RU 486 Still "Approvable," But Not Yet Ready for Approval

By Randall K. O'Bannon, Ph.D.
NRL Education Director

Responding to new material submitted by the Population Council, the Food and Drug Administration (FDA) has issued yet another letter declaring that while it still considered the abortifacient RU 486 "approvable," certain issues still needed to be resolved before the drug can receive final approval and be released for marketing and distribution in the United States. A very similar letter was issued in 1996.

The Population Council - - the U.S. patent holder of RU 486 - - cryptically indicated these were issues related to the "manufacturing" and "labeling" of the abortifacient. But neither the Population Council nor the FDA gave any further details following the letter's release on February 18.

The terms are so vague, they could cover a wide variety of seemingly unrelated concerns. Only the FDA and the Population Council know how serious or complex those remaining "labeling" and "manufacturing" issues are and how long it might take to address those concerns.

Although it put the best face on the situation, Population Council officials were obviously unhappy with the FDA's ruling.

"It's disappointing, but these things happen," Population Council spokesperson Sandra Waldman told the Washington Post (2/19/00). "It would have been nicer to be approved than approvable, but we are continuing in our discussions with the FDA. ... It will just take a little longer."

On the other hand, Waldman still insisted that the drug could be approved sometime later this year if those questions are resolved. Optimistic that the Population Council could meet the FDA's demands, Waldman told Reuters (2/18/00), "Eventually we'll have it."

These latest reassurances follow a longstanding pattern. The Population Council began telling reporters as early as 1999 that it would have the drug on the market as soon as year's end.

When that particular deadline passed, the council let it be known that it anticipated a favorable response from the FDA sometime within the first quarter of 2000.

This inability to secure final approval is only the latest setback in a series that has dogged the Population Council's RU 486 project since it first obtained U.S. rights to the abortifacient in 1994.

Although no one is speaking, based on history, what might those "manufacturing" and "labeling" issues be?

QUESTIONS ABOUT "MANUFACTURING"

Actually producing mifepristone [the generic name for RU 486] is no easy task. Synthesizing RU 486, an artificial hormone, is a complex and involved process.

One reason the Population Council had such difficulty in finding a manufacturer was because there are so few pharmaceutical firms that have the equipment or expertise to do this sophisticated chemical synthesis. And, of course, the issue is not merely synthesizing, but doing it correctly.

Danco is the company set up by the Population Council as a sublicensee to handle distribution of RU 486. In 1997, Danco filed a suit against Gedeon Richter, the Hungarian firm originally contracted to produce the raw RU 486. According to court documents (Danco v. Richter, New York Supreme Court), Danco said it was attempting to force Richter to fulfill its contract.

The court documents indicate that one of the sources of friction between the two companies was that Danco charged it had "noted a series of technical deficiencies in Gedeon Richter's stability protocol." Danco also raised questions about the quality of some of Gedeon Richter's samples. Why is this important?

Before the FDA approves any drug for sale, it conducts a thorough investigation of the manufacturing plant and its manufacturing processes to insure the chemical purity and stability of the drug product.

Apparently, large, reputable American drug manufacturers with the sort of experience and equipment to handle such a synthesis have stayed away from RU 486. This presented smaller companies - - or new start-up companies - - with a considerable manufacturing challenge were they to decide to take on production of the abortifacient compound.

If the Population Council has contracted with some small-scale drug firm to produce the RU 486, or decided to set up its own manufacturing plant in-house, that could take a great deal of time and effort to get the plant and process up to the FDA's standards.

This might be one possible "manufacturing" issue not yet resolved to the FDA's satisfaction.

Another possibility: the Washington Post (2/19/00) speculates that the Population Council's desire to keep the manufacturer's identity a secret may also be an issue with the FDA. In order to attract firms that might be reluctant to be associated with such a controversial drug, the Population Council has told manufacturers that their names would not be made public if they agreed to make the drug (a promise they were obviously unable to fulfill when Gedeon Richter's name became public in the Washington Post, 9/21/96).

The Post article indicates that, historically, the FDA has required information about the manufacturer to be published. This raises the issue as to whether the FDA would be willing to go along with the Population Council's arrangements. Information about the manufacturer is important to those who might be injured by the drug if they were to seek recompense for their injuries or losses.

"LABELING" ISSUES

Discussion at a 1996 FDA hearing on mifepristone, which resulted in the first "approvable" letter, dealt with issues such as dosages, warnings, and possible side effects. "Labeling," we learned, encompassed a broader range of issues than might first be expected.

It came out that "labeling" also includes issues such as training those who would administer the RU 486, an issue which proved to be a serious concern for the advisory committee.

