Executive summary and chronology

Citizen Petition
and Request for Administrative Stay
Of FDA Approval of Mifeprex for Medical Abortion
August 20, 2002
Three organizations, the American Association of Pro-life Obstetricians and Gynecologists, the Christian Medical Association, and Concerned Women for America, filed a Citizen’s Petition with the U.S. Food and Drug Administration (FDA) requesting it to immediately stay and revoke its decision of September 28, 2000 to approve the abortion drug Mifeprex™ (also referred to as “RU-486” or “mifepristone”). This drug is distributed by the Population Council in conjunction with Danco Laboratories, an entity created to assist the Population Council in bringing Mifeprex to the United States. The petition asks that the FDA Commissioner halt all distribution and marketing of the drug, which has been approved to end pregnancies through the 7th week of gestation. When it approved Mifeprex, the FDA mandated that it be used with the anti-ulcer drug misoprostol (Cytotec™) in a prescribed regimen (the “Mifeprex Regimen”). The Petitioners are non-profit organizations who share a great concern for women’s health issues. The American Association of Pro-Life Obstetricians and Gynecologists (“AAPLOG”) is a recognized interest group of the American College of Obstetricians and Gynecologists (“ACOG”) and currently represents more than 2,000 obstetricians and gynecologists throughout the United States. The Christian Medical Association, founded in 1931, is a professional organization of more than 16,000 members representing every medical specialty. Concerned Women for America (“CWA”), founded in 1979, is the largest public policy women’s organization in the United States with members in every state and a total membership exceeding 500,000. FDA’s approval of Mifeprex has jeopardized the health and safety of American women, who will be exposed to an unsafe drug regime. The petition alleges a variety of violations by the FDA of federal law and of the FDA’s standards for approval of New Drug Applications. Specifically, the petition details the following violations: • the approval of Mifeprex without the submission of data from adequate and well- 1 This Executive Summary is not intended to serve as a substitute for the full petition that was filed on this date with the FDA. • the creation of a final approved regimen for the use of Mifeprex that does not reflect safeguards employed in the clinical trials on which FDA relied: e.g., dangerously, eliminating the requirement for use of ultrasound to both date and locate the pregnancy; • the inappropriate use of an approval route, Subpart H, designed for and previously employed by the FDA only for drugs intended to treat serious or life-threatening illnesses; • the failure to require that the drug be tested in adolescents even though the drug may be and is being used in adolescents – an omission that runs contrary to a recently approved FDA rule requiring pediatric testing; • the influence exerted on the approval process by parties whose primary concern lay in easing access to abortion even at the risk of harming the health of the women having Mifeprex abortions; • the failure of the FDA to impose and enforce restrictions on the use of Mifeprex commensurate with the risk it poses to women; • the FDA’s failure to require the Population Council to honor in full its post-approval • the unprecedented endorsement by the FDA of an off-label use for misoprostol, the Defective Clinical Trials: The FDA Sacrificed its Own Standards

