New Drug Approval
FDA Needs to Enhance Its Oversight of Drugs Approved on the Basis of Surrogate Endpoints Gao ID: GAO-09-866 September 23, 2009Before approving a drug, the Food and Drug Administration (FDA) assesses a drug's effectiveness. This assessment may be based on evidence showing that a drug has a positive impact on a surrogate endpoint--a laboratory measure, such as blood pressure--instead of more direct clinical evidence, like preventing strokes. After approval, FDA often requires or requests a drug sponsor to further study the drug. Concerns have been raised about FDA's reliance on surrogate endpoints and its oversight of postmarketing studies. This report provides information on (1) all drug applications approved based on surrogate endpoints in FDA's accelerated approval process, (2) a subset of applications for potentially innovative drugs approved based on surrogate endpoints under FDA's traditional process, and (3) FDA's oversight of postmarketing studies. GAO identified drugs approved based on surrogate endpoints, obtained the status of related postmarketing studies, and reviewed FDA's oversight of a sample of 35 studies it required under its accelerated approval process, selected to include studies which were at varying levels of completion.
FDA approved 90 applications for drugs based on surrogate endpoints through its accelerated approval process from the creation of the process in 1992 through November 20, 2008, and about two-thirds of postmarketing studies have been closed. FDA created the accelerated approval process to expedite the approval of drugs which are designed to treat serious or life-threatening illnesses and are expected to provide meaningful therapeutic benefits compared to existing treatments. Under this process, 79 of the 90 applications were approved for drugs to treat cancer, HIV/AIDS, and inhalation anthrax. Because of the need to expedite approval, FDA approves drugs under this process based on surrogate endpoints which are not yet proven substitutes for clinical endpoints, but does require that drug sponsors complete postmarketing studies to confirm the drug's clinical benefit. FDA had required drug sponsors to conduct 144 postmarketing confirmatory studies associated with these 90 applications, and as of December 19, 2008, classified 64 percent as closed--meaning that drug sponsors had met FDA's requirements for these studies or FDA determined the studies were no longer needed or feasible. However, several of the remaining studies have been classified by FDA as open for an extended period. FDA approved 69 applications on the basis of surrogate endpoints for new molecular entities (NME)--potentially innovative drugs containing active chemical substances that have never been approved for marketing in the United States in any form--through its traditional approval process from January 1998 through June 30, 2008. These 69 NME drugs accounted for about one-third of the 204 applications for NME drugs which FDA approved through its traditional process during this period, many for drugs to treat cancer, heart disease, and diabetes. Unlike surrogate endpoints used in the accelerated process, FDA considers those used in the traditional process as valid substitutes for demonstrating the clinical benefit of drugs, and thus does not require sponsors to complete postmarketing confirmatory studies. However, FDA requested that sponsors complete 175 postmarketing studies to obtain other information on many of these NME drugs, and as of February 13, 2009, FDA classified about one-half as closed. Weaknesses in FDA's monitoring and enforcement process hamper its ability to effectively oversee postmarketing studies. FDA has not routinely been reviewing sponsors' annual submissions on the status of studies in a timely manner. It has little in the way of readily accessible, comprehensive data to monitor studies' progression and does not consider such oversight a priority. FDA is implementing initiatives to improve its oversight, but it is too early to tell if they will be effective. Although FDA has authority to expedite the withdrawal of a drug from the market if a sponsor does not complete a required confirmatory study with due diligence, or if a study fails to confirm a drug's clinical benefit, it has not specified the conditions thatwould prompt it to do so. It has never exercised its authority, even when such study requirements have gone unfulfilled for nearly 13 years.
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Director: Team: Phone:GAO-09-866, New Drug Approval: FDA Needs to Enhance Its Oversight of Drugs Approved on the Basis of Surrogate Endpoints
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Report to the Ranking Member, Committee on Finance, U.S. Senate:
United States Government Accountability Office:
GAO:
September 2009:
New Drug Approval:
FDA Needs to Enhance Its Oversight of Drugs Approved on the Basis of
Surrogate Endpoints:
GAO-09-866:
GAO Highlights:
Highlights of GAO-09-866, a report to the Ranking Member, Committee on
Finance, U.S. Senate.
Why GAO Did This Study:
Before approving a drug, the Food and Drug Administration (FDA)
assesses a drug‘s effectiveness. This assessment may be based on
evidence showing that a drug has a positive impact on a surrogate
endpoint”a laboratory measure, such as blood pressure”instead of more
direct clinical evidence, like preventing strokes. After approval, FDA
often requires or requests a drug sponsor to further study the drug.
Concerns have been raised about FDA‘s reliance on surrogate endpoints
and its oversight of postmarketing studies. This report provides
information on (1) all drug applications approved based on surrogate
endpoints in FDA‘s accelerated approval process, (2) a subset of
applications for potentially innovative drugs approved based on
surrogate endpoints under FDA‘s traditional process, and (3) FDA‘s
oversight of postmarketing studies. GAO identified drugs approved based
on surrogate endpoints, obtained the status of related postmarketing
studies, and reviewed FDA‘s oversight of a sample of 35 studies it
required under its accelerated approval process, selected to include
studies which were at varying levels of completion.
What GAO Found:
FDA approved 90 applications for drugs based on surrogate endpoints
through its accelerated approval process from the creation of the
process in 1992 through November 20, 2008, and about two-thirds of
postmarketing studies have been closed. FDA created the accelerated
approval process to expedite the approval of drugs which are designed
to treat serious or life-threatening illnesses and are expected to
provide meaningful therapeutic benefits compared to existing
treatments. Under this process, 79 of the 90 applications were approved
for drugs to treat cancer, HIV/AIDS, and inhalation anthrax. Because of
the need to expedite approval, FDA approves drugs under this process
based on surrogate endpoints which are not yet proven substitutes for
clinical endpoints, but does require that drug sponsors complete
postmarketing studies to confirm the drug‘s clinical benefit. FDA had
required drug sponsors to conduct 144 postmarketing confirmatory
studies associated with these 90 applications, and as of December 19,
2008, classified 64 percent as closed”meaning that drug sponsors had
met FDA‘s requirements for these studies or FDA determined the studies
were no longer needed or feasible. However, several of the remaining
studies have been classified by FDA as open for an extended period.
FDA approved 69 applications on the basis of surrogate endpoints for
new molecular entities (NME)”potentially innovative drugs containing
active chemical substances that have never been approved for marketing
in the United States in any form”through its traditional approval
process from January 1998 through June 30, 2008. These 69 NME drugs
accounted for about one-third of the 204 applications for NME drugs
which FDA approved through its traditional process during this period,
many for drugs to treat cancer, heart disease, and diabetes. Unlike
surrogate endpoints used in the accelerated process, FDA considers
those used in the traditional process as valid substitutes for
demonstrating the clinical benefit of drugs, and thus does not require
sponsors to complete postmarketing confirmatory studies. However, FDA
requested that sponsors complete 175 postmarketing studies to obtain
other information on many of these NME drugs, and as of February 13,
2009, FDA classified about one-half as closed.
Weaknesses in FDA‘s monitoring and enforcement process hamper its
ability to effectively oversee postmarketing studies. FDA has not
routinely been reviewing sponsors‘ annual submissions on the status of
studies in a timely manner. It has little in the way of readily
accessible, comprehensive data to monitor studies‘ progression and does
not consider such oversight a priority. FDA is implementing initiatives
to improve its oversight, but it is too early to tell if they will be
effective. Although FDA has authority to expedite the withdrawal of a
drug from the market if a sponsor does not complete a required
confirmatory study with due diligence, or if a study fails to confirm a
drug‘s clinical benefit, it has not specified the conditions that would
prompt it to do so. It has never exercised its authority, even when
such study requirements have gone unfulfilled for nearly 13 years.
What GAO Recommends:
GAO recommends that FDA clarify the conditions under which it would
utilize its authority to expedite the withdrawal of drugs under its
accelerated approval process. FDA disagreed with the need to develop
such clarifying guidance. GAO believes doing so would enhance FDA‘s
oversight.
View [hyperlink, http://www.gao.gov/products/GAO-09-866] or key
components. For more information, contact Marcia Crosse at (202) 512-
7114 or crossem@gao.gov.
[End of section]
Contents:
Letter:
Background:
FDA Has Approved Many Applications Based on Surrogate Endpoints through
Its Accelerated Approval Process and about Two-Thirds of Postmarketing
Studies Have Been Closed:
FDA Approved about One-Third of NME Drug Applications Based on
Surrogate Endpoints through Its Traditional Process and about Half of
the Postmarketing Studies Requested Have Been Closed:
FDA's Oversight of Postmarketing Studies Is Hindered by Weaknesses in
Its Monitoring and Enforcement:
Conclusions:
Recommendations:
Agency Comments and Our Evaluation:
Appendix I: Applications for Drugs Approved under FDA's Accelerated
Approval Process Using Surrogate Endpoints:
Appendix II: Applications for Drugs Approved under FDA's Traditional
Process Using Surrogate Endpoints:
Appendix III: Applications Selected and Questions Regarding FDA's
Oversight of Required Postmarketing Studies:
Appendix IV: Sales for Selected Drugs Approved Based on Surrogate
Endpoints under the Accelerated Approval Process:
Appendix V: Comments from the Department of Health and Human Services:
Appendix VI: GAO Contact and Staff Acknowledgments:
Tables:
Table 1: Summary of Surrogate Endpoints for Accelerated Application
Approvals, from June 19, 1992-November 20, 2008:
Table 2: Status of Postmarketing Studies Requested under the
Accelerated Approval Process, June 19, 1992-November 20, 2008:
Table 3: Summary of Surrogate Endpoints for NME Drug Application
Approvals, from January 1, 1998-June 30, 2008:
Table 4: Status of Postmarketing Studies Requested under the
Traditional Approval Process, January 1, 1998-June 30, 2008:
Table 5: NDAs and BLAs Approved Based on Surrogate Endpoints under the
Accelerated Approval Process, from June 19, 1992-November 20, 2008:
Table 6: NDAs Approved Based on Surrogate Endpoints under the
Traditional Approval Process, from January 1, 1998-June 30, 2008:
Table 7: List of 15 Accelerated Approval Applications Selected for
Review:
Table 8: Total U.S. Sales for Selected Drugs Approved under the
Accelerated Process:
Figures:
Figure 1: Applications Approved Using Surrogate Endpoints under FDA's
Accelerated Approval Process, June 19, 1992-November 20, 2008:
Figure 2: Percentage of Approved Applications Granted Accelerated
Approval for Cancer and HIV/AIDS Drugs, June 19, 1992-November 20,
2008:
Figure 3: Status of Postmarketing Studies FDA Required under Its
Accelerated Approval Process, June 19, 1992-November 20, 2008:
Figure 4: Elapsed Time from Drug Approval to Fulfillment for
Postmarketing Studies Required under the Accelerated Approval Process,
June 19, 1992-November 20, 2008:
Figure 5: Percentage of Postmarketing Studies Requested under the
Accelerated Approval Process by Disease, June 19, 1992-November 20,
2008:
Figure 6: Percentage of Applications for NME Drugs Approved Using
Surrogate Endpoints under FDA's Traditional Approval Process, January
1, 1998-June 30, 2008:
Figure 7: Percentage of Postmarketing Studies Requested under the
Traditional Process, by Disease, January 1, 1998-June 30, 2008:
Abbreviations:
ASR: annual status report:
BLA: Biologic License Application:
DARRTS: Document Archiving, Reporting and Regulatory Tracking System:
FDA: Food and Drug Administration:
FDAAA: Food and Drug Administration Amendments Act:
FDAMA: Food and Drug Administration Modernization Act of 1997:
HHS: Department of Health and Human Services:
NDA: new drug application:
NME: new molecular entity:
OIG: Office of Inspector General:
[End of section]
United States Government Accountability Office:
Washington, DC 20548:
September 23, 2009:
The Honorable Charles E. Grassley:
Ranking Member:
Committee on Finance:
United States Senate:
Dear Senator Grassley:
The Food and Drug Administration (FDA), an agency within the Department
of Health and Human Services (HHS), is the federal agency responsible
for ensuring the safety and effectiveness of medical products,
including drugs and biological products.[Footnote 1] Before a new drug
can be marketed in the United States, a drug sponsor must demonstrate
that it is safe and effective for its intended use, and obtain approval
from FDA.[Footnote 2] Sponsors can demonstrate safety and effectiveness
by conducting studies, known as clinical trials, on human volunteers
and then submitting the results, as part of an application, to FDA for
review.[Footnote 3] As part of its approval process, FDA reviews the
data in the application, including the results of the clinical trials.
If FDA determines that the drug's benefits outweigh its risks, it may
approve the sponsor's application to market a new drug.
FDA generally prefers that when conducting clinical trials, sponsors
demonstrate the effectiveness of a new drug by showing its impact on a
clinical endpoint--a direct measure of how a patient feels, functions,
or survives. Demonstrating the effectiveness of a new drug, however,
can require a sponsor to study the drug on thousands of patients over
several years, potentially costing hundreds of millions of dollars. As
an alternative to demonstrating a drug's effectiveness by its impact on
a clinical endpoint, sponsors may submit, and FDA may approve
applications based on clinical trials that demonstrate a new drug's
impact on a surrogate endpoint--a laboratory measure or physical sign
used as a substitute for a clinical endpoint--that reasonably predicts
a clinical benefit. For example, demonstrating that a drug can lower
blood pressure may be used as a surrogate endpoint to predict whether
the drug is effective in preventing strokes. Through the use of
surrogate endpoints, a drug sponsor can demonstrate the effect of a new
drug on a surrogate endpoint based on smaller and shorter trials than
would be required to prove the drug's effectiveness on a clinical
endpoint. Unlike establishing clinical effectiveness, however,
demonstrating the effect of a new drug on a surrogate endpoint does not
always directly prove any benefit to a patient. Thus, reliance on a
surrogate endpoint can create uncertainty because a drug's effect on a
clinical outcome may not be known until after the drug is approved and
further studied in patients.
FDA allows the use of surrogate endpoints in both the accelerated and
traditional approval processes. In 1992 FDA established an accelerated
approval process to expedite the approval of applications for certain
new drugs that are designed to treat serious or life-threatening
illnesses and which are expected to provide a meaningful therapeutic
benefit over existing therapy.[Footnote 4] Due to the need to expedite
approval of such drugs, under this process, FDA may accept, as a basis
for approval, evidence that demonstrates the drug's impact on surrogate
endpoints which are reasonably likely to predict clinical benefit, and
have not yet been demonstrated to be valid substitutes for clinical
endpoints. Because FDA's approval of a drug based on these surrogate
endpoints rarely establishes the drug's clinical benefits in relation
to a clinical endpoint, FDA has developed additional regulatory
requirements when sponsors use surrogate endpoints under the
accelerated process. Specifically, when FDA approves a drug based on a
surrogate endpoint under the accelerated approval process, FDA requires
a sponsor, as a condition of approval, to conduct postmarketing
confirmatory studies to validate that a drug's impact on a surrogate
endpoint also leads to clinical benefits for patients.
In contrast, under the traditional process--by which FDA reviews most
drugs--FDA recognizes the surrogate endpoints as valid substitutes for
clinical endpoints, and thus there are no such postmarketing study
requirements. In addition, under both the accelerated and traditional
approval processes, FDA may request--and sponsors may agree--to conduct
additional postmarketing studies to address other matters that FDA has
determined are worthy of further examination.[Footnote 5]
Regardless of whether a postmarketing study has been required or
requested by FDA, sponsors conducting such studies must comply with
provisions in the Food and Drug Administration Modernization Act of
1997 (FDAMA) and implementing regulations to report annually to FDA on
the status of postmarketing studies.[Footnote 6] According to FDA's
regulations, sponsors must continue to submit these reports each year
until FDA notifies the sponsor, in writing, that it has determined that
the study has been fulfilled or that the study is either no longer
feasible or would no longer provide useful information.[Footnote 7]
While FDA has long accepted surrogate endpoints to support drug
approval, the use of such endpoints can be controversial. Although the
use of surrogate endpoints can expedite drug approvals, it can also add
uncertainty when the relationship between a surrogate endpoint and
clinical benefit or endpoint has not been fully established. Recently,
concerns have surfaced about some drugs which FDA approved based on
surrogate endpoints. For example, in 2008 FDA approved the drug Avastin
to treat breast cancer based on its ability to limit tumor growth;
however, studies used to support approval also showed that the drug did
not improve overall survival. You asked us to examine FDA's oversight
of drugs approved based on surrogate endpoints. In this report we:
1. identify applications FDA has approved based on surrogate endpoints
through its accelerated approval process, including the surrogate
endpoints used for approval, as well as the status of any associated
postmarketing studies;
2. identify applications FDA has approved for selected new drugs based
on surrogate endpoints in its traditional approval process, including
the surrogate endpoints used for approval, as well as the status of any
associated postmarketing studies; and:
3. evaluate FDA's oversight of postmarketing studies.
To identify the applications for new drugs that FDA has approved on the
basis of surrogate endpoints under the accelerated approval process, we
obtained information from FDA, which included a list of all such
applications the agency approved from June 1992[Footnote 8] through
November 20, 2008 (appendix I contains a list of individual drugs,
application numbers, and specific surrogate endpoints used for approval
through the accelerated approval process). We analyzed this information
to determine the number of approvals per year, the endpoints used for
approval (e.g., measures of viral load), and the diseases that drugs
were approved to treat based on surrogate endpoints.
To identify the number and status of postmarketing studies FDA has
required or requested for those drugs approved based on surrogate
endpoints under the accelerated approval process, we obtained a list of
such studies from FDA. Because FDA may approve multiple applications
for the same drug, the same study can be associated with multiple
applications;[Footnote 9] therefore, we utilized a unique numerical
identifier assigned by FDA to each study to ensure that we did not
count the same study more than once. For those postmarketing studies
required under the accelerated approval process, FDA also provided
certain key dates related to the progress of these studies, including
the dates drug sponsors submitted their final study reports to FDA, and
the dates FDA notified sponsors it had approved these reports. We then
used this information, which was current as of December 19, 2008, to
determine, among other things, the number and percentage of
postmarketing studies by status and the average time it took sponsors
to fulfill their postmarketing study requirement. To provide the most
current information on the status of these studies, FDA had to research
electronic and paper files because the information was not readily
available in the database FDA uses to track the status of postmarketing
studies. To assess the reliability of the information FDA provided, we
compared the status and key dates for a sample of studies to the source
data contained in FDA's files. We determined the data were sufficiently
reliable for the purpose of our review.
Similar to the postmarketing studies FDA required under its accelerated
approval process, FDA did not have readily available data on studies it
requested, such as certain key dates related to progress of the studies
including the dates FDA approved final study reports. Because FDA
officials indicated that it would be too time consuming to generate
these time line data, as they did for the required studies, they only
provided us with status information from their database used to track
postmarketing studies. They provided us with data as of January 6,
2009. For these requested postmarketing studies, we also used a unique
numerical identifier assigned by FDA for each study to ensure that we
did not count the same study more than once. We then identified the
number and percentage of studies by status and by the length of time
studies have remained open. We could not determine how long it took
sponsors to fulfill studies, because the dates FDA determined the
studies were fulfilled were not readily available. We did not verify
the accuracy of this information. One limitation of using these data
was that status information may not be current if FDA had not updated
it in a timely manner. However, this represents the best information
available and is what FDA uses to track the progress of requested
postmarketing studies.
To identify applications for selected new drugs that FDA approved on
the basis of surrogate endpoints under the traditional process, we
limited our scope to a subset of drugs. Because FDA could not readily
identify the extent to which it approves applications based on
surrogate endpoints through its traditional process, we reviewed only
those applications FDA approved for new molecular entities (NMEs)--
potentially innovative drugs containing active chemical substances that
have never been approved for marketing in the United States in any
form.[Footnote 10] Although applications for NME drugs represented only
about 10 percent of all applications FDA approved during this period,
we limited our review to NME drugs because they represent the newest
and potentially most innovative drugs. As a result, we believe our
analyses would capture many of the key concerns related to the use of
surrogate endpoints for new drug approval. One limitation of our
analysis is that the percentage of NME drugs approved based on
surrogate endpoints cannot be projected to the other drugs FDA approved
through the traditional process during this period.
