Complaint Filed With FDA Against RU486

By Randall K. O'Bannon, Ph.D.
NRL-ETF Director of Education & Research

A 92-page "Citizen Petition" filed with the Food and Drug Administration is asking the FDA to rescind its approval of RU486, the French abortion pill, because of safety concerns and procedural violations in the drug approval process.

The petition, formally filed on August 20, details numerous ways in which the Clinton-Gore FDA bent or broke its own rules to get the drug on the market just prior to the 2000 election. Now, nearly two years later, the release of government documents has given petitioners and the public at large the opportunity to see just how many times and ways the agency cut corners to satisfy a political constituency and put women's lives and health at risk.

The petition was filed by the American Association of Pro-Life Obstetricians and Gynecologists, the Christian Medical Association, and Concerned Women for America.

The following article details just a small portion of the many serious concerns raised by pro-life groups, including National Right to Life and in NRL News, prior to and following the FDA's September 28, 2000 approval.

The Misuse of Subpart H
The FDA approved RU486 under "Subpart H," a special regulation designed to allow the agency to consider and approve higher-risk drugs under certain restrictions it considers necessary to ensure safe use of the product.

While an FDA advisory committee officially declared RU486 "safe" and "effective" in 1996, it also expressed serious reservations about the training of prescribers and their ability to handle complications that arose. The FDA delayed issuing final approval at that time pending the resolution of certain "labeling" and " manufacturing" issues.

It took the Population Council some four years to line up a manufacturer. When
reconsidering the application in early 2000, the FDA announced its intention to invoke the Subpart H regulation, indicating it wanted the distribution system revised to include "adequate training and certification of providers." In June 2000, the FDA proposed that distribution of the drug be limited 1) to those who were trained to perform surgical abortions, 2) to those who had training in assessing fetal age and diagnosing ectopic pregnancy using ultrasound, 3) to those who were trained and certified in the use of the drug and managing its complications, and 4) to those having admission privileges at a medical facility equipped to handle emergency resuscitation, surgery, and blood transfusion.

The Population Council protested. Word of the proposed restrictions was leaked to the press, and sympathetic members of the medical establishment were marshaled to protest the FDA's " unnecessary interference" in the practice of medicine. While maintaining the Subpart H designation, the agency backed down and simply required that doctors attest that they had "read and understood" the prescribing information, that they could date pregnancies and diagnose ectopics [i.e., ultrasound training no longer required], and that they could refer a woman to someone who could handle complications if they themselves could not.

Petitioners point out that the gutting of the earlier restrictions largely defeated the purpose of the FDA's invocation of the Subpart H regulations. If the FDA felt strongly enough about the risks of the drug to invoke Subpart H, then why didn't it follow through with the restrictions that it at one point thought necessary to insure RU486's safety?

"Rather than attempting to compensate for the inherent dangerousness of Mifeprex [RU486's U.S. trade name] by inappropriately resorting to the Subpart H approval mechanism," the petitioners argue, "FDA should have simply refused to approve Mifeprex."

Prostaglandin Partner of RU486 Never FDA Approved for That Use
The petition points out that the approval of RU486 was unusual in another respect. While the application considered by the FDA was officially for a single drug, mifepristone (RU486's generic name), the protocol it evaluated and approved was for a two-drug combination -- mifepristone and a prostaglandin, misoprostol.

Used alone, RU486 is only able to induce an abortion 60-80% of the time. This would not have been considered "effective" enough to gain approval. To increase the drug's "effectiveness," abortionists have patients return two days after taking RU486 to take a second pill, misoprostol, a prostaglandin (PG) that induces powerful uterine contractions to expel the tiny body of the child starved or suffocated by the RU486. This increases the method's "effectiveness" to somewhere between 90% and 95% for women pregnant for no more than 49 days. This is why it is often more appropriately referred to as the mifepristone/misoprostol method or the RU486/PG method.

G.D. Searle, the manufacturer of misoprostol (sold under the trade name Cytotec), however, never filed an application to have its drug approved for this use. "Absent such an application," the petition avers, "FDA lacked the basis for sanctioning a new indication [i.e., use] for misoprostol."

In fact, in a 1993 letter to the Wall Street Journal, Searle said, referring to Cytotec, "Searle strongly opposes its use with RU486 in abortion, either in the U.S. or elsewhere."

The uses for which a drug has been tested and approved by the FDA are laid out in the product's label. Any other uses are referred to as "off-label," and the FDA actively discourages manufacturers from promoting such uses, not wanting physicians or patients to be given the mistaken impression that the FDA has sanctioned such uses.

