Doxil

The FDA's accelerated approval of the abortion-inducing drug RU-486 without thorough testing is under fire by critics of the drug who say the FDA broke its own rules.

Six years ago, "newly unemployed" by a corporate downsizing, Lee Knowlen discovered that she was about to become a single mother -- and amid other stressful troubles she decided to have an abortion. Knowlen heard that the U.S. clinical trials for RU-486, or mifepristone, were then under way. She knew about the drug from the time she had spent living in Europe, where the chemical abortifacient already was in use. So she agreed to become part of the U.S. trials.

Knowlen tells Insight that her use of the experimental drug was a "success." Nevertheless, she grieved for her aborted child, and sought comfort in a formal grieving ceremony with her partner.

This deep ambivalence toward RU-486 had marked the stunning controversy over the drug since efforts began to legalize its use, an end finally achieved by proponents when the U.S. Food and Drug Administration (FDA) gave its formal approval on Sept. 28, 2000. Opponents charged that the approval process had been aborted by politics and ideology, putting it into a special accelerated category of drugs intended to make them available to dying patients, and by passing usual safety concerns and legal liability.

Pro-choice advocates and the Population Council hailed the approval as a long-awaited victory in the battle for women's rights. Opponents of abortion were furious. "Never before has the FDA approved a drug intended to kill people," said Rep. Tom Coburn, R-Okla. And it was a matter of some concern that FDA had approved the use of the controversial drug on the basis of a couple of foreign studies and a single U.S. clinical trial.

Newspapers and networks nonetheless were quick to cheer the potential benefits of RU-486; the Washington Post broke the story on Oct. 12, 2000, that the drug would be manufactured for the U.S. market by the state-owned Hua Lian Pharmaceutical factory in the People's Republic of China. Oddly, no one thought it important enough to report how RU-486 so quickly had moved from that clinical trial to the physician's practice at the very end of the Clinton administration.

In its Sept. 28, 2000, approval letter for mifepristone from an unnamed FDA official to Sandra P. Arnold, vice president of the Population Council, the FDA says the drug was approved for marketing "under 21 CFR 314 Subpart H," otherwise known as the accelerated-approval process. For a drug to qualify for such acceleration it "must provide meaningful or therapeutic benefits over existing treatments" and must be used to treat a serious or life-threatening illness.

In short, the Subpart H process is permitted only to allow speedy approval of experimental drugs whose safety cannot be established but the dangers of which are outweighed by the threat of a patient's current illness. To date, 0nly 30 drugs have been approved under Subpart H, with more than half of them providing treatment for HIV/AIDS patients and others for treatment of cancer (see "New Drug Approvals" p. 18).

Without such an approval the manufacturers would be held to strict liability for drugs that by their nature are incapable of being made safe and huge lawsuits likely would result to make distribution financially risky or impossible. According to tort specialists, such lawsuits might arise anyway.

Brad Clanton, counsel for the House Judiciary subcommittee on the Constitution, is one who has serious reservations about the ramifications of mifepristone's approval under Subpart H. "It's an accelerated process for approving drugs for people who are basically dying or are going to have some serious deformity if they don't get something [treatment] right away," Clanton says. "It was basically created for AIDS patients."

Clanton believes that the medical history of mifepristone invalidates the drug's approval under Subpart H because FDA rules require that the drug be intended to treat a serious or life-threatening disease or illness and that it provide meaningful therapeutic benefit over existing treatment. He says, "If you look at the FDA's own medical review, it shows that RU-486 is much worse on every single side effect.... It's obvious that it doesn't provide meaningful therapeutic benefit over existing procedures."

Clanton cites a clinical trial on women in China, Cuba and India that compared mifepristone-induced abortion to surgical abortion and was reported in the FDA's Medical Review for mifepristone, finalized on Nov. 22,1999. The study found that mifepristone abortion "had more adverse events, particularly bleeding, than did surgical abortion."

Others express safety concerns about the drug based on its Chinese manufacturer. House Commerce Committee Chairman Tom Bliley of Virginia wrote to FDA Commissioner Jane Henney on Oct. 18, 2000, raising concerns about the quality controls and manufacturing standards of RU-486's manufacturer as reported in the Oct. 12 Washington Post. Bliley warns that the manufacturer, under a different name, had difficulty passing an FDA inspection of its plant in 1990 and that the facility has not received an FDA inspection since. Bliley reports that a 1998 California Health Department analysis shows that the manufacturer of mifepristone, again under a different name, exported contaminated medicine into the United States.

