Food and Drug Administration
Approval and Oversight of the Drug Mifeprex Gao ID: GAO-08-751 August 7, 2008In September 2000, the Food and Drug Administration (FDA), part of the Department of Health and Human Services (HHS), approved the drug Mifeprex for use in terminating early term pregnancy. FDA approved the drug under a provision of its Subpart H regulations, allowing it to restrict the drug's distribution to assure its safe use. Critics have questioned aspects of the Mifeprex approval process, including the reliance on historically-controlled clinical trials that compare a drug's effects on a condition to the known course of the condition rather than to another drug or placebo. Critics argued that Mifeprex does not fit within the scope of Subpart H, which applies to drugs that treat serious or life-threatening illnesses. Concerns have also been raised about FDA's oversight of the drug since approval, including the agency's response to deaths in U.S. women who had taken the drug. In this report GAO (1) describes FDA's approval of Mifeprex, including the evidence considered and the restrictions placed on its distribution; (2) compares the Mifeprex approval process to the approval processes for other Subpart H restricted drugs; and (3) compares FDA's postmarket oversight of Mifeprex to its oversight of other Subpart H restricted drugs. GAO reviewed FDA regulations, policies, and records pertaining to its approval and oversight of Mifeprex and the eight other Subpart H restricted drugs. In addition, GAO interviewed FDA officials and external stakeholders.
FDA approved Mifeprex after evaluating the sponsor's initial and revised new drug application through three review cycles. In the first cycle, FDA concluded that the available data supported the safety and efficacy of Mifeprex and that, because the course of pregnancy was well-documented and the effects of the drug were self-evident, the use of historical controls was consistent with FDA regulations. FDA also concluded that before the drug could be approved, the sponsor needed to provide final data from an ongoing U.S. trial, and more detail on restricting the drug's distribution. In the second cycle, FDA concluded that while the U.S. trial data confirmed the drug's safety and efficacy, the sponsor needed to revise its distribution plan and address labeling and manufacturing deficiencies. In the final review, FDA concluded that termination of unwanted pregnancy is a serious condition and imposing restrictions under Subpart H was necessary. FDA approved Mifeprex, but required that the sponsor commit to conduct two postmarketing studies, imposed several distribution restrictions intended to ensure that only qualified physicians prescribe the drug, and required that patients attest to understanding the treatment's potential complications. The approval process for Mifeprex was consistent with the processes for the other Subpart H restricted drugs, although the details of FDA's approval depended on the unique risks and benefits of each drug. Common elements of the approval processes included that FDA needed to evaluate potential limitations in key clinical data (Mifeprex and six of the other drugs), did not approve the drugs in the first review cycle (Mifeprex and five others), and imposed similar types of distribution restrictions on Mifeprex and the other drugs, though the specific details of the restrictions varied across the drugs. FDA's postmarket oversight of Mifeprex has been consistent with its oversight of other Subpart H restricted drugs. To oversee compliance with distribution restrictions, FDA has reviewed data from all sponsors and conducted inspections for Mifeprex and two other drugs. To oversee compliance with postmarketing study commitments, FDA has relied on required updates from sponsors and found unfulfilled commitments for most drugs, including Mifeprex. To oversee compliance with adverse event reporting requirements, FDA has evaluated data in sponsors' reports and, for Mifeprex and seven other drugs, has conducted inspections that revealed deficiencies for most of these drugs, including Mifeprex. Lastly, FDA has taken similar steps to oversee postmarket safety across the drugs, such as analyzing adverse events. For Mifeprex, FDA investigated the deaths of six U.S. women who developed a severe infection after taking the drug and concluded that the evidence did not establish a causal relationship between Mifeprex and the infections. Finally, FDA has taken similar actions to address emerging safety concerns across the drugs, such as changing labeling. HHS reviewed a draft of this report and informed GAO that it did not have comments.
GAO-08-751, Food and Drug Administration: Approval and Oversight of the Drug Mifeprex
This is the accessible text file for GAO report number GAO-08-751
entitled 'Food and Drug Administration: Approval and Oversight of the
Drug Mifeprex' which was released on August 18, 2008.
This text file was formatted by the U.S. Government Accountability
Office (GAO) to be accessible to users with visual impairments, as part
of a longer term project to improve GAO products' accessibility. Every
attempt has been made to maintain the structural and data integrity of
the original printed product. Accessibility features, such as text
descriptions of tables, consecutively numbered footnotes placed at the
end of the file, and the text of agency comment letters, are provided
but may not exactly duplicate the presentation or format of the printed
version. The portable document format (PDF) file is an exact electronic
replica of the printed version. We welcome your feedback. Please E-mail
your comments regarding the contents or accessibility features of this
document to Webmaster@gao.gov.
This is a work of the U.S. government and is not subject to copyright
protection in the United States. It may be reproduced and distributed
in its entirety without further permission from GAO. Because this work
may contain copyrighted images or other material, permission from the
copyright holder may be necessary if you wish to reproduce this
material separately.
Report to Congressional Requesters:
United States Government Accountability Office:
GAO:
August 2008:
Food and Drug Administration:
Approval and Oversight of the Drug Mifeprex:
FDA Approval and Oversight of Mifeprex:
GAO-08-751:
GAO Highlights:
Highlights of GAO-08-751, a report to congressional requesters.
Why GAO Did This Study:
In September 2000, the Food and Drug Administration (FDA), part of the
Department of Health and Human Services (HHS), approved the drug
Mifeprex for use in terminating early term pregnancy. FDA approved the
drug under a provision of its Subpart H regulations, allowing it to
restrict the drug‘s distribution to assure its safe use. Critics have
questioned aspects of the Mifeprex approval process, including the
reliance on historically-controlled clinical trials that compare a
drug‘s effects on a condition to the known course of the condition
rather than to another drug or placebo. Critics argued that Mifeprex
does not fit within the scope of Subpart H, which applies to drugs that
treat serious or life-threatening illnesses. Concerns have also been
raised about FDA‘s oversight of the drug since approval, including the
agency‘s response to deaths in U.S. women who had taken the drug.
In this report GAO (1) describes FDA‘s approval of Mifeprex, including
the evidence considered and the restrictions placed on its
distribution; (2) compares the Mifeprex approval process to the
approval processes for other Subpart H restricted drugs; and (3)
compares FDA‘s postmarket oversight of Mifeprex to its oversight of
other Subpart H restricted drugs. GAO reviewed FDA regulations,
policies, and records pertaining to its approval and oversight of
Mifeprex and the eight other Subpart H restricted drugs. In addition,
GAO interviewed FDA officials and external stakeholders.
What GAO Found:
FDA approved Mifeprex after evaluating the sponsor‘s initial and
revised new drug application through three review cycles. In the first
cycle, FDA concluded that the available data supported the safety and
efficacy of Mifeprex and that, because the course of pregnancy was well-
documented and the effects of the drug were self-evident, the use of
historical controls was consistent with FDA regulations. FDA also
concluded that before the drug could be approved, the sponsor needed to
provide final data from an ongoing U.S. trial, and more detail on
restricting the drug‘s distribution. In the second cycle, FDA concluded
that while the U.S. trial data confirmed the drug‘s safety and
efficacy, the sponsor needed to revise its distribution plan and
address labeling and manufacturing deficiencies. In the final review,
FDA concluded that termination of unwanted pregnancy is a serious
condition and imposing restrictions under Subpart H was necessary. FDA
approved Mifeprex, but required that the sponsor commit to conduct two
postmarketing studies, imposed several distribution restrictions
intended to ensure that only qualified physicians prescribe the drug,
and required that patients attest to understanding the treatment‘s
potential complications.
The approval process for Mifeprex was consistent with the processes for
the other Subpart H restricted drugs, although the details of FDA‘s
approval depended on the unique risks and benefits of each drug. Common
elements of the approval processes included that FDA needed to evaluate
potential limitations in key clinical data (Mifeprex and six of the
other drugs), did not approve the drugs in the first review cycle
(Mifeprex and five others), and imposed similar types of distribution
restrictions on Mifeprex and the other drugs, though the specific
details of the restrictions varied across the drugs.
FDA‘s postmarket oversight of Mifeprex has been consistent with its
oversight of other Subpart H restricted drugs. To oversee compliance
with distribution restrictions, FDA has reviewed data from all sponsors
and conducted inspections for Mifeprex and two other drugs. To oversee
compliance with postmarketing study commitments, FDA has relied on
required updates from sponsors and found unfulfilled commitments for
most drugs, including Mifeprex. To oversee compliance with adverse
event reporting requirements, FDA has evaluated data in sponsors‘
reports and, for Mifeprex and seven other drugs, has conducted
inspections that revealed deficiencies for most of these drugs,
including Mifeprex. Lastly, FDA has taken similar steps to oversee
postmarket safety across the drugs, such as analyzing adverse events.
For Mifeprex, FDA investigated the deaths of six U.S. women who
developed a severe infection after taking the drug and concluded that
the evidence did not establish a causal relationship between Mifeprex
and the infections. Finally, FDA has taken similar actions to address
emerging safety concerns across the drugs, such as changing labeling.
HHS reviewed a draft of this report and informed GAO that it did not
have comments.
To view the full product, including the scope and methodology, click on
[http://www.gao.gov/cgi-bin/getrpt?GAO-08-751]. For more information,
contact Marcia Crosse at (202) 512-7114 or crossem@gao.gov.
[End of section]
Contents:
Letter:
Results in Brief:
Background:
FDA Approved Mifeprex under the Subpart H Restricted Distribution
Provision After Concluding That Clinical Evidence Supported Its Safety
and Efficacy:
Approval Process for Mifeprex Was Generally Consistent with That of the
Other Eight Subpart H Restricted Drugs:
FDA's Postmarket Oversight of Mifeprex Has Been Consistent with the
Agency's Oversight of the Other Subpart H Restricted Drugs:
Agency Comments:
Appendix I: Select Drugs Approved by FDA with Restricted Distribution:
Appendix II: Detailed Description of Distribution Restrictions for
Mifeprex:
Appendix III: Prescriber's Agreement for Mifeprex Distribution:
Appendix IV: GAO Contact and Staff Acknowledgments:
Tables:
Table 1: Timeline of Key Events in FDA's Approval of Mifeprex:
Table 2: Selected Features of Restricted Distribution Programs Imposed
by FDA at Time of Approval under Subpart H:
Table 3: Selected Features of FDA's Oversight of Postmarket Safety for
Drugs Approved under Subpart H, as of May 2008:
Abbreviations:
AERS: Adverse Event Reporting System:
CDC: Centers for Disease Control and Prevention:
ENL: erythema nodosum leprosum:
FDA: Food and Drug Administration:
FDAAA: Food and Drug Administration Amendments Act of 2007:
HHS: Department of Health and Human Services:
HIV/AIDS: human immunodeficiency virus / acquired immune deficiency
syndrome:
NDA: new drug application:
REMS: risk evaluation and mitigation strategy:
SGE: special government employee:
United States Government Accountability Office:
Washington, DC 20548:
August 7, 2008:
The Honorable Michael B. Enzi:
Ranking Member:
Committee on Health, Education, Labor, and Pensions:
United States Senate:
The Honorable Jim DeMint:
United States Senate:
The Honorable Roscoe G. Bartlett:
House of Representatives:
In September 2000, the Department of Health and Human Services' (HHS)
Food and Drug Administration (FDA) granted marketing approval to the
prescription drug Mifeprex (mifepristone) for the medical termination
of early term pregnancy.[Footnote 1] It remains the only drug approved
in the United States for this purpose. FDA approved the drug under a
provision of the agency's Subpart H regulations that allows FDA to
restrict the distribution or use of a drug in order to assure its safe
use.[Footnote 2] Under this provision FDA can require, as it did for
Mifeprex, that distribution be restricted to certain health care
providers with specific training or experience. Since the drug's
approval, more than 900,000 women are estimated to have taken Mifeprex
in the United States.
Before a drug can be marketed in the United States, the drug sponsor
must submit a new drug application (NDA) to FDA containing data
demonstrating the safety and efficacy of the drug.[Footnote 3] FDA
reviews the NDA to determine whether the drug's benefits outweigh its
risks.[Footnote 4] Once FDA completes its review, the agency issues an
action letter in which it either approves the drug as safe and
effective for its intended use (approval letter), informs the sponsor
that the drug is likely to be approved once the deficiencies FDA has
identified are resolved (approvable letter), or indicates that approval
cannot be obtained without substantial additional information (not
approvable letter).[Footnote 5] If FDA issues an approvable or not
approvable letter, a subsequent review cycle can begin once the sponsor
has addressed the issues FDA identified. FDA may require, as a
condition of approval, that a sponsor agree to restrict the drug's
distribution under the agency's Subpart H regulations.[Footnote 6]
Critics have raised concerns and questions regarding several aspects of
FDA's approval process for Mifeprex. For example, questions have been
raised about the reliance on data from historically controlled clinical
trials--trials that compare a drug's effects on a condition within the
study population to the known course of that same condition in patients
or populations that were not part of the trial--to support the safety
and efficacy of Mifeprex.[Footnote 7] FDA regulations allow for the use
of such historical controls when the course of the condition in
question is well-documented within a comparable population and the
effect of the drug is apparent. Questions have also been raised about
whether Mifeprex fit within the scope of Subpart H regulations, which
apply to drugs that are intended to treat a serious or life-threatening
illness. Critics have argued that unwanted pregnancy should not be
considered a serious or life-threatening illness. They have also
questioned whether FDA's use of Subpart H regulations was consistent
with its use of the regulations to approve other drugs.
Additionally, concerns have been raised about FDA's postmarket
oversight of Mifeprex, including its efforts to ensure the sponsor's
compliance with conditions of approval as well as the actions the
agency has taken in response to reported adverse events.[Footnote 8]
For approved drugs, FDA oversees sponsors' compliance with applicable
reporting requirements, distribution restrictions, and other conditions
of approval.[Footnote 9] FDA also monitors the drugs' postmarket safety
and efficacy. In the case of Mifeprex, six U.S. women have died from
severe bacterial infection after taking the drug, raising questions
about its safety. Some have questioned FDA's conclusion--which it
discussed at a May 2006 congressional hearing-- that the available
evidence had not established a causal relationship between Mifeprex and
the infections.
You asked us to review FDA's approval of Mifeprex and its oversight of
the drug since approval. In this report we (1) examine FDA's approach
to approving Mifeprex, including the types of evidence considered and
the restrictions placed on its distribution and use; (2) compare the
approval process for Mifeprex to the approval processes for other drugs
approved under the restricted distribution provision of Subpart H; and
(3) compare FDA's oversight of the use of Mifeprex since its approval
to the agency's oversight of the other drugs approved under the
restricted distribution provision of Subpart H.