Specifically, we reviewed information on all 219 applications for NME
drugs that FDA approved from January 1, 1998, through June 30, 2008,
and determined the proportion of applications FDA approved that were
based on surrogate and clinical endpoints. This time period provided
the most recent 10-year approval window at the time of our review. Of
the 219 NME drugs, we excluded 15 because they were not approved to
treat a specific disease.[Footnote 11] For the remaining 204 NME drugs,
we examined documents summarizing the results of clinical trials for
each of them. These documents, accessed from FDA's Web site, included
the drugs' original labeling and FDA's original medical reviews.
[Footnote 12] We reviewed these documents and determined whether or not
the primary endpoint--the principal measure used to determine whether
the drug was effective--for each of the 204 NME drugs was a surrogate
or clinical endpoint. We then submitted our analyses to FDA to confirm
that we correctly identified the endpoints as surrogate or clinical for
each of the 204 applications we reviewed (appendix II contains a list
of individual drugs, application numbers, and specific surrogate
endpoints used for approval through the traditional approval process).
After identifying the number of applications for NME drugs in our
sample approved on the basis of surrogate endpoints through the
traditional approval processes, we determined the number of approvals
per year, the specific endpoints used for approval, and the diseases
for which drugs were approved.
To identify the number and status of postmarketing studies FDA
requested for the approved NME drugs, we obtained a list of such
studies from FDA, including information on the status of each study at
the time of our review. FDA provided us with data on the status of
studies as of February 13, 2009. We then used the same approach for
analyzing information on these requested postmarketing studies as we
used for those studies requested by FDA under the accelerated approval
process, subject to the same limitations.
To evaluate FDA's oversight of postmarketing studies, we reviewed
relevant laws and regulations, and policy documents describing FDA's
program oversight and enforcement authority. We also examined internal
control standards, which include the need to establish policies and
procedures to help ensure effective and efficient operations.[Footnote
13] We interviewed FDA officials to identify the oversight activities
it engages in to monitor the postmarketing studies it has required or
requested sponsors to conduct. We also reviewed the enforcement tools
FDA uses or can use to ensure sponsors conduct these studies. To review
specific instances of FDA's monitoring and enforcement activities, we
selected a judgmental sample of 15 applications approved based on
surrogate endpoints under the accelerated program and the 35
postmarketing studies that FDA required drug sponsors to complete for
these drugs. These applications were selected to generate a sample that
included a variety of drugs and a range of studies at various stages of
completion. We provided FDA with a standard series of questions for
each of the 35 studies, and requested that FDA's medical reviewers, who
are responsible for monitoring these 35 studies, provide specific
information on them, including a description of the studies, FDA's
efforts to monitor these studies, and applicable enforcement actions
taken, if any, to prompt sponsors' compliance (appendix III identifies
the 15 applications which we selected, and provides the standard series
of questions we provided to FDA for each of the 35 postmarketing
studies). FDA officials indicated that several individuals were
involved in completing the questions provided for each of the 15
applications. FDA staff completed the first half of the questions
related to time lines, current statuses, and ASR submissions. The
medical reviewers or other staff provided information related to any
study completion problems, underlying issues, and monitoring
activities. To obtain a better understanding of FDA's oversight of
postmarket studies, we reviewed reports issued by HHS's Office of
Inspector General (HHS-OIG) and Booz Allen Hamilton, a contractor
retained by FDA in 2006 to conduct an independent analysis of the
agency's postmarket oversight processes and procedures. Finally, for
certain drugs approved under the accelerated approval process, we
obtained annual U.S. sales data from the time the applications for
these drugs were approved through December 2008 (appendix IV identifies
the applications and drugs and the total U.S. sales since approval). As
of December 19, 2008, these applications had not been converted to full
approval, and more than 5 years had elapsed since they were initially
approved. We obtained the annual sales data from IMS Health, a provider
of market information to the pharmaceutical and health care industries.
We conducted this performance audit from June 2008 through September
2009 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 and conclusions based on our audit objectives.
We believe that the evidence obtained provides a reasonable basis for
our findings and conclusions based on our audit objectives.
Background:
FDA's responsibilities for overseeing the safety and effectiveness of
drugs begin before a product is brought to market and continue after a
drug's approval. Its premarket responsibilities include reviewing a
drug sponsor's proposal for conducting clinical trials, as well as
reviewing applications. If FDA determines that a drug is safe and
effective--that its clinical benefits outweigh its potential health
risks--and that other requirements are met, it will approve the
application.[Footnote 14] Once it approves a new drug, FDA is charged
with monitoring the safety and effectiveness of the drug, which
includes overseeing a sponsor's progress in completing postmarketing
studies.
The Benefits and Risks of Surrogate Endpoints in Drug Approval:
Reliance on surrogate endpoints to predict clinical benefit can bring
treatment benefits to patients years before definitive information on a
drug's effect on clinical outcome is available, and at relatively low
cost. This is because a drug sponsor may be able to demonstrate the
effect of a new drug on a surrogate endpoint based on smaller and
shorter trials than would be required to prove the drug's effect on a
clinical endpoint. In order to further enhance drug development, some
have called for their expanded use as a basis for drug approval. For
example, FDA's 2004 report on the slowdown of innovative medical
therapies calls for the acceptance of new surrogate endpoints to guide
drug development.[Footnote 15] Based on this report, FDA cited the need
to clarify the conditions for the use of new surrogate endpoints in the
drug approval process. To facilitate this effort, FDA planned to
develop an inventory of surrogate endpoints which had been used as the
basis for approval of drugs through the traditional and accelerated
approval processes.
Despite the potential benefits of using surrogate endpoints, reliance
on these endpoints may introduce uncertainty regarding the risks and
benefits of a drug, and may lead to the adoption of useless or even
harmful therapies.[Footnote 16] This can arise if the effect on a
surrogate endpoint does not accurately predict whether treatments
provide benefits to patients, or if the drug has a smaller than
expected benefit and a larger than expected adverse effect, which might
not be recognized without large-scale, long-term clinical trials. For
example, several large trials assessing drugs based on surrogate
endpoints found those drugs to be clinically ineffective, and in some
cases, identified unexpected adverse effects such as increased rates of
death.[Footnote 17]
FDA Role in the Drug Development and Application Review Process:
Once a drug sponsor identifies a promising chemical compound or
biologic organism capable of curing or treating diseases, the sponsor
may decide to test it on humans. Before doing so, a sponsor must submit
the data that have been collected on the compound or organism in prior
studies and outline its plans for clinical trials. The clinical trial
stage gradually introduces experimental drugs to increasingly larger
numbers of patients to determine the drug's safety and efficacy. It is
during this stage that a sponsor determines whether it will evaluate a
drug's effectiveness using a clinical or surrogate endpoint.
Once a drug sponsor completes clinical trials, it may submit an
application to FDA for review. The application contains scientific and
clinical data intended to demonstrate that the drug is safe and
effective for its proposed use. Depending on factors such as the types
of disease the drug is designed to treat, whether other effective
treatments are available, and whether the sponsor assessed the drug
based on a surrogate or clinical endpoint, FDA will review the
application under either the accelerated or traditional approval
process. If the application is for a drug designed to treat serious or
life-threatening illnesses and the drug is expected to provide
meaningful therapeutic benefits compared to existing treatments, and
the sponsor evaluated the drug's impact on a surrogate endpoint that
only reasonably suggested clinical benefit, FDA will review the
application under its accelerated approval process. In general, if the
sponsor assessed the drug's impact on a clinical endpoint, or a
surrogate endpoint that FDA considers to be a valid substitute, FDA
will review the application under its traditional approval process.
According to FDA officials, they do not have specific criteria for
determining when they will accept a surrogate endpoint as a valid
substitute for a clinical endpoint, and such decisions are made on a
case-by-case basis. This determination is dependent on factors such as
the type of drug being approved and the disease being treated. However,
FDA generally considers surrogate endpoints as valid substitutes for
clinical endpoints when these endpoints have been shown to accurately
predict a clinical benefit over time through definitive studies. For
example, FDA considers lowering blood pressure as a valid surrogate
endpoint to establish a drug's clinical effectiveness in reducing the
risk of stroke.
Regardless of which process FDA uses, the application will be reviewed
by one of FDA's medical review divisions, depending on the disease
being treated by the drug. The medical review division evaluates data
contained in the application to determine whether the drug should be
approved. If the medical review division determines the sponsor has
demonstrated the drug is safe and effective for its intended use, and
has met other applicable requirements, FDA will issue an approval
letter. The approval letter outlines any postmarketing studies that FDA
has required or requested the sponsor to conduct while the drug is
being marketed for sale in the United States--including any associated
postmarketing study time frames a sponsor may need to meet.[Footnote
18] As a condition of approval under its accelerated approval process,
FDA requires that sponsors conduct postmarketing studies known as
confirmatory studies. FDA requires sponsors to conduct these
postmarketing studies to verify and describe the drug's clinical
benefits and thereby resolve any remaining uncertainty regarding the
drug's clinical benefit.[Footnote 19] In addition, FDA may request
sponsors to conduct postmarketing studies when it determines that
additional information, while not essential for approval, is important
in improving the prescribing, use, and quality of a drug or consistency
in drug manufacturing. For example, FDA may request sponsors, and
sponsors may agree, to continue to evaluate a drug's safety,
effectiveness, pharmacology, toxicology, or manufacturing controls. FDA
may request these studies under both the accelerated and traditional
review processes.
FDA's Oversight of Postmarketing Studies:
FDA's oversight of postmarketing studies consists of a variety of
monitoring and enforcement activities. After it outlines required and
requested studies in the approval letter, FDA is responsible for
monitoring sponsors' progress in completing the studies, and taking
actions to help ensure studies are completed. A key component of FDA's
oversight is the requirement that sponsors of all approved drugs report
annually on their progress or status towards completing postmarketing
studies. According to the implementing regulations, drug sponsors must
report on the status of required and requested postmarketing studies in
annual status reports (ASR), which are due within 60 days of the drug
application's approval anniversary date.[Footnote 20] Federal
regulations also require ASRs to contain, in part, information on the
description of the required and requested postmarketing studies, along
with the schedule for their completion.[Footnote 21]
FDA has established a goal of reviewing ASRs within 90 days of receipt
to confirm the accuracy of the information provided. FDA may use
information obtained from the ASRs to update a database that includes
information on postmarketing studies. The database, which was designed
to allow FDA to track and monitor the status of required and requested
postmarketing studies, and identify those studies which are falling
behind established time frames, includes information on dates the
studies were required or requested in the approval letter, a
description of the study, and its status. FDA also makes certain
information from this database regarding the status of postmarketing
studies available to the public, and is required to report certain
information annually in the Federal Register.[Footnote 22]
Based on its review of an ASR, FDA designates a status of either "open"
or "closed" for each required and requested postmarketing study every
year. FDA further classifies open studies into one of the following
five categories:[Footnote 23]
* Pending - Those required and requested studies that have not been
initiated, but are not yet delayed. Generally, the first patient has
not been enrolled in the study.
* Ongoing - Those required and requested studies that are proceeding
according to or ahead of any original schedule.
* Delayed - Those required and requested studies that are proceeding,
but are behind their original schedule.
* Terminated - Those required and requested studies that were ended
before their actual completion, but the sponsor has not yet submitted a
final report to FDA. A postmarketing study may be terminated because
the study would no longer provide useful information or the study is no
longer feasible. In some instances, there may be another postmarketing
study that the drug sponsor must conduct in lieu of the terminated
study.
* Submitted - Those required and requested studies that have been
completed--that is, the last patient has finished the protocol--or
terminated and a final study report has been submitted to FDA, but FDA
has not yet notified the drug sponsor that the study has been fulfilled
or released. Drug sponsors are required to continue to annually submit
an ASR on the status of its study until FDA provides written
confirmation that the obligations have been met.
FDA further classifies "closed" studies into one of the following two
categories:
* Fulfilled - Those required and requested studies that have been
completed and a final study report has been submitted and reviewed by
FDA. When FDA completes its review of a study and finds that the
postmarketing study has satisfied FDA's request or requirement, the
agency will issue a written confirmation to the drug sponsor that it
considers the study requested or required in the approval letter to
have been fulfilled.
* Released - Those required and requested studies that have not been
completed and have been found to be no longer needed or feasible. For
example, FDA may release a sponsor from the need to compete a study
because a new drug has been developed which renders the drug being
studied obsolete, thus eliminating the need to conduct the original
study.
Once a drug sponsor has completed a postmarketing study, it submits a
final study report to FDA for review. FDA's goal is to review the final
study report within 12 months of receipt and notify the sponsor whether
FDA considers the study closed. If the postmarketing study is a
confirmatory study required under the accelerated approval process, the
final study report should provide information confirming the drug's
clinical benefit. If it provides confirming information, and FDA agrees
that the report satisfies the confirmatory study requirements, then FDA
converts the drug from accelerated to full approval.[Footnote 24]
FDA's oversight of postmarketing studies may be aided by enforcement
tools, including administrative action letters and expedited withdrawal
procedures of a drug from the market, in certain cases.[Footnote 25] If
a sponsor fails to submit or is late in submitting an ASR, or if FDA
determines a sponsor is not making adequate progress in completing a
required or requested study, FDA may issue an administrative action
letter--commonly referred to by FDA as "Dunner" letters. FDA uses these
letters to remind sponsors about their need to meet federal
requirements related to either submission of ASRs or completing a
required or requested study. Also, under the accelerated approval
regulations, FDA may initiate procedures to withdraw a drug from the
market through an expedited process if required postmarketing studies
to confirm and verify a drug's clinical benefit are not performed with
due diligence.[Footnote 26] In contrast, FDA does not require that drug
sponsors complete requested postmarketing studies, regardless of
whether a drug has been approved under the accelerated or traditional
process. Such studies are typically related to safety, effectiveness,
pharmacology, toxicology, or manufacturing controls.
FDA Has Approved Many Applications Based on Surrogate Endpoints through
Its Accelerated Approval Process and about Two-Thirds of Postmarketing
Studies Have Been Closed:
FDA has approved 90 applications based on surrogate endpoints under its
accelerated approval process since the process was established in 1992.
During this period, FDA required or requested sponsors to conduct over
450 postmarketing studies associated with the approval of applications
for these drugs, and the majority of these studies have been classified
by FDA as closed--meaning that drug sponsors had met FDA's requirements
for these studies or FDA determined the studies were no longer needed
or feasible. However, several have been classified by FDA as open for
an extended period of time.
FDA Approved 90 Applications Based on Surrogate Endpoints under the
Accelerated Approval Process, the Majority for Drugs to Treat Cancer
and HIV/AIDS:
From June 19, 1992, through November 20, 2008, FDA approved a total of
90 applications based on surrogate endpoints, or an average of 5 per
year. FDA approved these applications for a total of 64 different
drugs.[Footnote 27] Over this period, there was variability in the
number of applications FDA approved annually based on surrogate
endpoints. For example, in 1992 and 1994, FDA approved 1 application
based on surrogate endpoints under the accelerated approval process,
while in 2004 it approved 10 applications (see figure 1).
Figure 1: Applications Approved Using Surrogate Endpoints under FDA's
Accelerated Approval Process, June 19, 1992-November 20, 2008:
[Refer to PDF for image: vertical bar graph]
FDA approved an average of 5 applications per year.
Year: 1992;
Applications approved: 1.
Year: 1993;
Applications approved: 3.
Year: 1994;
Applications approved: 1.
Year: 1995;
Applications approved: 6.
Year: 1996;
Applications approved: 9.
Year: 1997;
Applications approved: 3.
Year: 1998;
Applications approved: 9.
Year: 1999;
Applications approved: 8.
Year: 2000;
Applications approved: 9.
Year: 2001;
Applications approved: 3.
Year: 2002;
Applications approved: 6.
Year: 2003;
Applications approved: 7.
Year: 2004;
Applications approved: 12.
Year: 2005;
Applications approved: 4.
Year: 2006;
Applications approved: 6.
Year: 2007;
Applications approved: 3.
Year: 2008;
Applications approved: 6.
Source: GAO analysis of FDA data.
[End of figure]
Almost all--79 of the 90 applications--were for drugs to treat three
diseases. Specifically, 38 of the applications were for drugs to treat
cancer, 30 were for drugs to treat HIV/AIDS, and 11 were for drugs to
treat inhalation anthrax. The remaining 11 applications were for drugs
to treat a variety of other diseases (appendix I contains a list of
individual drugs, application numbers, and specific surrogate endpoints
used for approval through the accelerated approval process).
Since FDA began using the accelerated process in 1992, there has been a
general shift in approvals based on surrogate endpoints from
applications for HIV/AIDS drugs to applications for cancer drugs. In
the first 9 years of the accelerated approval process, from 1992
through 2000, applications for drugs to treat HIV/AIDS made up 48
percent of the approvals, while applications for drugs to treat cancer
made up 26 percent of these applications. Conversely, from 2001 through
2008, applications for drugs to treat cancer made up over half--59
percent--of the applications approved, while drugs to treat HIV/AIDS
accounted for only 18 percent of approved applications (see figure 2).
Figure 2: Percentage of Approved Applications Granted Accelerated
Approval for Cancer and HIV/AIDS Drugs, June 19, 1992-November 20,
2008:
[Refer to PDF for image: vertical bar graph]
Year: 1992-1996;
Cancer applications approved: 28%;
HIV/AIDS applications approved: 50%.
Year: 1997-2000;
Cancer applications approved: 25%;
HIV/AIDS applications approved: 46%.
Year: 2001-2004;
Cancer applications approved: 68%;
HIV/AIDS applications approved: 12%.
Year: 2005-2008;
Cancer applications approved: 47%;
HIV/AIDS applications approved: 26%.
Source: GAO analysis of FDA data.
[End of figure]
Consistent with the types of applications approved under the
accelerated process, the specific surrogate endpoints most frequently
used to obtain approval were those used to demonstrate the
effectiveness of cancer and HIV/AIDS drugs. Specifically, FDA approved,
* 38 applications for cancer drugs based on how the drugs impacted
tumors, as measured by various tumor assessment surrogate endpoints
such as response rate (e.g., tumor shrinkage), length of time until the
cancer spread, or length of time until the drug no longer worked;
* 30 applications for HIV/AIDS drugs based on the drugs' ability to
lower the viral load of HIV in the blood stream, as measured by the
drugs' impact on the surrogate endpoint HIV-RNA; and:
* the remaining 22 applications for drugs to treat other diseases--
including inhalation anthrax and various bacterial infections--based on
a variety of surrogate endpoints (see table 1).
Table 1: Summary of Surrogate Endpoints for Accelerated Application
Approvals, from June 19, 1992-November 20, 2008:
Disease: Cancer;
Surrogate endpoint(s) used for approval:
* Tumor assessment;
* Response rate;
* Disease-free survival;
* Progression-free survival;
* Time to treatment failure;
* Cytogenic and/or hemotologic response as measured in marrow or blood;
* Other;
Number of applications: 38.
Disease: HIV/AIDS;
Surrogate endpoint(s) used for approval:
* Viral load (HIV-RNA);
* CD4 count;
* p24 antigen existence;
* Other;
Number of applications: 30.
Disease: Inhalation anthrax;
Surrogate endpoint(s) used for approval:
* Drug exposure in monkeys compared to human plasma concentrations;
* Serum CIPRO concentrations;
* Other;
Number of applications: 11.
Disease: Other diseases;
Surrogate endpoint(s) used for approval:
* Various;
Number of applications: 11.
Total:
Number of applications: 90.
Source: GAO analysis of FDA data.
[End of table]
FDA Required 144 Confirmatory Postmarketing Studies under the
Accelerated Process, and About Two-Thirds Have Been Closed:
From June 1992 through November 20, 2008, FDA required drug sponsors to
conduct 144 postmarketing confirmatory studies associated with drugs
approved based on surrogate endpoints under the accelerated approval
process. Consistent with the types of drugs FDA approved under the
process, FDA required the majority of these studies--119 or 79 percent--
for drugs approved to treat cancer or HIV/AIDS. Specifically, FDA
required 82 studies for drugs to treat cancer, and another 37 studies
for drugs to treat HIV/AIDS. The remaining studies were for drugs to
treat a variety of other diseases.
