Opponents Of The Drug Are Impeding Medical Progress

If RU 486 (Mifepristone) were not an abortifacient, or an abortion-inducing agent, public attention would focus on its potential broad medical applicability. Unfortunately, "right-to-life" abortion opponents have effectively threatened the French manufacturer of the drug, Roussel Uclaf, and its parent firm, Hoechst AG, with an organized, worldwide economic boycott unless the drug is withdrawn from use. This threat of economic reprisal against the manufacturer has seriously delayed the potential medical applications of RU 486. The political strength of the "right-to-life" forces put unprecedented White House and congressional pressure on the Food and Drug Administration, motivating the agency to place RU 486 on an import alert embargo in June 1989. Under the FDA embargo, for scientists to get laboratory supplies of RU 486, a researcher must contact the FDA or risk confiscation. The embargo has no medical basis, and no clinical application of RU 486 is possible without FDA Investigational New Drug (IND) approval. RU 486's availability in France is highly restricted and limited to its combined use with prostaglandin E2, not available in the United States. Rep. Ron Wyden (D-Ore.), chairman of the House Committee on Small Business, stated at a hearing last November that "an embargo sends a message that the drug is dangerous and that the FDA is prejudiced against it." Wyden is currently trying to reverse the embargo. Efforts to make RU 486 medically available in the U.S. have been strengthened by recent resolutions by the American Association for the Advancement of Science, by the New Hampshire legislature's appeal for its clinical availability in abortion in that state, and by similar appeals by Mayor David Dinkins of New York. In June 1990, the American Medical Association also came out with a resolution supporting RU 486's clinical applications in abortion. Fifteen hundred scientists, academicians, and health care workers have signed petitions, and more than 200,000 signatures have been collected by the Feminist Majority Foundation, a pro-choice lobbying group in Boston, demanding that Roussel Uclaf make this drug more available for testing or clinical use. Unfortunately, the public sees this effort as being directed only at RU 486's role in medical abortion, when public concern should also be directed to its broad medical applicability. Apart from its antiprogestin, abortifacient or contraceptive action, RU 486 is a potent blocker of corticosteroid receptors, and in preliminary study, RU 486 has shown significant activity in the treatment of breast cancer and inoperable meningioma. RU 486 also has potential value in aiding cervical dilation, lactation, and the treatment of endometriosis. RU 486's block to corticosteroid action has shown unequivocal success in the treatment of Cushing's disease, a disorder of excess adrenocortical secretion. In patients with this disorder, the drug has reversed the osteoporosis, thinning of skin, muscle atrophy, obesity, adult onset diabetes, depression, hypertension, and immunosuppression associated with excess corticosteroid action. With regard to these symptoms, the disease manifestations of Cushing's can be considered a model of aging. Data from humans and animals suggest that the syndrome of aging may involve enhanced or prolonged response to corticosteroids. Based on this, RU 486 could have broad application to both stress-mediated disease and many of the degenerative diseases seen with progressive age. In addition, many tumors, including those of the breast, bowel, and kidney; hepatomas; endometrial cancer; and fibrosarcomas can show corticosteroid dependency, suggesting that RU 486 may have clinical value against a broader range of inoperable tumors than those that are progesterone-dependent. However, we need to evaluate toxicity, as prolonged use could enhance scarring and inhibit acute stress responses (such as shock). We will know the chronic therapeutic effect of this drug only if we can clinically test it in prolonged studies. My own efforts to develop RU 486 in clinical studies for the treatment of advanced breast cancer and AIDS were aborted by Roussel Uclaf following right-to-life boycott threats in March 1989. This occurred despite the results shown by RU 486 in treatment of breast cancer in a 1987 phase I study. In estrogen-positive, chemotherapy-refractory breast cancer patients in Montpellier, France, RU 486 produced objective tumor regression (in six of 22 patients) that was prolonged (more than three months) in four patients. There is also growing in vitro data showing that RU 486 can directly inhibit breast cancer cell proliferation. But although successful clinical data have been available since 1987, Roussel Uclaf is apparently