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. 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. 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. This submission included updated safety  data from ongoing trials and international postmarket experience,  international product labeling, and revisions to the distribution plan. 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. 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. 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. 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. 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. 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. (See table 3 for an overview of FDA’s  postmarket oversight of these drugs.) 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. 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. FDA officials  have said that the relationship between the infections and the use of  unapproved regimens of Mifeprex and misoprostol remains unknown. 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. Agency Comments

We provided HHS with a draft of this report for review.
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.