To examine FDA's approval of Mifeprex, we reviewed relevant laws,
regulations, policies, and guidance. We reviewed FDA records including
an archive of documents pertaining to the approval of
Mifeprex.[Footnote 10] We also reviewed documentation from an FDA
advisory committee meeting,[Footnote 11] testimony statements and the
related transcript, FDA responses to congressional requests, an August
2002 citizen's petition and responses from outside organizations, and
other documentation pertaining to FDA's approval of Mifeprex. We
interviewed FDA officials and external stakeholders who had access to
technical information or had conducted analyses pertaining to Mifeprex
that were not available through FDA. These included a representative of
the sponsor of the Mifeprex application and its licensee,[Footnote 12]
the American College of Obstetricians and Gynecologists and the
American Association of Pro Life Obstetricians and Gynecologists.
To compare the approval process for Mifeprex to those of other drugs,
we reviewed FDA documentation pertaining to FDA's approval of the other
eight drugs that the agency had approved under the restricted
distribution provision of Subpart H as of February 2007.[Footnote 13]
Specifically, we examined key documents related to FDA's internal
review and approval processes as well as documentation from advisory
committee meetings in order to identify commonalities and differences
in FDA's process across the nine Subpart H restricted drugs, including
Mifeprex. In our examination we focused on issues that had arisen
during FDA's review of Mifeprex to determine whether similar issues had
arisen in FDA's review of the other drugs, and how FDA had addressed
those issues for the other drugs.
To compare FDA's oversight of the use of Mifeprex since approval to the
agency's oversight of the other Subpart H restricted drugs, we reviewed
relevant regulations and FDA guidance. We also examined FDA
documentation on the agency's oversight of sponsors' compliance with
distribution restrictions, postmarketing study commitments, and adverse
event reporting requirements for the nine Subpart H restricted drugs.
In addition, we reviewed FDA's process for evaluating and responding to
postmarket data on adverse events for each drug. Lastly, we interviewed
FDA officials and staff who are responsible for postmarket oversight of
these drugs. We conducted our work from February 2007 through August
2008 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.
Results in Brief:
On September 28, 2000, FDA approved Mifeprex under the restricted
distribution provision of its Subpart H regulations after examining the
NDA through three review cycles. In its first review, FDA concluded
that the available evidence supported the safety and efficacy of
Mifeprex. This conclusion was based in part on FDA's determination that
because the course of pregnancy was well-documented and the effects of
the treatment were self-evident, the reliance on historical controls in
three key clinical trials--two conducted in France and one ongoing in
the United States--was appropriate and consistent with FDA regulations.
FDA issued an approvable letter in September 1996 concluding that the
sponsor needed to provide additional information, such as the final
data from the U.S. trial and a detailed plan to restrict the drug's
distribution, before an approval decision could be made. The second
review cycle began when the sponsor submitted a complete response to
this letter. FDA issued a second approvable letter in February 2000
after concluding that the new data confirmed the safety and efficacy of
Mifeprex for the U.S. market but also that the sponsor needed to revise
its distribution plan and address labeling and manufacturing
deficiencies. In its final review, FDA deliberated about the
distribution restrictions and conditions of use needed to assure the
safe use of the drug. FDA concluded that termination of an unwanted
pregnancy is a serious condition and that the drug can allow patients
to avoid a surgical procedure and therefore Mifeprex fit within the
scope of Subpart H. FDA further concluded that the drug could only be
used safely if distribution was limited to qualified physicians. The
sponsor argued that the drug did not treat a serious condition and that
because they had voluntarily agreed to the restrictions FDA had
requested, it was neither appropriate nor necessary to impose the
restrictions under Subpart H. However, the sponsor eventually
acquiesced to FDA's requirement that approval be under Subpart H. After
FDA concluded that the sponsor had adequately revised its distribution
plan and addressed the remaining issues identified in FDA's reviews, it
approved the Mifeprex NDA under Subpart H with several restrictions.
These included requiring that prescribing physicians attest to
possessing specific skills, agree to fully discuss the treatment with
patients, and agree to report certain adverse events to the sponsor;
that the drug be distributed directly to physicians by an authorized
distributor; and that patients attest to fully understanding the
treatment and its potential complications. The drug was also approved
subject to the sponsor's commitment to conduct two postmarket studies
related to patient outcomes.
The approval process for Mifeprex was generally consistent with the
approval processes for the other eight Subpart H restricted drugs, but
the details of FDA's approval process for each drug depended on the
drug's unique risks and benefits. One common element across the
approval processes for seven of the drugs, including Mifeprex, was that
FDA needed to evaluate potential limitations--such as lack of
concurrent controls or small sample sizes--in key clinical trials
supporting the NDA. For some of these drugs other than Mifeprex, FDA
concluded that there were weaknesses in the data submitted in the NDA
that needed to be addressed. Another common element for six of the
drugs, including Mifeprex, was that FDA issued at least one prior
action letter before ultimately approving the drug for marketing under
Subpart H. Additionally, the types of distribution restrictions that
FDA imposed on Mifeprex were similar to those the agency imposed on the
other drugs, though the details of the restrictions varied depending on
the drug. Lastly, eight of the drugs, including Mifeprex, were approved
with two or more postmarketing study commitments, each with one or more
commitments related to adverse events or patient outcomes of interest.
FDA's postmarket oversight of Mifeprex has been consistent with the
agency's postmarket oversight of the other Subpart H restricted drugs.
To oversee the drug sponsors' compliance with distribution
restrictions, FDA has relied on data submitted by sponsors for all of
the drugs. For three of the drugs, one of them Mifeprex, FDA has also
completed inspections of the sponsor or its distributors. To oversee
compliance with postmarketing study commitments, FDA has relied on
updates in required reports from sponsors. Most of the drugs, including
Mifeprex, have at least one study commitment that remains unfulfilled.
To oversee compliance with adverse event reporting requirements, FDA
has relied on sponsors' reports for all of the drugs and has also
conducted inspections of the sponsor or its manufacturers for eight of
them. FDA has cited the sponsors of seven of the drugs, including
Mifeprex, for adverse event reporting deficiencies. To oversee the
postmarket safety of all of the Subpart H restricted drugs, FDA has
routinely conducted reviews of adverse event reports to monitor for
safety concerns. In the case of Mifeprex, FDA investigated the deaths
of six U.S. women who developed a fatal infection following treatment
with Mifeprex for medical abortion. FDA has determined that in all six
of the deaths, the women used a Mifeprex treatment regimen that has not
been approved by FDA. Based on its investigations, FDA has concluded
that a causal relationship between the use of Mifeprex and the fatal
infections has not been established. FDA has also monitored other kinds
of adverse events and has concluded that, with the exception of the
cases of fatal infection, reported serious adverse events associated
with Mifeprex have been within or below the ranges it expected.
Additionally, for Mifeprex and the other drugs, FDA has taken similar
actions--such as issuing warnings and requesting changes to the product
labeling--to communicate safety information to consumers and health
care providers.
HHS reviewed a draft of this report and informed us that it did not
have general comments. In addition, HHS provided technical comments
which we incorporated as appropriate.
Background:
The Mifeprex NDA provided for the use of Mifeprex, in combination with
another drug, for the medical termination of pregnancy. The treatment
regimen described in the NDA involved taking Mifeprex orally, and then
taking the drug misoprostol orally 2 days later unless termination of
the pregnancy had already occurred.[Footnote 14] Patients return for a
follow-up visit with their prescribing physician 2 weeks later to
ensure that the termination of the pregnancy has been completed. The
treatment regimen works by both interrupting the hormones that the body
needs to maintain a pregnancy and inducing the uterine cramping
necessary to cause a medical abortion.
At the time that the drug sponsor submitted the Mifeprex NDA, in March
1996, mifepristone had already been approved in multiple countries. The
drug was first approved for the medical termination of pregnancy in
France and China in 1988.[Footnote 15] It was approved subsequently in
the United Kingdom in 1991, in Sweden in 1992, and various other
European countries throughout the 1990s. In general, the treatment
regimens approved in these countries were similar to those studied in
the Mifeprex NDA, though in some cases the specific drug used in
combination with mifepristone was different.
FDA Application Review Process:
FDA reviews drug applications to determine whether they provide
sufficient evidence to demonstrate that a drug is safe and effective
for the proposed use, including whether the benefits of the drug
outweigh its risks. FDA's formal process for new drug approval begins
after a drug sponsor submits an application, typically following a long
period of research and development. During a preliminary review, FDA
determines whether the application is sufficiently complete to be
reviewed and if so, designates it for either standard or priority
review, depending on the therapeutic potential of the drug.[Footnote
16] The agency then assigns a team of reviewers--including medical
officers, chemists, statisticians, microbiologists, pharmacologists,
and other experts--within the relevant FDA review division. This review
team, which is usually led by a medical officer, conducts a
comprehensive evaluation of the clinical and non-clinical information
in the application including the safety and efficacy data for the drug,
the design and quality of the studies used to support the application,
and the proposed labeling for the drug and also reviews the results of
inspections of the facilities where the drug is manufactured.[Footnote
17] The review team compiles the results of its analyses and recommends
either an approval, approvable, or not approvable action.
FDA managers, usually including the review team's supervisor and senior
management within the applicable review division, determine what action
to take on an application, based on the recommendations of the review
team. These managers examine the review team's analysis and
individually decide whether to concur with the recommendation. The
final decision on the action the agency should take is usually, but not
always, made by the director of the applicable review division. In some
cases, actions must be reviewed and agreed to by the relevant FDA
office.
This review process may span several cycles. For those applications not
approved during the first review cycle--both approvable and not
approvable--the second FDA review cycle begins once the sponsor submits
an amendment to the application providing responses to the deficiencies
FDA identified in its previous review. These amendments often contain
additional studies, analyses, data, or clarifying information to
address FDA's concerns. The responsible review team reviews the
information provided by the sponsor, conducts any additional analyses
that are required, reviews the results of any additional inspections
that have been conducted, and again recommends either an approval,
approvable, or not approvable action. As with the first review cycle,
the process ends once FDA management reviews the recommendations of the
review team and makes its decision on the action to take on the
application.
Restricting Drug Distribution and Subpart H Regulations:
To address concerns FDA identifies regarding the safe use of a drug,
the agency may condition approval by requiring that the sponsor agree
to restrict the drug's distribution. FDA has established restricted
distribution programs for approved drugs primarily by requiring that a
drug's approval be under the restricted distribution provision of
Subpart H regulations. According to the scope of the regulations,
Subpart H applies to new drugs that "have been studied for their safety
and effectiveness in treating serious or life-threatening illnesses and
that provide meaningful therapeutic benefit to patients over existing
treatments" for the condition.[Footnote 18] FDA may approve a drug
under the restricted distribution provision of these regulations if it
meets these criteria and the agency concludes that the drug is
effective but can be safely used only if distribution or use is
restricted. For example, FDA may require that distribution of a drug be
limited to certain facilities or physicians with special training.
As of February 2007, nine drugs--Actiq, Accutane, Lotronex, Mifeprex,
Plenaxis, Revlimid, Thalomid, Tracleer, and Xyrem--had either an NDA or
supplemental NDA approved under the restricted distribution provision
of Subpart H.[Footnote 19] For each of the drugs, either during the
application review process or based on postmarket data, FDA identified
concerns about the safe use of the drug that led the agency to apply
Subpart H. The drugs were approved to treat a range of conditions, such
as breakthrough cancer pain, specific symptoms of narcolepsy, and
severe acne.
FDA has also required that drug sponsors agree to restrict the
distribution of drugs without imposing Subpart H. Clozaril, Tikosyn,
and Trovan are three examples of drugs that have restricted
distribution programs that were imposed outside of Subpart H. (See app.
I for a table describing drugs FDA has approved with restricted
distribution programs and the conditions they are intended to treat).
While Clozaril was first approved in 1989, FDA imposed distribution
restrictions on both Tikosyn and Trovan after Subpart H regulations had
been promulgated.
A second approval provision of Subpart H provides FDA with
flexibilities that allow the agency to accelerate the approval process
for drugs that provide meaningful therapeutic benefits over
alternatives for serious or life-threatening illnesses.[Footnote 20]
Specifically, under the provision, FDA may approve a drug on the basis
of clinical trials establishing that the drug has an effect on a
surrogate endpoint--such as weight gain or reduced occurrence of
infections in patients with HIV--that is reasonably likely to predict a
clinical benefit or on the basis of an effect on a clinical endpoint
other than survival or irreversible morbidity.[Footnote 21] This allows
FDA to approve a drug before measures of effectiveness that would
usually be required for approval are available. However, under this
approval provision, drug sponsors are ordinarily required to conduct
postmarket studies to confirm and further describe the drug's clinical
benefit. As of February 2007, FDA had used this provision to approve 52
drugs, most of which are intended to treat HIV/AIDS or various cancers.
FDA's Role in Postmarket Oversight:
Because some risks may not become known until after a drug's approval
and use in a wider segment of the population, FDA has a range of
postmarket oversight responsibilities once a drug is approved for
marketing in the United States. FDA's postmarket oversight
responsibilities include assessing sponsors' compliance with
requirements for a given drug, such as postmarketing study commitments,
adverse event reporting, and restricted distribution requirements. In
addition, FDA monitors reported adverse events to assess the postmarket
safety of approved drugs and may take action if it develops a concern
about a drug's safety.
With regard to postmarketing study commitments, FDA oversees sponsors'
compliance with regulations that require sponsors of all approved drugs
to report to FDA annually on their progress in meeting the commitments.
FDA requires that sponsors report on the status of these studies in an
annual report that also includes updates on the distribution of the
drug, labeling changes, clinical literature published on the drug, and
the drug's marketing.[Footnote 22] FDA designates unfulfilled study
commitments as submitted, pending, ongoing, delayed, released, or
terminated.
FDA also oversees sponsors' compliance with regulations that require
sponsors of all approved drugs to report periodically to FDA on safety
information and specific types of adverse events that occur in
association with an approved drug.[Footnote 23] Sponsors must provide
in periodic reports (quarterly for the first 3 years after approval and
annually thereafter) a narrative summary and analysis of adverse event
information. For adverse events that are considered both serious and
unexpected,[Footnote 24] sponsors are required to submit a report--
known as a "Postmarketing 15-day Alert Report"--to FDA within 15
calendar days from the time the sponsor was informed of the event. To
assess sponsors' compliance with these adverse event reporting
requirements, FDA reviews sponsors' reports and conducts inspections of
the sponsors' reporting policies and procedures.
