education, and Related Agencies Appropriations Act, 2006, Pub. L. No.
109-149, 119 Stat. 2833, 2857; Department of Defense, Emergency
Supplemental Appropriations to Address Hurricanes in the Gulf of
Mexico, and Pandemic Influenza Act, 2006, Pub. L. No. 109-148, 119
Stat. 2680, 2783, 2786; Emergency Supplemental Appropriations Act for
Defense, the Global War on Terror and Hurricane Recovery, 2006, Pub.
L. No. 109-234, 120 Stat. 479; and Revised Continuing Appropriations
Resolution, 2007, Pub. L. No. 110-5, 121 Stat. 8, 33. Many of these
appropriations are available without fiscal year limitation.
[27] Supplemental Appropriations Act, 2009, Pub. L. No. 111-32, 123
Stat. 1859, 1884-86.
[28] Each such presidential notification must designate amounts as
emergency funds required to address critical needs related to emerging
influenza viruses.
[29] HHS, Amended Spending Plan for 2009 Supplemental Funding
(Washington, D.C., 2010), as reported to Congress in August 2010.
According to HHS, the amended spending plan will provide funding for
further development of medical countermeasures as recommended in The
Public Health Emergency Medical Countermeasures Review.
[30] See Departments of Labor, Health and Human Services, and
Education, and Related Agencies Appropriations Act, 2009, Pub. L. No.
111-8, 123 Stat. 524, 779, and Departments of Labor, Health and Human
Services, and Education, and Related Agencies Appropriations Act,
2009, Pub. L. No. 111-117, 123 Stat. 3034, 3255. Portions of these
appropriations are available without fiscal year limitation.
[31] According to HHS, the required criteria for manufacturers to
receive this funding were (1) develop cell-based influenza vaccine
technology, (2) obtain FDA licensure of cell-based influenza vaccine,
and (3) construct a domestic cell-based influenza vaccine facility.
[32] HHS contracted with DynPort Vaccine Company LLC (DynPort), which
collaborated with Baxter International Inc. (Baxter) to develop a
seasonal and a pandemic influenza vaccine using cell-based technology.
Baxter oversaw the development of the vaccine, including supporting
licensure efforts for the seasonal vaccine. Baxter also oversaw the
completion of clinical trials for the pandemic vaccine. DynPort
managed the overall project as well as clinical trials. For the
purposes of this report, we refer to this contract as DynPort/Baxter
because of the collaboration between the two manufacturers.
[33] The policy of sanofi pasteur is to spell its name without capital
letters.
[34] According to HHS, HHS and Novartis Vaccines shared the cost of
the construction of the new production facility, with HHS funding
approximately 40 percent of the total cost and Novartis Vaccines
funding the remaining 60 percent.
[35] In April 2008, prior to entering into this contract with HHS,
Protein Sciences submitted a licensing application to FDA for its
seasonal recombinant influenza vaccine which, as of March 2011, was
still under review. According to a Protein Sciences official, FDA is
expected to complete its review this year.
[36] DOD also provides funding through its Blue Angel initiative to
other entities, such as universities and other federal agencies.
[37] This testing was done through DOD's Accelerated Manufacture of
Pharmaceuticals program, one of the programs included in DOD's Blue
Angel initiative. This program focuses on the creation of a production
process capable of making 3 million doses of any vaccine, including
influenza vaccine, within 12 weeks of identifying a particular
microbe. Under this program, DOD entered into contracts with
manufacturers totaling approximately $51.6 million. Because the
Accelerated Manufacture of Pharmaceuticals program is not specific to
influenza, we did not include it when determining the amount of
federal investments made for the research and development of
alternative technologies for use in producing influenza vaccines.
[38] HHS awarded the contract for adjuvant research and development to
IOMAI Corporation. Because Intercell AG acquired IOMAI Corporation in
August 2008, we refer to Intercell AG.
[39] The Biomedical Advanced Research and Development Authority within
HHS's Office of the Assistant Secretary for Preparedness and Response
provided this funding through an interagency agreement with NIH for
the mix-and-match studies. The Biomedical Advanced Research and
Development Authority coordinates the development and procurement of
medical countermeasures for public health emergencies. The National
Institute of Allergy and Infectious Diseases, within NIH, is
conducting this research. This institute also supports other research
related to influenza, including providing research resources to help
develop influenza vaccine candidates and supporting projects focusing
on routes of vaccine administration.