The nation’s food and drug laws embody a commitment to fostering advances in the
prevention, diagnosis, and treatment of illness and to ensuring that drugs are safe and effective
for their intended use prior to their release to the medical community and the public. From the
outset, the process used by the FDA to bring RU-486 to the U.S. market was fraught with
violations of the FDA’s established norms for ensuring drug safety and effectiveness.
Those norms, commonly referred to as the “gold standard,” require, for example, that new drug applications be accompanied by data derived from adequate and well-controlled investigations of both the safety and effectiveness of new drugs. In practice, this FDA standard, applied to new drug applications for decades, has mandated the use of two “successful and well-controlled” studies in order to eliminate bias and other factors that could undermine the validity of the data generated by the studies. The demonstration of Mifeprex’s safety and effectiveness would have required controlled clinical trials to establish the drug to be at least equivalent to surgical abortion in terminating pregnancies. The clinical trials relied on by the FDA in approving Mifeprex failed to do this. Moreover, the FDA agreed to substantial narrowing of the sponsor’s post-approval study commitments, thus guaranteeing that post-approval trials will also be deficient. Deviation of the Clinical Trials from the Approved Mifeprex Regimen FDA approved a regimen that does not contain important safeguards that were employed in the U.S. Clinical Trial. In the U.S. Clinical Trial, for example, the investigators relied on transvaginal ultrasonography (along with menstrual history and pelvic examination) to confirm the gestational age of each pregnancy. The use of ultrasonography also excluded women with ectopic pregnancies. Moreover, physicians participating in the U.S. Clinical Trial were capable of performing surgical abortions and were trained in the administration of the mifepristone-misoprostol procedure with admitting privileges at medical facilities that could provide emergency care and hospitalization. In addition, all of the women who participated in the trial were monitored for four hours after ingesting misoprostol and lived and worked within an hour of facilities that could handle emergencies. FDA has not retained these requirements governing physician training, ultrasound, post-misoprostol waiting period, or patient proximity to emergency care. The current use of Mifeprex subjects women to dangers of massive bleeding, infection, need for transfusions and misdiagnosis of ectopic pregnancies far in excess of the current standard of surgical abortions. Additionally, FDA’s regimen is not being followed. Advertisements, web sites and news interviews of physicians and clinics offering Mifeprex routinely describe regimens that deviate from FDA’s requirements, putting their patients’ health at risk. Since the early 1990s Petitioners and others have expressed great concern about the potential dangers likely to arise from the legalization and widespread use of a loosely regulated form of pharmaceutical abortion in the United States. Questions were raised about the heightened dangers faced by women with ectopic pregnancies and those whose pregnancies have progressed arnings about the potentially deadly consequences of a deregulatory system of administration for mifepristone abortions went unheeded, and the post-approval reports of life-threatening and fatal adverse events appear to bear out the safety concerns underlying these warnings. The FDA’s Warning to Doctors on April 17, 2002 On April 17, 2002, Danco Laboratories issued a letter and the FDA posted a webpage to alert health care providers to “New Safety Information.” The “New Safety Information” consisted of reports of serious adverse events that had been experienced by women who were undergoing or had recently completed the Mifeprex Regimen. At least two patients had suffered from ruptured ectopic pregnancies and one of these women died. The letter also reported “[t]wo cases of serious systemic bacterial infection (one fatal).” Finally, a 21-year-old woman suffered a heart attack three days after she completed the Mifeprex Regimen. In addition, last September, the death of a woman participating in the Canadian trials of mifepristone led to a halt in those trials. In fact, the FDA, through its Adverse Event Reporting System, has received reports of numerous injuries, including life-threatening adverse events suffered by two 15-year-old girls. 2 The gestational age of a pregnancy is based on the first day of a woman’s last menstrual period, which is designated as Day 1 of the pregnancy. On Day 49, a woman is deemed to be seven weeks pregnant, which means she has experienced 49 days of amenorrhea (time elapsed since the beginning of her last menstrual period). Ovulation for the small percentage of woman with a perfect 28-day cycle typically takes place between Days 12 and 14 and fertilization typically takes place 24 to 48 hours later. Abuse of Subpart H In response to the AIDS crisis, the FDA began to look at ways to streamline the approval of drugs intended to treat serious and life-threatening illnesses. This process culminated in 1992 with the adoption of the FDA’s “Subpart H” – Accelerated Approval Regulations. Drugs were to be approved under Subpart H only if they could be shown to be safe and effective and to provide a meaningful therapeutic benefit over existing therapies. The FDA approved Mifeprex for the termination of pregnancy under Subpart H, which had previously been used to approve AIDS, cancer and leprosy drugs. Mifeprex was an inappropriate candidate for Subpart H because it neither treats a serious or life-threatening illness nor provides a therapeutic benefit over existing treatments. The FDA’s improper use of Subpart H appears to have been driven by the agency’s concern about the inherent risks of the Mifeprex Regimen. The FDA approved Mifeprex under a restricted distribution provision that allows the agency to impose safety restrictions on drugs approved under its auspices. The FDA, confronted by the Population Council’s refusal to establish voluntary restrictions on distribution, viewed Subpart H as the only available regulatory vehicle that had the potential to make Mifeprex safe. The inappropriate application of this Subpart H provision served the agency’s immediate need to condition the drug’s approval on certain safety measures. This plan was thwarted, however, when details of FDA’s proposed restrictions were leaked to the press. Intense political and public pressure was brought to bear on the Agency. The FDA succumbed to the pressure and approved the drug with empty restrictions that are now being disregarded with impunity by abortion providers across the country. Rather than engage in such legal maneuvering, the FDA should simply have refused to approve Mifeprex. Off-Label for Misoprostol Federal law restrains the FDA from regulating the off-label use of the drugs and devices it approves for the U.S. market, but the FDA strives to ensure that drugs are not promoted in ways contrary to the labeling FDA has approved. In the case of Mifeprex, this routine understanding was turned on its head. The FDA mandated the off-label use of misoprostol as part of the Mifeprex abortion regimen and did this in the face of strenuous objections from the manufacturer of misoprostol. Interference in the Approval Process The Petition underscores how the FDA approval process for Mifeprex was manipulated from the outset. Government officials, including the President, the Secretary of the Department of Health and Human Services, and the FDA Commissioner, intervened first to secure ownership rights to the drug for an American organization and then to secure the drug’s approval. The approval of Mifeprex in September 2000 was bathed with the appearance of impropriety when Dr. Susan Allen became permanent director of the agency’s division charged with reviewing the drug in June of that year. Prior to working at the FDA, Dr. Allen was the CEO of a sister-entity of the Population Council licensed to distribute, manufacture, and market its only drug, mifepristone. Failure to Require Testing in Adolescent Girls The Petition establishes that the FDA waived, without explanation or justification, its requirement that new drugs that may be used in adolescents be tested among this population prior to approval. The Pediatric Rule was established by the FDA in 1998 as a way of ensuring that a drug’s unique effects on children and adolescents are taken into account before a drug is approved. The FDA has consistently acknowledged the importance of the Pediatric Rule. When it approved Mifeprex, the FDA waived the Pediatric Rule without adequate explanation. By failing to require adolescent testing, the FDA unnecessarily and unaccountably endangered the health of the substantial number of adolescent girls who may use the Mifeprex Regimen. Conclusion For all these reasons, the FDA’s approval of the Mifeprex Regimen contravened relevant statutes, regulations, and past agency practice. The American trial of the Mifeprex Regimen goes on and the subjects are the unsuspecting American women and girls who will take the drug under the assumption that the FDA’s imprimatur means it is safe. This petition calls on the FDA to uphold the law as written and to apply the same standard to Mifeprex as it would – and has done – for other drugs. The approval of Mifeprex should be stayed and its further distribution immediately halted.

Source: http://www.cmda.org/WCM/media/abortion/RU486_Petition_Executive_Summary.pdf