At the time of our review, we found FDA had classified 92, or 64
percent, of the 144 required studies as closed--meaning that drug
sponsors had met FDA's requirements for these studies or FDA determined
the studies were no longer needed or feasible. In contrast, FDA had
classified 52 of the 144 studies, or 36 percent, as open, and that
sponsors had made varying levels of progress in completing them (see
figure 3)[Footnote 28].
Figure 3: Status of Postmarketing Studies FDA Required under Its
Accelerated Approval Process, June 19, 1992-November 20, 2008:
[Refer to PDF for image: illustration with 3 pie-charts]
All required postmarketing studies (total=144):
Closed: (92): 64%;
Open (52): 36%.
Closed postmarketing studies:
Fulfilled (73): 79%;
Released (19): 21%.
Open postmarketing studies:
Ongoing (17): 33%;
Submitted (16): 31%;
Delayed (10): 19%;
Pending (7): 13%;
Terminated (2): 4%.
Source: GAO analysis of FDA data.
Note: Status as of December 19, 2008.
[End of figure]
Of the 92 closed studies, sponsors had fulfilled requirements for 73 of
them. This means that sponsors had completed these studies and
submitted them to FDA, and upon review, FDA determined sponsors had
fulfilled their study requirements. There were an additional 19 studies
which FDA classified as released, meaning it had released the sponsors
from the study requirements because it determined the studies were
either no longer feasible or would no longer provide useful
information.
Based on our analyses of the 71 fulfilled studies, we found that in
general, sponsors were able to fulfill about two-thirds of their study
requirements in less than 5 years, with time frames ranging from 7
months to more than 12 years. In contrast, nearly one-third, or 23, of
these studies took over 5 years to fulfill (see figure 4).[Footnote 29]
Figure 4: Elapsed Time from Drug Approval to Fulfillment for
Postmarketing Studies Required under the Accelerated Approval Process,
June 19, 1992-November 20, 2008:
[Refer to PDF for image: vertical bag graph]
Elapsed time: Less than 1 year;
Number of studies: 2.
Elapsed time: Between 1 and 2 years;
Number of studies: 12.
Elapsed time: Between 2 and 3 years;
Number of studies: 15.
Elapsed time: Between 3 and 4 years;
Number of studies: 11.
Elapsed time: Between 4 and 5 years;
Number of studies: 8.
Elapsed time: Over 5 years;
Number of studies: 23.
Source: GAO analysis of FDA data.
Note: Status as of December 19, 2008.
[End of figure]
The amount of time needed to fulfill study requirements was generally
longer for those studies involving drugs to treat cancer. Specifically,
61 percent of the postmarketing studies that took over 5 years (14 of
23) were studies for drugs to treat cancer. Conversely, only 9 percent
of studies which took over 5 years (2 of 23), were studies for drugs to
treat HIV/AIDS. According to FDA officials, the greater length of time
needed to fulfill required confirmatory studies for drugs to treat
cancer has resulted from the approach generally used to approve many
cancer drugs under the accelerated process. In particular, most of the
cancer drugs gained accelerated approval based on single arm clinical
trials,[Footnote 30] which studied these drugs' impacts in small
numbers of patients with resistant tumors. According to FDA officials,
this approach has been used to approve drugs targeting resistant tumors
because these patients have no other effective therapy and it would be
too difficult and time consuming for sponsors to conduct more in-depth
randomized control studies.[Footnote 31] Because patients need access
to these drugs as soon as possible, FDA deemed this approach sufficient
for accelerated approval. However, in order to establish clinical
benefits of the drugs through the required confirmatory postmarketing
studies, the sponsors needed to conduct randomized control trials
comparing the drugs to either a placebo or another drug(s). To do this,
sponsors must design and conduct new randomly controlled clinical
trials and recruit new patients, many of whom may be reluctant to sign
up for a clinical trial when an approved drug is already on the market.
In contrast, according to FDA officials, it is typically easier for a
sponsor to complete a required confirmatory study for HIV/AIDS drugs
because sponsors may simply continue the study which led to the
original accelerated approval of the drug and do not have to design new
studies to fulfill the postmarketing study requirements. For example,
sponsors typically obtain accelerated approval for HIV/AIDS drugs based
on a 24-week randomized clinical trial, and to meet the confirmatory
study requirement they continue the same study for an additional 24
weeks, using the same patients and the same endpoints.
The 52 studies FDA classified as open covered a variety of statuses,
and thus were at varying levels of completion. Specifically, 7 were
pending and had not yet begun, 10 were delayed and thus behind the
sponsor's original schedule, and 17 were ongoing, and thus on or ahead
of schedule. Additionally, 2 were terminated, meaning the sponsor had
stopped the study, but had not submitted results to FDA. The remaining
16 had been submitted by the sponsor to FDA, and were awaiting FDA's
review. Based on our analyses of these 52 open studies, we found the
majority--approximately 65 percent--were for drugs approved to treat
cancer. In contrast, only 6 percent of the open studies were for drugs
approved to treat HIV/AIDS. Based on information provided to us by FDA,
we determined that the average age of the 52 open studies was just over
4 years and the majority--37 of the 52 studies, or 71 percent--had been
required since 2004. However, we found that 15 studies had been open
for more than 5 years, including several open for more than 8 years.
For example, on May 17, 2000, FDA approved an application for the drug
Mylotarg to treat certain patients with acute myeloid leukemia based on
its ability to control cancer in blood cells. As a condition of
accelerated approval FDA required the drug sponsor to conduct one
confirmatory study, and as of December 19, 2008, more than 8 years
later, the study was ongoing, with an anticipated completion date of
October 2014.
FDA Requested over 300 Postmarketing Studies under the Accelerated
Process, and About Two-Thirds Have been Closed:
In addition to the 144 confirmatory studies FDA required from June 1992
through November 20, 2008, FDA also requested--and sponsors agreed to
conduct--317 other postmarketing studies associated with drugs approved
through the accelerated process based on surrogate endpoints. FDA
requested the majority of these studies--90 percent--for drugs approved
to treat HIV/AIDS and cancer. Specifically, FDA requested 194 studies
for drugs to treat HIV/AIDS, and another 91 studies for drugs to treat
cancer. FDA requested the remaining studies for drugs to treat a
variety of other diseases (see figure 5).
Figure 5: Percentage of Postmarketing Studies Requested under the
Accelerated Approval Process by Disease, June 19, 1992-November 20,
2008:
[Refer to PDF for image: pie-chart]
HIV/AIDS (194): 61%;
Cancer (91): 29%;
Other (32): 10%.
Source: GAO analysis of FDA data.
[End of figure]
Based on the status FDA assigned each study at the time of our review,
FDA had classified 203 of the 317 requested studies, or 64 percent, as
closed, meaning that drug sponsors had satisfied FDA's request for
these studies or FDA determined the studies were no longer needed or
feasible.[Footnote 32] Additionally, we found that FDA had classified
114, or 36 percent, as open, and sponsors had made varying levels of
progress in completing them (see table 2). These percentages are
similar to those for studies FDA required sponsors to complete.
Table 2: Status of Postmarketing Studies Requested under the
Accelerated Approval Process, June 19, 1992-November 20, 2008:
Status of open studies: Pending;
Number of studies (% of Total): 57 (18%).
Status of open studies: Ongoing;
Number of studies (% of Total): 21 (7%).
Status of open studies: Delayed;
Number of studies (% of Total): 6 (2%).
Status of open studies: Terminated;
Number of studies (% of Total): 0 (0%).
Status of open studies: Submitted;
Number of studies (% of Total): 30 (9%).
Total open:
Number of studies (% of Total): 114 (36%).
Status of closed studies: Fulfilled;
Number of studies (% of Total): 166 (52%).
Status of closed studies:
Released; Number of studies (% of Total): 37 (12%).
Total closed:
Number of studies (% of Total): 203 (64%).
Total:
Number of studies (% of Total): 317 (100%).
Source: GAO analysis of FDA data.
Note: Status as of January 6, 2009.
[End of table]
Based on information FDA provided, we found that the length of time
studies have been open varies by status. Specifically, those studies
classified as pending had been open, on average, for about 5.5 years,
with more than 40 percent pending for over 8 years. In addition,
studies classified as ongoing and delayed had been open, on average,
for 5.3 and 4 years respectively, and those classified as submitted
have been open on average about 5.6 years.[Footnote 33] We could not
calculate the amount of time it took sponsors to close a requested
study, because, according to FDA, the dates studies were fulfilled or
released were not readily available.
FDA Approved about One-Third of NME Drug Applications Based on
Surrogate Endpoints through Its Traditional Process and about Half of
the Postmarketing Studies Requested Have Been Closed:
From January 1, 1998, through June 30, 2008, FDA approved about one-
third of NME drug applications based on surrogate endpoints under its
traditional process. Many of these applications were for drugs to treat
cancer, heart disease, and diabetes. FDA requested 175 postmarketing
studies associated with these NMEs, and about one-half have been
classified by FDA as closed.
About One-Third of the Applications for NME Drugs Approved under the
Traditional Process Were Based on Surrogate Endpoints, Many for Drugs
to Treat Cancer, Cardiovascular Disease, and Diabetes:
From January 1, 1998, through June 30, 2008, FDA approved 204
applications for NMEs to treat diseases through the traditional
approval process.[Footnote 34] Of these 204 applications, FDA approved
69, or about 34 percent, on the basis of surrogate endpoints.[Footnote
35] The percentage of NME approvals based on surrogate endpoints per
year varied, ranging from 17 percent in 1999 to 54 percent in 2005.
Additionally, in most years from January 1998 through June 2008, NME
applications that were approved based on surrogate endpoints comprised
less than half of all NME approvals in any given year (see figure 6).
Figure 6: Percentage of Applications for NME Drugs Approved Using
Surrogate Endpoints under FDA's Traditional Approval Process, January
1, 1998-June 30, 2008:
[Refer to PDF for image: vertical bar graph]
Year: 1998;
Percentage of Applications Approved: 35.
Year: 1999;
Percentage of Applications Approved: 17.
Year: 2000;
Percentage of Applications Approved: 36.
Year: 2001;
Percentage of Applications Approved: 24.
Year: 2002;
Percentage of Applications Approved: 43.
Year: 2003;
Percentage of Applications Approved: 39.
Year: 2004;
Percentage of Applications Approved: 32.
Year: 2005;
Percentage of Applications Approved: 54.
Year: 2006;
Percentage of Applications Approved: 25.
Year: 2007;
Percentage of Applications Approved: 50.
Year: 2008;
Percentage of Applications Approved: 40.
Source: GAO analysis of FDA data.
Note: 2008 data include NME drug approvals only through June 30, 2008.
[End of figure]
The most frequently used surrogate endpoints in the traditional process
were those to establish the effectiveness of drugs to treat cancer,
cardiovascular disease, and diabetes. Specifically, 13 of the 69
applications--or 19 percent of applications approved--were for drugs to
treat cancer, using various tumor assessments as surrogate endpoints,
including response rates, similar to those used in the accelerated
process. In addition, 11 of the 69 applications, or 16 percent, were
approved for drugs to treat cardiovascular disease, based on their
ability to decrease blood pressure or control cholesterol levels.
Furthermore, 10 of the 69, or 14 percent were for diabetes drugs, based
on their ability to lower blood sugar levels (see table 3). Drugs to
treat a variety of other diseases--including renal disease and
hepatitis B--accounted for the remaining 35 applications, and their
approval was based on a variety of surrogate endpoints (appendix II
contains a list of individual drugs, application numbers, and specific
surrogate endpoints used for approval of NME drugs through the
traditional approval process).
Table 3: Summary of Surrogate Endpoints for NME Drug Application
Approvals, from January 1, 1998-June 30, 2008:
Disease: Cancer;
Surrogate endpoint(s) used for approval:
* Tumor assessment;
* Time to progression;
* Response rate;
* Progression-free survival;
* Other (e.g., serum testosterone levels);
Number of applications: 13.
Disease: Cardiovascular conditions;
Surrogate endpoint(s) used for approval:
* Blood pressure;
* Lipid levels (cholesterol and triglycerides);
Number of applications: 11.
Disease: Diabetes mellitus;
Surrogate endpoint(s) used for approval:
* Blood sugar;
* Fasting plasma glucose levels;
* HbA1c levels;
Number of applications: 10.
Disease: Other diseases;
Surrogate endpoint(s) used for approval:
* Various;
Number of applications: 35.
Total:
Number of applications: 69.
Source: GAO analysis of FDA data.
[End of table]
Our analysis of NME drug applications represents only a small subset of
all applications which FDA may have approved based on surrogate
endpoints under the traditional approval process during this time
period. From January 1, 1998, through June 30, 2008, FDA approved about
2,000 other applications; however, it does not track whether they
approved these applications based on surrogate endpoints. Thus the
extent to which FDA used these and other surrogate endpoints as a basis
for approval is unclear.[Footnote 36]
FDA Requested 175 Postmarketing Studies under Its Traditional Process,
and About One-Half Have Been Closed:
From January 1, 1998, through June 30, 2008, FDA requested 175
postmarketing studies for NMEs approved based on surrogate endpoints
under the traditional process. During this time frame, FDA requested
studies for drugs to treat a variety of diseases. Of the 175 studies,
FDA requested 43, or 25 percent, for drugs to treat cancer. In
addition, FDA requested 31 studies, or 18 percent, for drugs to treat
hepatitis B. The remaining studies were for drugs to treat a variety of
other diseases, including renal disease, diabetes, HIV/AIDS, and
cardiovascular disease (see figure 7).
Figure 7: Percentage of Postmarketing Studies Requested under the
Traditional Process, by Disease, January 1, 1998-June 30, 2008:
[Refer to PDF for image: pie-chart]
Cancer (43): 25%;
Hepatitis B (31): 18%;
Renal disease (25): 14%;
HIV/AIDS (22): 13%;
Diabetes (19): 11%;
Cardiovascular disease (10): 6%;
Other (25): 14%.
Source: GAO analysis of FDA data.
[End of figure]
Based on the status FDA assigned each study at the time of our review,
FDA had classified 94 of the 175 requested studies, or 54 percent, as
closed, meaning that drug sponsors had satisfied FDA's request for
these studies or FDA determined the studies were no longer needed or
feasible. Additionally, we found that FDA had classified 81, or 46
percent, as open, and sponsors had made varying levels of progress in
completing them (see table 4).
Table 4: Status of Postmarketing Studies Requested under the
Traditional Approval Process, January 1, 1998-June 30, 2008:
Status of open studies: Pending;
Number of studies (% of Total): 33 (19%).
Status of open studies: Ongoing;
Number of studies (% of Total): 21 (12%).
Status of open studies: Delayed;
Number of studies (% of Total): 7 (4%).
Status of open studies: Terminated;
Number of studies (% of Total): 4 (2%).
Status of open studies: Submitted;
Number of studies (% of Total): 16 (9%).
Status of open studies: Total open;
Number of studies (% of Total): 81 (46%).
Status of closed studies: Fulfilled;
Number of studies (% of Total): 87 (50%).
Status of closed studies:
Released; Number of studies (% of Total): 7 (4%).
Status of open studies: Total closed;
Number of studies (% of Total): 94 (54%).
Status of open studies: Total;
Number of studies (% of Total): 175 (100%).
Source: GAO analysis of FDA data.
Note: Status as of February 13, 2009.
[End of table]
Based on information FDA provided, we found that the length of time
studies have been open varies by status. Specifically, those studies
classified as pending had been open, on average, for 3.8 years, ranging
from less than 1 year to 10.9 years. In addition, studies classified as
ongoing and delayed had been open, on average, for 2.9 and 5.8 years
respectively, and those classified as submitted have been open on
average 4.2 years.[Footnote 37] We could not calculate the amount of
time it took sponsors to close a requested study, because, according to
FDA, the dates studies were fulfilled or released were not readily
available.
FDA's Oversight of Postmarketing Studies Is Hindered by Weaknesses in
Its Monitoring and Enforcement:
FDA has not been routinely monitoring the status of postmarketing
studies, primarily because oversight of these studies is not considered
a priority. Regarding its enforcement of postmarketing study
requirements, we found FDA has not fully utilized its available
enforcement tools, even when sponsors have failed to complete required
studies.
FDA Has Not Been Routinely Monitoring the Status of Postmarketing
Studies, although Initiatives to Improve Its Monitoring Are Underway:
FDA has not been routinely reviewing ASRs to confirm the accuracy of
information and verify the status of studies within its goal of 90
days. Our review of information provided by FDA for 35 specific
required postmarketing studies showed that just over half of the ASRs
provided for 19 of these studies had never been reviewed by FDA medical
reviewers, and that for those that had been reviewed, about half were
not done in a timely manner (see appendix III for a copy of the
information request we submitted to FDA for these postmarketing
studies). FDA medical reviewers indicated that they were not able to
complete scheduled reviews of ASRs, and according to FDA officials,
this task was a lower priority compared to their other
responsibilities, such as review of applications for new drugs.
This finding is consistent with the results reported by the HHS-OIG in
2006[Footnote 38] as well as FDA's contractor, Booz Allen Hamilton, in
2008.[Footnote 39] Both found that FDA was not completing reviews of
ASRs in a timely manner and had not made such reviews a priority. For
example, the HHS-OIG 2006 study, which examined FDA's review of ASRs
submitted during fiscal year 2004, found that FDA did not meet its goal
of reviewing ASRs in 90 days 55 percent of the time. For 26 percent of
these ASRs, it took FDA more than 180 days to complete its review.
Similarly, the contractor's study, which examined FDA's review of ASRs
for requested studies, found that FDA reviewers were missing the
agency's goal of reviewing ASRs in 90 days 47 percent of the time. Both
HHS-OIG and the contractor reported that the monitoring of
postmarketing studies is not a top priority of the agency.
Specifically, the HHS-OIG reported that FDA officials indicated that
other tasks, including reviewing drug applications and documenting FDA/
industry meetings, are higher priorities than reviewing postmarketing
studies and ASRs. In addition, the contractor similarly reported that a
reason for missing review deadlines was heavy reviewer workload and
that postmarketing study review-related tasks, including review of
ASRs, were often given a lower priority as compared to application
reviews.
Without routine monitoring, FDA's database does not contain complete
and reliable information, including key dates and study information
needed to track the progression of postmarketing studies. When we
requested information on time frames associated with the progression of
postmarketing studies, FDA could not provide it to us from its
database. This is because FDA had not entered into the database the key
dates such as when studies started, are scheduled for completion, and
their current status. To provide us with the information we requested,
FDA had to comb through multiple data systems and paper files to
recreate milestones and status outcome by study. This problem is not
new. The HHS-OIG reported in 2006 that FDA was not entering into the
database the information from ASRs, noting, for example, that for
primarily requested studies, the study start dates were present for
only 6 percent and original projected completed dates were present for
only 21 percent. As a result, the HHS-OIG recommended that FDA improve
its database for monitoring postmarketing studies so that it provides
timely, accurate, and useful information and ensure that studies are
being monitored.
Given that FDA's medical reviewers are not routinely reviewing ASRs and
do not have reliable information readily available to track the status
of postmarketing studies, the agency cannot effectively monitor these
studies. FDA does not know the current status of many postmarketing
studies or whether they are progressing towards completion. In
addition, FDA does not know whether drug sponsors are submitting
complete and accurate ASRs in a timely manner. As a result, FDA lacks
current, reliable, and easily accessible information on the status of
open postmarketing studies, and meeting federal reporting requirements
is difficult.[Footnote 40] The information available regarding
postmarketing studies can only be as accurate and complete as the data
contained in FDA's postmarketing database.
FDA has three initiatives in place to address the agency's oversight
weaknesses. First, to ensure FDA has current information on the status
of open postmarketing studies and facilitate the timely review of ASRs,
FDA retained the contractor in 2008 to review ASRs for all
postmarketing studies classified as open. As part of this effort, the
contractor will support the work performed in FDA's medical review
divisions and conduct an initial review of all newly submitted ASRs.