For drugs approved under the restricted distribution provision of
Subpart H, FDA oversees sponsors' compliance with the restrictions
placed on the drugs' distribution or use. To assess compliance with
restrictions, FDA reviews information such as summaries of sponsors'
distribution programs in annual reports and in some cases separate
reports required by the agency to provide details and updates on
distribution programs. In addition, FDA may conduct inspections of a
sponsor's corporate headquarters, manufacturing sites, or contractors,
such as specialty distributors, to evaluate whether distribution
policies and procedures comply with the approved restrictions for a
given drug. If FDA identifies deficiencies during an inspection, it may
issue a formal citation--known as a Form FDA 483. In addition, FDA may
communicate less serious findings as written or oral "observations" or
"recommendations."[Footnote 25]
To monitor postmarket safety of approved drugs, FDA reviews clinical
literature, routinely evaluates the available data on reported adverse
events, and conducts investigations of the nature and patterns of these
events. FDA compiles data from sponsor's reports on adverse events,
along with data from voluntary reports submitted to the MedWatch
program, in its Adverse Event Reporting System (AERS)
database.[Footnote 26] FDA safety evaluators analyze data from AERS and
in the clinical literature to detect signs of potential safety
concerns. These evaluations may reveal the need for further studies of
a drug or may result in FDA action to ensure the safety of the
drug.[Footnote 27]
If FDA identifies problems with a sponsor's compliance with agency
requirements or identifies postmarket safety concerns, the agency can
take a range of actions to address the concern and communicate safety
information to healthcare providers and the public. For example, FDA
may revise the restrictions on a drug's distribution, request changes
to a drug's labeling, issue patient advisories or public health alerts,
or request that a sponsor issue letters to health care providers or
pharmacists to alert them to safety concerns. FDA may also issue a
regulatory letter citing violations of laws or regulations. Typically,
FDA issues a Warning letter for violations that may lead FDA to pursue
further enforcement action if not corrected or issues an untitled
letter for violations that do not meet this threshold. FDA also has the
authority to withdraw a drug's marketing approval for safety-related
and other reasons,[Footnote 28] although it rarely does so.
Additionally, Subpart H regulations establish an expedited process for
withdrawing a drug's marketing approval, in certain
circumstances.[Footnote 29]
FDA Approved Mifeprex under the Subpart H Restricted Distribution
Provision After Concluding That Clinical Evidence Supported Its Safety
and Efficacy:
FDA approved Mifeprex after three review cycles. In its initial review,
FDA concluded that reliance on historical controls in three key
clinical trials was appropriate and consistent with FDA regulations and
that the available data supported the safety and efficacy of the drug.
In an approvable letter, FDA notified the sponsor that it needed to
provide additional data and more detail on its proposal to restrict the
drug's distribution before an approval decision could be made. A second
review cycle began when the sponsor submitted data responding to this
letter. The agency issued a second approvable letter after finding that
new data confirmed Mifeprex's safety and efficacy but also that the
sponsor needed to revise its distribution plan and address labeling and
manufacturing deficiencies. FDA further concluded that the drug was a
candidate for approval under Subpart H. In the final review cycle, FDA
concluded that the sponsor's revised distribution plan and other
revisions were sufficient to address FDA's comments. FDA also concluded
that Mifeprex met the scope of Subpart H and that approval under the
restricted distribution provision of Subpart H was necessary to ensure
that only qualified physicians prescribed the drug. On September 28,
2000, FDA approved Mifeprex under the restricted distribution provision
of Subpart H with several restrictions and two postmarketing study
commitments. (See table 1 for a timeline of key events in the Mifeprex
approval process.)
Table 1: Timeline of Key Events in FDA's Approval of Mifeprex:
Date: First review cycle: March 1996;
Event: The sponsor submitted a new drug application (NDA) for the use
of Mifeprex in combination with the drug misoprostol for the medical
termination of intrauterine pregnancy.
Date: First review cycle: July 1996;
Event: FDA Reproductive Health Drugs Advisory Committee meeting.
Date: First review cycle: September 1996;
Event: FDA issued an approvable letter listing issues that the sponsor
needed to address before the application could be approved.
Date: Second review cycle: August 1999;
Event: After delays securing a manufacturer, the sponsor completed its
responses to FDA's 1996 approvable letter.
Date: Second review cycle: February 2000;
Event: FDA issued a second approvable letter, listing issues that the
sponsor needed to address prior to approval.
Date: Third review cycle: March 2000;
Event: The sponsor completes its responses to FDA's second approvable
letter.
Date: Third review cycle: September 2000;
Event: FDA approved Mifeprex under the restricted distribution
provision of Subpart H.
Date: Third review cycle: November 2000;
Event: Distribution of Mifeprex began in the United States.
Source: GAO analysis of FDA and drug sponsor data.
[End of table]
FDA's Initial Review Cycle and Approvable Action (March to September
1996):
FDA's initial review began when the drug sponsor submitted the Mifeprex
NDA in March 1996. After conducting a preliminary review of the NDA,
FDA designated the application for priority review, establishing a goal
that the agency would issue an action letter within 6 months. FDA's
rationale for the designation was that as the first drug that would be
approved for its particular indication, Mifeprex was a therapeutic
advance because women using the drug could potentially avoid the risks
of surgery and anesthesia involved in a surgical termination of a
pregnancy.
FDA assigned a team of reviewers within the Division of Reproductive
and Urologic Drug Products to review the evidence in the Mifeprex NDA.
The key safety and efficacy data in the NDA consisted of three
historically controlled clinical trials, two conducted in France and
one conducted in the United States. These trials studied the Mifeprex
treatment regimen--mifepristone in combination with misoprostol--in a
total of more than 4,000 women. At the time the NDA was submitted, the
French trials were complete and the U.S. trial was ongoing. As a
result, during the first review cycle, the review team analyzed the
complete safety and efficacy data from the French clinical trials, but
only summary data on serious adverse events from the U.S. clinical
trial. FDA reviewers also considered results from other trials
conducted in Europe from 1983 through 1996 in which mifepristone was
studied either alone or in combination with misoprostol or similar
drugs. In addition, the review team considered safety information from
extensive postmarketing experience in Europe, including a postmarket
safety database containing information on women who had used
mifepristone. Lastly, the review team considered the non-clinical data
in the application, including data on the drug's chemistry and
manufacturing.
In its review of the Mifeprex data, FDA reviewers determined that the
reliance on historical controls in the key clinical trials was
appropriate and consistent with FDA regulation. According to FDA,
historical control designs can make it more difficult to evaluate which
effects can be attributed to the drug being studied.[Footnote 30]
However, FDA regulations list historical controls as an acceptable type
of control when the natural history of the condition being treated is
well-documented and when the effects of the drug are self-
evident.[Footnote 31] In the case of the Mifeprex NDA, FDA determined
that the historically controlled trials provided substantial evidence
of safety and efficacy because the outcomes of women taking the
Mifeprex regimen were compared with the well-documented data on the
natural course of pregnancy, including rates of miscarriage, and the
effect of the drug--termination of a pregnancy--was obvious.[Footnote
32]
To assist the review team in its assessment of Mifeprex, FDA convened
the Reproductive Health Drugs Advisory Committee in July 1996 and asked
the members to examine the data and vote on their conclusions regarding
the drug's safety and efficacy. Six of the eight voting members voted,
with two abstentions, that the available evidence demonstrated that the
benefits of the regimen outweighed its risks for the proposed
indication in the United States. However, the members agreed
unanimously that FDA should provide the final safety and efficacy data
from the U.S. clinical trial for their review. The advisory committee
also discussed the basic elements of a voluntary restricted
distribution system proposed by the drug's sponsor, which would require
that Mifeprex be distributed directly to physicians, that prescribing
physicians meet certain training requirements, and that patients meet
certain conditions before receiving the drug. The advisory committee
voted unanimously that they agreed with the concept of restricting
distribution of the drug but had reservations about how the proposed
system would assure that physicians had adequate credentials. The
members recommended that the sponsor conduct postmarket studies to
address six unanswered questions about the treatment regimen and the
distribution system. The members also provided extensive comments on
the draft labeling proposed by the sponsor.
The FDA review team concluded that the NDA was approvable, based on its
assessment of the clinical and non-clinical data and the input from the
advisory committee. The medical officer leading the review team
concluded that the available clinical data indicated "that medical
abortion can be safely delivered in a wide variety of United States
settings." The data from the French trials showed the treatment to be
roughly 95 percent effective at terminating pregnancy through 49 days
gestation. The data from the French clinical trials also showed that
almost all patients experienced some side effects--such as uterine
cramping and bleeding--most of which were expected based on the way the
drug works. Though serious adverse events were considered rare, some
women experienced bleeding that required medical intervention, and
approximately 0.2 percent of patients required transfusion. The medical
officer concluded that the preliminary U.S. data on adverse events did
not appear to differ significantly from the French trials.[Footnote 33]
In September 1996, FDA issued an approvable letter for the use of
Mifeprex in combination with the drug misoprostol for the termination
of intrauterine pregnancy up to 49 days gestation. In memos documenting
concurrence with the review team, and in the approvable letter itself,
FDA management outlined the clinical and non-clinical issues the
sponsor needed to address prior to approval. First, the full data from
the U.S. clinical trial were needed to establish safety and efficacy of
the Mifeprex regimen in the U.S. health care setting. Second, FDA
agreed with the sponsor's proposal to limit the drug's distribution,
but the sponsor had not yet submitted sufficient detail on how it would
be implemented to allow for the plan to be fully evaluated.[Footnote
34] Third, the drug labeling proposed by the sponsor needed to be
revised to provide more information on the treatment and to address
comments from the advisory committee. Fourth, the sponsor would need to
commit to pursue the postmarket studies suggested by the advisory
committee. Finally, the sponsor would need to address certain
deficiencies in chemistry and manufacturing data identified in FDA's
review.
FDA's Second Review Cycle and Approvable Action (August 1999 to
February 2000):
FDA's second review cycle for the Mifeprex NDA officially began once
the sponsor had completed its responses to the first approvable letter.
However, these responses were delayed because of difficulties the
sponsor encountered in securing a manufacturer for the drug product. In
the interim, the sponsor submitted a range of data to FDA, including
the final safety and efficacy results from the U.S. clinical trial,
updated safety data from other trials of mifepristone and international
postmarketing experience with the drug, formal revisions of the product
labeling, and outstanding chemistry and manufacturing data. In August
1999, the sponsor completed its responses to the approvable letter by
submitting an overview of the key principles of the restricted
distribution system as well as responses to the postmarketing study
commitments. At the time of this submission, the sponsor was still
working with its planned distributor on the details of the restricted
distribution system.
Based on the updated data, the review team recommended approval for the
Mifeprex NDA once the sponsor had clarified the details of the drug's
distribution, revised the drug labeling, and addressed deficiencies in
the chemistry and manufacturing data. The medical officer concluded
that the final results from the U.S. clinical trial were acceptable and
confirmed the results of the French trials that the regimen was safe
and effective.[Footnote 35] The medical officer concluded that the
comments from the July 1996 advisory committee meeting were fully
considered and, to the extent possible, implemented.[Footnote 36] The
medical officer also concluded that additional detail was needed to
determine whether the sponsor's proposed distribution plan was
sufficient. The non-clinical reviews during this review cycle--which
included inspections of manufacturing facilities[Footnote 37]--
identified deficiencies in the drug's chemistry data and manufacturing
processes that needed to be addressed, as well as sections of the
drug's labeling that needed to be revised.
In January 2000, the sponsor submitted a more detailed plan describing
how the proposed distribution restrictions would be implemented. The
plan had three key elements. First, the Mifeprex regimen would only be
administered under the supervision of qualified physicians who had
agreed to provide the treatment according to several guidelines.
Specifically, prescribing physicians would be required to attest to
being able to accurately assess the duration of a pregnancy, diagnose
an ectopic pregnancy,[Footnote 38] and assure that patients have access
to appropriate follow up care if needed to manage complications. The
physicians would also need to agree to fully explain the procedure to
each patient and obtain her signed consent, record the unique product
serial number for tracking purposes, and report any serious adverse
event or on-going pregnancy to the sponsor. Second, the drug would only
be distributed directly to physicians after an authorized distributor
had verified that the physician had registered with it and had a signed
attestation on file. Third, patients would be required to meet certain
conditions before receiving the drug, such as signing a patient
agreement attesting to her understanding of the potential complications
of the treatment.
FDA management concluded that the proposed distribution plan did not
provide for adequate training and certification of prescribing
physicians and needed to be revised before the NDA could be approved.
In February 2000, FDA issued a second approvable letter for Mifeprex,
notifying the sponsor that it needed to revise its proposed
distribution plan, address deficiencies in the drug's chemistry data
and manufacturing, and revise the drug's labeling. The letter also
stated that FDA had considered the application under the restricted
distribution provision of Subpart H and that distribution restrictions
would be necessary in order to assure the safe use of the drug. The
approvable letter further reminded the sponsor of its commitment to
pursue postmarketing study commitments to address questions that were
raised at the time of the advisory committee meeting.
FDA's Final Review Cycle and Marketing Approval for Mifeprex (March to
September 2000):
In March 2000, the sponsor submitted its complete response to FDA's
February 2000 approvable letter. This submission included updated
safety data from ongoing trials and international postmarket
experience, international product labeling, and revisions to the
distribution plan. The sponsor also provided additional data and
revisions--including updated chemistry and manufacturing data, a
revision to the distribution plan, and revised labeling--to address
comments from FDA that arose during the review cycle. The agency's
review of these submissions included multiple meetings and
teleconferences with the sponsor and input from a consultant who was a
special government employee (SGE) and a member of the Reproductive
Health Drugs Advisory Committee.[Footnote 39]
During the final review cycle, FDA's deliberations--which involved a
wide range of agency staff and management, including at times the
Commissioner--focused on four key issues: whether prescribing
physicians should be required to participate in a formal training and
certification program, whether to require that approval be under
Subpart H, what conditions of use should be specified, and what
postmarketing study commitments would be needed to assure the safe use
of the drug.
* Physician Training: In its deliberations, FDA considered requiring
that physicians participate in specific training and have their
qualifications certified before being allowed to prescribe Mifeprex, as
opposed to relying on the sponsor's proposed system of self-
attestation. However, FDA concluded that such a requirement was not
necessary. FDA officials told us that the agency determined that its
concern about ensuring that prescribers were adequately qualified could
be addressed by requiring that the sponsor make educational materials
and training programs readily available and requiring that prescribing
physicians sign an agreement attesting to their qualifications. The SGE
consultant agreed with this conclusion. FDA officials also told us that
the agency wanted to minimize the burden that the restricted
distribution program would place on providers and patients by requiring
only what was necessary to address safety concerns.[Footnote 40]
In July 2000, the sponsor submitted its revised distribution plan. This
plan addressed FDA's comments by providing increased emphasis in the
product labeling on the educational materials and trainings available
to physicians and the importance of participating in the training. The
other key elements of the plan--including the specific qualifications
that physicians were required to meet and agreements regarding
discussing the treatment and adverse event reporting--were essentially
unchanged from those the sponsor proposed in its January 2000 plan.