[40] Typically, the same manufacturer produces both the antigen and
the adjuvant to be used together in the vaccine.
[41] The challenge of low demand and subsequent discussions of
challenges associated with high research and development costs and
regulatory challenges do not refer to times when there is an ongoing
pandemic, during which demand may increase because of increased risk
of disease and death.
[42] CDC, Final Estimates for 2009-10 Seasonal Influenza and Influenza
A (H1N1) 2009 Monovalent Vaccination Coverage - United States, August
2009 through May 2010 (Atlanta, Ga.: 2010). CDC acknowledges that its
survey-based estimates of seasonal vaccination rates for the 2009-10
season are overestimates since the projected number of persons
receiving seasonal influenza vaccination exceeds the number of doses
distributed in the United States. However, CDC notes that these
estimates are consistent with previously published interim estimates.
[43] For example, see Pritish K. Tosh, Thomas G. Boyce, and Gregory A.
Poland, "Flu Myths: Dispelling the Myths Associated with Live
Attenuated Influenza Vaccine," Mayo Clinic Proceedings, no. 83 (2008):
77-84. Also, see Deborah A. Gust, Natalie Darling, Allison Kennedy,
and Ben Schwartz, "Parents with Doubts About Vaccines: Which Vaccines
and Why," Pediatrics, no. 122 (2008): 718-725.
[44] GAO, Influenza Vaccine: Issues Related to Production,
Distribution, and Public Health Messages, [hyperlink,
http://www.gao.gov/products/GAO-08-27] (Washington, D.C.: Oct. 31,
2007), 40.
[45] The other two most important sources for parents cited by
respondents were family members (46 percent) and friends (22 percent).
Allison Kennedy, Katherine LaVail, Glen Nowak, Michelle Basket, and
Sarah Landry, "Confidence about Vaccines in the United States:
Understanding Parents' Perceptions," Health Affairs, vol. 30, no. 6
(2011): 1151-59.
[46] For example, a 2008 phone survey of adults conducted by the
National Foundation for Infectious Diseases found that almost 40
percent of respondents reported that they had never discussed
influenza vaccination with their physician or other health care
worker. National Foundation for Infectious Diseases, National Consumer
Survey: Doctors and Patients Not Talking Enough About Influenza
Vaccination (Bethesda, Md., September 2008).
[47] PCAST, Report to the President on Reengineering the Influenza
Vaccine Production Enterprise.
[48] Two manufacturer representatives we spoke with noted that the
current egg-based influenza vaccine is a low-profit product. According
to one report we reviewed, the profit margin of the seasonal influenza
vaccine is estimated to be about 20 percent, compared with the 50
percent to 95 percent profit margins that are typical in the
pharmaceutical market, with highest margins for novel, proprietary
drugs. PCAST, Report to the President on Reengineering the Influenza
Vaccine Production Enterprise.
[49] Regulatory science is a term used by FDA and others to refer to
the tests and measures that are used to assess the safety, efficacy,
quality, and performance of FDA-regulated products.
[50] FDA Science Board, FDA Science and Mission at Risk: Report of the
Subcommittee on Science and Technology, a special report prepared at
the request of FDA (Washington, D.C., 2007); HHS, Medical
Countermeasures Enterprise Review; PCAST, Report to the President on
Reengineering the Influenza Vaccine Production Enterprise; and the
Institute of Medicine, Building a National Framework for the
Establishment of Regulatory Science for Drug Development: Workshop
Summary (Washington, D.C., 2010).
[51] HHS, Medical Countermeasures Enterprise Review.
[52] FDA Science Board, FDA Science and Mission at Risk.
[53] According to FDA, officials consult with manufacturers through
meetings, which can include technical and regulatory meetings on the
pathway to licensure for their specific products. FDA officials said
they also provide feedback to manufacturers during advisory committee
meetings. Advisory committees, composed of outside experts, provide
scientific and medical advice to FDA on the safety, effectiveness, and
appropriate use of certain products. In this context, they provide a
forum for public discussion of issues that may benefit manufacturers
in developing new products.