This initial review is intended to help ensure that ASRs are reviewed
within FDA's 90-day review goal. Based on its review, the contractor
will determine whether the status of the postmarketing studies that
sponsors listed in the ASR is correct, and meet biweekly with FDA staff
to discuss ongoing issues. FDA staff will use this information to
determine the appropriate status of open studies and update its
tracking database.[Footnote 41] This year FDA renewed its contract with
Booz Allen Hamilton, which is now scheduled to expire in 2014, to
continue review of outstanding and new ASRs associated with
postmarketing studies.
The second initiative is the creation of a new tracking coordinator
position within each medical review division with responsibility for a
variety of tasks related to the tracking of postmarketing studies.
First, the tracking coordinators will ensure that reviewers are kept
informed of key postmarketing schedule dates. They will also verify the
accuracy of postmarketing study information and monitor whether
expected activities are conducted within specified time lines. Further,
the coordinator will serve as a key point of contact to interface with
the contractor and ensure that status information provided by the
contractor is entered into the postmarketing database. Currently,
tracking coordinator responsibilities are shared between other existing
positions within the divisions. FDA officials indicated that they were
not sure whether the tracking coordinator position would be filled by
one person in each medical review division or if the duties would be
divided among many individuals in each division.
To the extent that the ASR reviews and tracking coordinator initiatives
are successful, FDA's third initiative--the Document Archiving,
Reporting and Regulatory Tracking System (DARRTS)--could facilitate the
monitoring of postmarketing studies for NDAs.[Footnote 42] DARRTS is a
Web-based system, which according to FDA officials should allow FDA
staff greater access to information and provide enhancements over the
current database, such as creating management reports on specific drugs
and their respective studies.
FDA Has Not Fully Utilized Its Enforcement Tools Related to Required
Postmarketing Studies:
FDA has not fully utilized its two enforcement tools--issuing
administrative action letters and withdrawing a drug from the market in
certain cases--to encourage and compel drug sponsors to complete
required confirmatory postmarketing studies. FDA has the discretion to
issue administrative action letters to drug sponsors if 1) sponsors are
late or fail to submit ASRs, or 2) FDA determines that sponsors are not
sufficiently progressing in completing their studies.
The extent to which FDA has issued administrative action letters
related to its oversight of postmarketing studies required under the
accelerated approval process is unclear. According to FDA officials,
they do not have a centralized database which tracks the letters they
have issued to sponsors when sponsors were late or failed to submit
ASRs, or when FDA determined that sponsors were not sufficiently
progressing in completing their studies. Our review of FDA's oversight
of a sample of postmarketing studies required under the accelerated
approval process suggests its use may be limited when sponsors do not
submit their ASRs within required time frames. Specifically, we found
that sponsors were late in submitting ASRs for 12 postmarketing studies
in our sample. However, FDA issued an administrative action letter to
the sponsor of only 1 of these 12 studies.
In addition to sending administrative action letters for drugs approved
under the accelerated approval process, FDA also may begin expedited
proceedings to withdraw a drug's approval in a number of situations
including if it determines that: 1) sponsors are not completing
required confirmatory postmarketing studies with due diligence, or 2) a
study failed to confirm the drug's clinical benefit. According to FDA
officials, the agency has never withdrawn from the market a drug
approved through the accelerated process due to either of these issues.
Our review of the 90 applications approved based on a surrogate
endpoint under the accelerated approval process revealed several
circumstances that appeared to meet the regulatory conditions for
withdrawal, but FDA was hesitant to use its enforcement authority.
Specifically, we found that for 36 of the 90 applications, drug
sponsors had not fulfilled their confirmatory study requirements by
establishing the clinical effectiveness of those drugs. This includes
several applications for drugs that FDA had approved more than 10 years
ago and for which sponsors had not yet completed all of their required
studies, and others where the studies failed to confirm the drug's
clinical effectiveness. An example of sponsors not completing
confirmatory studies includes the case of ProAmatine:
* FDA approved ProAmatine in 1996 to treat individuals with low blood
pressure based on the surrogate endpoint of raising 1-minute standing
systolic blood pressure. As a condition of approval, it required the
sponsor, Shire Pharmaceuticals, to conduct a confirmatory study to
validate long-term clinical benefits. However, the sponsor was not able
to design and conduct a sufficiently adequate clinical study, and the
clinical benefit of the drug has never been established. Despite this,
the sponsor benefited from market exclusivity between 1996 and 2003,
and sales of this drug generated millions of dollars for the company
(see appendix IV for total U.S. sales since approval for ProAmatine and
six other drugs for which applications had not converted to full
approval as of December 19, 2008). Furthermore, once ProAmatine's
market exclusivity ended in 2003, FDA approved five generic versions of
the drug, although the clinical benefit of the drug was never
confirmed. Recognizing that the study requirement related to ProAmatine
was still outstanding; in August 2007 FDA posted a letter on its Web
site inquiring about certain legal and regulatory issues related to the
generic manufacturers' potential completion of the confirmatory study.
In August 2008, according to officials, FDA posted another letter in
which it threatened to withdraw approval of ProAmatine and the generic
drugs based on its accelerated approval authority if no company
completed the required studies.[Footnote 43] At the same time it
indicated that 3 years of market exclusivity would be available if a
company completes the study and it confirms clinical benefit. As of
June 2009, nearly 13 years after it approved ProAmatine, FDA had not
initiated the withdrawal of ProAmatine or the generic versions, but FDA
officials indicated that it planned to issue a final administrative
action letter to the sponsor and generic manufacturers in a final
effort to obtain completion of the required study.
An example of sponsors completing confirmatory studies which failed to
confirm the drug's clinical effectiveness includes the case of Iressa:
* FDA approved Iressa in May 2003 to treat patients with non-small cell
lung cancer based on the surrogate endpoint that showed that it causes
significant shrinkage in tumors in about 10 percent of patients. As a
condition of approval, FDA required the sponsor to conduct a
postmarketing study to verify the expected clinical benefit. In
December 2004, FDA announced that the results of the clinical trial in
1,700 patients indicated that the drug did not prolong survival.
Despite this, FDA did not utilize its authority to withdraw the drug
from the market. However, it did take the step of restricting Iressa's
use to a subset of patients who had already taken the medicine and
whose doctor believed it was helping them. FDA directed new patients
wanting to take Iressa to two other available therapies shown in
studies to improve survival in patients whose cancer has progressed
while on previous therapies.
According to FDA officials, they have not developed guidance to specify
the conditions under which they would exercise their authority to
withdraw approval of a drug that the agency approved based on surrogate
endpoints under the accelerated approval process. Under the
regulations, FDA can initiate expedited withdrawal procedures for drugs
approved based on surrogate endpoints when sponsors fail to perform
required confirmatory postmarketing studies with due diligence, or a
study failed to confirm the drug's clinical effectiveness. Although the
regulations outline conditions under which FDA could utilize expedited
withdrawal authority for drugs approved under the accelerated approval
process based on surrogate endpoints, withdrawal is not required and
the agency has latitude in determining when to exercise this authority.
The officials recognized that they have not specified criteria for
defining how they would implement the due diligence requirement of the
regulations, such as determining how long it should take a sponsor to
complete a study or when a sponsor is taking too long, which could
result in a drug's withdrawal from the market. Without such guidance,
officials indicated that it is not clear as to when or how to enforce
the due diligence criteria for withdrawal, but acknowledged that
ProAmatine may have been a case where they could have fully utilized
their withdrawal authority. Officials further stated that it would be
difficult to develop specific criteria for due diligence for withdrawal
that could be generally applied to the wide range of diseases treated
by drugs approved under the accelerated approval process. Additionally,
they questioned the need for such specific criteria, because other than
the case of ProAmatine, they have rarely faced circumstances where drug
sponsors were reluctant to work toward completing their postmarketing
study. Regarding cases when a confirmatory study failed to demonstrate
a drug's clinical benefit, agency officials indicated they would be
hesitant to withdraw a drug in such cases. For example, they said that
despite the confirmatory study results, Iressa may still be effective
for a number of patients.
Conclusions:
The use of surrogate endpoints has been accepted by FDA as a means of
demonstrating the efficacy of drugs approved through both its
traditional and accelerated approval processes. While the use of
surrogate endpoints can expedite the approval of drugs, reliance on
these endpoints also introduces uncertainty regarding the risks and
benefits of a drug because the clinical effectiveness is not directly
measured. Thus their use can lead to the adoption of useless or even
harmful therapies if the effect on a surrogate endpoint does not
accurately predict whether treatments provide benefits to patients, or
if the drug has a smaller than expected benefit and a larger than
expected adverse effect.
With the creation of the accelerated approval process in 1992, FDA
expanded the use of surrogate endpoints, thus expediting the approval
of certain drugs for serious or life-threatening diseases. While the
availability of these drugs provided new treatment options to patients,
it also introduced new elements of uncertainty, as FDA allowed the use
of surrogate endpoints which had not yet been shown to be valid
predictors of a drug's clinical effectiveness. Thus, patients could
potentially find themselves taking drugs approved under the accelerated
process that may not be clinically effective in treating their illness.
Recognizing the need to mitigate this uncertainty and risk, FDA
required that drug sponsors conduct postmarketing studies with due
diligence to confirm that such drugs actually have clinical benefits.
It also implemented a process for monitoring the progression and
completion of these studies, including establishing a database to track
the progression of the studies, and instituting expedited withdrawal
procedures for drugs when studies are not completed or if they failed
to confirm clinical benefits.
Despite these tools, weaknesses in FDA's monitoring and enforcement
process hamper its ability to effectively oversee postmarketing
studies. FDA has not routinely and consistently reviewed the ASRs
submitted by drug sponsors, and information the agency needs to ensure
that sponsors are completing required confirmatory studies in a timely
manner was not consistently entered into its tracking database.
Therefore, the agency has lacked an effective management information
system capable of generating data needed to effectively monitor the
progress of such studies. FDA has recently implemented several
initiatives to enhance its oversight of postmarketing studies, which
may provide the agency with an opportunity to develop reliable data
needed to adequately monitor the progress of studies and improve
oversight. Additionally, FDA's plans to designate personnel to serve as
focal points for monitoring postmarketing studies may provide a greater
emphasis on oversight of such studies. It is too early to tell if these
initiatives will be successful. While FDA's new system, DARRTS, may
have features superior to the tracking database it is replacing, the
root cause of many problems associated with the previous system was not
the system itself, but the failure to enter information into it. The
ultimate success of FDA's new initiatives is largely dependent on the
timely review and prompt entry of ASRs into DARRTS.
While FDA has implemented measures to enhance its monitoring of
postmarketing studies, the agency has taken a passive approach to
enforcing confirmatory study requirements. It has never exercised its
authority to withdraw a drug it approved based on surrogate endpoints
under the accelerated approval process, even when such studies have
been outstanding for nearly 13 years. Further, FDA has not attempted to
clarify the circumstances under which it would exercise this authority
and has never developed specific time frames for sponsors to complete
their confirmatory studies. The combination of its ineffective
monitoring and lack of criteria outlining when a drug should be
withdrawn from the market make it difficult for FDA to utilize its
enforcement authority. Consequently, drugs which have not proven to be
clinically effective may remain on the market while their associated
confirmatory studies remain incomplete.
Recommendations:
To clarify FDA's enforcement authority under the accelerated approval
process, we recommend that the Commissioner of FDA take the following
action:
* Clarify the conditions under which the agency would utilize its
authority to expedite the withdrawal of drugs approved based on
surrogate endpoints under the accelerated approval process if sponsors
either fail to complete required confirmatory studies with due
diligence, or if studies are completed, but fail to demonstrate the
clinical effectiveness of the drugs.
Agency Comments and Our Evaluation:
We provided a draft of this report to HHS for review. HHS provided
written comments from FDA, which are reprinted in appendix V. In its
comments, FDA disagreed with our recommendation to clarify the
conditions under which it would utilize its authority to expedite the
withdrawal of drugs approved based on surrogate endpoints under the
accelerated approval process. FDA also said that it thought we
minimized the success of the accelerated approval program. The agency
stressed that this program has provided millions of patients access to
new treatments sooner than would have been possible under the
traditional approval process. In addition, FDA described its efforts to
improve monitoring of the completion of required and requested
postmarketing studies. FDA also provided technical comments, which we
incorporated as appropriate.
Regarding our recommendation, FDA indicated that it would be difficult,
if not impossible, to provide further clarification as to when it might
utilize its authority to expedite withdrawal of a drug approved on the
basis of surrogate endpoints. FDA acknowledged that there have been
cases where confirmation of the clinical benefit of drugs approved
under the accelerated approval program did not occur in a timely
manner. However, FDA stressed that, unless there are clear safety
concerns emanating from the confirmatory trial, it must carefully
assess each case and consider the underlying reasons and consequences
of all regulatory options, including their potential impact on
patients. In expressing its disagreement and the need for case-by-case
assessments, FDA cited the examples of two drugs mentioned in our
report--ProAmatine and Iressa. In the case of ProAmatine, for which
adequate clinical trials have never been completed to establish the
drug's benefit, FDA stated that it would not be appropriate to initiate
expedited withdrawal, as ProAmatine is the only approved therapy for
the condition that it treats. FDA stated that rather than providing an
example of the agency failing to exercise its authority to withdraw
approval, ProAmatine provides a good example of the complex issues it
must consider when a clinical benefit has not been confirmed and the
drug approved remains the only FDA-approved treatment for a serious or
life-threatening condition. Regarding Iressa, FDA noted that, despite
the fact that the clinical trials failed to confirm the drug's clinical
benefit, they nonetheless suggested there were some positive outcomes
for certain patients. Therefore, rather than withdraw approval of
Iressa, FDA indicated that it took an appropriate and balanced approach
by restricting access to those patients who were already receiving
treatment and whose physicians felt they were benefiting from Iressa
and to other patients based on physician assessments.
We recognize that FDA faces challenges in determining whether it should
initiate the expedited withdrawal of a drug approved under the
accelerated approval process. Acknowledging that the clinical benefit
of these drugs is uncertain at the time of their approval, FDA's 1992
regulations provided that expedited withdrawal of drugs may be
appropriate when confirmatory studies fail to show clinical benefits.
Indeed, FDA's ability to require sponsors to complete clinical trials
with due diligence and its authority to undertake the expedited
withdrawal of a drug if a clinical benefit is not confirmed are
specifically cited by FDA in its comments as two important safeguards
intended to minimize the risks inherent in the accelerated approval
process. Although nearly 17 years have elapsed since FDA issued the
accelerated approval regulations, the agency has not attempted to
define the circumstances under which the authority that this important
safeguard provides would be used.
While FDA commented that it would consider exercising its withdrawal
authority if a clear safety concern emerged from a confirmatory trial,
which would certainly be appropriate, the regulations governing the use
of surrogate endpoints and the purpose of the required studies are
focused on establishing the clinical benefit of a drug, not its safety.
We agree that it may be challenging for FDA to develop guidance to
clarify the conditions under which it would utilize its expedited
withdrawal authority. However, we do not agree that it is impossible--
or even too difficult--to do so, nor do we believe that such guidance
would have to be so prescriptive as to prevent FDA from considering the
unique circumstances of individual cases. As the scientific experts
charged with overseeing the use of drugs it approves, FDA should be in
a position to implement this recommendation. In our view, this would
serve two purposes. First, this would clarify within FDA when this
option should be considered in order to mitigate risks to patients
taking drugs which FDA has approved. Second, it would serve to clarify,
for drug sponsors, FDA's expectations regarding performance
requirements related to completing required confirmatory studies, and
the consequences of not meeting requirements. This would put drug
sponsors on notice that, although FDA has not utilized this authority
to date, it remains a viable option, and would enhance the agency's
ability to effectively carry out its oversight responsibilities.
Without specific parameters governing the use of this authority, such
as definitive time frames or other requirements for when sponsors need
to complete confirmatory studies, there appears to be little likelihood
that FDA would ever utilize its authority, thus potentially diminishing
the value of what FDA considers an important safeguard.
Regarding the examples of ProAmatine and Iressa, we recognize that FDA
faced numerous scientific and ethical issues in overseeing the use of
these drugs, and that it ultimately needed to balance such factors when
determining the best approach to take in overseeing the completion of
required confirmatory studies. However, we chose to discuss these drugs
because the very circumstances surrounding them illustrated specific
oversight issues which FDA considered when it developed the 1992
accelerated approval regulations. The circumstances involving these
drugs also highlighted the challenges that FDA faces in determining how
to conduct its oversight responsibilities. As delineated in the
regulations, the purpose of these confirmatory studies is to verify and
describe the clinical benefits of these drugs. When sponsors fulfill
these requirements, they establish the clinical evidence similar to
what would ordinarily have been required were the drugs reviewed under
the traditional approval process. In neither of these two instances has
this level of evidence been established--no adequate study has ever
been completed to confirm the clinical benefits of ProAmatine and,
while the studies for Iressa were conducted, they failed to confirm any
clinical benefit.
Specifically, in the case of ProAmatine, as we noted in our report, FDA
officials acknowledged that this matter may have gone on too long
without being resolved. Although FDA's comments indicate that it
believes the sponsor conducted trials with due diligence, 13 years have
elapsed, and although the drug is also available generically,
sufficient confirmatory trials have not been completed. As FDA
indicates in its comments, obtaining the completion of the trials has
become a complex matter and it is still seeking ways to encourage one
or more of the generic manufacturers to conduct the confirmatory
clinical trials. Thus, we believe that this example raises questions
about whether the sponsor had displayed due diligence in meeting the
confirmatory study requirements as well as what circumstances would
lead the agency to exercise its withdrawal authority. We provided the
example of Iressa to illustrate the challenges that FDA faces in
overseeing the accelerated approval process. In developing the 1992
regulations, FDA specifically anticipated a situation similar to that
posed by Iressa--the completion of a confirmatory study that failed to
demonstrate a drug's clinical benefit. Although 17 years have passed,
FDA has not established guidance clarifying how it would exercise its
expedited withdrawal authority in such circumstances. While FDA's
actions in these two cases may have been appropriate, they nonetheless
serve to illustrate the need to clarify use of the expedited withdrawal
authority, consistent with our recommendation.
Regarding FDA's statement that the accelerated approval process has
been very successful, and has resulted in the early approval of many
significant therapeutic advances for patients, we believe that this
conclusion is a matter of scientific judgment, and beyond the scope of
our review. However, our report clearly identified both the purpose of
the accelerated approval process, and the specific drugs that FDA has
approved using this process. Thus, we believe we provide an accurate
factual description of the drugs approved on the basis of surrogate
endpoints through this process since it was instituted in 1992.
Further, we do not believe that our emphasis on examples of FDA's
decisions regarding specific drugs and the results of their associated
confirmatory studies, in any way minimizes the benefits provided by the
accelerated process. Instead they are meant to illustrate challenges
associated with FDA's oversight of such an important program.
Finally, regarding FDA's ongoing efforts to improve its oversight of
postmarketing studies in both the accelerated and traditional approval
processes, FDA acknowledged that its oversight of postmarketing studies
in general has been inadequate, and agreed that improvements are
needed. The agency indicated that because of inadequate staffing and
information technology resources and competing priorities, its past
tracking of postmarketing studies has not been timely. FDA stated that
it has begun to implement a number of improvements to ensure
appropriate oversight, more efficient tracking, and expeditious review
of postmarketing submissions from sponsors, but stated that these
efforts were not fully reflected in our report. We believe our report's
discussion of FDA's efforts to improve the monitoring of postmarketing
studies sufficiently addresses FDA's ongoing initiatives. Specifically,
we discuss its contract with Booz Allen Hamilton, the establishment of
new tracking coordinator positions which are outlined in its revised
Manual of Policies and Procedures, and planned improvements in data
reporting capabilities through the DARRTS system. In particular, FDA
highlighted the results of efforts from its contractor, Booz Allen
Hamilton, which FDA said resulted in extensive updating of the data in
the agency's tracking database. However, the results of these updates
to the database by FDA's contractor became available subsequent to our
work, and thus could not be reflected in the data we presented in this
report. The fact that extensive updates needed to be made, however,
confirms our assessment that FDA's monitoring and oversight has been
ineffective. We are encouraged that FDA is taking steps to facilitate
timely oversight of postmarketing studies through improved tracking
provided by its contractor and a new database.