The Bliley letter also states that the FDA inspector for the manufacturer's October 1999 inspection found that the Chinese firm had chosen to copy information about methods of manufacture from the U.S. New Drug Application (NDA) of another company rather than translate a description of their own methods from Chinese into English. The inspector left after the Chinese firm promised to redo its Chemistry and Manufacturing Controls application to reflect its own methods rather than those of the other company.

There are other problems as well that raise safety alarms. A citizen's petition filed in 1995 by Americans United for Life against approval of a NDA for mifepristone cites a 1989 World Health Organization (WHO) Task Force report that mifepristone is only 63 percent effective when taken without the follow-up drug misoprostol. This is significant because misoprostol, which has not been cleared for use with RU-486, is a prescription ulcer medication whose manufacturer, Searle, distributed a letter on Aug. 23, 2000, warning that misoprostol "is not approved for the induction of labor or abortion." The Wall Street Journal reported on Oct. 18, 2000, that former FDA general counsel Peter Barton Hutt has warned that FDA was setting an "extraordinary precedent" by encouraging an unapproved and off-label use for a drug.

Clouds of haze surround RU-486, as old foes line up once again to take sides. But a legitimate question about the means the FDA used to bypass normal procedures to approve the drug remains and will have to be worked out during the new Bush administration.

New Drug Approvals

Approved Under the Accredited Approval Process

Accelerated Approval is a mechanism through which a drug product for serious life-threatening diseases for which no other alternative therapies are available can be approved for general marketing without having to show that it offers a clinical benefit for the patient.

RELATED ARTICLE: Chemical Abortion vs. Surgical

Pro-choice, abortion and radical feminist groups for years have been lobbying the Food and Drug Administration (FDA) to approve mifepristone, the RU-486 abortifacient, citing its "successful" use in Europe as proof of the drug's efficacy and safety for use in the United States. Despite the heavy bleeding, nausea and cramping that routinely are associated with mifepristone, a drug that induces miscarriage, many doctors who feel comfortable with the drug from a medical standpoint say there are other factors to consider when comparing surgical and chemical abortion.

Gene Rudd, associate executive director of the Christian Medical and Dental Association and a licensed obstetrician/gynecologist in Bristol, Tenn., doesn't think pro-lifers who warn of the medical dangers, such as heavy bleeding and cramping, have much of a "case" when it comes to the physical side effects of the drug. Rudd says he believes that the possible negative side effects of the drug shown in the earlier U.S. clinical tests are within the acceptable range of side effects for any new medication.

Rudd does, however, have serious concerns about the possible adverse psychological effects of the drug. "The consumers expect to get a magic bullet [by taking mifepristone]," he says. "What they are not being told is that they are permitting themselves to go through the experience of a miscarriage." Rudd says that every woman he has known who has suffered a miscarriage has considered it a traumatic experience. "I think the reason it is being promoted is for ideological purposes, not because it is the best choice for medical consumers," he says.

Carolyn L. Westhoff, associate professor of obstetrics/gynecology and public health at Columbia University, is a medical doctor who participated in the U.S. clinical trial of mifepristone and claims that many women had positive experiences aborting with the drug. "I think that, in general, when women are reasonably told about the range of things that they might expect to experience, so that they don't have a lot of surprises while the treatment is actually going on, they tend to be very satisfied," Westhoff says. She cites a heightened sense of control.

But other specialists, such as Watson Bowes, a retired OB-GYN practitioner and professor emeritus at the University of North Carolina at Chapel Hill, think that this heightened sense of control might be what in the end does the most damage to a woman's psyche.

"Many studies show that women prefer this [drug]," Bowes says. "The reason they choose this is because they want to have more control." But if a woman goes to a doctor who performs a surgical abortion, according to Bowes, then "he did it." Whereas, if a woman chooses to take a pill, she must say to herself, "I did it."

Bowes asks, "Will there be more remorse? Will there be more guilt? We won't know this for quite some time." To which antiabortion advocates reply that a baby will be dead just the same.

-- ST

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COPYRIGHT 2001 Gale Group