After voting to declare the drug "safe" and "effective," members of the advisory panel were anxious to hear who would be prescribing the abortifacient and how they would be trained to date pregnancies and handle possible complications. This is crucial since the drug's "effectiveness" drops after the 49th day of pregnancy.

Judging by the transcripts, panel members were appalled when a Population Council representative testified that physicians not trained in obstetrics or surgery would take part in short-term seminars where they would be taught to date pregnancies and perform surgical abortions as back-up when the chemical method failed, as it inevitably does some of the time.

Panelist Mary Jo O'Sullivan scoffed at the idea that doctors would be able to draw upon knowledge gained in medical school to date pregnancies. Another panelist, Ricardo Azziz, said that the idea that physicians who had never performed surgery before could be trained to perform complicated surgical procedures in a seminar "rather radical."

Azziz said he was concerned that this not be tied to the drug approval process. Azziz did not elaborate and we can only speculate that by this he meant the panel's recommendation to approve of the two-drug abortion technique should not be construed as an endorsement of the training procedure.

Panel member Vivian Lewis elaborated further on the issue of possible complications. "If you are talking about in an emergency situation," she said, "having the skill to be able to do this [handle complications] deftly, appropriately, and with minimal complication, such a person who has never been trained in that and who has only attended a seminar is the worst possible choice of person to do that." [All quotes are taken from a transcript of the July 19, 1996, FDA hearing on mifepristone.]

Again, whether these were the issues specified in the FDA's 1996 "approvable" letter and/or whether they remain as issues in the "approvable" letter just released is known only to those in the FDA's and Population Council's immediate circle.

Discussion at the 1996 hearing also centered around "contraindications" - - medical conditions or personal habits, such as heavy smoking, for which the safety risk was unknown or thought to be heightened.

Another concern was typified by the remarks of Dr. Diana Petitti. She observed, "I would like to comment that safety is a relative term and that although this may be safe for this indication, I think that some of the information that I have seen in the popular press and some of the rhetoric

surrounding this regimen and this drug leads people to think that safe is equivalent to free of adverse effects."

All these concerns might come under the rubric of "labeling."

A great deal of concern was expressed by certain members of the 1996 advisory panel as to what would be done about women who failed to return for their second or third visits. Data published since then on the American trials showed that 5% of women in that trial did not return for their final visit.

In addition to concerns about the health of these women, panelists expressed worries about what would happen if these women who did not come back were still pregnant and carried their babies to term. If the baby was born with some sort of disability, noted panelist Cassandra Henderson, it would be difficult to prove the disability was not caused by the abortion drugs.

Whether this, too, could be a "labeling" issue is unclear, though it does represent another area of concern for the FDA.

CLINTON SUPPORT VITAL

The politicization of the FDA in the context of RU 486 has been clear from the beginning of the Clinton Administration. Just three days into office, the president signed an executive order directing the Department of Health and Human Services (the FDA's parent agency) to "promptly assess initiatives by which the Department of Health and Human Services can promote the testing, licensing, and manufacturing in the United States of RU 486 or other antiprogestins" (1/22/93).

The FDA has done nearly everything in its power to push the drug through the process - - mediating negotiations between Roussel Uclaf, the French company which developed the pill, and the Population Council; allowing the application to proceed before data from the American trial was fully tabulated; reviewing the drug in just six months' time, etc.

Yet if the FDA approves a drug whose purity is questionable or allows the drug to be prescribed by unqualified personnel under very minimal restrictions, the potential for harm, not only to public health, but to the agency's public image, is enormous.

Given the agency's recent record with medications like Fen-Phen (the diet pill combination approved, then withdrawn because of problems it caused with patients' heart valves), another recall could prove embarrassing to the FDA.

HOW "SAFE" AND "SIMPLE" IS RU 486?

Far from the myth of a "simple," "safe" procedure, taking the abortifacient RU 486 is an involved, complicated, multi-step process. As proposed by the Population Council, the RU 486 abortion requires two-drugs and three-visits.

A woman receives the RU 486 pills in her first visit after an examination and counseling.

She then comes back for a second visit two days later to take a second drug, a prostaglandin (usually misoprostol).

The RU 486 blocks the action of the hormone progesterone, leading to the breakdown of the uterine lining that provides the developing baby's nourishment. The baby starves or suffocates to death.

The misoprostol initiates powerful uterine contractions to expel the shriveled corpse. About half of the women abort in the four hours they spend in the doctor's office during this second visit. The rest abort at home, at work, on the bus, or not at all.

A third visit, coming two weeks after the first, confirms whether or not the abortion has taken place. The range of "failure" to abort is between 8% and 23%.