On May 17, the House Government Reform Subcommittee on Criminal Justice, Drug Policy and Human Resources held a hearing entitled, “RU-486: Demonstrating a Low Standard for Women’s Health?” The hearing reviewed the safety of mifepristone, sometimes referred to as RU-486 or by its brand name, Mifeprix®. Mifepristone, approved by the Food and Drug Administration (FDA) in September 2000, is a drug that is used to terminate pregnancy early in the first trimester.
Chair Mark Souder (R-IN) said that “it’s very clear that there is a serious problem with RU-486, and failing to address this problem by disguising it, ignoring it, minimizing it or causing confusion is a shameful failure for anyone with the ability and desire to protect women from needless harm.” Rep. Henry Waxman (D-CA) said that the hearing should examine the best scientific evidence and if it “turns out to demonstrate that the risks do in fact outweigh the benefits, then the FDA should make a decision accordingly.”
Since the drug’s approval, and continuing through March 31, 2006, 950 cases of adverse reaction have been reported to the FDA’s Adverse Event Reporting System (AERS). Of those cases, 116 documented instances in which a patient needed a blood transfusion and 12 recorded possibly related deaths. Of the 12 deaths, five were caused by rare bacterial infections, either c.sordellii and or c.perfrigens. The subcommittee expressed particular concern about these severe or fatal reactions.
Dr. Janet Woodcock, current deputy commissioner for operations and former director of the Center for Drug Evaluation and Research (CDER) at the FDA testified that mifepristone was approved during her tenure as CDER director. She gave a detailed description of the drug’s approval process: mifepristone was first submitted for FDA approval in 1996; on September 28, 2000, after reviewing three clinical trials, the agency approved the drug under Subpart H regulations (21 CFR 314). In cases where a drug or device can be shown only to be safe and effective with limited distribution, Subpart H requires the FDA to issue post-marketing restrictions. For mifepristone, those restrictions included providing the drug only to physicians able to determine the duration of a pregnancy, evaluate ectopic pregnancies, provide surgical intervention in cases of incomplete abortion, give each patient information about the drug, and report all adverse events or continued pregnancies to the manufacturer and the FDA.
Dr. Woodcock went on to describe the FDA’s response to cases reported by AERS. First, the agency approved two revisions to the mifepristone labeling and medication guide. In November 2004, the FDA strengthened the warning label to add information about possible bacterial infections, bleeding, and death following the use of the drug. In July 2005, the warning label was further strengthened by describing “atypical presentations of serious infections,” including prolonged heavy bleeding without fever or significant clinical findings. The agency also tested specific manufacturing lots for contamination, issued public health advisories, and sought expert advice in the form of a conference held May 11, 2006, at the Centers for Disease Control and Prevention. Dr. Woodcock’s conclusion was that it is “not [currently] possible to determine if the use of mifepristone results in an increased risk of c.sordellii or if [the FDA] has identified an emerging risk in pregnancy” but that the agency would “continue to communicate to the public, healthcare practitioners, and patients emerging safety information that becomes available that would assist them in making proper choices regarding their health.”
Rep. Souder asked Dr. Woodcock why mifepristone was being used in conjunction with other drugs and/or at dosages differing from the FDA approved regimen. Dr. Woodcock noted that many medications are prescribed in combination and that “about 21 percent of physicians deviate from the approved regimen” when prescribing drugs. She went on to assure the subcommittee that the FDA treated mifepristone “the same as all other drugs in the approval process.” Her explanation did not satisfy Rep. Jean Schmidt (R-OH), who asked why the drug was not immediately being withdrawn from the market. Dr. Woodcock answered that the agency did not have sufficient information to distinguish the possible causes of death: “We don’t know if medical abortion increases the likelihood of infection. This type of infection is also caused in miscarriage, vaginal delivery, and c-section.”
Mr. David “Monty” Patterson testified that his daughter Holly took mifepristone in September 2003 and died a week later from c.sordellii infection. Following Holly’s death, Mr. Patterson began to research the effects of mifepristone using scientific and medical literature, and talking to doctors, legislators, and federal agencies. Most recently, he attended the CDC conference where three scientists presented information that mifepristone has “serious and lethal implications in animal models.” He urged the FDA to “explore active epidemiology, study animal models…provide the medical community reliable means and methods to recognize serious adverse events…and to implement a confident reporting apparatus of these events so they can accurately evaluate the safety and health consequences with use of the drug.”
During the mifepristone approval process, Dr. Susan Wood was the director of policy and program development at the Department of Health and Human Services’ Office on Women’s Health. Dr. Wood praised the close surveillance of adverse effects associated with the drug’s use but noted “systems need to be improved and expanded…We cannot be confident that we have identified all or most of the adverse events and deaths.” Dr. Wood also noted the controversy surrounding mifepristone’s possible effect on immune suppression but dismissed the suggestion, saying it “does not seem to be a compelling mechanism. If the immune system were suppressed, we would also expect to see a rise in other more common infections.”
Dr. Lisa Rarick, a board-certified obstetrician-gynecologist and former CDER employee, expanded on Dr. Woodcock’s testimony regarding the approval process of mifepristone at the FDA. She also provided more detail regarding possible immunosuppression, saying, “Immune suppression-associated infection would not appear as reports of one organism [the c.sordellii] but would present as infections with any or all of the bacteria present in the female reproductive tract.”
The testimony of Dr. Donna J. Harrison, also a board-certified ob-gyn and chair of the subcommittee on mifepristone of the American Association of Pro Life Obstetricians and Gynecologists, contradicted that of Dr. Wood. Dr. Harrision provided the subcommittee with a very detailed analysis of 850 of the 950 adverse events reported to the FDA. In particular, she highlighted animal models where “mifepristone was able to effectively block immune response in animal models…increasing the mortality rate from 13 percent to 100 percent.” She went on to report that the risk of death from one of the bacterial infections is approximately 1/100,000, or 10 times the rate from surgical abortion. Besides fatal outcomes, she noted that 43 women experienced severe pelvic infections and 15 of the 116 women requiring blood transfusions lost more than half their total blood volume. Taken together, these adverse outcomes certainly would meet the FDA’s own explanation of when to withdraw a drug from the market, said Dr. Harrison.
During questions, Rep. Souder asked Drs. Rarick and Wood why the immune response animal models presented data contrary to their assertions. Dr. Wood explained that the issue was “extraordinarily complex,” while Dr. Rarick said, “There may be some relationship [between mifepristone and immunosuppression]. Do we know mifepristone causes these infections? Might they? Possibly.”
Rep. Waxman asked Dr. Rarick: “We don’t know what caused the infection, is that correct?” She responded, “Yes. I think the FDA is actively looking at whether Mifeprix® is causing the infections.”
Rep. Schmidt expressed particular concern over how the drug came to market and asked Dr. Rarick to explain the control group and any double-blind studies conducted on mifepristone. Dr. Rarick explained that contraceptives and abortifacients are not studied in the same fashion as other drugs as it would be unethical to give a placebo to a woman seeking to prevent or to terminate a pregnancy. Instead, historical analysis and probability studies are used to determine the safety and efficacy of the drug or device.
Rep. Diane Watson (D-CA) asked Dr. Rarick if she believed that women’s health standards were lower than other groups. She replied that “Mifeprix was held to the highest standards of review” and that an appropriate next step was to review all pregnancy-related events, surveillance, and maternal mortality. If the agency “believes the risks outweigh the benefits, they will take appropriate action.” Dr. Rarick added that “no one is trying to minimize [adverse] events.” Rep. Watson urged a follow-up hearing as the FDA continues its review process.
