Food and Drug Administration: Approval and Oversight of the Drug Mifeprex
Published: 2008-08-07T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: 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.
section_title: What GAO Found
paragraphs: 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.

section_title: Letter
paragraphs: 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. 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. 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. FDA reviews the NDA  to determine whether the drug’s benefits outweigh its risks. 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). 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.
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. 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. For approved drugs, FDA oversees  sponsors’ compliance with applicable reporting requirements, distribution  restrictions, and other conditions of approval. 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. We also  reviewed documentation from an FDA advisory committee meeting,  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, 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. 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.
subsections: section_title: Background
paragraphs: 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. 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. 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.
subsections: section_title: FDA Application Review Process
paragraphs: 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. 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.  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.
section_title: Restricting Drug Distribution and Subpart H Regulations
paragraphs: 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. 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. 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. 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. 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.
section_title: FDA’s Role in Postmarket Oversight
paragraphs: 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. 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. 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, 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.”
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. 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.
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, although it rarely does so. Additionally,  Subpart H regulations establish an expedited process for withdrawing a  drug’s marketing approval, in certain circumstances.
section_title: FDA Approved Mifeprex under the Subpart H Restricted Distribution Provision After Concluding That Clinical Evidence Supported Its Safety and Efficacy
paragraphs: 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.)
subsections: section_title: FDA’s Initial Review Cycle and Approvable Action (March to September 1996)
paragraphs: 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. 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. 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.
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.
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. 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.
section_title: FDA’s Second Review Cycle and Approvable Action (August 1999 to February 2000)
paragraphs: 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. The  medical officer concluded that the comments from the July 1996 advisory  committee meeting were fully considered and, to the extent possible,  implemented. 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—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, 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.
section_title: FDA’s Final Review Cycle and Marketing Approval for Mifeprex (March to September 2000)
paragraphs: 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.
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.
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. 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.  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.  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.
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.
section_title: Approval Process for Mifeprex Was Generally Consistent with That of the Other Eight Subpart H Restricted Drugs
paragraphs: 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. 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. 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. 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. 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.
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. (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.  Additionally, for seven of the drugs, FDA required that distribution be  limited to authorized distributors or pharmacies. 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.
Finally, eight of the nine Subpart H restricted drugs were approved with  two or more postmarketing study commitments. 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.
section_title: FDA’s Postmarket Oversight of Mifeprex Has Been Consistent with the Agency’s Oversight of the Other Subpart H Restricted Drugs
paragraphs: 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.)
subsections: section_title: 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
paragraphs: 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. 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.
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. 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.
section_title: To Oversee Compliance with Postmarketing Study Commitments, FDA Relied on Sponsors’ Data That Found That Most Have Unfulfilled Commitments
paragraphs: 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.
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.
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). 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. 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.
section_title: To Oversee Compliance with Adverse Event Reporting Requirements, FDA Reviewed Sponsors’ Data, Conducted Inspections and Identified Deficiencies for Most of the Drugs
paragraphs: 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. 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. Between 2001 and May 2008, FDA had conducted 19  such inspections with a range of none to four inspections conducted for  each drug. 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.
section_title: To Oversee Postmarket Safety, FDA Used Similar Methods to Review Reported Adverse Events and Took a Variety of Actions in Response to Emerging Concerns
paragraphs: 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, 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. 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. 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. 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.”  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. 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. FDA also has established a Web site with  information about Mifeprex, questions and answers about the drug, and  links to other safety-related information. 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.
section_title: Agency Comments
paragraphs: 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  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.
section_title: Appendix I: Select Drugs Approved by FDA with Restricted Distribution
subsections: section_title: Condition treated
paragraphs: Application type  (year first approved  under Subpart H)
Severe recalcitrant nodular acne.
Supplemental   NDA (2005)
Management of breakthrough cancer pain in patients with malignancies who  are already receiving and who are tolerant to opioid therapy.
NDA (1998)
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.
Supplemental   NDA (2002)
Medical termination of intrauterine pregnancy through 49 days’ pregnancy.
NDA (2000)
Palliative treatment of men with advanced symptomatic prostate cancer, with  specified risks or symptoms.
NDA (2003)
Treatment of a limited subset of patients with transfusion dependent anemia.  NDA (2005)
Treatment of multiple myeloma patients who have received at least one prior  therapy.
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.
NDA (1998)
Newly diagnosed multiple myeloma.
Pulmonary arterial hypertension.
NDA (2001)
Cataplexy associated with narcolepsy.
NDA (2002)
Application type  (year first  approved)
Management of severely ill schizophrenic patients who fail to respond  adequately to standard drug treatment for schizophrenia.
NDA (1989)
Irregular heartbeats (atrial fibrillation and atrial flutter).
NDA (1999)
Serious, life- or limb-threatening infections in an inpatient healthcare setting.  n/a (1997)
section_title: Appendix II: Detailed Description of Distribution Restrictions for Mifeprex
paragraphs: 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.
section_title: Appendix III: Prescriber’s Agreement for Mifeprex Distribution
subsections: section_title: Acknowledgments
paragraphs: 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.