* Approval under Subpart H Regulations: FDA had maintained through the
first two review cycles that distribution restrictions would be
required for Mifeprex. However, minutes from meetings between FDA and
the sponsor indicate that the agency was still considering whether it
was necessary to impose those restrictions under Subpart H during the
final review cycle. During the second review cycle, FDA had concluded
that the restricted distribution provision could be applied to
Mifeprex.[Footnote 41] FDA eventually concluded that it would be
necessary to do so. In its documented rationale for this conclusion,
FDA stated that the drug met the scope of the regulations because the
termination of an unwanted pregnancy is a serious condition, and that
the drug provided a meaningful therapeutic benefit over existing
therapies by allowing patients to avoid the procedure required with
surgical termination of pregnancy. FDA officials told us that the
agency has broad discretion to determine which conditions or illnesses
may be considered serious or life threatening, and that in the case of
Mifeprex it considered the potential in any pregnancy for serious or
life-threatening complications--such as hemorrhage--in its
determination.[Footnote 42] Additionally, FDA concluded that Mifeprex
could only be used safely if distribution was limited to physicians who
could assess the duration of a pregnancy, diagnose an ectopic
pregnancy, and provide patients with access to surgical intervention if
necessary.
Throughout the approval process, the sponsor was opposed to approval
under Subpart H. Specifically, the sponsor argued that the drug did not
fit within the scope of Subpart H because pregnancy itself is not a
serious or life threatening illness. The sponsor also argued that the
intent of the restricted distribution provision was to allow for
restricted distribution of highly toxic or risky drugs, and that
Mifeprex did not fit this description.[Footnote 43] The sponsor also
expressed concern that approving the drug under Subpart H could
unfairly mark Mifeprex as risky and deter women from using the drug.
Lastly, the sponsor held that imposing Subpart H was unnecessary
because it had voluntarily committed to the distribution restrictions
requested by FDA. However, in a September 2000 letter to FDA, the
sponsor agreed to FDA's requirement that approval be under Subpart H,
while noting that it still believed that applying these regulations to
Mifeprex was not appropriate.
* Conditions of Use: FDA reviewed data and held multiple meetings with
the sponsor regarding the specific conditions of use that should be
required for Mifeprex. For example, FDA deliberated about whether it
was necessary to require that prescribing physicians possess the
ability to perform follow-up surgical interventions in the event that
it was necessary to manage complications. The sponsor maintained that
such a requirement was inconsistent with the practice of medicine,
because management of incomplete miscarriages was routinely handled by
referring patients to outside providers with specialized surgical or
emergency care training. On this issue, FDA concluded that access to
follow-up care could be ensured by requiring adequate information in
the labeling and requiring that physicians attest to having made
arrangements for their patients to have access to any needed surgical
or emergency care. The SGE consultant agreed with FDA's conclusion. FDA
disagreed with the sponsor on other suggested conditions of use. For
example, the sponsor provided data to support allowing patients to self-
administer the misoprostol dose at home, instead of requiring them to
return to their prescribing physicians. FDA concluded that the
available data did not support the safety of home use of misoprostol
and that such use should not be included in the final product label. As
a part of its deliberations about the conditions of use, FDA also
concluded that approved labeling should include a medication guide to
provide patients with information about the risks and benefits of the
drug and the approved conditions of use and treatment regimen.[Footnote
44]
* Postmarketing Study Commitments: In both the September 1996 and
February 2000 approvable letters, FDA had reminded the sponsor of its
commitment to conduct a series of six postmarket studies to address
comments raised in the 1996 advisory committee meeting. FDA reviewed
data and met with the sponsor during the final stages of its review to
revisit these commitments in light of experience gained with the
treatment regimen since the advisory committee meeting, concerns about
potential infringement on the privacy of patients, and the potential
resources needed to fulfill all six commitments. FDA concluded that the
originally proposed commitments could be sufficiently addressed in two
redesigned studies. The first was a study on the safety outcomes of a
group of patients receiving the treatment under the care of physicians
with surgical intervention skills compared to physicians who refer
their patients for surgical intervention when necessary. The second was
a surveillance study to determine the outcomes of ongoing pregnancies
that were not surgically terminated after a failure of the Mifeprex
regimen, including the health of any children born. FDA also concluded
that the outstanding questions could be incorporated into the two
postmarket studies and an audit of signed patient agreement forms.
Once the sponsor had addressed the issues that FDA raised during the
third review cycle, both the review team responsible for the Mifeprex
NDA and FDA management concluded that the drug should be approved. The
medical officer concluded that the updated safety data did not reveal
any new issues that would change the ratio of benefit-to-risk for the
drug. The medical officer also reviewed revised product labeling
related to the distribution of the drug. Based on these reviews, the
medical officer recommended approval of the application. The non-
clinical reviews during this review cycle included additional
inspections of manufacturing facilities. After the sponsor had
addressed several issues, including deficiencies identified in a second
inspection of the drug manufacturing facilities, the non-clinical
reviewers also recommended approval of the application. FDA management
concurred with the recommendations of the review team that the Mifeprex
NDA should be approved.
On September 28, 2000, FDA approved Mifeprex under the restricted
distribution provision of Subpart H. The sponsor began distribution of
Mifeprex in November 2000. FDA approved the drug with the two
postmarketing study commitments discussed above and with several key
restrictions on distribution. First, prescribing physicians must sign a
prescriber's agreement attesting to possessing the training and skills
needed to administer the treatment regimen, and also agreeing to
provide patients with the approved medication guide. They must also
attest that they will fully discuss the treatment with patients and
report to the sponsor any serious adverse events or ongoing pregnancies
that are not terminated after a failure of the Mifeprex regimen.
Second, the drug must be distributed directly to prescribing physicians
by an authorized distributor only after the distributor has verified
that the physician has a signed agreement on file. Third, patients must
sign a patient agreement attesting to having read, discussed, and
understood the risks and potential complications of the treatment. For
a more detailed list of the individual components of the restricted
distribution program for Mifeprex, see appendix II. For a copy of the
approved prescriber's agreement, see appendix III.
Approval Process for Mifeprex Was Generally Consistent with That of the
Other Eight Subpart H Restricted Drugs:
Although each drug had unique risks and benefits, the approval process
for Mifeprex was generally consistent with the approval processes for
the other eight Subpart H restricted drugs. Each of the drugs had
unique risks and benefits that were specific to their indication and
target populations. For some of the drugs, the safety issues that
prompted FDA to apply Subpart H were similar, with the potential for
causing birth defects, the potential for liver or other serious
toxicities, and appropriate patient selection being the most common
issues. However, there were also safe use concerns that were unique to
particular drugs. For example, for Mifeprex, ensuring patient access to
follow-up care was a key safety concern, while for Actiq a key concern
was ensuring that children did not accidentally ingest the
drug.[Footnote 45] Each of the drugs represented potential advances in
the treatment of their targeted condition and in two cases--Mifeprex
and Xyrem--the drug was the first approved to treat that condition.
(See app. I for a table including each of the Subpart H restricted
drugs and their approved indications.)
One common element across the approval processes for the Subpart H
restricted drugs was that for seven of the drugs, including Mifeprex,
FDA needed to evaluate potential limitations in key clinical data
supporting the NDA. Specifically, with the exception of Accutane and
Lotronex, the drugs were approved on the basis of studies without
concurrent controls or data that were limited by relatively small
sample sizes or data collection issues.[Footnote 46] FDA approved the
Mifeprex NDA on the basis of historically controlled clinical trials
that studied the drug in several thousand patients. FDA concluded that
the use of historical controls was not a limitation because the course
of pregnancy was well-documented and the effect of the treatment was
self-evident. Revlimid, Thalomid, Plenaxis, and Xyrem were also each
approved on the basis of data that included at least one key clinical
study that lacked a concurrent control.[Footnote 47] In contrast to the
Mifeprex data, FDA concluded that the lack of concurrent controls in
these studies was a weakness because data on the course of the disease
in a comparable population was not available to be used as a reliable
historical control. For example, Thalomid was approved on the basis of
clinical trial data from the published literature as well as a series
of retrospective case studies for several dozen patients.[Footnote 48]
Additionally, five of the drugs--Actiq, Revlimid, Thalomid, Tracleer,
and Xyrem--were approved on the basis of key clinical studies with
relatively small sample sizes of several hundred patients or less.
Finally, for Actiq, Plenaxis, Thalomid, and Xyrem, FDA identified data
collection issues, such as incomplete documentation, in some of the key
data sources.
Another common element was that for six of the drugs, including
Mifeprex, FDA issued at least one prior action letter before ultimately
approving the drug for marketing. FDA issued one approvable letter
before ultimately approving Thalomid and Tracleer. Both Mifeprex and
Xyrem received two approvable letters. In some cases the types of
issues FDA cited--such as insufficient safety or efficacy data, the
need for additional information on the restricted distribution system,
or chemistry and manufacturing issues--were similar. For all four of
these drugs, the adequacy of proposed distribution restrictions was a
significant issue. For Xyrem, FDA's initial approvable action was also
linked to the sufficiency of the data provided in the application. FDA
issued not approvable letters for both Actiq and Plenaxis prior to
their eventual approval. In the case of Actiq, FDA cited multiple
deficiencies, such as reliance on a key clinical study with flaws and
an inadequate plan for risk management. For Plenaxis, FDA initially
concluded that the risks of the drug exceeded its benefits because of
the potential for severe, systemic allergic reactions in patients.
As a result of these complexities, the approval process for the Subpart
H restricted drugs was typically longer than the process for other
drugs. Across the seven drugs with NDAs approved under Subpart H, an
average of almost 25 months elapsed from the time that the sponsor
submitted its NDA to the time FDA approved the NDA. The length of time
to approval ranged from almost 9 months for Revlimid to more than 54
months for Mifeprex. In comparison, in analyses conducted for our 2006
report on new drug development, we found that it took FDA on average
almost 18 months to approve NDAs submitted from 1996 through
2002.[Footnote 49]
We also found that the types of distribution restrictions FDA imposed
on Mifeprex were similar to those imposed on the other Subpart H
restricted drugs, though the specifics of the restrictions depended on
FDA's safe use concern for the drug.[Footnote 50] (See table 2.) For
all of the drugs except Actiq, FDA required some form of program
enrollment or registration process. For example, for Mifeprex and three
other drugs, FDA required that patients sign written agreements and
that physicians enroll in a prescribing program and attest to their
qualifications. For five of the drugs, FDA required formal registries
of all prescribing physicians and patients.[Footnote 51] Additionally,
for seven of the drugs, FDA required that distribution be limited to
authorized distributors or pharmacies.[Footnote 52] And for eight of
the drugs, FDA required that the sponsor establish a process to ensure
that dispensing or distribution of the drug was contingent on
verification that physicians and others had enrolled or registered in
the distribution program, or that patients had complied with certain
safety measures. FDA also required that all of the sponsors implement
some form of educational program for patients, prescribers, or
pharmacists, though FDA did not require that prescribing physicians
participate in formal training for any of the drugs. For six of the
nine drugs, FDA required that the sponsor report periodically to the
agency specifically on implementation of their restricted distribution
programs. For seven of the drugs, FDA required that sponsors report to
the agency on specific adverse events--such as fetal exposures or liver
toxicity--more frequently than is required for other drugs. In the case
of Mifeprex and Xyrem, at the time the drugs were approved, FDA did not
require that the sponsors submit additional adverse event reports
beyond those required for all approved drugs, but did require that
physicians agree to report specific types of adverse events to the
sponsor.
Table 2: Selected Features of Restricted Distribution Programs Imposed
by FDA at Time of Approval under Subpart H:
Features Required at Approval: Program enrollment or registration[A];
Mifeprex (mife-pristone): [Check];
Lotronex (alosetron hydro-chloride): [Check];
Actiq (oral transmucosal fentanyl citrate): [Empty];
Thalomid (thalidomide): [Check];
Tracleer (bosentan): [Check];
Xyrem (sodium oxybate): [Check];
Plenaxis (abarelix for injectable suspension): [Check];
Revlimid (lenali- domide): [Check];
Accutane (isotretinoin): [Check].
Features Required at Approval: Limited distribution channels[B];
Mifeprex (mife-pristone): [Check];
Lotronex (alosetron hydro-chloride): [Empty];
Actiq (oral transmucosal fentanyl citrate): [Empty];
Thalomid (thalidomide): [Check];
Tracleer (bosentan): [Check];
Xyrem (sodium oxybate): [Check];
Plenaxis (abarelix for injectable suspension): [Check];
Revlimid (lenali- domide): [Check];
Accutane (isotretinoin): [Check].
Features Required at Approval: Dispensing or distribution contingent on
verification[C];
Mifeprex (mife-pristone): [Check];
Lotronex (alosetron hydro-chloride): [Check];
Actiq (oral transmucosal fentanyl citrate): [Empty];
Thalomid (thalidomide): [Check];
Tracleer (bosentan): [Check];
Xyrem (sodium oxybate): [Check];
Plenaxis (abarelix for injectable suspension): [Check];
Revlimid (lenali-domide): [Check];
Accutane (isotretinoin): [Check].
Features Required at Approval: Sponsor developed educational
programs[D];
Mifeprex (mife-pristone): [Check];
Lotronex (alosetron hydro- chloride): [Check];
Actiq (oral transmucosal fentanyl citrate): [Check];
Thalomid (thalidomide): [Check];
Tracleer (bosentan): [Check];
Xyrem (sodium oxybate): [Check];
Plenaxis (abarelix for injectable suspension): [Check];
Revlimid (lenali- domide): [Check];
Accutane (isotretinoin): [Check].
Features Required at Approval: Reporting specific to implementation of
restricted distribution program;
Mifeprex (mife-pristone): [Empty];
Lotronex (alosetron hydro-chloride): [Check];
Actiq (oral transmucosal fentanyl citrate): [Check];
Thalomid (thalidomide): [Check];
Tracleer (bosentan): [Check];
Xyrem (sodium oxybate): [Empty];
Plenaxis (abarelix for injectable suspension): [Check];
Revlimid (lenali-domide): [Empty];
Accutane (isotretinoin): [Check].
Features Required at Approval: Additional adverse event reporting by
the sponsor[E];
Mifeprex (mife-pristone): [Empty];
Lotronex (alosetron hydro-chloride): [Check];
Actiq (oral transmucosal fentanyl citrate): [Check];
Thalomid (thalidomide): [Check];
Tracleer (bosentan): [Check];
Xyrem (sodium oxybate): [Empty];
Plenaxis (abarelix for injectable suspension): [Check];
Revlimid (lenali-domide): [Check];
Accutane (isotretinoin): [Check].
Source: GAO analysis of FDA data.
[A] Program enrollment or registration requirements varied across the
drugs. For Accutane, Lotronex, Mifeprex, and Plenaxis, FDA required
that physicians enroll in a prescribing program and attest to their
qualifications. For Accutane, Revlimid, Thalomid, Tracleer, and Xyrem,
FDA required formal registries of all prescribing physicians and
patients. FDA also required registration of pharmacies, wholesalers, or
distributors for Thalomid, Revlimid, and Accutane.
[B] The specific limitations imposed on distribution channels varied
across the drugs, and in some cases more than one limitation was
required. These limitations included, for example, requiring that a
drug only be distributed directly to prescribing physicians, allowing
only authorized distributors or wholesalers to ship a drug, and
allowing only registered or centralized pharmacies to dispense a drug.