As agreed with your office, unless you publicly announce the contents
of this report earlier, we plan no further distribution until 30 days
from the report date. At that time, we will send copies to the
Commissioner of FDA and appropriate congressional committees. The
report also will be available at no charge on GAO's 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.
Sincerely yours,
Signed by:
Marcia Crosse:
Director, Health Care:
[End of section]
Appendix I: Applications for Drugs Approved under FDA's Accelerated
Approval Process Using Surrogate Endpoints:
Since the Food and Drug Administration (FDA) began approving drugs
under the accelerated approval process in 1992, it has approved 90
applications based on surrogate endpoints. In several cases, FDA
approved multiple applications for the same drug; as a result, as of
November 20, 2008, FDA had approved 64 drugs associated with these
applications under the accelerated approval process. Table 5 provides a
description of each of these 64 drugs, their new drug application (NDA)
or biologic license application (BLA) numbers, and the surrogate
endpoints used for approval.
Table 5: NDAs and BLAs Approved Based on Surrogate Endpoints under the
Accelerated Approval Process, from June 19, 1992-November 20, 2008:
Drug name: Hivid;
NDA/BLA number: 20199;
Approval date: June 19, 1992;
Approved indication: Monotherapy and combination therapy for treatment
of Human Immunodeficiency Virus infection in specific patients;
Surrogate endpoint(s) used to approve application: CD4 count (infection
fighting white blood cells) and p24 existence (antigen which indicates
HIV infection).
Drug name: Betaseron;
NDA/BLA number: 103471[A];
Approval date: July 23, 1993;
Approved indication: Treatment of relapsing-remitting multiple
sclerosis;
Surrogate endpoint(s) used to approve application: MRI evaluations of
brain lesions[B].
Drug name: Biaxin;
NDA/BLA number: 50697;
Approval date: Dec. 23, 1993;
Approved indication: Treatment of disseminated mycobacterial infections
due to specific bacteria;
Surrogate endpoint(s) used to approve application: Clearance of
bacteremia[B].
Drug name: Biaxin;
NDA/BLA number: 50698;
Approval date: Dec. 23, 1993;
Approved indication: Treatment of disseminated mycobacterial infections
due to specific bacteria;
Surrogate endpoint(s) used to approve application: Clearance of
bacteremia[B].
Drug name: Zerit;
NDA/BLA number: 20412;
Approval date: June 24, 1994;
Approved indication: Treatment of advanced Human Immunodeficiency Virus
infection in specific adult patients;
Surrogate endpoint(s) used to approve application: CD4 count (infection
fighting white blood cells) and p24 existence (antigen which indicates
HIV infection).
Drug name: Casodex;
NDA/BLA number: 20498;
Approval date: Oct. 4, 1995;
Approved indication: Combination therapy for the treatment of advanced
prostate cancer;
Surrogate endpoint(s) used to approve application: Time to treatment
failure[B].
Drug name: Epivir;
NDA/BLA number: 20564;
Approval date: Nov. 17, 1995;
Approved indication: Combination therapy for treatment of Human
Immunodeficiency Virus infection in certain circumstances;
Surrogate endpoint(s) used to approve application: CD4 count (infection
fighting white blood cells) and viral load (HIV-RNA).
Drug name: Epivir;
NDA/BLA number: 20596;
Approval date: Nov. 17, 1995;
Approved indication: Combination therapy for treatment of Human
Immunodeficiency Virus infection in certain circumstances;
Surrogate endpoint(s) used to approve application: CD4 count (infection
fighting white blood cells) and viral load (HIV-RNA).
Drug name: Doxil;
NDA/BLA number: 50718;
Approval date: Nov. 17, 1995;
Approved indication: Treatment of Kaposi's sarcoma in specific patients
with Acquired Immunodeficiency Syndrome;
Surrogate endpoint(s) used to approve application: Response rate[C].
Drug name: Doxil;
NDA/BLA number: 50718-SE1-006;
Approval date: June 28, 1999;
Approved indication: Treatment of metastatic carcinoma of the ovary in
specific patients;
Surrogate endpoint(s) used to approve application: Response rate[C].
Drug name: Invirase;
NDA/BLA number: 20628;
Approval date: Dec. 6, 1995;
Approved indication: Combination therapy for treatment of advanced
Human Immunodeficiency Virus infection in specific patients;
Surrogate endpoint(s) used to approve application: CD4 count (infection
fighting white blood cells) and viral load (HIV-RNA).
Drug name: Norvir;
NDA/BLA number: 20659;
Approval date: Mar. 1, 1996;
Approved indication: Treatment of Human Immunodeficiency Virus
infection;
Surrogate endpoint(s) used to approve application: CD4 count (infection
fighting white blood cells) and viral load (HIV-RNA).
Drug name: Norvir;
NDA/BLA number: 20680;
Approval date: Mar. 1, 1996;
Approved indication: Treatment of Human Immunodeficiency Virus
infection;
Surrogate endpoint(s) used to approve application: CD4 count (infection
fighting white blood cells) and viral load (HIV-RNA).
Drug name: Crixivan;
NDA/BLA number: 20685;
Approval date: Mar. 13, 1996;
Approved indication: Treatment of Human Immunodeficiency Virus
infection when antiretroviral therapy is warranted;
Surrogate endpoint(s) used to approve application: CD4 count (infection
fighting white blood cells) and viral load (HIV-RNA).
Drug name: Ethyol;
NDA/BLA number: 20221-SE1-002;
Approval date: Mar. 15, 1996;
Approved indication: Treatment for the toxicities associated with
intensive regimens of specific chemotherapy;
Surrogate endpoint(s) used to approve application: Creatinine clearance
and response rate to assess tumor protection.
Drug name: Taxotere;
NDA/BLA number: 20449;
Approval date: May 14, 1996;
Approved indication: Treatment of locally advanced or metastatic breast
cancer in specific patients;
Surrogate endpoint(s) used to approve application: Response rate[C].
Drug name: Camptosar;
NDA/BLA number: 20571;
Approval date: June 14, 1996;
Approved indication: Treatment of metastatic carcinoma of the colon or
rectum in certain circumstances;
Surrogate endpoint(s) used to approve application: Response rate[C].
Drug name: Viramune;
NDA/BLA number: 20636;
Approval date: June 21, 1996;
Approved indication: Combination antiretroviral treatment for Human
Immunodeficiency Virus infection in specific patients;
Surrogate endpoint(s) used to approve application: CD4 count (infection
fighting white blood cells) and viral load (HIV-RNA).
Drug name: Viramune;
NDA/BLA number: 20636-SE1-009;
Approval date: Sept. 11, 1998;
Approved indication: Combination antiretroviral treatment for Human
Immunodeficiency Virus-1 infection in pediatric patients;
Surrogate endpoint(s) used to approve application: CD4 count (infection
fighting white blood cells) and viral load (HIV-RNA).
Drug name: Viramune;
NDA/BLA number: 20933;
Approval date: Sept. 11, 1998;
Approved indication: Combination antiretroviral treatment for Human
Immunodeficiency Virus-1 infection in pediatric patients;
Surrogate endpoint(s) used to approve application: CD4 count (infection
fighting white blood cells) and viral load (HIV-RNA).
Drug name: ProAmatine;
NDA/BLA number: 19815;
Approval date: Sept. 6, 1996;
Approved indication: Treatment of idiopathic orthostatic hypotension;
Surrogate endpoint(s) used to approve application: Increase in 1-minute
standing systolic blood pressure.
Drug name: Viracept;
NDA/BLA number: 20778;
Approval date: Mar. 14, 1997;
Approved indication: Treatment of Human Immunodeficiency Virus
infection in children when antiretroviral therapy is indicated;
Surrogate endpoint(s) used to approve application: CD4 count (infection
fighting white blood cells) and viral load (HIV-RNA).
Drug name: Viracept;
NDA/BLA number: 20779;
Approval date: Mar. 14, 1997;
Approved indication: Treatment of Human Immunodeficiency Virus
infection when antiretroviral therapy is indicated;
Surrogate endpoint(s) used to approve application: CD4 count (infection
fighting white blood cells) and viral load (HIV-RNA).
Drug name: Rescriptor;
NDA/BLA number: 20705;
Approval date: April 4, 1997;
Approved indication: Treatment of Human Immunodeficiency Virus-1
infection;
Surrogate endpoint(s) used to approve application: CD4 count (infection
fighting white blood cells) and viral load (HIV-RNA).
Drug name: Xeloda;
NDA/BLA number: 20896;
Approval date: April 30, 1998;
Approved indication: Treatment of a specific type of metastasis breast
cancer in certain patients;
Surrogate endpoint(s) used to approve application: Response rate[C].
Drug name: Sulfamylon;
NDA/BLA number: 19832;
Approval date: June 5, 1998;
Approved indication: Treatment of bacterial infections in certain
circumstances;
Surrogate endpoint(s) used to approve application: Necessity to change
topical antimicrobial treatment during the first 5 days of application
due to infection or colonization.
Drug name: Priftin;
NDA/BLA number: 21024;
Approval date: June 22, 1998;
Approved indication: Treatment of pulmonary tuberculosis;
Surrogate endpoint(s) used to approve application: Negative sputum
culture at 6 month post-treatment (6 month relapse rate).
Drug name: Sustiva;
NDA/BLA number: 20972;
Approval date: Sept. 17, 1998;
Approved indication: Treatment of Human Immunodeficiency Virus
infection;
Surrogate endpoint(s) used to approve application: Viral load (HIV-
RNA).
Drug name: Ziagen;
NDA/BLA number: 20977;
Approval date: Dec. 17, 1998;
Approved indication: Combination antiretroviral treatment for Human
Immunodeficiency Virus infection;
Surrogate endpoint(s) used to approve application: Viral load (HIV-
RNA).
Drug name: Ziagen;
NDA/BLA number: 20978;
Approval date: Dec. 17, 1998;
Approved indication: Combination antiretroviral treatment for Human
Immunodeficiency Virus infection;
Surrogate endpoint(s) used to approve application: Viral load (HIV-
RNA).
Drug name: Ontak;
NDA/BLA number: 103767[A];
Approval date: Feb. 5, 1999;
Approved indication: Treatment of a specific type of persistent or
recurrent Cutaneous T-cell Lymphoma;
Surrogate endpoint(s) used to approve application: Response rate[C].
Drug name: DepoCyt;
NDA/BLA number: 21041;
Approval date: April 1, 1999;
Approved indication: Treatment of lymphmatous meningitis;
Surrogate endpoint(s) used to approve application: Response rate
(complete cytologic response with absence of neurologic
progression)[C].
Drug name: Agenerase;
NDA/BLA number: 21007;
Approval date: April 15, 1999;
Approved indication: Combination antiretroviral treatment for Human
Immunodeficiency Virus-1 infection;
Surrogate endpoint(s) used to approve application: Viral load (HIV-
RNA).
Drug name: Agenerase;
NDA/BLA number: 21039;
Approval date: April 15, 1999;
Approved indication: Treatment of Human Immunodeficiency Virus
infection;
Surrogate endpoint(s) used to approve application: Viral load (HIV-
RNA).
Drug name: Temodar;
NDA/BLA number: 21029;
Approval date: Aug. 11, 1999;
Approved indication: Treatment of refractory anaplastic astrocytoma in
specific adult patients;
Surrogate endpoint(s) used to approve application: Progression free
survival at 6 months and objective response.
Drug name: Synercid;
NDA/BLA number: 50747;
Approval date: Sept. 21, 1999;
Approved indication: Treatment of serious or life-threatening
infections associated with vancomycin-resistant enterococcus faecium
bacteremia;
Surrogate endpoint(s) used to approve application: Clearance of
vancomycin-resistant Enterococcus faecium bacteremia.
Drug name: Celebrex;
NDA/BLA number: 21156;
Approval date: Dec. 23, 1999;
Approved indication: To reduce the number of adenomatous colorectal
polyps in familial adenomatous polyposis, and as an adjunct to usual
care;
Surrogate endpoint(s) used to approve application: Mean reduction in
colorectal polyp count.
Drug name: Mylotarg;
NDA/BLA number: 21174;
Approval date: May 17, 2000;
Approved indication: Treatment of CD33+ acute myeloid leukemia in
specific patients;
Surrogate endpoint(s) used to approve application: Complete responses
(blasts, bone marrow, CBC, transfusions)[C].
Drug name: Cipro;
NDA/BLA number: 19537-SE1-038;
Approval date: Aug. 30, 2000;
Approved indication: Treatment of inhalation anthrax (post-exposure);
Surrogate endpoint(s) used to approve application: Serum CIPRO
concentrations.
Drug name: Cipro;
NDA/BLA number: 19847-SE1-024;
Approval date: Aug. 30, 2000;
Approved indication:
Treatment of inhalation anthrax (post-exposure);
Surrogate endpoint(s) used to approve application: Serum CIPRO
concentrations.
Drug name: Cipro;
NDA/BLA number: 19857-SE1-027;
Approval date: Aug. 30, 2000;
Approved indication: Treatment of inhalation anthrax (post-exposure);
Surrogate endpoint(s) used to approve application: Serum CIPRO
concentrations.
Drug name: Cipro;
NDA/BLA number: 19858-SE1-021;
Approval date: Aug. 30, 2000;
Approved indication: Treatment of inhalation anthrax (post-exposure);
Surrogate endpoint(s) used to approve application: Serum CIPRO
concentrations.
Drug name: Cipro;
NDA/BLA number: 20780-SE1-008;
Approval date: Aug. 30, 2000;
Approved indication: Treatment of inhalation anthrax (post-exposure);
Surrogate endpoint(s) used to approve application: Serum concentrations
(compared to effective animal concentrations).
Drug name: Kaletra;
NDA/BLA number: 21226;
Approval date: Sept.15, 2000;
Approved indication: Combination antiretroviral treatment for Human
Immunodeficiency Virus-1 infection in specific patients;
Surrogate endpoint(s) used to approve application: Viral load (HIV-
RNA).
Drug name: Kaletra;
NDA/BLA number: 21251;
Approval date: Sept. 15, 2000;
Approved indication: Combination antiretroviral treatment for Human
Immunodeficiency Virus-1 infection in specific patients;
Surrogate endpoint(s) used to approve application: Viral load (HIV-
RNA).
Drug name: Trizivir;
NDA/BLA number: 21205;
Approval date: Nov. 14, 2000;
Approved indication: Treatment of Human Immunodeficiency Virus
infection;
Surrogate endpoint(s) used to approve application: Viral load (HIV-
RNA).
Drug name: Campath;
NDA/BLA number: 103948[A];
Approval date: May 7, 2001;
Approved indication: Treatment of B-cell chronic lymphocytic leukemia
in specific patients;
Surrogate endpoint(s) used to approve application: Response rate[C].
Drug name: Gleevec;
NDA/BLA number: 21335;
Approval date: May 10, 2001;
Approved indication: Treatment of chronic myeloid leukemia in certain
circumstances;
Surrogate endpoint(s) used to approve application:
Hematologic/cytogenic response.
Drug name: Gleevec;
NDA/BLA number: 21335-SE1-001;
Approval date:Feb. 1, 2002;
Approved indication: Treatment of Kit (CD117) positive unresectable
and/or metastatic malignant gastrointestinal stromal tumors;
Surrogate endpoint(s) used to approve application: Response rate[C].
Drug name: Gleevec;
NDA/BLA number: 21335-SE1-004;
Approval date:Dec. 20, 2002;
Approved indication: Treatment of Philadelphia chromosome positive
chronic myeloid leukemia in specific patients;
Surrogate endpoint(s) used to approve application: Time to accelerated
phase or blast crisis.
Drug name: Gleevec;
NDA/BLA number: 21588;
Approval date: April 18, 2003;
Approved indication: Treatment of newly diagnosed adult patients with
Philadelphia chromosome positive chronic myeloid leukemia in specific
patients under certain circumstances;
Surrogate endpoint(s) used to approve application:
Hematologic/cytogenic response (CML); response rate (GIST); time to
accelerated phase or blast crisis (1st line CML)[C].
Drug name: Gleevec;
NDA/BLA number: 21335-SE5-003;
Approval date: May 20, 2003;
Approved indication: Treatment of pediatric patients with Ph+ chronic
phase chronic myeloid leukemia whose disease has recurred after stem
cell transplant or who are resistant to interferon alpha therapy;
Surrogate endpoint(s) used to approve application: Cytogenic response.
Drug name: Gleevec;
NDA/BLA number: 21588-SE5-001;
Approval date: May 20, 2003;
Approved indication: Treatment of pediatric patients with Ph+ chronic
phase chronic myeloid leukemia whose disease has recurred after stem
cell transplant or who are resistant to interferon alpha therapy;
Surrogate endpoint(s) used to approve application: Cytogenic response.
Drug name: Gleevec;
NDA/BLA number: 21588-SE1-016;
Approval date: Sept. 27, 2006;
Approved indication: Treatment of newly diagnosed Philadelphia positive
chronic myeloid leukemia in pediatric patients;
Surrogate endpoint(s) used to approve application: Major hematologic
and complete cytogenic response.
Drug name: Viread;
NDA/BLA number: 21356;
Approval date: Oct. 26, 2001;
Approved indication: Combination antiretroviral treatment of Human
Immunodeficiency Virus-1 infection in adults;
Surrogate endpoint(s) used to approve application: Viral load (HIV-
RNA).
Drug name: Zevalin;
NDA/BLA number: 125019[A];
Approval date: Feb. 19, 2002;
Approved indication: Treatment of relapsed or refractory low-grade,
follicular or transformed B-cell non-Hodgkin's lymphoma in specific
patients;
Surrogate endpoint(s) used to approve application: Response rate[C].
Drug name: Eloxatin;
NDA/BLA number: 21492;
Approval date: Aug. 9, 2002;
Approved indication: Treatment of metastatic carcinoma of the colon or
rectum in specific patients;
Surrogate endpoint(s) used to approve application: Response rate[C].
Drug name: Armidex;
NDA/BLA number: 20541-SE1-010;
Approval date: Sept. 5, 2002;
Approved indication: Adjuvant treatment of postmenopausal women with
specific breast cancer;
Surrogate endpoint(s) used to approve application: Disease free
survival.
Drug name: Fuzeon;
NDA/BLA number: 21481;
Approval date: Mar. 13, 2003;
Approved indication: Combination antiretroviral treatment for Human
Immunodeficiency Virus-1 infection in specific patients;
Surrogate endpoint(s) used to approve application: Viral load (HIV-
RNA).
Drug name: Fabrazyme;
NDA/BLA number: 103979[A];
Approval date: April 24, 2003;
Approved indication: Treatment of Fabry disease;
Surrogate endpoint(s) used to approve application: Intracellular
substrate accumulation in the vascular endothelium.
Drug name: Iressa;
NDA/BLA number: 21399;
Approval date: May 5, 2003;
Approved indication: Treatment of locally advanced or metastatic non-
small cell lung cancer in specific patients under certain
circumstances;
Surrogate endpoint(s) used to approve application: Response rate[C].
Drug name: Velcade;
NDA/BLA number: 21602;
Approval date: May 13, 2003;
Approved indication: Treatment of multiple myeloma in specific patients
under certain circumstances;
Surrogate endpoint(s) used to approve application: Response rate[C].
Drug name: Erbitux;
NDA/BLA number: 125084[A];
Approval date: Feb. 12, 2004;
Approved indication: In combination with other drugs for the treatment
of EGFR-expressing, metastatic colorectal carcinoma in specific
patients;
Surrogate endpoint(s) used to approve application: Response rate[C].
Drug name: Truvada;
NDA/BLA number: 21752;
Approval date: Aug. 2, 2004;
Approved indication: Combination antiretroviral treatment for Human
Immunodeficiency Virus-1 infection in adults;
Surrogate endpoint(s) used to approve application: Viral load (HIV-
RNA).