unwilling to financially support breast cancer studies with RU 486 on its own. The company is currently negotiating with the National Cancer Institute with the expectation that the U.S. government will wind up paying for the studies. Although Ariel Mouttet, director of Roussel Uclaf's international marketing, has stated that "it is totally crazy to test the efficacy of RU 486 on AIDS," RU 486 has application to HIV infection based upon data that there is a serum factor in AIDS patients that enhances corticosteroid lympholysis--lymphocyte death as a result of the presence of excess corticosteroid. Because RU 486 has immune upregulating or restorative action, as seen in Cushing's disease and animal models, it should be looked at as a stimulus to immune response. In these cases, it might counteract the immunosuppression seen in aging, in cancer, or in viral or stress-related diseases. In view of fierce opposition to RU 486's role as an abortifacient, it is odd that Roussel Uclaf has not pushed harder for exploration of its role as a medically useful steroid antagonist. And when the company supports clinical research it is inconsistent. Recently I obtained a $20,000 grant from a private foundation to hold a conference geared to the possibilities of using RU 486 in aging studies with animal models, but the company refused to provide matching support. Without the manufacturer's help the conference cannot be held. Yet the firm is supporting clinical research in Alzheimer's disease and depression. And Roussel Uclaf is actively fostering the abortifacient application of RU 486 in countries, such as the United Kingdom and Sweden, where this is politically feasible. The medical constituency that can benefit from RU 486 far exceeds those opposed to the drug because of its abortifacient or contragestational action. In this regard, Roussel Uclaf and Hoechst must seek to serve this "crisis constituency" of those severely ill or debilitated that conceivably can be helped by this drug. Even in noncrisis illness, RU 486 has significant value. As mentioned earlier, the drug is of value against endometriosis, which produces menstrual pain and reduces fertility and affects 10 percent of women in reproductive age. RU 486 also has value in inducing cervical dilation in labor and enhances lactation. All these potential or proven applications must be made visible to the public to create a constituency that could prevail upon Roussel Uclaf to expand its basic research and clinical testing. The problem that has impaired RU 486's medical availability relates to the obvious intent of the "pro-life" forces to reverse Roe v. Wade. Antiabortion forces are well aware that medical availability of RU 486 will create a black market that would compromise their control of pregnancy if Roe v. Wade is repealed. We must be aware that, because of the political polarization engendered by the abortion issue, any future drug development for alternative uses of progesterone or corticosteroid antagonist would have to be blocked by antiabortion forces because of implied threat to pregnancy by any steroid antagonist. While the ostensible right-to-life objection is abortion, these activists are also hostile to the action of any drug that will block nidation or fertilization with or without fetal differentiation. The clinical availability of RU 486 is both a moral and a governmental issue. Political pressure and governmental attitude are key factors in drug development. In France, for instance, when Roussel Uclaf stopped research on RU 486 in 1988 because of fears of economic boycott from antiabortion groups, the government, which owns 33 percent of the stock in the company, intervened and forced the company to continue its studies. If the 400,000 women in this country with breast cancer could be shown the potential value of this drug, they and their families could become an important source of agitation for RU 486's availability, as would the other millions of patients who could benefit from the study of RU 486 as a therapy for their disease. The "crisis constituency"--those with the syndromes of aging, cancer, and numerous other diseases--must be stimulated to add their protest to petitions already circulating that demand the medical availability of RU 486. We need visible scientific conferences, workshops, and discussion to make scientists, physicians, and the public aware of the potential medical value of this drug in order to provide the ethical balance that gives attention to the living as well as the unborn. William Regelson is professor of medicine, microbiology, and biomedical engineering at the Medical College of Virginia, Virginia Commonwealth University in Richmond.

Opponents Of The Drug Are Impeding Medical Progress

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