[C] The verification mechanisms varied across the drugs. For example,
for Mifeprex, an authorized distributor must verify that a physician
has a signed prescriber agreement on file before distributing the drug.
For Lotronex, before dispensing and drug, pharmacists must verify that
prescriptions include a sticker that is only available to physicians
enrolled in the prescribing program. For Accutane, Revlimid, and
Thalomid, a registered pharmacy is required to confirm prescription
authorizations and that patients have complied with requirements to use
one or more methods of contraception before dispensing the drug.
[D] In general, sponsors were required to develop educational materials
(such as patient information videos) for patients, and make educational
materials and training programs readily available to prescribing
physicians, pharmacists, and other groups involved in the restricted
distribution program. For some of the drugs, dispensing pharmacists
were required to participate in formal training. At the time of Subpart
H approval, FDA required medication guides for all of the drugs except
Actiq, Plenaxis, and Thalomid.
[E] Sponsors for seven of the drugs were required to submit 15-day
alert reports on specific adverse events. Sponsors of four of the drugs
were required to provide updates more frequently than typically
required for events related to FDA's safe use concern for the drug. For
Mifeprex, as part of their prescriber agreement, physicians agreed to
report ongoing pregnancies, hospitalizations, transfusions, and other
serious events to the sponsor. For Xyrem, FDA required that physicians
agree to collect and report to the sponsor information on specific
adverse events and inappropriate use of the drug.
[End of table]
Finally, eight of the nine Subpart H restricted drugs were approved
with two or more postmarketing study commitments.[Footnote 53] Each of
these had at least one commitment that involved developing a postmarket
study to monitor adverse events or patient outcomes of interest for
that drug. The number of study commitments FDA required ranged from 2
to 10, depending on the drug. Additionally, for most of the drugs,
including Mifeprex, the study protocols for the various commitments had
not been finalized at the time of approval.
FDA's Postmarket Oversight of Mifeprex Has Been Consistent with the
Agency's Oversight of the Other Subpart H Restricted Drugs:
The actions FDA has taken to oversee Mifeprex have been consistent with
the actions it has taken to oversee the other Subpart H restricted
drugs. FDA has relied primarily on information submitted by the
sponsors of all the Subpart H restricted drugs and inspections for
three of the drugs to oversee compliance with restricted distribution
requirements. FDA has also relied on updates submitted by these
sponsors to oversee compliance with postmarketing study commitments and
has found that most have unfulfilled commitments. To oversee compliance
with adverse event reporting requirements, FDA has reviewed a variety
of safety information including reports submitted by the sponsors of
all nine of the drugs restricted under Subpart H and has conducted
inspections to evaluate compliance with reporting of adverse events for
eight of the drugs. As a result, for most of the drugs, FDA has
identified deficiencies in compliance with adverse event reporting
requirements. To oversee reported adverse events FDA has used similar
methods--such as monitoring, investigating, and addressing safety
concerns--for Mifeprex and the other eight Subpart H restricted drugs.
As a result of its oversight of safety data, FDA has identified
postmarket safety concerns for most of the drugs and has used a variety
of methods to communicate safety information to health care providers
and the public. (See table 3 for an overview of FDA's postmarket
oversight of these drugs.)
Table 3: Selected Features of FDA's Oversight of Postmarket Safety for
Drugs Approved under Subpart H, as of May 2008:
Oversight Activities and Findings: FDA has completed inspection(s) to
oversee compliance with distribution restriction requirements[A];
Mifeprex (mife-pristone): [Check];
Lotronex (alosetron hydro-chloride): [Empty];
Actiq (oral transmucosal fentanyl citrate): [Empty];
Thalomid (thalidomide): [Empty];
Tracleer (bosentan): [Check];
Xyrem (sodium oxybate): [Check];
Plenaxis (abarelix for injectable suspension): [Empty];
Revlimid (lenali-domide): [Empty];
Accutane (isotretinoin): [Empty].
Oversight Activities and Findings: FDA has classified at least one
postmarketing study commitment as unfulfilled[B];
Mifeprex (mife- pristone): [Check];
Lotronex (alosetron hydro-chloride): [Check];
Actiq (oral transmucosal fentanyl citrate): [Check];
Thalomid (thalidomide): [Check];
Tracleer (bosentan): [Check];
Xyrem (sodium oxybate): [Empty];
Plenaxis (abarelix for injectable suspension): [Check];
Revlimid (lenali-domide): [Check];
Accutane (isotretinoin): n/a.
Oversight Activities and Findings: FDA has conducted inspection(s) to
oversee compliance with adverse event reporting requirements[C];
Mifeprex (mife-pristone): [Check];
Lotronex (alosetron hydro-chloride): [Check];
Actiq (oral transmucosal fentanyl citrate): [Check];
Thalomid (thalidomide): [Check];
Tracleer (bosentan): [Check];
Xyrem (sodium oxybate): [Check];
Plenaxis (abarelix for injectable suspension): [Check];
Revlimid (lenali-domide): [Empty];
Accutane (isotretinoin): [Check].
Oversight Activities and Findings: FDA has identified a postmarket
safety concern leading to communication of new safety information to
public or health care providers[D];
Mifeprex (mife-pristone): [Check];
Lotronex (alosetron hydro-chloride): [Check];
Actiq (oral transmucosal fentanyl citrate): [Check];
Thalomid (thalidomide): [Check];
Tracleer (bosentan): [Check];
Xyrem (sodium oxybate): [Check];
Plenaxis (abarelix for injectable suspension): [Empty];
Revlimid (lenali-domide): [Check];
Accutane (isotretinoin): [Check].
Source: GAO analysis of FDA data.
Note: FDA provided or confirmed data on these selected features of
oversight through May 2008.
[A] In May 2008, FDA officials told us that they had conducted such
inspections for three additional drugs. However, the reports from those
inspections were not yet available. Inspections were in addition to
report review.
[B] FDA classifies unfulfilled postmarketing study commitments as
ongoing, pending, delayed, released, or terminated;
FDA has documented that the sponsor for Xyrem has fulfilled two of its
postmarketing study commitments and has submitted the final report for
the third and final commitment.
[C] Inspections were in addition to report review conducted for all of
the drugs. In the case of Revlimid, FDA inspected Celgene--the sponsor
of both Revlimid and Thalomid--before Revlimid was approved in December
2005.
[D] Communication of new safety information includes activities such as
changing product labeling, issuing Public Health Advisories and Safety
Alerts, and distributing letters to health care providers.
[End of table]
To Oversee Compliance with Distribution Restrictions, FDA Relied on
Information Submitted by All Drug Sponsors and Its Own Inspections for
Some of the Drugs, Including Mifeprex:
For all nine of the drugs that have been approved under the restricted
distribution provision of Subpart H, FDA has relied mainly on
information submitted by sponsors in required reports to oversee the
sponsors' compliance with distribution restrictions. For six of the
drugs--not including Mifeprex--FDA relied on reports specific to the
drugs' restricted distribution programs.[Footnote 54] The type of
information provided by the sponsors in these documents included data
on the operation of the restricted distribution program, such as
requirements for distributors, pharmacies, prescribers, and patients
participating in the program. In addition, to oversee compliance with
the restricted distribution programs for most of the drugs--including
Mifeprex--FDA has relied on annual reports, supplemental applications,
or periodic reports for required updates on the postmarket use of the
drugs, including summaries of updates to the restricted distribution
program.[Footnote 55]
Through the end of 2007, FDA had conducted inspections specifically to
oversee sponsors' compliance with distribution restrictions for three
of the drugs--Mifeprex, Tracleer, and Xyrem. In the case of Mifeprex,
in 2002 FDA conducted routine inspections of two of the drug's
distributors to oversee their compliance with distribution
restrictions. FDA inspectors reviewed standard operating procedures and
other information in order to oversee adherence to the requirements of
the restricted distribution program such as procedures for maintaining
signed provider agreements, distributing medication guides with
shipments of the drug, and maintaining the physical security of the
drug. For one of the inspections of Mifeprex distributors, FDA did not
issue a citation. For the other inspection, FDA issued a citation in
which the agency cited four inconsistencies between the approved
distribution plan and the distributor's standard operating procedures.
For example, FDA cited the distributor for the absence of certain
written procedures pertaining to the distribution of the drug. The
sponsor responded to this citation, noting that at the time of approval
the distribution plan did not require that distributors prepare such
written procedures. Other examples of the inconsistencies FDA noted
were serial numbers that had not been properly recorded on a shipping
label as required for tracking purposes and the requirement that a
medication guide be provided with each dose of the drug was not
reflected in the written procedures for processing orders. As a result
of its 2006 inspection of the Tracleer restricted distribution program,
FDA did not issue a formal citation, but provided recommendations to
the sponsor. In its 2007 inspection of the Xyrem restricted
distribution program, FDA did not identify any specific
deficiencies.[Footnote 56] However, many of the responsibilities for
the program are contracted out to a pharmacy, which was not inspected.
The inspection report notes that, for that reason, FDA could not verify
whether the sponsor had fulfilled the requirements for the drug's
restricted distribution program.
Although FDA's inspections for Mifeprex and Tracleer led to
recommendations for improving the respective restricted distribution
programs, through the end of 2007, FDA had not conducted inspections of
compliance with restricted distribution requirements for six Subpart H
restricted drugs. FDA officials told us that the agency has conducted
inspections of compliance with distribution restrictions for three
additional drugs since the beginning of 2008.[Footnote 57],[Footnote
58]
To Oversee Compliance with Postmarketing Study Commitments, FDA Relied
on Sponsors' Data That Found That Most Have Unfulfilled Commitments:
For the eight Subpart H restricted drugs approved with postmarketing
study commitments, FDA has relied on sponsors' annual reports for
updates on the status of each commitment. FDA's reviews of these
reports are the basis for its determination of the status of each
commitment as fulfilled, submitted, pending, ongoing, delayed,
released, or terminated. FDA officials told us that the status of
postmarketing study commitments for Subpart H drugs is monitored the
same way as those commitments for other drugs.
Seven of the eight Subpart H restricted drugs approved with
postmarketing study commitments had at least one commitment that was
not fulfilled as of September 2007.[Footnote 59] Of these seven drugs,
most have study commitments that FDA has classified as ongoing,
pending, or delayed.[Footnote 60] In the case of Mifeprex, FDA had
categorized both of the drug's postmarketing study commitments--to
which the sponsor agreed at time of the drug's approval in 2000--as
ongoing until December 2007 when the agency changed the status of one
of the commitments to released. For the first commitment--a study to
compare outcomes for patients whose health care providers perform a
surgical abortion with outcomes for patients who are referred to
another facility for follow-up care in the event of treatment failure-
-the sponsor has reported difficulty in enrolling participants into the
study. FDA told us that according to the sponsor, the "vast majority of
prescribers" can provide surgical abortion services on site. FDA has
opted not to terminate the study, and has categorized it as ongoing.
FDA officials told us that this gives the agency additional flexibility
in the event that provider or practice patterns change over time,
making enrollment of study participants more feasible. The sponsor also
has reported enrollment challenges in the case of the second study
commitment for Mifeprex--to conduct surveillance of ongoing pregnancies
following failure of treatment. FDA officials told us that postmarket
experience with the drug has shown that most patients opt to have a
surgical abortion in the event that the Mifeprex regimen is not
successful in terminating the pregnancy. In December 2007, FDA released
the sponsor from this commitment because it determined that the study
will no longer provide helpful information because of low enrollment.
FDA has worked with some of the sponsors of the Subpart H restricted
drugs to make adjustments to agreed upon commitments that have not been
completed.[Footnote 61] FDA officials told us that the agency has in
some cases made changes to a sponsor's postmarketing study commitments
or requested new commitments in addition to those specified at
approval. For example, FDA recommended several additional postmarketing
study commitments for Thalomid following the agency's approval of an
expanded indication for the drug. In the case of Tracleer, FDA
recommended changes to some of the drug's study commitments. FDA had
not requested additions or changes to the postmarketing study
commitments for Mifeprex until the agency released the sponsor from its
commitment to conduct surveillance of ongoing pregnancies following
failure of treatment.
To Oversee Compliance with Adverse Event Reporting Requirements, FDA
Reviewed Sponsors' Data, Conducted Inspections and Identified
Deficiencies for Most of the Drugs:
To oversee compliance with adverse event reporting requirements, FDA
has both reviewed data submitted by sponsors in required reports and
conducted inspections. Sponsor reporting for the drugs has included
annual reports in which the sponsor provided a summary of the adverse
events reported in the previous year; periodic update reports which
inform FDA of adverse events monthly, quarterly, or at some other
interval established by FDA; and 15-day alert reports for events that
are both serious and unexpected. In addition, in some cases sponsors
have agreed or FDA has required them to provide 15-day alert reports
for other types of serious adverse events. For example, the sponsor of
Mifeprex agreed to provide 15-day alert reports for cases of serious
infection and ruptured ectopic pregnancy in women who used the drug,
and FDA required the sponsor of Thalomid to report suspected or
confirmed pregnancy in women taking that drug.[Footnote 62] In some
cases, including for Mifeprex, FDA specifically documented its
assessments of adverse event reporting contained in annual, periodic
update, or 15-day alert reports or reports submitted to the AERS
database. FDA officials told us that staff review all submitted
reports, but do not always document their reviews.
In addition to relying on reports submitted by the sponsors, FDA has
conducted inspections specifically to oversee the sponsors' compliance
with adverse event reporting requirements for eight of the nine drugs,
including Mifeprex.[Footnote 63] Between 2001 and May 2008, FDA had
conducted 19 such inspections with a range of none to four inspections
conducted for each drug.[Footnote 64] In the case of Mifeprex, FDA has
conducted three inspections--in 2002, 2004, and 2006--related to
adverse event reporting. In these inspections, FDA reviewed a variety
of documents pertaining to adverse event reporting for Mifeprex,
including standard operating procedures, product labeling, MedWatch
reporting forms, 15-day alert reports, complaint file, periodic update
reports on adverse events, and annual NDA reports. In addition, FDA
documented reviews of samples of the sponsor's adverse event reports
for completeness, accuracy, and timeliness.
As a result of the Mifeprex inspections, FDA issued citations for
deficiencies related to the accuracy, completeness, or timeliness of
some reports as well as for the sponsor's failure to follow certain
procedures for handling some adverse event follow-up activities. In
each of the Mifeprex inspections, FDA identified some examples of
misclassified reports--events which FDA said should have been submitted
as 15-day alert reports rather than in periodic reports. For example,
FDA cited the sponsor for not classifying some events resulting in
hospitalization as serious events and thus not reporting those events
as 15-day alert reports. In another inspection, FDA found that some of
the sponsor's procedures for reporting and following up on adverse
events were inadequate or had not been developed. These deficiencies
were similar to those FDA found for other drugs, and FDA identified
fewer problematic reports for Mifeprex than for some of the other
Subpart H restricted drugs. Following each of the inspections for
Mifeprex, the sponsor provided a written response to FDA in which it
either agreed to address FDA's findings or noted its disagreement with
the deficiencies FDA cited. For example, following the first
inspection, the sponsor agreed to address the examples of misclassified
or incomplete reporting FDA cited and to reinforce procedures for
handling adverse event-related correspondence with its staff. In some
cases the sponsor disagreed with FDA's characterization of a deficiency
or presented evidence to refute a claim that it had not complied with a
reporting requirement or procedure.