Drug name: Alimta;
NDA/BLA number: 21677;
Approval date: Aug. 19, 2004;
Approved indication: Treatment of patients with locally advanced or
metastatic non-small cell lung cancer after prior chemotherapy;
Surrogate endpoint(s) used to approve application: Response rate[C].
Drug name: Luveris;
NDA/BLA number: 21322;
Approval date: Oct. 8, 2004;
Approved indication: Concomitantly use for stimulation of follicular
development in infertile hypogonadotropic hypogonadal women with
profound LH deficiency;
Surrogate endpoint(s) used to approve application: Follicular
development.
Drug name: Femara;
NDA/BLA number: 20726-SE1-011;
Approval date: Oct. 29, 2004;
Approved indication: Extended adjuvant treatment of early breast cancer
in specific postmenopausal women;
Surrogate endpoint(s) used to approve application: Disease free
survival.
Drug name: Femara;
NDA/BLA number: 20726-SE1-012;
Approval date: Dec. 28, 2005;
Approved indication: Adjuvant treatment of postmenopausal women with
hormone receptor positive early breast cancer;
Surrogate endpoint(s) used to approve application: Disease free
survival.
Drug name: Levaquin;
NDA/BLA number: 20634-SE1-035;
Approval date: Nov. 24, 2004;
Approved indication: Treatment of inhalation anthrax (post-exposure);
Surrogate endpoint(s) used to approve application: Drug exposure in
surviving Rhesus monkeys compared to human plasma concentrations.
Drug name: Levaquin;
NDA/BLA number: 20635-SE1-035;
Approval date: Nov. 24, 2004;
Approved indication: Treatment of inhalation anthrax (post-exposure);
Surrogate endpoint(s) used to approve application: Drug exposure in
surviving Rhesus monkeys compared to human plasma concentrations.
Drug name: Levaquin;
NDA/BLA number: 21721-SE1-003;
Approval date: Nov. 24, 2004;
Approved indication: Treatment of inhalational anthrax (post-exposure);
Surrogate endpoint(s) used to approve application: Plasma
concentrations.
Drug name: Levaquin;
NDA/BLA number: 20634-SE5-047;
Approval date: May 5, 2008;
Approved indication: Treatment of inhalational anthrax (post-exposure)
in pediatric patients (over 6 months of age) in certain circumstances;
Surrogate endpoint(s) used to approve application: PK modeling in
pediatric patients to extrapolate plasma concentration/exposure from
adult data.
Drug name: Levaquin;
NDA/BLA number: 20635-SE5-051;
Approval date: May 5, 2008;
Approved indication: Treatment of inhalational anthrax (post-exposure)
in pediatric patients (over 6 months of age) in certain circumstances;
Surrogate endpoint(s) used to approve application: PK modeling in
pediatric patients to extrapolate plasma concentration/exposure from
adult data.
Drug name: Levaquin;
NDA/BLA number: 21721-SE5-015;
Approval date: May 5, 2008;
Approved indication: Treatment of inhalational anthrax (post-exposure)
in pediatric patients (over 6 months of age) in certain circumstances;
Surrogate endpoint(s) used to approve application: PK modeling in
pediatric patients to extrapolate plasma concentration/exposure from
adult data.
Drug name: Bexxar;
NDA/BLA number: 125011-24[A];
Approval date: Dec. 22, 2004;
Approved indication: Treatment of relapsed or refractory, low grade,
follicular or transformed CD20 positive non-Hodgkin's lymphoma in
specific patients;
Surrogate endpoint(s) used to approve application: Response rate[C].
Drug name: Clolar;
NDA/BLA number: 21673;
Approval date: Dec. 28, 2004;
Approved indication: Treatment of pediatric patients 1 to 21 years old
with relapsed or refractory acute lymphoblastic leukemia after at least
two prior regimens;
Surrogate endpoint(s) used to approve application: Complete response
rate and complete response without platelet recovery[C].
Drug name: Aptivus;
NDA/BLA number: 21814;
Approval date: June 22, 2005;
Approved indication: Treatment of Human Immunodeficiency Virus-1
infection in specific adult patients under certain circumstances;
Surrogate endpoint(s) used to approve application: Viral load (HIV-
RNA).
Drug name: Arranon;
NDA/BLA number: 21877;
Approval date: Oct. 28, 2005;
Approved indication: Treatment of T-cell acute lymphoblastic leukemia
and T-cell lymphoblastic lymphoma in specific patients;
Surrogate endpoint(s) used to approve application: Complete response
rate[C].
Drug name: Exjade;
NDA/BLA number: 21882;
Approval date: Nov. 2, 2005;
Approved indication: Treatment of chronic iron overload due to blood
transfusions in patients 2 years of age and older;
Surrogate endpoint(s) used to approve application: Lowering of liver
iron content.
Drug name: Sutent;
NDA/BLA number: 21968;
Approval date: Jan. 26, 2006; Approved indication:
Treatment of advanced renal cell carcinoma; Surrogate endpoint(s) used
to approve application: Response rate[C].
Drug name: Thalomid;
NDA/BLA number: 21430;
Approval date: May 25, 2006;
Approved indication: Treatment of newly diagnosed multiple myeloma;
Surrogate endpoint(s) used to approve application: Response rate (serum
or urine paraprotein)[C].
Drug name: Prezista;
NDA/BLA number: 21976;
Approval date: June 23, 2006;
Approved indication: Treatment of human immunodeficiency virus
infection in specific patients;
Surrogate endpoint(s) used to approve application: Viral load (HIV-
RNA).
Drug name: Sprycel;
NDA/BLA number: 21986;
Approval date: June 28, 2006;
Approved indication: Treatment of chronic myeloid leukemia with
resistance or intolerance to prior therapy including imatinib in
adults;
Surrogate endpoint(s) used to approve application: Major cytogenic
response.
Drug name: Vectibix;
NDA/BLA number: 125147[A];
Approval date: Sept. 27, 2006;
Approved indication: Treatment of specific metastatic colorectal
carcinoma with disease progression on or following fluoropyrimidine
oxaliplatin and irinotecan containing chemotherapy regimens;
Surrogate endpoint(s) used to approve application: Progression-free
survival.
Drug name: Selzentry;
NDA/BLA number: 22128;
Approval date: Aug. 6, 2007;
Approved indication: Treatment of CCR5-tropic Human Immunodeficiency
Virus-1;
Surrogate endpoint(s) used to approve application: Viral load (HIV-
RNA).
Drug name: Isentress;
NDA/BLA number: 22145;
Approval date: Oct. 12, 2007; Approved indication: Treatment of Human
Immunodeficiency Virus infection in specific patients; Surrogate
endpoint(s) used to approve application: Viral load (HIV-RNA).
Drug name: Tasigna;
NDA/BLA number: 22068;
Approval date: Oct. 29, 2007;
Approved indication: Treatment of chronic phase and accelerated phase
Philadelphia chromosome positive chronic myelogenous leukemia in
specific adult patients;
Surrogate endpoint(s) used to approve application: Major cytogenic
response and hematologic response.
Drug name: Intelence;
NDA/BLA number: 22187;
Approval date: Jan. 18, 2008;
Approved indication: Combination antiretroviral treatment for Human
Immunodeficiency Virus-1 infection in specific patients;
Surrogate endpoint(s) used to approve application: Viral load (HIV-
RNA).
Drug name: Avastin;
NDA/BLA number: 125085-91[A];
Approval date: Feb. 22, 2008;
Approved indication: Treatment of breast cancer in specific patients;
Surrogate endpoint(s) used to approve application: Progression-free
survival.
Drug name: Promacta;
NDA/BLA number: 22291;
Approval date: Nov. 20, 2008;
Approved indication: Treatment of thrombocytopenia in specific
patients;
Surrogate endpoint(s) used to approve application: An increase from the
baseline platelet count to a count greater than or equal to 50,000/mcL.
Source: GAO analysis of FDA data.
[A] Applications for therapeutic BLAs. These therapeutic biologics were
transferred from the Center for Biologics Evaluation and Research to
the Center for Drug Evaluation and Research on June 30, 2003.
[B] In addition to the surrogate endpoint used for approval, there was
evidence of clinical benefit supporting the approval of this
application.
[C] Response rate and complete response surrogate endpoints are tumor
assessment endpoints which measure the proportion of patients with
tumor size reduction of a predefined amount and for a minimum time
period.
[End of table]
[End of section]
Appendix II: Applications for Drugs Approved under FDA's Traditional
Process Using Surrogate Endpoints:
Between January 1998 and June 2008, the Food and Drug Administration
(FDA) approved 204 New Molecular Entity (NME) drugs under its
traditional process. Of those 204, 69 NME drugs were approved using
surrogate endpoints. Table 6 provides a description of each of the 69
NME drugs, their new drug application (NDA) numbers, and the surrogate
endpoints used for approval.
Table 6: NDAs Approved Based on Surrogate Endpoints under the
Traditional Approval Process, from January 1, 1998-June 30, 2008:
Drug name: Refludan;
NDA number: 20807;
Approval date: Mar. 6, 1998;
Approved indication: Anticoagulation treatment in patients with heparin-
induced thrombocytopenia and thromboembolic disease;
Surrogate endpoint(s) used to approve application: Time courses of
platelets and activated partial thromboplastin time for regimen A1, A2,
and B, and on the time course of Ecarin clotting time (ECT) for regimen
C.
Drug name: Lotemax;
NDA number: 20583;
Approval date: Mar. 9, 1998;
Approved indication: Treatment of post-operative inflammation and
uveitis[A];
Surrogate endpoint(s) used to approve application: Measurements of cell
and flare and resolution of anterior chamber cell.
Drug name: Actonel;
NDA number: 20835;
Approval date: Mar. 27, 1998;
Approved indication: Treatment of Paget's disease of bone in specific
patients;
Surrogate endpoint(s) used to approve application: Serum alkaline
phosphatase levels.
Drug name: Azopt;
NDA number: 20816;
Approval date: April 1, 1998;
Approved indication: Treatment of elevated intraocular pressure in
specific patients;
Surrogate endpoint(s) used to approve application: Intraocular pressure
levels.
Drug name: Zemplar injection;
NDA number: 20819;
Approval date: April 17, 1998;
Approved indication: Prevention and treatment of secondary
hyperparathyroidism associated with chronic renal failure;
Surrogate endpoint(s) used to approve application: Intact parathyroid
hormone levels.
Drug name: Atacand;
NDA number: 20838;
Approval date: June 4, 1998;
Approved indication: Treatment of hypertension;
Surrogate endpoint(s) used to approve application: Systolic and
diastolic pressure levels.
Drug name: Vitravene;
NDA number: 20961;
Approval date: Aug. 26, 1998;
Approved indication: Treatment of cytomegalovirus retinitis in specific
patients with Acquired Immunodeficiency Syndrome;
Surrogate endpoint(s) used to approve application: Median time to
cytomegalovirus retinitis progression.
Drug name: Valstar;
NDA number: 20892;
Approval date: Sept. 25, 1998;
Approved indication: Treatment of BCG-refractory carcinoma in situ of
the urinary bladder in specific patients;
Surrogate endpoint(s) used to approve application: Time to recurrence
of disease after treatment compared to recurrence after previous
courses of intravesical therapy.
Drug name: Renagel;
NDA number: 20926;
Approval date: Oct. 30, 1998;
Approved indication: Treatment of end-stage renal disease;
Surrogate endpoint(s) used to approve application: Serum phosphorous
levels.
Drug name: Micardis;
NDA number: 20850;
Approval date: Nov. 10, 1998;
Approved indication: Treatment of hypertension;
Surrogate endpoint(s) used to approve application: Blood pressure
levels.
Drug name: Ferrlecit;
NDA number: 20955;
Approval date: Feb. 18, 1999;
Approved indication: Treatment for iron deficiency in specific patients
undergoing chronic hemodialysis;
Surrogate endpoint(s) used to approve application: Hemoglobin levels.
Drug name: Avandia;
NDA number: 21071;
Approval date: May 25, 1999;
Approved indication: Treatment of type 2 diabetes mellitus;
Surrogate endpoint(s) used to approve application: Blood sugar (fasting
plasma glucose and HBA1c levels).
Drug name: Hectorol;
NDA number: 20862;
Approval date: June 9, 1999;
Approved indication: Treatment of secondary hyperparathyroidism in
specific patients;
Surrogate endpoint(s) used to approve application: Intact parathyroid
hormone levels.
Drug name: Actos;
NDA number: 21073;
Approval date: July 15, 1999;
Approved indication: Treatment of type 2 diabetes mellitus;
Surrogate endpoint(s) used to approve application: Blood sugar (fasting
plasma glucose and HBA1c levels).
Drug name: Aromasin;
NDA number: 20753;
Approval date: Oct. 21, 1999;
Approved indication: Treatment of advanced breast cancer in
postmenopausal women;
Surrogate endpoint(s) used to approve application: Objective response
rate (partial and complete)[B].
Drug name: Protonix;
NDA number: 20987;
Approval date: Feb. 2, 2000;
Approved indication: Treatment of erosive esophagitis associated with
gastroesophageal reflux disease;
Surrogate endpoint(s) used to approve application: Healing of lesions
to grade 1 or 0 in the Hetzel-Dent scale.
Drug name: Lantus;
NDA number: 21081;
Approval date: April 20, 2000;
Approved indication: Treatment of type 1 diabetes mellitus in adults or
pediatric patients or type 2 diabetes mellitus in specific adult
patients;
Surrogate endpoint(s) used to approve application: Blood sugar
(glycated hemoglobin levels).
Drug name: Welchol;
NDA number: 21176;
Approval date: May 26, 2000;
Approved indication: Treatment of elevated LDL cholesterol in specific
patients;
Surrogate endpoint(s) used to approve application: LDL cholesterol
levels.
Drug name: NovoLog;
NDA number: 20986;
Approval date: June 7, 2000;
Approved indication: Treatment of diabetes mellitus in adult patients;
Surrogate endpoint(s) used to approve application: Glycemic control,
the rates of hypoglycemia, and the incidence of ketosis.
Drug name: Trelstar Depot;
NDA number: 20715;
Approval date: June 15, 2000;
Approved indication: Treatment of advanced prostate cancer;
Surrogate endpoint(s) used to approve application: Achievement of
castration by Day 29 and maintenance of castration levels of serum
testosterone from Day 57 through Day 253.
Drug name: Rescula;
NDA number: 21214;
Approval date: Aug. 3, 2000;
Approved indication: Treatment of open-angle glaucoma or ocular
hypertension;
Surrogate endpoint(s) used to approve application: Intraocular pressure
levels.
Drug name: Cetrotide;
NDA number: 21197;
Approval date: Aug. 11, 2000;
Approved indication: Treatment of premature luteinizing hormone surges
in women undergoing controlled ovarian stimulation;
Surrogate endpoint(s) used to approve application: Luteinizing hormone
surge.
Drug name: Trisenox;
NDA number: 21248;
Approval date: Sept. 25, 2000;
Approved indication: Treatment of acute promyelocytic leukemia;
Surrogate endpoint(s) used to approve application: Cytogenic conversion
to no detection of the acute promyelocytic leukemia chromosome
rearrangement.
Drug name: Starlix;
NDA number: 21204;
Approval date: Dec. 22, 2000;
Approved indication: Treatment of type 2 diabetes mellitus;
Surrogate endpoint(s) used to approve application: Blood sugar (fasting
plasma glucose and HBA1c levels).
Drug name: Foradil Aerolizer;
NDA number: 20831;
Approval date: Feb. 16, 2001;
Approved indication: Treatment of asthma and prevention of
bronchospasm;
Surrogate endpoint(s) used to approve application: Forced expiratory
volume in one second.
Drug name: Lumigan;
NDA number: 21275;
Approval date: Mar. 16, 2001;
Approved indication: Treatment of elevated intraocular pressure in
certain populations;
Surrogate endpoint(s) used to approve application: Intraocular pressure
levels.
Drug name: Travatan;
NDA number: 21257;
Approval date: Mar. 16, 2001;
Approved indication: Treatment of intraocular pressure in certain
populations;
Surrogate endpoint(s) used to approve application: Intraocular pressure
levels.
Drug name: Natrecor;
NDA number: 20920;
Approval date: Aug. 10, 2001;
Approved indication: Treatment of acute decompensated congestive heart
failure in specific populations;
Surrogate endpoint(s) used to approve application: Pulmonary capillary
wedge pressure levels.
Drug name: Zometa;
NDA number: 21223;
Approval date: Aug. 20, 2001;
Approved indication: Treatment of hypercalcimia of malignancy;
Surrogate endpoint(s) used to approve application: Complete response
(lowering of the corrected serum calcium)[B].
Drug name: Benicar;
NDA number: 21286;
Approval date: April 25, 2002;
Approved indication: Treatment of hypertension;
Surrogate endpoint(s) used to approve application: Peak and trough
blood pressure levels.
Drug name: Faslodex;
NDA number: 21344;
Approval date: April 25, 2002;
Approved indication: Treatment of metastatic breast cancer;
Surrogate endpoint(s) used to approve application: Response rate and
time to progression[B].
Drug name: Hepsera;
NDA number: 21449;
Approval date: Sept. 20, 2002;
Approved indication: Treatment of chronic hepatitis B;
Surrogate endpoint(s) used to approve application: Knodell
Necroinflammatory Score (i.e. liver biopsy).
Drug name: Inspra;
NDA number: 21437;
Approval date: Sept. 27, 2002;
Approved indication: Treatment of hypertension;
Surrogate endpoint(s) used to approve application: Sitting diastolic
and systolic blood pressure at trough.
Drug name: Zetia;
NDA number: 21445;
Approval date: Oct. 25, 2002;
Approved indication: Treatment of elevated total cholesterol levels and
LDL-C;
Surrogate endpoint(s) used to approve application: Cholesterol levels.
Drug name: Extraneal;
NDA number: 21321;
Approval date: Dec. 20, 2002;
Approved indication: Single daily exchange for the long dwell during
continuous ambulatory peritoneal dialysis or automated peritoneal
dialysis for the treatment of chronic renal failure;
Surrogate endpoint(s) used to approve application: Ultrafiltration
rate.
Drug name: Somavert;
NDA number: 21106;
Approval date: Mar. 25, 2003;
Approved indication: Treatment of acromegaly in specific patients;
Surrogate endpoint(s) used to approve application: Serum IGF-I levels.
Drug name: Reyataz;
NDA number: 21567;
Approval date: June 20, 2003;
Approved indication: Treatment of Human Immunodeficiency Virus-1
infection;
Surrogate endpoint(s) used to approve application: CD4 count (infection
fighting white blood cell) and viral load (HIV-RNA).
Drug name: Emtriva;
NDA number: 21500;
Approval date: July 2, 2003;
Approved indication: Treatment of Human Immunodeficiency Virus-1
infection in adults;
Surrogate endpoint(s) used to approve application: CD4 count (infection
fighting white blood cell) and viral load (HIV-RNA).
Drug name: Zavesca;
NDA number: 21348;
Approval date: July 31, 2003;
Approved indication: Treatment of mild to moderate type 1 Gaucher
disease;
Surrogate endpoint(s) used to approve application: Liver and spleen
volume after 12 months of treatment.
Drug name: Crestor;
NDA number: 21366;
Approval date: Aug. 12, 2003;
Approved indication: Treatment of cholesterol levels;
Surrogate endpoint(s) used to approve application: Cholesterol levels.
Drug name: Radiogardase;
NDA number: 21626;
Approval date: Oct. 2, 2003;
Approved indication: Treatment of internal contamination with
radioactive cesium and/or radioactive thallium;
Surrogate endpoint(s) used to approve application: Whole body effective
half life of cesium or thallium.
Drug name: Plenaxis;
NDA number: 21320;
Approval date: Nov. 25, 2003;
Approved indication: Palliative treatment for men with advanced
symptomatic prostate cancer for specific reasons;
Surrogate endpoint(s) used to approve application: Avoid orchiectomy
and lower serum testosterone levels.