[54] PCAST, Report to the President on Reengineering the Influenza
Vaccine Production Enterprise.
[55] FDA, Guidance for Industry: Clinical Data Needed to Support the
Licensure of Seasonal Inactivated Influenza Vaccines (Rockville, Md.,
May 2007), and Guidance for Industry: Clinical Data Needed to Support
the Licensure of Pandemic Influenza Vaccines (Rockville, Md., May
2007).
[56] CDC, "Interim Results: State-Specific Influenza Vaccination
Coverage - United States, August 2010-February 2011," Morbidity and
Mortality Weekly Report, vol. 60, no. 22 (2011): 737-43.
[57] The National Vaccine Program Office is specifically leading this
effort. The National Vaccine Program Office is the office within HHS's
Office of the Assistant Secretary for Health that coordinates the
federal government's vaccine-and immunization-related activities.
[58] HHS, 2010 National Vaccine Plan: Protecting the Nation's Health
through Immunization, (Washington, D.C., 2010).
[59] See Pub. L. No. 109-148, 119 Stat. 2786; Pub. L. No. 109-234, 119
Stat. 479; Pub. L. No. 111-32, 123 Stat. 1884; Pub. L. No. 111-8, 123
Stat. 779; Pub. L. No. 111-17, 123 Stat. 3255. Many of these
appropriations are available without fiscal year limitation.
[60] Contracts entered into for this purpose will limit the government
contribution for the construction of new facilities to 49 percent,
with private entities contributing the remaining 51 percent. For the
retrofitting of existing facilities, HHS's maximum contribution would
be 75 percent, with private entities contributing the remaining 25
percent.
[61] A mandatory criterion for eligibility under the HHS contract
solicitation (solicitation #11-100-SOL-00011) is that an offeror
provide evidence of a commitment to supply plans for producing
finished pandemic influenza vaccine within 12 weeks of receipt of a
virus strain and 50 million doses within 4 months of strain receipt.
[62] See The Department of Defense and Full-Year Continuing
Appropriations Act, 2011, Pub. L. No. 112-10, § 1835, 125 Stat. 38,
162.
[63] HHS, Medical Countermeasures Enterprise Review.
[64] FDA, Regulatory Science Initiative Framework.
[65] FDA, Regulatory Science Initiative Framework.
[66] FDA, Guidance for Industry: Characterization and Qualification of
Cell Substrates and Other Biological Materials Used in the Production
of Viral Vaccines for Infectious Disease Indications (Rockville, Md.,
February 2010), and Guidance: Clinical Data of Pandemic Influenza
Vaccines.
[67] There are two types of influenza vaccine approved for use in the
United States: (1) an inactivated virus vaccine injected into muscle
and (2) a live attenuated vaccine, which contains weakened influenza
viruses and is administered as a nasal spray. Also, a modified viral
strain is developed from the circulating virus strain. Influenza
vaccine manufacturers optimize the growth of this modified strain,
which is called a seed strain. This seed strain is used to produce
antigen--the active substance of the vaccine that stimulates a
protective immune response--and is then collected and purified.
[68] The vaccine's antigen needs to be derived from a strain that is
well matched to a specific influenza strain--in wide circulation in
humans--so that the antibodies formed in response to the vaccine
protect against infection. Antibodies are molecules produced by the
immune system that help fight infections.
[69] Producing these fertilized eggs is more difficult than producing
eggs for human consumption. The fertilized eggs are typically 9 to 12
days old, and FDA requires that these eggs meet particular sanitation
and other requirements.
[70] HHS refers to this technology as recombinant/molecular
technology. According to HHS, this technology is also used for
researching and developing a universal influenza vaccine. The National
Institutes of Health, which is conducting research on a universal
vaccine, defines it as a vaccine that would theoretically provide
protection against any strain of influenza without needing to be
updated or administered every year to protect against newly emerging
annual or pandemic strains. Also, in this report, we are referring to
adjuvants made using a combination of oil and water; there are
different types of adjuvants that can be used with vaccines.
[End of section]
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