As a result of FDA's inspections for the other seven drugs, the agency
issued written citations to six of the sponsors for deficiencies. In
addition, FDA noted only "oral observations" for the other sponsor.
Similar to the Mifeprex inspections, FDA staff reviewed information
such as sponsor documentation and standard operating procedures related
to adverse event reporting for the other seven drugs for which it
conducted inspections. As it did for the Mifeprex inspections, FDA
reviewed samples of adverse event reports for completeness, accuracy,
or timeliness for most of the other drugs. As it did with Mifeprex, FDA
cited some sponsors for deficiencies such as incomplete or late
reporting of adverse events or failure to adhere to certain procedures
for reporting. For example, FDA cited the sponsor of Thalomid for
failure to submit several reports of serious and unexpected adverse
events as a 15-day alert report and for late reporting of some other
adverse events that included deaths and hospitalizations. In addition,
FDA issued an untitled letter to the sponsor citing its failure to
review and submit 82 reports of serious and unexpected adverse events
within the required time frame.
FDA was not always consistent in how it documented deficiencies in
adverse event reporting. In some of its inspections FDA documented the
same type of deficiency as a citation while in others it noted them as
oral observations or discussion points. For example, FDA did not issue
a citation for the sponsor of Tracleer after inspectors noted 52 late
15-day reports--instead discussing the late reports with the sponsor at
the close of the inspection. However, in its first inspection of the
sponsor for Mifeprex, FDA issued a citation for failure to file a
single 15-day report within the required 15 days. FDA also cited the
sponsor for 6 late 15-day reports in each of its two subsequent
inspections, although the sponsor refuted this finding in written
responses following each inspection. As in the case of Mifeprex,
sponsors responded to FDA in writing to describe actions they had taken
to address deficiencies or to disagree with FDA's conclusions following
an inspection.
To Oversee Postmarket Safety, FDA Used Similar Methods to Review
Reported Adverse Events and Took a Variety of Actions in Response to
Emerging Concerns:
FDA has used similar methods to oversee postmarket safety--monitoring,
investigating, and taking action on emerging safety concerns--for
Mifeprex and the other eight Subpart H restricted drugs. For Mifeprex,
FDA has routinely reviewed the available information on reported
adverse events from sources such as annual reports, periodic update
reports, 15-day alerts, and data from its AERS database. Since the time
Mifeprex was approved, FDA has documented regular reviews and
summarized the available data on adverse event reports to monitor the
drug's safety. FDA believes that, because the distribution system for
Mifeprex requires that prescribing physicians agree to report
hospitalizations and other serious adverse events, it is unlikely there
are significant numbers of these events that are not reported to FDA.
However, FDA acknowledges that because the reporting system is
voluntary, the agency cannot be certain that they have reports of all
serious adverse events.
FDA officials have concluded that, with the exception of the cases of
fatal infection, the reported serious adverse events associated with
Mifeprex have been within or below the ranges expected based upon the
medical literature on adverse events following medical abortion. In its
May 2006 response to congressional inquiries regarding
Mifeprex,[Footnote 65] FDA stated that the most commonly reported
serious adverse events had been blood loss requiring a transfusion,
infection, and ectopic pregnancy. FDA estimated that 0.023 percent of
U.S. women who had taken Mifeprex have required transfusion, compared
to a transfusion rate of 0.15 percent observed in international studies
of the drug. FDA also noted that the rate of ectopic pregnancy among
U.S. women who had used Mifeprex was 0.005 percent, compared to the
overall rate of 1.3 to 2 percent in all U.S. pregnancies. Based on the
medical literature, FDA estimated that fewer than 1 percent of patients
will develop an infection of any kind following medical abortion with
Mifeprex.
According to FDA, as of May 2008, among the estimated 915,000 U.S.
women who had taken Mifeprex for termination of pregnancy since its
approval, the agency was aware of seven deaths that may be related to
the use of the drug.[Footnote 66] Six of the deaths were due to severe
infection, and one death involved an undiagnosed ectopic pregnancy. Of
the cases involving infection, five of the women were infected with a
rare bacterium, Clostridium sordellii, while one woman was infected
with the bacterium Clostridium perfringens. With assistance from the
Centers for Disease Control and Prevention (CDC) and other outside
experts, FDA has investigated all reported infection-related deaths in
U.S. women who have taken the Mifeprex regimen for termination of
pregnancy. These investigations included requesting the medical records
and autopsy reports for each case; evaluating available adverse event
data from the United States, the United Kingdom, and the World Health
Organization; consulting with scientific experts and health care
providers from inside and outside FDA; and microbiological testing to
identify the bacterium involved. In addition, FDA evaluated samples
from the drug lots of Mifeprex and misoprostol associated with some of
the deaths to test for contamination with the bacteria.[Footnote 67]
FDA found that in the six cases of death due to infection, the women
used a regimen of Mifeprex and misoprostol that has not been approved
by FDA.[Footnote 68] FDA has stated that it is aware that many health
care providers use modified regimens, and while some of the regimens
have been described in the medical literature, FDA has not evaluated
the safety and effectiveness of any other regimen than the one
described in the drug's approved labeling.
To further explore the nature of the infections, FDA initiated an
interagency scientific workshop in May 2006 with CDC and the National
Institutes of Health entitled "Emerging Clostridial Disease." These
agencies had observed a general increase in the United States in
reports of serious clostridial infections including infections in women
who had used Mifeprex, that raised questions about Clostridium's
relationship to fatal illness and pregnancy. According to the meeting
minutes, participants discussed recent cases of clostridial infection-
-including those occurring among women who had taken Mifeprex and
misoprostol for termination of pregnancy and those who had not--
reviewed what was currently known about these infections, and discussed
how to conduct surveillance to ensure that cases and trends of
clostridial infections are monitored. At the workshop, a CDC official
reported on the history of clostridial infections, including a cluster
of ten fatal cases reported in the literature between 1977 and 2001
among previously healthy women. Of the ten cases, eight of the women
became infected following childbirth, one became infected following a
medical abortion, and the other case was unrelated to pregnancy.
As a result of its investigative efforts, FDA has concluded that the
evidence does not indicate that Mifeprex caused the fatal infections.
In response to congressional inquiry, FDA stated that "the nature of
the relationship between taking a single dose of the drug and the
reported cases of serious infection with a rare bacterium is highly
uncertain."[Footnote 69] Laboratory testing of samples from the drug
lots of Mifeprex and misoprostol associated with some of the deaths due
to infection has shown no evidence of contamination with the
bacteria.[Footnote 70] FDA officials have said that the relationship
between the infections and the use of unapproved regimens of Mifeprex
and misoprostol remains unknown. Some research has suggested that the
use of Mifeprex may suppress the immune system which could lead to
infection. However, FDA has noted that if this were the case, the
agency would expect to see a higher rate of other types of serious
infections in patients who had used the drug, which has not been the
case. FDA has noted that findings by the CDC and in the medical
literature suggest that pregnancy itself--rather than the medication--
may be the critical risk factor for women who have become infected with
Clostridium sordellii.
FDA, working with the drug's sponsor, has taken a variety of steps--
such as issuing warnings and making changes to the product labeling--to
address safety concerns for Mifeprex that were identified through
postmarket monitoring and investigation. For example, in response to
reports of ruptured ectopic pregnancy, FDA developed a questions and
answers document about the condition and worked with the drug's sponsor
to alert health care providers and to highlight the importance of
careful screening for the condition. In addition, FDA approved a
labeling change to provide information about the importance of
evaluating patients for ectopic pregnancy. In response to concerns
about serious infections and associated deaths--all of which involved
an off-label use of the drug--FDA issued Public Health Advisories to
notify healthcare providers about patient deaths and the treatment
regimens used in those cases, and to remind them of the regimen FDA has
approved, and that FDA has not established the safety of alternative
regimens. In addition, FDA issued a news release, reviewed letters from
the sponsor to health care providers and emergency room directors to
alert them to the safety concerns regarding serious infection, and
approved changes to product labeling including revisions to the warning
to include information about the deaths due to serious
infection.[Footnote 71] FDA also has established a Web site with
information about Mifeprex, questions and answers about the drug, and
links to other safety-related information.[Footnote 72] FDA used
labeling changes--including updating the medication guide that
prescribers agree to discuss with their patients--and information
posted on its Web site to remind consumers and health care providers
that FDA has not assessed the safety and efficacy of any regimen other
than the one approved for the drug and indicated in its labeling.
FDA has similarly monitored adverse events for the other Subpart H
restricted drugs. As FDA has done with Mifeprex, the agency has
documented periodic safety reviews of the available information it had
on reported adverse events for all of the other drugs. FDA's reviews
analyzed data on reported adverse events from sources such as annual
NDA reporting, periodic update reports, 15-day alerts, and data from
the AERS database. Some FDA reviews summarized the available data on a
specific type of adverse event--like liver toxicity, or severe
bleeding--or adverse events in general, in order to determine whether
the data suggest an emerging safety concern for the drug. In addition,
in some cases, as it did with Mifeprex, FDA has sought the advice and
assistance of other federal agencies and outside experts to investigate
serious adverse events.
As a result of its monitoring activities, FDA has identified postmarket
safety concerns for most of the Subpart H restricted drugs and has
taken similar actions to address them. When FDA has found safety
concerns related to a Subpart H restricted drug, it has worked with the
drug's sponsor to employ a variety of measures to ensure the drug's
safe use. These have included adding or strengthening a warning on the
label, issuing a Public Health Advisory, and sending letters to health
care providers to alert them to a safety risk. FDA has approved safety-
related labeling changes, such as boxed warnings, for eight of the nine
drugs. In the case of four of the drugs, including Mifeprex, the agency
issued a Public Health Advisory or Safety Alert. The sponsors of five
of the drugs including Mifeprex sent a letter to health care providers
who prescribe (or may prescribe) the drug to alert them of safety
concerns or to communicate new information regarding the drug. For
example, in the case of Tracleer, adverse event reports revealed an
increased risk of liver damage in patients who were treated with the
drug. As a result, FDA and the sponsor notified health care providers
of the risk by issuing a Safety Alert, highlighting the need for
continued monitoring of liver function in patients using the drug. The
sponsor added a boxed warning about potential liver injury to the
labeling and issued a letter to health care providers to alert them to
the potential risk. In general, the actions FDA took in response to
safety concerns were similar across all of the drugs.
Agency Comments:
We provided HHS with a draft of this report for review. HHS informed us
that it did not have general comments on the draft report. In addition,
HHS provided technical comments, which we incorporated as appropriate.
As we agreed with your offices, unless you publicly announce the
contents of this report earlier, we plan no further distribution of it
until 30 days from the date of this letter. We will then send copies to
others who are interested and make copies available to others who
request them. In addition, the report will be available at no charge on
GAO's Web site at [hyperlink, http://www.gao.gov].
If you or your staffs 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 IV.
Signed by:
Marcia Crosse:
Director, Health Care:
[End of section]
Appendix I: Select Drugs Approved by FDA with Restricted Distribution:
Table 4:
Drugs approved under the restricted distribution provision of Subpart
H: Accutane (isotretinoin);
Condition treated: Severe recalcitrant nodular acne;
Application type (year first approved under Subpart H): Supplemental
NDA (2005).
Drugs approved under the restricted distribution provision of Subpart
H: Actiq (oral transmucosal fentanyl citrate);
Condition treated: Management of breakthrough cancer pain in patients
with malignancies who are already receiving and who are tolerant to
opioid therapy;
Application type (year first approved under Subpart H): NDA (1998).
Drugs approved under the restricted distribution provision of Subpart
H: Lotronex (alosetron hydrochloride);
Condition treated: Severe diarrhea predominant irritable bowel syndrome
(IBS) in women who have: chronic IBS symptoms (generally lasting 6
months or longer), had anatomic or biochemical abnormalities of the
gastrointestinal tract excluded, and failed to respond to conventional
therapy;
Application type (year first approved under Subpart H): Supplemental
NDA (2002).
Drugs approved under the restricted distribution provision of Subpart
H: Mifeprex (mifepristone);
Condition treated: Medical termination of intrauterine pregnancy
through 49 days' pregnancy;
Application type (year first approved under Subpart H): NDA (2000).
Drugs approved under the restricted distribution provision of Subpart
H: Plenaxis (abarelix for injectable suspension);
Condition treated: Palliative treatment of men with advanced
symptomatic prostate cancer, with specified risks or symptoms;
Application type (year first approved under Subpart H): NDA (2003).
Drugs approved under the restricted distribution provision of Subpart
H: Revlimid (lenalidomide);
Condition treated: Treatment of a limited subset of patients with
transfusion dependent anemia;
Application type (year first approved under Subpart H): NDA (2005).
Condition treated: Drugs approved under the restricted distribution
provision of Subpart HThalomid (thalidomide): Treatment of multiple
myeloma patients who have received at least one prior therapy;
Application type (year first approved under Subpart H): Drugs approved
under the restricted distribution provision of Subpart HThalomid
(thalidomide): Supplemental NDA.
Drugs approved under the restricted distribution provision of Subpart
H: Thalomid (thalidomide);
Condition treated: Acute treatment of cutaneous manifestations of
moderate to severe erythema nodosum leprosum (ENL) and as maintenance
therapy for prevention and suppression of the cutaneous manifestations
of ENL recurrences;
Application type (year first approved under Subpart H): NDA (1998).
Condition treated: Drugs approved under the restricted distribution
provision of Subpart HTracleer (bosentan): Newly diagnosed multiple
myeloma;
Application type (year first approved under Subpart H): Drugs approved
under the restricted distribution provision of Subpart HTracleer
(bosentan): Two Supplemental NDAs[A].
Drugs approved under the restricted distribution provision of Subpart
H: Tracleer (bosentan);
Condition treated: Pulmonary arterial hypertension;
Application type (year first approved under Subpart H): NDA (2001).
Drugs approved under the restricted distribution provision of Subpart
H: Xyrem (sodium oxybate);
Condition treated: Cataplexy associated with narcolepsy;
Application type (year first approved under Subpart H): NDA (2002).
Drugs approved under the restricted distribution provision of Subpart
H: Select Drugs with restricted distribution imposed outside of Subpart
H;
Condition treated: [Empty];
Application type (year first approved under Subpart H): Application
type (year first approved).
Drugs approved under the restricted distribution provision of Subpart
H: Clozaril (clozapine);
Condition treated: Management of severely ill schizophrenic patients
who fail to respond adequately to standard drug treatment for
schizophrenia;
Application type (year first approved under Subpart H): NDA (1989).