Drug name: Spiriva Handihaler;
NDA number: 21395;
Approval date: Jan. 30, 2004;
Approved indication: Treatment of bronchospasm associated with chronic
obstructive pulmonary disease;
Surrogate endpoint(s) used to approve application: Forced expiratory
volume in one second, with peak effect occurring within 3 hours
following the first dose.
Drug name: Sensipar;
NDA number: 21688;
Approval date: Mar. 8, 2004;
Approved indication: Treatment of secondary hyperparathyroidism in
patients with chronic kidney disease on dialysis;
Surrogate endpoint(s) used to approve application: Intact parathyroid
hormone levels.
Drug name: Apidra;
NDA number: 21629;
Approval date: April 16, 2004;
Approved indication: Treatment of diabetes mellitus in adult patients;
Surrogate endpoint(s) used to approve application: Blood sugar
(glycated hemoglobin and HbA1c equivalents).
Drug name: Vidaza;
NDA number: 50794;
Approval date: May 19, 2004;
Approved indication: Treatment of myelodysplastic syndrome subtypes:
refractory anemia or refractory anemia with ringed sideroblasts,
refractory anemia with excess blasts, refractory anemia with excess
blasts in transformation, and chronic myelomonocytic leukemia;
Surrogate endpoint(s) used to approve application: Response rate[B].
Drug name: Pentetate Calcium Trisodium;
NDA number: 21749;
Approval date: Aug. 11, 2004;
Approved indication: Treatment of known or suspected internal
contamination with plutonium, americium, or curium to increase rates of
elimination;
Surrogate endpoint(s) used to approve application: Ratio of urine
radioactivity before treatment to the maximum urine radioactivity after
treatment (excretion enhancement factor).
Drug name: Pentetate Zinc Trisodium;
NDA number: 21751;
Approval date: Aug.11, 2004;
Approved indication: Treatment of known or suspected internal
contamination with plutonium, americium, or curium to increase rates of
elimination;
Surrogate endpoint(s) used to approve application: Ratio of urine
radioactivity before treatment to the maximum urine radioactivity after
treatment (excretion enhancement factor).
Drug name: Fosrenol;
NDA number: 21468;
Approval date: Oct. 26, 2004;
Approved indication: Treatment of end stage renal disease;
Surrogate endpoint(s) used to approve application: Serum phosphate
levels.
Drug name: Omacor[C];
NDA number: 21654;
Approval date: Nov. 10, 2004;
Approved indication: Treatment of very high triglyceride levels in
adults;
Surrogate endpoint(s) used to approve application: Triglyceride levels.
Drug name: Symlin;
NDA number: 21332;
Approval date: Mar. 16, 2005;
Approved indication: Treatment of type 1 or type 2 diabetes mellitus;
Surrogate endpoint(s) used to approve application: Blood sugar (HbA1c
levels).
Drug name: Mycamine;
NDA number: 21506;
Approval date: Mar. 16, 2005;
Approved indication: Treatment of esophageal candidiasis or prophalaxis
against fungal infection;
Surrogate endpoint(s) used to approve application: Endoscopic
appearance of the esopageal mucosa.
Drug name: Baraclude;
NDA number: 21797;
Approval date: Mar. 29, 2005;
Approved indication: Treatment of chronic hepatitis B in adults;
Surrogate endpoint(s) used to approve application: Knodell
Necroinflammatory Score (i.e. liver biopsy).
Drug name: Byetta;
NDA number: 21773;
Approval date: April 28, 2005;
Approved indication: Treatment of type 2 diabetes mellitus;
Surrogate endpoint(s) used to approve application: Blood sugar (HbA1c
levels).
Drug name: Levemir;
NDA number: 21536;
Approval date: June 16, 2005;
Approved indication: Treatment of diabetes mellitus in adults who
require basal insulin for control of hyperglycemia;
Surrogate endpoint(s) used to approve application: Blood sugar (fasting
blood glucose and HBA1c levels).
Drug name: Nexavar;
NDA number: 21923;
Approval date: Dec. 20, 2005;
Approved indication: Treatment of advanced renal cell carcinoma;
Surrogate endpoint(s) used to approve application: Progression free
survival.
Drug name: Vaprisol;
NDA number: 21697;
Approval date: Dec. 29, 2005;
Approved indication: Treatment of euyolemic hyponatremia in
hospitalized patients;
Surrogate endpoint(s) used to approve application: Serum sodium
concentration levels.
Drug name: Sutent;
NDA number: 21938;
Approval date: Jan. 26, 2006;
Approved indication: Treatment of gastrointestinal stromal tumor and
advanced renal cell carcinoma;
Surrogate endpoint(s) used to approve application: Time to progression.
Drug name: Pylera;
NDA number: 50786;
Approval date: Sept. 28, 2006;
Approved indication: Treatment of helicobacter pylori infection and
duodenal ulcer disease;
Surrogate endpoint(s) used to approve application: C-urea breath tests.
Drug name: Januvia;
NDA number: 21995;
Approval date: Oct. 16, 2006;
Approved indication: Treatment of type 2 diabetes mellitus;
Surrogate endpoint(s) used to approve application: Blood sugar (fasting
blood glucose, HBA1c levels and post prandial glucose).
Drug name: Tyzeka;
NDA number: 22011;
Approval date: Oct. 25, 2006;
Approved indication: Treatment of chronic hepatitis B in specific
populations of adults;
Surrogate endpoint(s) used to approve application: Composite serologic
endpoint requiring suppression of HBV DNA to a specific amount in
conjunction with another serum.
Drug name: Tekturna;
NDA number: 21985;
Approval date: Mar. 5, 2007;
Approved indication: Treatment of hypertension;
Surrogate endpoint(s) used to approve application: Seated trough cuff
blood pressure.
Drug name: Tykerb;
NDA number: 22059;
Approval date: Mar. 13, 2007;
Approved indication: Treatment of advanced metastatic breast cancer;
Surrogate endpoint(s) used to approve application: Time to progression.
Drug name: Somatuline Depot;
NDA number: 22074;
Approval date: Aug. 30, 2007;
Approved indication: Treatment of acromegalic patients who have
inadequate response to surgery and/or radiotherapy;
Surrogate endpoint(s) used to approve application: Growth hormone and
insulin growth factor levels.
Drug name: Ixempra;
NDA number: 22065;
Approval date: Oct. 16, 2007;
Approved indication: Treatment of metastatic or locally advanced breast
cancer;
Surrogate endpoint(s) used to approve application: Progression free
survival.
Drug name: Kuvan;
NDA number: 22181;
Approval date: Dec. 13, 2007; Approved indication: Treatment of
hyperphenylalaninemia;
Surrogate endpoint(s) used to approve application: Blood phenylalanine
levels.
Drug name: Bystolic; NDA number: 21742;
Approval date: Dec. 17, 2007;
Approved indication: Treatment of hypertension;
Surrogate endpoint(s) used to approve application: Trough sitting
systolic/diastolic blood pressure.
Drug name: Treanda;
NDA number: 22249;
Approval date: Mar. 20, 2008;
Approved indication: Treatment of chronic lymphocytic leukemia;
Surrogate endpoint(s) used to approve application: Objective response
and progression-free survival[B].
Drug name: Durezol;
NDA number: 22212;
Approval date: June 23, 2008;
Approved indication: Treatment of inflammation and pain in the eye
associated with ocular surgery;
Surrogate endpoint(s) used to approve application: Complete clearing
(count = 0).
Source: GAO analysis of FDA data.
[A] Also approved for treatment of giant papillary conjunctivitis and
seasonal allergic conjunctivitis. However, these indications were
approved based on clinical endpoints and are not included in the table.
[B] Response rate is a measure of the proportion of patients with tumor
size reduction of a predefined amount and for a minimum time period.
[C] In July 2007, the name of this drug was changed from Omacor to
Lovaza.
[End of table]
[End of section]
Appendix III: Applications Selected and Questions Regarding FDA's
Oversight of Required Postmarketing Studies:
To review specific instances of the Food and Drug Administration's
(FDA) monitoring and enforcement activities, we selected a judgmental
sample of 15 applications approved based on surrogate endpoints under
the accelerated program and the 35 postmarketing studies that FDA
required drug sponsors to complete for these drugs. These applications
were selected to generate a sample that included a variety of drugs and
a range of studies at various stages of completion. We then provided
FDA with a standard series of questions for each of the 35 studies, and
requested that FDA's medical reviewers, who are responsible for
monitoring these 35 studies, provide specific information on them,
including a description of the studies, FDA's efforts to monitor these
studies, and applicable enforcement actions taken, if any, to prompt
sponsors' compliance. FDA officials indicated that several individuals
were involved in completing the questions provided for each of the 15
applications. FDA staff completed the first half of the questions
related to description of the studies. The medical reviewers or other
review staff provided information on the agency's monitoring efforts
and enforcement actions. The applications we selected and the
information request are provided below.
Table 7: List of 15 Accelerated Approval Applications Selected for
Review:
Drug name: ProAmatine;
NDA/BLA number: 19815;
Approval date: Sept. 6, 1996.
Drug name: Xeloda;
NDA/BLA number: 20896;
Approval date: April 30, 1998.
Drug name: Sulfamylon;
NDA/BLA number: 19832;
Approval date: June 5, 1998.
Drug name: Priftin;
NDA/BLA number: 21024;
Approval date: June 22, 1998.
Drug name: Remicade;
NDA/BLA number: 103772;
Approval date: Aug. 24, 1998.
Drug name: Viramune;
NDA/BLA number: 20933;
Approval date: Sept. 11, 1998.
Drug name: Sustiva;
NDA/BLA number: 20972;
Approval date: Sept. 17, 1998.
Drug name: Ziagen;
NDA/BLA number: 20977;
Approval date: Dec. 17, 1998.
Drug name: Celebrex;
NDA/BLA number: 21156;
Approval date: Dec. 23, 1999.
Drug name: Gleevec;
NDA/BLA number: 21588;
Approval date: April 18, 2003.
Drug name: Zevalin;
NDA/BLA number: 125019;
Approval date: Feb. 19, 2002.
Drug name: Fuzeon;
NDA/BLA number: 21481;
Approval date: Mar. 13, 2003.
Drug name: Fabrazyme;
NDA/BLA number: 103979;
Approval date: April 24, 2003.
Drug name: Iressa;
NDA/BLA number: 21399;
Approval date: May 5, 2003.
Drug name: Velcade;
NDA/BLA number: 21602;
Approval date: May 13, 2003.
Source: GAO analysis of FDA data.
[End of table]
Information Request on the Monitoring and Oversight of Drugs Approved
Based on Surrogate Endpoints:
Instructions: Please review the pre-filled information and provide
information on your monitoring of the drug sponsor's completion of
postmarketing studies required under the accelerated approval program.
When you have completed this request, please return it to GAO via email
at Lichtenfeldd@GAO.gov. Please contact David Lichtenfeld at (312) 220-
7663 if you have any questions.
NDA Number:
Approval Date:
Drug Name:
Division:
Number of required studies:
Commitment IDs and Status:
Source: FDA-provided data on required postmarketing commitments (as of
December 19, 2008).
For study # please provide answers to the following questions:
1. What is the study description as outlined in the approval letter or
annual status report (ASR)?
2. Was there ever an original study schedule or timeline established
for this study? If yes, when was it established and how was it
documented (e.g. in approval letter, first ASR etc.)?
3. If a study schedule was not established, how have you determined the
current status of the study?
4. When was this study assigned its current status?
5. Has/did the drug sponsor submit all required ASRs for this study,
and were they submitted within required timeframes?
6. If the sponsor did not submit all required ASRs in a timely manner,
what action(s) did FDA take to obtain the sponsor's compliance (e.g.,
initiate a teleconference, issue administrative letter)?
Please provide any available documentation demonstrating FDA's effort
to follow-up with the drug sponsor regarding ASR submissions for this
study.
7. Has FDA reviewed all of the ASRs submitted for this study, and have
they been reviewed within FDA review timeframes”within 90 days of
receipt?
8. If FDA has not reviewed all of the ASRs according to its policy,
what barriers have prevented FDA from conducting these reviews? In
addition, when will FDA complete its reviews of any outstanding ASRs
for this study?
9. Based on its review of ASRs submitted for this study, has FDA
identified any problems or concerns with the drug sponsor's progress in
completing this study? For example, did FDA's reviews reveal that the
study had been either pending or delayed for an extended period of
time, or did its reviews provide indications that the sponsor would not
be able to complete the study within established timeframes? If so,
what actions did FDA take to compel the sponsor to complete the study?
Please provide any available documentation demonstrating FDA's efforts
to follow-up with the sponsor regarding progress for this study.
10. Based on its review of ASRs submitted for this study, has FDA
identified any significant underlying issues affecting the sponsor's
ability to complete this study? For example, did the sponsor experience
any problems designing the study or enrolling patients that affected
the progress of the study? If so, what actions did FDA take to help the
sponsor improve the progress of the study?
Please provide any available documentation demonstrating FDA's efforts
to follow-up with the sponsor regarding this study's completion.
11. Outside of ASR reviews, has FDA used any other mechanisms to
monitor the progress of this study (e.g. routine conference calls or
other routine communication with the sponsor)?
12. If the status of this study is fulfilled, what factors contributed
to the completion of the study?
13. Please provide any additional comments you believe are relevant to
the oversight and monitoring of this study.
Name of FDA Reviewer Who Answered these Questions:
How long has the Reviewer been responsible for monitoring this study:
(Please check the appropriate box.)
1-2 years:
3-4 years:
5-6 years:
7-8 years:
9-10 years:
over 10 years:
[End of section]
Appendix IV: Sales for Selected Drugs Approved Based on Surrogate
Endpoints under the Accelerated Approval Process:
Listed in table 8 are seven applications for drugs approved based on
surrogate endpoints under the accelerated approval process, and total
U.S. sales, since approval, associated with those drugs. This listing
includes applications, which as of December 19, 2008, had not been
converted to full approval, and more than 5 years had elapsed since
they were initially approved.
Table 8: Total U.S. Sales for Selected Drugs Approved under the
Accelerated Process:
Application type: NDA;
Application number: 19815;
Drug name: ProAmatine;
Approval date: Sept. 6, 1996;
Total U.S. sales since approval[A]: $257,574,554.
Application type: NDA;
Application number: 19832;
Drug name: Sulfamylon;
Approval date: June 5, 1998;
Total U.S. sales since approval[A]: $72,963,020[B].
Application type: NDA;
Application number: 21024[C];
Drug name: Priftin;
Approval date: June 22, 1998;
Total U.S. sales since approval[A]: $177,502.
Application type: NDA;
Application number: 50747;
Drug name: Synercid;
Approval date: Sept. 21, 1999;
Total U.S. sales since approval[A]: $206,741,816.
Application type: NDA;
Application number: 21174;
Drug name: Mylotarg;
Approval date: May 17, 2000;
Total U.S. sales since approval[A]: $206,982,392.
Application type: NDA;
Application number: 21399;
Drug name: Iressa;
Approval date: May 5, 2003;
Total U.S. sales since approval[A]: $416,699,000.
Application type: BLA;
Application number: 103979;
Drug name: Fabrazyme;
Approval date: April 24, 2003;
Total U.S. sales since approval[A]: $56,308,877.
Source: GAO analysis of FDA data and National Sales Perspectives (™)
IMS Health, Inc.
[A] Sales data through December 2008.
[B] Annual sales since 1998 for Sulfamylon include sales for this
approval and an earlier approval, which occurred prior to the
implementation of the accelerated approval process.
[C] The Food and Drug Administration converted the application for
Priftin to full approval on June 1, 2009.
[End of table]
[End of section]
Appendix V: 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:
September 8, 2009:
Marcia Crosse:
Director, Health Care:
U.S. Government Accountability Office:
441 G Street N.W.
Washington, DC 20548:
Dear Ms. Crosse:
Enclosed are comments on the U.S. Government Accountability Office's
(GAO) report entitled: New Drug Approval: FDA Needs to Enhance its
Oversight of Drugs Approved on the Basis of Surrogate Endpoints (GAO-09-
866).
The Department appreciates the opportunity to review this report before
its publication.
Sincerely,
Signed by:
Andrea Palm:
Acting Assistant Secretary for Legislation:
Enclosure:
[End of letter]
FDA's General Comments to the United States Government Accountability
Office's Draft Report Entitled, New Drug Approval: FDA Needs to Enhance
Its Oversight of Drugs Approved on the Basis of Surrogate Endpoints
(GAO-09-866):
The Food and Drug Administration (FDA) welcomes the opportunity to
comment on the Government Accountability Office's (GAO) findings in the
draft report and respond to the single recommendation made by GAO to
FDA.
FDA believes that the accelerated approval program has been very
successful. It has resulted in the early approval of many significant
therapeutic advances for patients with serious or life-threatening
illnesses who desperately need access to new treatments, in some cases
years before the drug would have been available under regular approval
procedures. For patients with HIV/AIDS and cancer, especially, the
accelerated approval program has dramatically expanded the therapeutic
armamentarium and significantly improved their quality of life and
survival.
By focusing primarily on the limited number of cases where the
postmarketing trials to confirm clinical benefit either have taken
longer to complete than expected or have not demonstrated clinical
benefit in the manner that had been anticipated, GAO's report minimizes
the fact that, as reflected in GAO's own analysis, overall the
accelerated approval program functions precisely as intended and
designed. First, through the accelerated approval program, millions of
patients with serious or life-threatening illnesses have had earlier
access to new safe and effective treatments. Second, in the vast
majority of cases, the confirmatory trials have been or are being
completed in a timely manner, have confirmed clinical benefit, and have
led to conversion to regular approval. These findings are important for
patients and also provide validation of the underlying public health
principles of the accelerated approval program.
FDA developed the accelerated approval program with full recognition of
the risk that drugs might be approved and later found not to confer
clinical benefit to patients. After much input from stakeholders, FDA
determined that this was a risk worth taking because patients with
serious or life-threatening illnesses and their physicians are willing
to accept more risk when making treatment decisions. FDA also sought to
minimize the risk that patients would be exposed to approved treatments
that were not safe and effective by incorporating four important
safeguards into the program. First, the evidentiary standard for
accelerated approval and regular approval is the same, meaning that
there must be substantial evidence that the drug has the purported
effect on the surrogate endpoint and there must be adequate safety data
for FDA to conclude that the benefits of the drug outweigh the risks.
Second, the surrogate endpoint must be considered reasonably likely to
predict clinical benefit. Third, clinical trials to confirm clinical
benefit are required after approval and must be completed with due
diligence by the sponsor. Finally, FDA can undertake expedited
withdrawal procedures if clinical benefit is not confirmed.
The facts as outlined in GAO's report show that the surrogate endpoints
used as the basis for accelerated approval have, in most cases, served
as accurate predictors of clinical benefit. This is demonstrated by the
fact that two thirds of the required confirmatory studies are now
considered closed by FDA and over half of the drugs approved under
accelerated approval have been converted to regular approval. FDA's
oversight of this program, including careful selection of surrogates
and extensive efforts to work closely with sponsors to design and
ensure timely completion of confirmatory trials, has served to make it
a success.
FDA has previously acknowledged that its oversight of postmarketing
requirements (PMR) and commitments (PMC) in general has been
inadequate; however oversight of postmarketing trials of drugs approved
under accelerated approval has always been an important FDA priority.
As noted above, nearly two thirds of the required confirmatory trials
are now considered complete by FDA. This is clear evidence that both
FDA and sponsors have taken their postmarketing obligations under this
program seriously.
With regard to oversight of the much larger overall portfolio of PMRs
and PMCs, FDA agrees that improvements are needed. In the past, because
of inadequate staffing and information technology resources and
competing workload priorities, the Center for Drug Evaluation and
Research (CDER) has been unable to thoroughly track PMRs and PMCs or to
review annual status reports and final study reports in a timely
fashion. With increased resources from Congressional appropriations and
statutory requirements, CDER has begun to implement a number of process
improvements to ensure appropriate oversight, more efficient tracking,
and expeditious review of postmarketing submissions. These improvements
were not complete at the time of this GAO investigation and are not
fully reflected by the data included in the report. These efforts
include the following:
* Publication of a new PMR/PMC Development Manual of Policies and
Procedures (MAPP) and significant revision of the PMR/PMC Tracking
MAPP;
* Establishment of the new roles of PMR/PMC Development and Tracking
Coordinators within each new drug review division;
* Implementation of new PMR/PMC functions in the document archiving and
records retention system database (DARRTS), which will improve PMR/PMC
tracking by enhancing FDA's ability to capture data and generate
reports; and;
* Contracting with Booz Allen Hamilton (BAH) to assist FDA staff with
the review of annual status reports and to conduct an independent
review of the backlog of all open PMRs and PMCs.