By explicitly mandating the use of misoprostol in conjunction with RU486, however, the FDA is in the awkward position of mandating an off-label use. The petition says this results in Mifeprex being misbranded, in that its own label promotes an unapproved use of another drug.

Failure of Trials to Meet Objective, Scientific Standards
In order to distinguish a drug's effects from spontaneous changes of condition, placebo effects, or biased observations, the FDA has typically required evidence from at least one (usually, two) of what it calls "well controlled" trials to determine whether a drug is effective for its intended use. The petition contends that the FDA did not follow this practice in its consideration of RU486.

In "controlled" trials, the drug under investigation is compared to a placebo or to some known effective treatment to determine its comparative efficacy. The FDA normally prefers that these be "blind" randomized trials, in which subjects are randomly split into at least two groups. Neither doctors nor patients know who is receiving the investigational drug and who is receiving the placebo. Where other treatments are available for the same condition, the drug is sometimes compared with those treatments.

Trials conducted of RU486/PG were not blinded, randomized, or " concurrently controlled" (i.e., they did not compare the efficacy and safety of RU486/PG with surgical methods). Instead, the FDA relied on data from two foreign (French) clinical trials and one clinical trial conducted in the U.S.

In none of these trials was there a control group, in none of the cases were patient outcomes statistically compared with surgical abortion. Because chemical abortions by their very nature come with more bleeding, more side effects, and a lower " success" rate than surgical abortions, it is unlikely they would have fared well in a blind comparison.

One legal commentator cited in the petition noted that one should be wary of studies without concurrent controls "because their conclusions can be manipulated more easily."

Wariness would appear warranted in this case. The U.S. trials were conducted at abortion clinics, many of them affiliated with America's top abortion chain, Planned Parenthood, which has a vested interest in promoting a new abortion product. This can effect reported results. "In the absence of concurrent controls and blinding," petitioners point out, "the duration and intensity of cramping, nausea, bleeding, pain, and any emotional or psychological effects of the treatments would be subject to investigator and patient bias."

There are questions regarding the French data as well. An FDA auditor who looked at records from the French trials found a number of problems -- missing and intentionally misdated files, missing lab reports and ultrasound documents, under reported and misreported side effects, a surgical evacuation reported as an expulsion, etc. -- yet did not stop the studies from being used to back the RU486 application.

Dropping of Critical Safeguards
When the FDA dropped the restrictions it was considering on the distribution of RU486 in the months just prior to approval (see above), the petition says it put women's health in jeopardy. The pills promoters argued that the restrictions weren't necessary and only served the purpose of stifling the market for the drug. Petitioners say the death of two women, the serious injury of four others reported in the Washington Post in April 2000 and further analysed in the May NRL News prove otherwise.

Had the requirement for ultrasound training remained in place, the three women whose tubes ruptured could have had their ectopic pregnancies detected and treated. A doctor with the appropriate surgical skills may have been able to save the life of the woman who died.

Special training in use of the drugs might have helped doctors distinguish between standard side effects of chemical abortions and the signs of a serious infection that killed one woman and afflicted another. Those with formal training in use of these drugs might also have been more hesitant to give a prostaglandin to the 21-year-old with a family history of cardiac disease who suffered a heart attack.

Statistics on hemorrhage and hospitalizations from the trials suggest that there may be women who will bleed to death if they do not get immediate treatment. The FDA's decision to drop the requirement that doctors prescribing the pill have surgical skills or practice within an hour of an appropriately equipped emergency care facility would appear to make such an outcome more, not less, likely.

Failure to Enforce FDA Mandated Protocols
Prescribers are ignoring even the minimal standards left in place by the FDA, the petition points out, and organizations promoting the pill are encouraging deviations from the protocol.

Already in the press, there have been accounts of clinics offering the pill to women weeks beyond the FDA-sanctioned cutoff date, administering the misoprostol vaginally instead of orally, and allowing women to take the misoprostol at home and skip the FDA-mandated second visit. The National Abortion Federation, which represents many of the abortion clinics in the United States, sent out promotional materials telling abortionists that use of the RU486/PG method up to 63 days' gestation and the home administration of misoprostol were "safe and effective ... and ... highly acceptable to patients."

The petition points out that shortly after approval, the FDA told one U.S. senator, "If restrictions are not adhered to, FDA may withdraw approval." One of the conditions of the Subpart H designation is that the "burden is on the applicant to ensure that the conditions of use under which the applicant's product was approved are being followed."