Drugs approved under the restricted distribution provision of Subpart
H: Tikosyn (dofetilide);
Condition treated: Irregular heartbeats (atrial fibrillation and atrial
flutter);
Application type (year first approved under Subpart H): NDA (1999).
Drugs approved under the restricted distribution provision of Subpart
H: Trovan (trovafloxacin/ alatrofloxacin);
Condition treated: Serious, life-or limb-threatening infections in an
inpatient healthcare setting;
Application type (year first approved under Subpart H): n/ a[B] (1997).
Source: GAO analysis of FDA data.
Note: We list each drug by its trade name with its chemical name in
parentheses.
[A] These supplemental NDAs were approved under both the restricted
distribution and surrogate endpoint provisions of Subpart H.
[B] Trovan was not originally approved with distribution restrictions.
Based on postmarket evidence of serious liver injury in some patients,
the sponsor agreed to FDA's requests to limit the distribution of
Trovan to patients with specific symptoms only in inpatient settings.
However, these restrictions were not associated with a supplemental
application.
[End of table]
[End of section]
Appendix II: Detailed Description of Distribution Restrictions for
Mifeprex:
FDA approved Mifeprex with the following specific restrictions on
distribution:
* Mifeprex must be provided by or under the supervision of a physician
who possesses adequate qualifications and agrees to provide the
treatment according to several guidelines. To accomplish this, the
system required that prescribing physicians register with an authorized
distributor by providing a signed Prescriber's Agreement attesting to
the following:
* Possesses the ability to assess the duration of pregnancy accurately.
* Possesses the ability to diagnose ectopic pregnancies.
* Possesses the ability to provide surgical intervention in cases of
incomplete abortion or severe bleeding, or has made plans to provide
such care through other qualified physicians, and are able to assure
patient access to medical facilities equipped to provide blood
transfusions and resuscitation, if necessary.
* Has read and understood the prescribing information about Mifeprex.
* Will provide each patient with a medication guide and fully explain
the procedure to each patient, provide her with a copy of the
medication guide and Patient Agreement, give her an opportunity to read
and discuss both the medication guide and the Patient Agreement, obtain
her signature on the Patient Agreement and sign it as well.
* Will notify the sponsor or its designate in writing as discussed in
the Package Insert under the heading DOSAGE AND ADMINISTRATION in the
event of an ongoing pregnancy, which is not terminated subsequent to
the conclusion of the treatment procedure.
* Will report any hospitalization, transfusion or other serious events
to the sponsor or its designate.
* Will record the Mifeprex package serial number in each patient's
record.
* Provisions for the physical security of the drug during distribution
such as:
* Direct distribution of the drug through select authorized
distributors to physicians who have signed the Prescriber's Agreement,
which includes providing their medical license number. Distributors are
required to ensure that the physician is registered before distributing
the drug.
* Secure manufacturing, receiving, distribution, shipping, and return
procedures, including unique serial numbers on packaging and tamper-
proof seals.
[End of section]
Appendix III: Prescriber's Agreement for Mifeprex Distribution:
The following is the prescriber's agreement at the time of the Mifeprex
approval. Under the restricted distribution program for Mifeprex, the
agreement is provided--by the sponsor's licensee Danco Laboratories,
Inc.--to all providers to be signed and returned before the prescriber
can receive any shipments of Mifeprex.
MIFEPREXTM:
(Mifepristone) Tablets, 200 mg:
Prescriber's Agreement:
We are pleased that you wish to become a provider of Mifeprex*
(Mifepristone) Tablets, 200 mg, which is indicated for the medical
termination of intrauterine pregnancy through 49 days from the first
day of the patient's last menstrual period (see full prescribing
information). Prescribing Information, Mifeprex Medication Guides and
PATIENT AGREEMENT forms will be provided together with your order of
Mifeprex.
Prior to establishing your account and receiving your first order, you
must sign and return this letter to the distributor, indicating that
you have met the qualifications outlined below and will observe the
guidelines outlined below. If you oversee more than one office
facility, you will need to list each facility on your order form prior
to shipping the first order.
By signing the reverse side, you acknowledge receipt of the
Prescriber's Agreement and agree that you meet these qualifications and
that you will follow these guidelines for use. You also understand that
if you do not follow these guidelines, the distributor may discontinue
distribution of the drug to you.
Under Federal law, Mifeprex must be provided by or under the
supervision of a physician who meets the following qualifications:
* Ability to assess the duration of pregnancy accurately.
* Ability to diagnose ectopic pregnancies.
* Ability to provide surgical intervention in cases of incomplete
abortion or severe bleeding, or have made plans to provide such care
through others, and are able to assure patient access to medical
facilities equipped to provide blood transfusions and resuscitation, if
necessary.
* Has read and understood the prescribing information of Mifeprex. The
prescribing information is attached to this letter, and is also
available by calling our toll free number, 1-877-4 Early Option (1-877-
432-7596), or logging on to our website, [hyperlink,
http://www.earlyoptionpill.com].
In addition to these qualifications, you must provide Mifeprex in a
manner consistent with the following guidelines.
* Under Federal law, each patient must be provided with a Medication
Guide. You must fully explain the procedure to each patient, provide
her with a copy of the Medication Guide and Patient Agreement, give her
an opportunity to read and discuss them, obtain her signature on the
Patient Agreement, and sign it yourself.
* The patient's follow-up visit at approximately 14 days is very
important to confirm that a complete termination of pregnancy has
occurred and that there have been no complications. You must notify
Danco Laboratories in writing as discussed in the Package Insert under
the heading Dosage And Administration in the event of an on-going
pregnancy which is not terminated subsequent to the conclusion of the
treatment procedure.
* While serious adverse events associated with the use of Mifeprex are
rare, you must report any hospitalization, transfusion or other serious
event to Danco Laboratories, identifying the patient solely by package
serial number to ensure patient confidentiality.
* Each package of Mifeprex has a serial number. As part of maintaining
complete records for each patient, you must record this serial number
in each patient's record.
Danco Laboratories, LLC:
P.O. Box 4816:
New York, NY 10185:
1-877-4 Early Option (1-877-432-7596):
[hyperlink, http://www.earlyoptionpill.com:
[End of section]
Appendix IV: GAO Contact and Staff Acknowledgments:
GAO Contact:
Marcia Crosse, (202) 512-7114 or crossem@gao.gov.
Acknowledgments:
In addition to the contact named above, Martin T. Gahart, Assistant
Director; Jill Center; Chad Davenport; and Cathy Hamann made key
contributions to this report. Julian Klazkin also contributed.
[End of section]
Footnotes:
[1] Mifeprex is the trade name for the mifepristone product marketed in
the United States. Mifepristone is the name of the underlying drug
substance. Mifepristone is also sometimes called "RU-486," a reference
to the name the drug had during laboratory testing.
[2] Subpart H of FDA's drug approval regulations--titled "Accelerated
Approval of New Drugs for Serious or Life-Threatening Illnesses"--
applies to drugs that are intended to treat serious or life-threatening
illnesses and provide a meaningful therapeutic benefit to patients over
existing treatments. The regulations contain two approval provisions.
One provides a process through which FDA may restrict the distribution
or use of a drug to assure its safe use. The other provides FDA with
flexibilities that allow the agency to accelerate the approval process
for certain drugs on the basis of clinical trial endpoints that are
considered reasonably likely to predict clinical benefit. See 21 C.F.R.
§§ 314.500-560 (2007).
[3] A drug sponsor is the person or entity who assumes responsibility
for the marketing of a new drug, including responsibility for complying
with applicable laws and regulations.
[4] FDA also reviews supplemental NDAs, which sponsors submit to
support proposed changes to a drug's label, a new dosage or strength of
the drug, a new patient population or intended use, or changes to the
way the drug is manufactured after a drug has an approved NDA.
[5] FDA issued a final rule on July 10, 2008, amending its drug
approval regulations. The final rule, among other things, discontinues
FDA's use of approvable letters and not approvable letters. Instead, in
the event that FDA determines it will not approve an application in its
current form, the agency will send applicants a "complete response
letter" to indicate that the review cycle for an application is
complete and to describe the specific deficiencies the agency
identified in the application. The amended regulations are effective on
August 11, 2008. See 73 Fed. Reg. 39588-89 (July 10, 2008).
[6] 21 C.F.R. § 314.520 (2007). From 1992--the year that the
regulations were promulgated--through February 2007, nine drugs,
including Mifeprex, had either an NDA or supplemental NDA approved
under this restricted distribution provision. Under the Food and Drug
Administration Amendments Act of 2007 (FDAAA), FDA may determine that a
risk evaluation and mitigation strategy (REMS) is necessary to ensure
that the benefits of a drug outweigh its risks. The REMS provisions of
FDAAA went into effect on March 25, 2008. As part of a REMS, FDA can
require "elements to assure safe use," which include restrictions
similar to those that can be required under Subpart H regulations. 21
U.S.C. § 355-1(a), (e), (f); Pub. L. No. 110-85, §§ 901, 909(a), 121
Stat. 823, 922, 926-38, 950.
[7] 21 C.F.R. § 314.126(b)(2)(v) (2007). In contrast, clinical trials
that use concurrent controls demonstrate the safety and efficacy of a
drug by comparing its effects on patients in a treatment group to the
effects of a different treatment--such as another drug or a placebo--on
patients in a control group within the same study population.
[8] The term postmarket refers to activities occurring after a drug has
been approved for marketing. FDA uses the term adverse drug event to
refer to any untoward medical event associated with the use of a drug
in humans.
[9] FDA regulations require sponsors of approved drugs to submit
various postmarket safety reports. See 21 C.F.R. §§ 314.80, 314.81
(2007). Additionally, sponsors of approved drugs must report to FDA
annually on the progress of any postmarket studies required by FDA or
agreed to by the sponsor. 21 U.S.C. § 356b; 21 C.F.R. §
314.81(b)(2)(vii) (2007). FDA uses such postmarket studies to gather
additional information about a drug's safety, efficacy, or use once it
is marketed.
[10] In response to a Freedom of Information Act request, FDA posted
certain documents pertaining to its approval of Mifeprex on the
agency's Web site (see [hyperlink,
http://www.fda.gov/cder/archives/mifepristone/default.htm]). The
documents, which total over 9,000 pages, include a range of sometimes
redacted material such as handwritten notes or email communications,
communications between the drug sponsor and FDA, meeting minutes,
copies of international labeling, and study protocols.
[11] FDA may convene an advisory committee to obtain advice from
scientific experts and representatives of the public regarding a drug.
FDA requests advice from advisory committees on a variety of matters,
including aspects of drug applications and postmarket safety concerns
for drug products. The primary role of an advisory committee is to
provide independent advice that will contribute to the quality of the
agency's regulatory decision-making. Although the committees provide
recommendations to the agency, final decisions are made by FDA.
[12] The Population Council, a non-profit organization involved in
reproductive health and population issues, sponsored the Mifeprex
application. During the NDA review process, the Population Council
contracted with Danco Laboratories, L.L.C. to serve as its licensee
with responsibility for commercial manufacturing and marketing of the
drug. Following the drug's approval, the Population Council transferred
ownership of the Mifeprex NDA to Danco.
[13] We initiated our work in February 2007. In June 2007, FDA approved
one additional drug--Letairis--under the restricted distribution
provision of Subpart H. This drug was not included in our review.
[14] Misoprostol is one of several drugs that had been studied in
combination with mifepristone for the medical termination of pregnancy
because they have been shown to induce uterine contractions. However,
it is approved for marketing in the United States for a different
indicated use.
[15] The company that discovered mifepristone and manufactured it for
marketing in France--Roussel Uclaf--did not want to produce the drug
for the U.S. market. Instead, the U.S. sponsor retained a contract
manufacturer. For a more detailed discussion of the history of the
development of mifepristone for the U.S. market, see: Congressional
Research Service, Abortion: Termination of Early Pregnancy with RU-486
(Mifepristone), (Washington, D.C.: 2001).
[16] FDA may grant priority review status when it determines that a
drug may provide significant benefits in the treatment, diagnosis, or
prevention of a disease as compared to marketed drugs or non-drug
therapies, such as surgery, or provide a treatment where no adequate
therapy exists.
[17] The non-clinical data in an NDA pertains to, for example a drug's
chemistry, manufacturing, and controls as well as its toxicology and
pharmacology.
[18] 21 C.F.R. § 314.500 (2007).
[19] 21 C.F.R. § 314.520 (2007). The sponsor for Plenaxis--approved in
2003 for the palliative care of certain patients with advanced prostate
cancer--withdrew the product from the market in 2006. Additionally,
three generic versions of Accutane have been approved for marketing
under this restricted distribution provision.
[20] See 21 C.F.R. § 314.510 (2007).
[21] According to FDA, although some surrogate endpoints are recognized
as well-established and have long been a basis for approval (such as
change in blood pressure or cholesterol), accelerated approval
regulations allow reliance on a "surrogate endpoint that, while
'reasonably likely' to predict clinical benefit, is not so well-
established as the surrogates ordinarily used as bases of approval in
the past." 57 Fed. Reg. 58942, 58944 (Dec. 11, 1992).
[22] See 21 C.F.R. § 314.81 (2007).
[23] See 21 C.F.R. § 314.80 (2007).
[24] Unexpected events are those that are not included in the current
labeling for a drug.
[25] FDA uses the same reporting scheme--noting citations,
observations, or recommendations--for its inspections to assess sponsor
compliance with adverse event reporting.
[26] MedWatch is a voluntary reporting program through which health
professionals and consumers can report adverse reactions, product
problems, and use errors related to drugs and other products approved
by FDA.
[27] GAO has previously reported on and made recommendations regarding
FDA's postmarket oversight of approved drugs. See GAO, Drug Safety:
Improvements Needed in FDA's Postmarket Decision-making and Oversight
Process. GAO-06-402. (Washington, D.C.: Mar. 31, 2006).
[28] 21 U.S.C. § 355(e).
[29] Under Subpart H regulations, FDA may withdraw a drug's marketing
approval after providing for a hearing, in the following circumstances;
(1) a postmarketing clinical study fails to verify clinical benefit;
(2) the sponsor fails to perform the required postmarketing study with
due diligence; (3) use after marketing demonstrates that postmarketing
restrictions are inadequate to assure safe use of the drug product; (4)
the sponsor fails to adhere to the postmarketing restrictions agreed
upon; (5) the promotional materials are false or misleading; or (6)
other evidence demonstrates that the drug product is not shown to be
safe or effective under its conditions of use. 21 C.F.R. § 314.530
(2007).
[30] See FDA, Guidance for Industry: E 10 Choice of Control Group and
Related Issues in Clinical Tials (Rockville, Md.: May 2001).