BAH's audit has led to extensive updates to the data in FDA's tracking
database and revealed that most of the industry postmarketing studies
and trials are proceeding according to the agreed-upon timeline. FDA
plans to continue its contract with BAH to ensure that the new
processes are implemented and the data in the database are accurate
and up-to-date going forward. FDA also plans to make the BAH audit
report available to the public.
Response to GAO's Recommendation:
GAO recommended that to clarify FDA's enforcement authority under the
accelerated approval process, the Commissioner of FDA take the
following action: Clarify the conditions under which the agency would
utilize its authority to expedite the withdrawal of drugs approved
based on surrogate endpoints under the accelerated approval process if
sponsors fail to complete required confirmatory studies with due
diligence, or if studies are completed, but fail to demonstrate the
clinical effectiveness of the drugs.
FDA acknowledges that there have been cases where confirmation of the
clinical benefit of drugs approved under accelerated approval did not
occur in a timely manner. FDA considers the lack of progress or
completion of confirmatory trials seriously and works closely with
sponsors to get the required trials back on track for completion. In
some cases it has been difficult to design or successfully enroll
patients in the confirmatory trials and FDA and sponsors have worked
together to find acceptable solutions, including alternate trial
designs or expanding enrollment to international sites. FDA also has
conducted public reviews of outstanding confirmatory trials for
oncology drugs to focus attention on the delays and to seek advice from
its advisory committee experts on ways to get the necessary trials
completed.
When trials are not being completed in a timely manner or completed
trials do not appear to confirm clinical benefit, FDA must carefully
assess each case and consider the underlying reasons and the
consequences of all regulatory options, including their potential
impact on patients. The fact that a trial has not been completed in
what appears to be a timely manner can reflect the failure of a sponsor
to exercise due diligence in the conduct of the trial, but it can also
reflect, for example, difficulty in identifying and enrolling
appropriate patients. Failure to confirm clinical benefit in a
completed trial may reflect the possibility that the drug does not in
fact confer clinical benefit, but it also may reflect, for example,
unforeseen limitations in trial design, rather than clear evidence of
lack of effectiveness. The most appropriate regulatory approach must be
governed by the unique factors of the particular case.
By definition, drugs approved under accelerated approval represent
significant therapeutic advances for patients with serious and life-
threatening illnesses. FDA must carefully evaluate what other options
are available to patients at the time it is considering regulatory
action for failure to confirm clinical benefit. In some cases a drug
for which clinical benefit has not been confirmed may be the only
approved therapeutic option for patients with the disease. Removing the
drug from the market and leaving patients with no treatment may be
unacceptable. In such a case FDA must consider the benefits of
continued availability of the drug, which by definition under the
accelerated approval program was shown to have an effect on the
surrogate endpoint that was the basis for approval, versus the risk
that patients may actually be using an ineffective drug and exposing
themselves only to its risks. FDA must also consider the possibility
that, despite results from confirmatory studies that may appear to
indicate that a drug does not provide clinical benefit, there may be a
subset of patients for whom the drug may nevertheless be effective.
Further, in addition to withdrawal of approval, FDA has other
regulatory tools that can be considered and applied as appropriate.
These include requiring a Risk Evaluation and Mitigation Strategy
(REMS) under the new authority granted to FDA in the Food and Drug
Administration Amendments Act of 2009 (FDAAA) or limiting access to the
drug under an Investigational New Drug application (IND).
Two specific drugs were mentioned in the report and warrant comment:
ProAmatine (midodrine hydrochloride) was approved by FDA as a treatment
for patients with orthostatic hypotension, a condition in which a
patient's blood pressure decreases upon standing, which can lead to
syncope (fainting) and falls. Orthostatic hypotension is a serious
disabling condition and there are no other FDA approved drugs for this
condition. The surrogate endpoint used for approval was an increase in
systolic blood pressure on standing. Although FDA routinely uses blood
pressure as a validated surrogate endpoint for the treatment of
hypertension, in the case of ProAmatine, FDA faced the opposite
situation, i.e., a drug intended to increase blood pressure in patients
with hypotension. Here FDA was not certain that the observed increase
in systolic blood pressure would lead to clinical benefit, and the
sponsor was required to conduct postapproval clinical trials to assess
relevant clinical endpoints (e.g., decrease in symptoms).
The sponsor conducted postapproval trials as required, and while FDA
did not consider the trials adequate to confirm clinical benefit, there
were trends observed that suggested the drug may in fact have clinical
benefit. Since this drug is the only approved therapy for this
condition, FDA has not concluded that it would be appropriate to
initiate expedited withdrawal of the approval. We note that the
ProAmatine case is complicated by the fact that there are approved
generic versions of the product. FDA has worked through complex legal
and regulatory issues to find ways to encourage one or more of the
generic sponsors to conduct the necessary clinical trials. FDA is
continuing to evaluate options in this case.
Rather than an example of FDA failing to exercise its authority to
withdraw approval, ProAmatine is a good example of the complex issues
FDA must consider when clinical benefit has not been confirmed and the
drug approved under accelerated approval remains the only FDA-approved
treatment for a serious or life-threatening condition. FDA must
carefully balance exercising its regulatory authority versus
considering the best interests of patients with the disease or
condition.
The second drug mentioned in the GAO report is Iressa (gefitinib).
Iressa was approved by FDA as a treatment for patients with advanced
non-small cell lung cancer, a serious and life-threatening form of
cancer for which there were few treatment options at the time Iressa
was approved. The sponsor conducted a large, randomized, controlled
clinical trial in over 1700 patients with less advanced lung cancer and
the trial failed to show an improvement in survival time for patients
treated with Iressa; i.e., clinical benefit was not confirmed. By the
time the postmarketing trial results for Iressa were available; another
similar drug (Tarceva) had been approved and had demonstrated an
increase in survival time in patients with non-small cell lung cancer.
In considering this case, FDA noted that while the controlled clinical
trial failed to show a survival benefit for the overall study
population, there was clear evidence in individual patients of
significant clinical benefit (e.g., shrinkage of large tumors and
prolonged survival in patients with end-stage disease) that could not
be ascribed to factors other than drug effect. There was also a
suggestion, though not yet proven by controlled clinical trials, that
certain patients might be responsive to Iressa due to the genetic
markers on their tumor cells while other patients might not respond.
This was thought to possibly explain the dramatic individual responses
seen in some patients and the lack of response seen in others. This
could also explain the failure to see a clinical benefit in a mixed
population of patients, many of whom might not be responsive to Iressa
due to the genetic makeup of their tumors.
After considering all the available information, FDA believed that it
was appropriate to direct patients beginning treatment for non-small
cell lung cancer to treatment with Tarceva, because clinical benefit in
the form of a survival advantage had been confirmed. FDA also believed
that patients who were already being treated with Iressa and in whom a
clinical response was observed might appropriately choose, after
consultation with their doctors, to remain on Iressa. Rather than
withdraw approval of Iressa, FDA worked with the sponsor to restrict
access to those patients who were already receiving treatment and whose
physician felt were deriving clinical benefit from the drug. Since
marketing of Iressa was restricted, patients with other diseases whose
physicians might have prescribed the drug for those different
indications were accommodated through access under an Investigational
New Drug Application.
FDA believes that this combination of regulatory actions was an
appropriate and balanced approach given the unique circumstances in
this case. The sponsor of Iressa has continued to investigate the
factors that might predict response to the drug, and it is possible
that future clinical trials in properly selected patients will
demonstrate clinical benefit.
In both of these examples, the sponsors pursued confirmatory clinical
trials with due diligence, but despite careful consideration and review
by both industry and the FDA, the trials did not demonstrate clinical
benefit. In both cases, review of the data suggests limitations in
elements of trial design that may have led to the seemingly negative
results.
GAO recommends that FDA "clarify the conditions under which the agency
would utilize its authority to expedite the withdrawal of drugs
approved based on surrogate endpoints under the accelerated approval
process if sponsors either fail to complete required confirmatory
trials with due diligence, or if studies are completed, but fail to
demonstrate the clinical effectiveness of the drugs." Outside of a
situation where a confirmatory trial clearly demonstrates harm to the
patients (e.g., decreased survival for patients with cancer treated
with the accelerated approval drug), FDA believes that each case must
considered on its merits and that the criteria in the existing
regulations and statutory provisions (including the provisions in Title
IX of FDAAA that authorize civil, criminal, and civil monetary
penalties for failure to conduct a postmarketing confirmatory trial)
provide FDA with sufficient authority and flexibility to make balanced
decisions that protect the program from abuse by sponsors and ensure
that patients will continue to have access to needed treatments. In
light of the complexities outlined above and the need for a case-by-
case assessment, FDA believes it would be difficult, if not impossible,
to provide further clarification as to when it might utilize its
authority to expedite withdrawal of drug approved on the basis of
surrogate endpoints. FDA remains committed to closely overseeing
required postmarketing trials for drugs approved under accelerated
approval and believes that the improvements being implemented in its
overall PMR/PMC program will allow for continued success of the
program.
[End of section]
Appendix VII: GAO Contact and Staff Acknowledgments:
GAO Contact:
Marcia Crosse, (202) 512-7114 or crossem@gao.gov:
Acknowledgments:
In addition to the contact named above, Geri Redican-Bigott, Assistant
Director; Shaunessye Curry; Krister Friday; Mollie Hertel; Julian
Klazkin; David Lichtenfeld; Rich Lipinski; and Thanh Lu made key
contributions to this report.
[End of section]
Footnotes:
[1] Biological products are products derived from living sources--such
as humans, animals, and microorganisms--that are intended for
preventing, treating, or curing diseases or conditions. They include
vaccines, blood products, and proteins. See 42 U.S.C. § 262(i), 21
C.F.R. § 600.3(h)(2008). For the remainder of this report we use the
term "drug" to refer to both therapeutic biological products and
chemically synthesized drugs.
[2] Drug sponsors typically are the applicants who submit new drug
applications (NDAs) and biological license applications (BLAs) to FDA
for review. A drug sponsor may assume responsibility for the marketing
of a new drug, including responsibility for complying with applicable
laws and regulations.
[3] FDA's approval of an NDA or BLA means a sponsor can market the new
drug. Throughout the remainder of this report we refer to FDA's
approval of NDAs and BLAs as approval of "drugs".
[4] 21 C.F.R. pt. 314 subpt. H (2008), 21 C.F.R. pt. 601 subpt. E
(2008).
[5] Throughout this report we refer to those postmarketing studies
which FDA requested and sponsors committed, in writing, to conduct as
"requested" postmarketing studies.
[6] See Pub. L. No. 105-115, § 130, 111 Stat. 2296, 2331-2 (codified at
21 U.S.C. § 356b).
[7] 21 C.F.R. §§ 314.81(b)(2)(vii), 601.70(a), (b)(2008). The
regulations also explain that status reports of postmarketing studies
are required for studies that address (1) clinical safety, (2) clinical
efficacy, (3) clinical pharmacology, and (4) nonclinical toxicology.
Drug sponsors, but not those producing biologics, must also submit
annual reports on postmarketing studies that they have agreed to
conduct, or that are conducted on their behalf that concern chemistry,
manufacturing, controls, or product stability. 21 C.F.R. §
314.81(b)(2)(viii)(2008).
[8] FDA issued final regulations for the accelerated approval process
on December 11, 1992, but approved one application under this process,
prior to issuing the final regulations. We have included this
application in the scope of our review.
[9] For example, if a drug can be taken either as a pill or via
injection, FDA may approve a separate application for each route of
administration.
[10] The scope of applications included in this review was limited to
NDAs for NMEs. This review does not include any new BLAs.
[11] FDA approved 15 NMEs for drugs used to aid in diagnosing diseases
or in aiding the absorption of other drugs. Because these 15 were not
used to actually treat a disease, we excluded them from our analyses.
[12] We obtained this material from FDA's Web site, [hyperlink,
www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/].
[13] For example, under the standards for internal control, information
should be recorded and communicated to management and others within an
entity who need it and within a time frame that enables them to carry
out their internal control and other responsibilities. See GAO,
Standards for Internal Control in the Federal Government, [hyperlink,
http://www.gao.gov/products/GAO/AIMD-00-21.3.1] (Washington, D.C.: Nov.
1999) and its supplemental guide, Internal Control Management and
Evaluation Tool, [hyperlink, http://www.gao.gov/products/GAO-01-1008G]
(Washington, D.C.: Aug. 2001).
[14] FDA will not approve an application if, for example, the methods
used in, and the facilities and controls used for, the manufacture,
processing, and packing of such drug are inadequate to preserve its
identity, strength, quality, and purity. 21 U.S.C. § 355(d)(3).
[15] FDA, Innovation or Stagnation: Challenge and Opportunity on the
Critical Path to New Medical Products (March 2004).
[16] R. Temple, Are Surrogate Markers Adequate to Assess Cardiovascular
Disease Drugs? The Journal of the American Medical Association, August
25, 1999; 282(8):790-795.
[17] For example, see D.S. Echt, P.R. Liebson, L.B. Mitchell, et al,
Mortality and Morbidity in Patients Receiving encainide, flecainide, or
placebo. The Cardiac Arrhythmia Suppression Trial, New England Journal
of Medicine, 1991; 324:781-788.
[18] According to FDA officials, prior to 2001, they did not always
establish time frames for completing postmarketing studies.
[19] In addition to confirmatory studies, sponsors may be required to
conduct postmarketing studies in other instances. For example, under
the Pediatric Research Equity Act of 2003 sponsors may be required to
study products in children. When a sponsor is required under the act to
study its product in pediatric populations, FDA can defer the required
studies until after the product is approved in adults. Pub. L. No. 108-
55, § 2(a), 117 Stat. 1936 (codified at 21 U.S.C. §
355c(a)(3)(A)(i)(I)). Further, if FDA approves a drug based solely on
animal studies, when human efficacy studies are not ethical or
feasible, it requires the sponsor to subsequently conduct studies to
verify and describe the drug's efficacy and to assess its safety in
humans when such studies become feasible and ethical. C.F.R. pts. 314
subpt. I; 601 subpt. H (2008). Finally, the Food and Drug
Administration Amendments Act of 2007 (FDAAA) provided FDA with
additional authority to require postmarket safety studies in certain
instances. Pub. L. No. 110-85, § 901(a), 121 Stat. 823, 922 (codified
at 21 U.S.C. § 355(o)).
[20] 21 C.F.R. §§ 314.81(b)(2), (b)(2)(vii), 601.70(a)-(c)(2008). The
current reporting requirements became effective on April 30, 2001. In
2001, drug sponsors were required to submit their first progress report
by October 30 for those postmarketing studies that addressed clinical
efficacy, clinical safety, clinical pharmacology, or nonclinical
toxicology.
[21] 21 C.F.R. §§ 314.81(b)(2)(vii)(a)(6), (7); 601.70(b)(6),
(7)(2008).
[22] 21 U.S.C. 356b(c),(d).
[23] See 21 C.F.R. §§ 314.81(b)(2)(vii)(a)(8); 601.70(b)(8)(2008).
[24] According to FDA, conversion from accelerated to full approval
means the sponsor has demonstrated, through clinical testing, that the
drug is clinically effective in treating a specific disease or medical
condition.
[25] In 2007, FDAAA provided FDA with authority to assess civil
monetary penalties against those who have not conducted required
postmarketing studies under the accelerated approval process. Pub. L.
No. 110-85, §§ 901(a), 902(b) (codified at 21 U.S.C. §§ 333(f)(4),
355(p)). As of July 2009, FDA officials indicated they have never used
this new authority.
[26] 21 C.F.R §§ 314.530(a)(2), 601.43(a)(2)(2008).
[27] In several instances FDA approved multiple applications for the
same drug through the accelerated approval process. Thus FDA approved a
smaller number of drugs than applications. For example, in some cases a
drug had several routes of administration (e.g., tablet, intravenous
solution, oral suspension), and FDA approved a separate application for
each.
[28] Two of these open studies are for the drug Levaquin, which was
approved to treat the effects of inhalation anthrax. According to FDA
officials, these studies will remain in the pending status
indefinitely, because the sponsor cannot, for ethical reasons, test the
medication on humans unless there is an anthrax attack or other
widespread exposure.
[29] We determined the time to fulfill a study by measuring the amount
of time that elapsed from the date the study was required in the
approval letter to the date FDA determined the study was fulfilled. FDA
was unable to provide the fulfillment dates for 2 of the 73 fulfilled
studies; therefore the total number of studies used in figure 4 is 71.
[30] In a single arm trial there is one treatment group of patients who
all take the drug being studied; there is not a separate group of
patients taking another drug or a placebo for comparison. According to
FDA, single arm trials can provide an accurate assessment of tumor
response in patients with highly resistant tumors.
[31] A randomized control trial is a study in which participants are
randomly assigned to a group taking the drug under study, a placebo, or
a comparison drug. FDA considers a randomized control trial as the most
reliable type of trial.
[32] Status information on requested postmarketing studies under the
accelerated approval process was provided by FDA as of January 6, 2009.
[33] We determined the amount of time studies had been open by
measuring the amount of time which elapsed from the date the study was
requested to January 6, 2009.
[34] In addition to these 204 NMEs, FDA approved an additional 15 NMEs
for drugs used to aid in diagnosing diseases or in aiding the
absorption of other drugs. Because these 15 were not used to treat a
disease, we excluded them from our analyses.
[35] These 69 applications include one for a drug that was approved for
many indications (diseases). This drug was approved for some of these
indications primarily based on a surrogate endpoint and some were
approved based on a clinical endpoint. Therefore, we included this drug
in our scope.
[36] FDA and others have suggested that the identification of validated
surrogate endpoints already used in drug approvals, as well as criteria
for accepting new potential surrogate endpoints, may encourage more
efficient drug development. See GAO, New Drug Development: Science,
Business, Regulatory and Intellectual Property Issues Cited as
Hampering Drug Development Efforts, GAO-07-49 (Washington, D.C.: Nov.
17, 2006). FDA planned to develop a comprehensive inventory of all
surrogate endpoints used to approve new drugs, including those under
the traditional process. FDA officials told us that they were able to
compile a partial list of such endpoints, but due to other competing
priorities, this inventory was never completed.
[37] We determined the amount of time studies had been open by
measuring the amount of time which elapsed from the date the study was
requested to February 13, 2009.
[38] For more information, see HHS' Office of Inspector General's
report entitled FDA's Monitoring of Postmarketing Study Commitments
(June 2006).
[39] FDA retained Booz Allen Hamilton in 2006 to conduct an independent
analysis of the agency's postmarket processes and procedures. In
Postmarketing Commitments Study Final Report, issued in January 2008,
the contractor highlighted further problems, and made recommendations
designed to improve FDA's monitoring and oversight of postmarketing
studies.
[40] FDA is required to report annually in the Federal Register and to
congressional committees the status of postmarketing studies that are
the subject of annual status reports submitted to FDA. 21 U.S.C. §§
356b(c), 356b note.
[41] According to FDA officials, their contractor has already
identified numerous instances where status information was incorrect,
such as when studies listed as pending were, in fact, ongoing. Based on
this information FDA will be updating its database with the correct
information, and this will be reflected in its next annual report in
the Federal Register.
[42] DARRTS became operational for NDAs in July 2009. FDA will continue
to use its current system to oversee postmarketing studies related to
BLAs. Data related to BLAs are scheduled to be integrated into DARRTS
in 2010.
[43] According to FDA officials, the agency did not mail these letters
directly to the five generic manufacturers, but contacted certain key
industry officials regarding FDA's posting of these letters.
[End of section]
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