Danco, the U.S. distributor of RU486, in its prescriber materials, warns doctors that failure to follow the approved guidelines may result in their prescribing privileges being withdrawn. Yet Richard Hausknecht, the self-described "maverick" who serves as the medical director for Danco and is supposed to be the chief enforcer of the FDA approved protocol, has mentioned use of RU486 up to 56 days and offers vaginal administration of misoprostol, with the implication the woman can take it at home, as a treatment option, none of which is part of the approved protocol."

In light of such practices, the petitioners say that Danco and the Population Council have shirked their duty to monitor compliance and "have not effectively constrained providers of Mifeprex to adhere to the approved regimen," warranting the withdrawal of the drug's approval.

Trial Results Obtained Under Unrepresentative Conditions
While trials are normally supposed to mimic those expected in actual practice, the petition points out that the regimen the FDA approved for the U.S. is missing several important safeguards that were present in the U.S. trials.

Doctors testing RU486/PG in the U.S. used ultrasound to date pregnancies and identify women with ectopic pregnancies. They had surgical abortion experience, were trained in use of the RU486/PG method, and had admitting privileges at appropriately equipped emergency facilities. The FDA proposed placing these conditions on the drug once it hit the market, but dropped them after the sponsor and its allies in the medical establishment objected.

Other conditions that were part of the trial did not make the final cut. Women taking the prostaglandin misoprostol during the second visit stayed at the clinic for a four-hour observation period. About half the women aborted during this four-hour window, with a number experiencing their most serious side effects during this period.

A determination that the drugs were safe under a protocol involving ultrasound, a four-hour observation period, etc., would not serve as a valid indicator of the safety of the method absent these conditions.

Lack of Pediatric Testing
The FDA "Pediatric Rule" requires that new drugs be tested on minors before being cleared for their use. Petitioners say the FDA waived this rule for RU486 without giving an adequate justification for the waiver.

When explaining the basis for the pediatric rule in 1998, the FDA pointed out that "the absence of pediatric labeling information poses significant risks for children." Guidance it gave to the pharmaceutical industry in December 2000 specifically stated that during adolescence, a period of sexual development, "medicinal products may interfere with the actions of sex hormones and impede development." These hormonal changes, the same document states, may "influence the results of clinical studies." Such concerns were ignored in the case of RU486, petitioners claim.

The FDA has certain conditions for a waiver, but the petition claims these were not met. While the FDA did in one memo say there was "no biological reason to expect menstruating females under age 18 to have a different physiological regimen," the petition claims that the FDA was not authorized to extrapolate this conclusion from adult studies because those studies were not "adequate and well-controlled" (see above).

Petitioners label as "medically unsound" the idea that the data on the effects of RU486/PG on pregnant adults can be extrapolated to pregnant adolescents. The fact that two of the six patients reported as experiencing the most serious adverse events were 15- year-olds suggests the petitioners' concern is warranted.

Reduction of Phase IV Commitments
While the FDA uses clinical trials to ascertain a drug's immediate safety and efficacy, it uses Phase IV, or postmarketing studies, to assess its long-term effects and answer further questions about a drug's applicability to certain medical sub-groups.

Originally, when the FDA declared the drug "approvable" in 1996, it indicated it wanted to the Population Council to conduct Phase IV studies 1) to monitor the adequacy of the distribution and credentialing system, 2) to assess long-term effects of multiple uses of the drug, 3) to follow the outcome of women who had surgical abortion following failed chemical abortions, 4)to ascertain how often women complete the whole regimen and find out what happened to women who did not, 5) to study the safety and efficacy in women under 18 or over 35 who smoke, and 6) to find out what happened to children born when the method "fails."

When it granted final approval in 2000, however, the agency asked only for 1) a study comparing outcomes between prescribers having surgical intervention skills and those lacking those skills and 2) a study on the outcomes of continuing pregnancies. The three petitioners maintain that the original questions are still open and important.

Petitioners Call for Revocation of RU486 Approval
The petitioners call the actions of the Clinton-Gore FDA in regard to RU486 "arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with the law." They say the agency approved the drug despite the presence of substantial risks to women's lives and health.

They request from the FDA an immediate stay on the drug's distribution while the concerns of the petition are addressed and ask for a full audit of all records from the French and American clinical trials. Ultimately, they say, in light of these procedural violations and safety concerns, the approval of RU486 "must be revoked."

The U.S. Code of Federal Regulations outlining the Citizen Petition process gives the agency 180 days to respond to the petition. The FDA may accept the petition, deny the petition, or issue a tentative response indicating why the agency has been unable to reach a decision.