[31] 21 C.F.R. § 314.126(b)(2)(v) (2007). The regulation also states
that studies that are "adequate and well-controlled" provide the
primary basis for determining whether there is "substantial evidence"
in support of the claims of effectiveness for new drugs. Among other
things, an adequate and well-controlled study provides sufficient
details of study design, conduct, and analysis to allow critical
evaluation, and the design must permit a valid comparison with a
control to provide a quantitative assessment of the drug's effect.
[32] FDA has cited examples of other drugs that have relied upon
historical controls. According to FDA, for contraceptives the effect of
the drug can be compared to the well-documented rate of pregnancy in
sexually active women between the ages of 15 and 35 in the absence of
contraception. For example, FDA approved the contraceptive drug
products Lybrel, Implanon, Yaz, and NuvaRing on the basis of
historically controlled clinical trials.
[33] The medical officer noted that it was only possible to make
general comparisons across these events because definitions and
reporting requirements were different in the two countries.
Additionally, while the sponsor had not yet completed its analysis of
the safety and efficacy data from the U.S. clinical trial, information
from the studies was forwarded to the sponsor weekly. The medical
officer concluded, based on preliminary examination of this
information, that the final results of the U.S. trials were likely to
be similar to the results of the French trials.
[34] FDA management's concurrence memos noted that because the sponsor
had voluntarily proposed a restricted distribution system, imposing
restrictions through Subpart H regulations did not appear warranted.
[35] The U.S. clinical trial data showed the treatment to be 92 percent
effective for terminating pregnancy through 49 days gestation, which
was slightly lower than the 95 percent from the French trials. Adverse
event rates were also slightly higher in the U.S. trials. The medical
officer attributed these differences to the relative inexperience of
U.S. clinicians with the treatment. In addition, the medical officer
concluded that the updated information from international studies,
postmarket experience, and the published literature was consistent with
the results from the U.S. and French trials.
[36] In November 1999, FDA provided advisory committee members the
final results from the U.S. clinical trial for their review and
comment. FDA did not receive any comments from the members on these
results.
[37] The drug substance (mifepristone) in the Mifeprex product was
manufactured by the Shanghai Haulian Pharmaceutical Co., Ltd., with the
manufacturing facilities located in China. Initial FDA inspections
found the manufacturer not in compliance with FDA's good manufacturing
practice standards.
[38] Ectopic pregnancy--which occurs when a fertilized egg improperly
implants outside of the uterus--is a contraindication for receiving the
Mifeprex regimen. Accurate screening to ensure that patients with an
ectopic pregnancy do not receive the treatment was a concern because a
ruptured ectopic pregnancy is a life-threatening condition and its
symptoms are similar to the side effects of the Mifeprex regimen.
[39] According to FDA, it is not uncommon for the agency to consult
with members of its advisory committees who have special expertise in a
particular drug under review. Generally, an SGE is defined as an
officer or employee who is retained, designated, appointed, or employed
by the government to perform temporary duties, with or without
compensation, for not more than 130 days during any period of 365
consecutive days. 18 U.S.C. § 202(a).
[40] Subpart H regulations state that any restrictions imposed will be
commensurate with the specific safety concerns presented by the drug
product. 21 C.F.R. § 314.520(b) (2007).
[41] FDA had also noted that approving the drug under Subpart H would
allow the agency to impose similar restrictions on any future generic
mifepristone products approved for the same indication. The patent for
Mifeprex expired in October 2004, but as of May 2008, no generic
versions of mifepristone have been approved for marketing.
[42] The terms "serious" and "life-threatening" are not defined in
Subpart H regulations, but were discussed in the preambles to the
proposed and final rules. In its proposed rule, FDA stated that the
seriousness of a disease is a matter of judgment, but generally is
based on its impact on survival, day-to-day functioning, or other
factors, and provided examples of conditions that could be within the
scope of the regulation. FDA noted that many diseases or conditions can
be serious for some populations in some or all of their phases and
explicitly reserved the discretion to determine whether the regulations
were applicable to a given product. See 57 Fed. Reg. 13234-5 (Apr. 15,
1992), 57 Fed. Reg. 58942, 58946 (Dec. 11, 1992); See also 21 C.F.R. §§
312.34, 312.81 (2007), and FDA, Guidance for Industry: Fast Track Drug
Development Programs--Designation, Development, and Application Review
(Rockville, Md.: Jan. 2006).
[43] In support of its arguments about the intent of the regulations,
the sponsor cited the pertinent language from preambles to the proposed
and final rules. See footnote 42.
[44] FDA may require that a drug be distributed with a medication guide
that provides patients with information about the safe and effective
use of the drug. See 21 C.F.R. pt. 208 (2007).
[45] Actiq contains the controlled substance fentanyl in a lozenge
formulation intended to allow for more rapid delivery of the medication
for pain management in patients who have developed a tolerance. Because
of the formulation there are concerns that Actiq may be perceived by
children as a lollipop.
[46] Both Accutane and Lotronex were approved under Subpart H after
they had first been marketed in the United States. In the case of
Lotronex, the sponsor withdrew the drug from the market in 2000 because
of safety concerns. In 2002, FDA approved a supplemental NDA under
Subpart H, allowing the drug to be marketed with a restricted
distribution program and substantially more limited indication. For
Accutane, which was originally approved for marketing in 1982, FDA
approved a supplemental NDA under the restricted distribution provision
of Subpart H in 2005 in order to require a more formal restricted
distribution program that linked Accutane prescribing and dispensing to
pregnancy testing results.
[47] FDA approved Plenaxis on the basis of one uncontrolled clinical
trial in the indicated population--men with advanced symptomatic
prostate cancer--and three concurrently-controlled clinical trials in
men with less advanced prostate cancer. FDA approved Xyrem on the basis
of one uncontrolled key safety trial, and two concurrently-controlled
clinical trials.
[48] FDA considers such case studies to be historically controlled. In
this case, the reviewing division concluded that the data were not
sufficient to demonstrate the safety and efficacy of Thalomid. However,
that decision was overridden by both the Director of the relevant FDA
office and the Director of FDA's Center for Drug Evaluation and
Research, based on their individual analyses of the available data.
[49] 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). In contrast, the
drugs approved under the surrogate endpoint provision of Subpart H have
generally been approved more rapidly than drugs approved under the
restricted distribution provision of Subpart H and than drugs approved
outside of Subpart H.
[50] Additionally, except for Plenaxis, FDA convened a meeting of the
relevant advisory committee prior to each drug's approval under Subpart
H to obtain expert input regarding the appropriate actions to address
the agency's safe use concerns, including the distribution restrictions
that should be required. The advisory committee meetings that FDA has
held for the drugs Accutane and Lotronex occurred after each drug was
first marketed in the United States, but prior to their approvals under
Subpart H.
[51] FDA has used various types of registries as a mechanism to collect
data on patients, providers, and others as a tool for monitoring
outcomes of interest.
[52] Two of the drugs--Actiq and Xyrem--were approved as controlled
substances and therefore subject to the restrictions imposed by the
Controlled Substances Act. Requirements imposed under this act are
enforced by the Drug Enforcement Administration and are distinct from
the distribution restrictions imposed on these drugs by FDA under
Subpart H. See, e.g., 21 U.S.C. § 822; 21 C.F.R. § 1301.11 (2007).
[53] FDA's approval of Accutane under Subpart H through a supplemental
NDA did not include any postmarket study commitments.
[54] FDA approved six of the nine Subpart H restricted drugs with a
requirement that the sponsor report periodically to FDA specifically on
implementation of the respective restricted distribution program. Under
FDAAA, sponsors of all drugs with an approved REMS will be required to
submit periodically to FDA an assessment of their REMS. Pub. L. No. 110-
85, § 901(b), 823 Stat. 929, 932, codified at 21 U.S.C. § 355-1.
[55] Though FDA's Subpart H regulations provide an expedited process
for withdrawing marketing approval for a drug if FDA determines that
promotional materials are false or misleading, the agency has not done
so for a Subpart H drug. See 21 C.F.R. § 314.530(a)(5) (2007). However,
it has issued warning letters citing the sponsors for two of the drugs-
-Thalomid and Tracleer--for promoting unapproved use of the drug in
violation of FDA regulations.
[56] FDA's inspection report notes that the sponsor refused to provide
FDA access to full reports from audits that the sponsor had conducted
to evaluate its contractors' compliance with agreed upon
responsibilities under the restricted distribution program.
[57] In 2008, FDA conducted initial inspections specific to the
restricted distribution programs for Accutane, Actiq, and Revlimid. In
addition, FDA conducted a second such inspection for the Tracleer
program. As of May 13, 2008, the results from these inspections were
not available.
[58] In February 2007, agency officials told us that they were working
to establish a process to conduct regular inspections to oversee
sponsors' compliance with distribution restrictions for Subpart H
restricted drugs. Since that time, agency officials told us that FDA
had decided to combine the inspection of restricted distribution
programs with inspections examining compliance with adverse event
reporting requirements. However, agency officials noted in May 2008
that FDA is reevaluating its process for conducting inspections in
light of recent legislative changes. Under FDAAA, FDA is required to
evaluate, at least annually, for one or more drugs that have elements
to assure safe use as part of their REMS, whether those elements assure
the safe use of the drug, are not unduly burdensome on patient access,
and to the extent practicable minimize the burden on the health care
delivery system. 21 U.S.C. § 355-1(f)(5)(B).
[59] FDA has documented that the sponsor for Xyrem has fulfilled two of
its postmarket study commitments and has submitted the final report for
the third and final commitment.
[60] In its June 2006 report on FDA's management of postmarket studies,
the Department of Health and Human Services Office of the Inspector
General found that it is common across all drugs approved by FDA with
postmarket study commitments for sponsors to have unfulfilled
commitments.
[61] FDA may withdraw approval of a drug approved under Subpart H if a
sponsor does not carry out its required postmarketing studies with due
diligence. 21 C.F.R. § 314.530(a)(2) (2007). According to FDA, the
regulations only require postmarketing study commitments for drugs
approved under the surrogate endpoint provision (21 C.F.R. § 314.510)
and not for drugs approved under the restricted distribution provision
(21 C.F.R. § 314.520). FDAAA provides FDA with additional authority
with regard to requiring postmarketing studies and/or trials. See 21
U.S.C. § 355(o)(3).
[62] Mifeprex labeling specifically cautions against the use of the
drug in women with ectopic pregnancy. The sponsor has noted that the
condition is not an adverse drug experience as FDA defines the term.
[63] As of May 2008 FDA had not conducted an adverse event reporting
inspection for the sponsor of Revlimid since this drug was approved
under Subpart H. The agency inspected Celgene--the sponsor of Revlimid
and Thalomid--in 2001, 2002, 2004, and 2005, but these inspections
occurred before Revlimid was approved in December 2005. FDA officials
told us they did not have specific goals for how frequently sponsors
are inspected to monitor compliance with adverse event reporting
requirements.
[64] These inspections include two inspections of the sponsor of
Accutane (isotretinoin). FDA conducted an additional four adverse event
reporting inspections of sponsors or the manufacturer of generic
isotretinoin products.
[65] FDA statement to the Subcommittee on Criminal Justice, Drug
Policy, and Human Resources, Committee on Government Reform, May 17,
2006.
[66] In her testimony to Congress on May 17, 2006, Dr. Janet Woodcock
stated FDA was aware of five infection-related deaths in U.S. women. In
the course of GAO's research for this study, FDA reported that an
additional infection-related death occurred in 2007. In her testimony,
Dr. Woodcock also discussed three other cases of deaths in U.S. women
who had taken Mifeprex that, following investigation, were determined
unlikely to be related to the use of the drug. In addition, she
discussed three women in other countries whose deaths were related to
the use of mifepristone and misoprostol for medical abortion.
[67] The product tracking provision of the restricted distribution
program for Mifeprex enabled FDA to locate the lot numbers for the
drugs administered in each of the cases.
[68] In the case of five of the deaths in the U.S. due to infection,
the women used an oral dose of Mifeprex, followed by a dose of
misoprostol taken intravaginally. In the other case of death due to
infection, the woman used an oral dose of Mifeprex followed by a dose
of misoprostol taken by inserting it in the pouch of the cheek. The
regimen approved by FDA calls for swallowing doses of both Mifeprex and
misoprostol.
[69] See FDA letter to Representative Mark E. Souder, then-Chairman of
the Subcommittee on Criminal Justice, Drug Policy, and Human Resources,
Committee on Government Reform, U.S. House of Representatives, July 31,
2006.
[70] FDA officials told us that the agency did not test for bacterial
contamination of the specific lot associated with the most recent death
because examination of the prior lots revealed no contamination.
[71] FDA officials told us that the sponsor distributed a letter to all
health care providers who had signed the prescriber's agreement as of
the time of the distribution of the letter and distributed a letter to
all emergency room directors in the United States.
[72] FDA's Web site for Mifeprex safety information is located at:
[hyperlink,http://www.fda.gov/cder/drug/infopage/mifepristone/default.ht
m]
GAO's Mission:
The Government Accountability Office, the audit, evaluation and
investigative arm of Congress, exists to support Congress in meeting
its constitutional responsibilities and to help improve the performance
and accountability of the federal government for the American people.
GAO examines the use of public funds; evaluates federal programs and
policies; and provides analyses, recommendations, and other assistance
to help Congress make informed oversight, policy, and funding
decisions. GAO's commitment to good government is reflected in its core
values of accountability, integrity, and reliability.
Obtaining Copies of GAO Reports and Testimony:
The fastest and easiest way to obtain copies of GAO documents at no
cost is through GAO's Web site [hyperlink, http://www.gao.gov]. Each
weekday, GAO posts newly released reports, testimony, and
correspondence on its Web site. To have GAO e-mail you a list of newly
posted products every afternoon, go to [hyperlink, http://www.gao.gov]
and select "E-mail Updates."
Order by Mail or Phone:
The first copy of each printed report is free. Additional copies are $2
each. A check or money order should be made out to the Superintendent
of Documents. GAO also accepts VISA and Mastercard. Orders for 100 or
more copies mailed to a single address are discounted 25 percent.
Orders should be sent to:
U.S. Government Accountability Office:
441 G Street NW, Room LM:
Washington, D.C. 20548:
To order by Phone:
Voice: (202) 512-6000:
TDD: (202) 512-2537:
Fax: (202) 512-6061:
To Report Fraud, Waste, and Abuse in Federal Programs:
Contact:
Web site: [hyperlink, http://www.gao.gov/fraudnet/fraudnet.htm]:
E-mail: fraudnet@gao.gov:
Automated answering system: (800) 424-5454 or (202) 512-7470:
Congressional Relations:
Ralph Dawn, Managing Director, dawnr@gao.gov:
(202) 512-4400:
U.S. Government Accountability Office:
441 G Street NW, Room 7125:
Washington, D.C. 20548:
Public Affairs:
Chuck Young, Managing Director, youngc1@gao.gov:
(202) 512-4800:
U.S. Government Accountability Office:
441 G Street NW, Room 7149:
Washington, D.C. 20548:
