Introduction

Antiprogestin Drugs: Ethical, Legal and Medical Issues Rebecca J. Cook and David A. Grimes

Following are 14 papers that address medical and health service issues, patient perspectives and ethical and legal issues. The primary focus is on the use of antiprogestin drugs as abortifacients, although the conference included consideration of use of such drugs for purposes of contraception, and treatment, for instance, of Cushing syndrome and possibly breast cancer. RU 486 is being tested in Canada for treatment of breast cancer, and more evidence has recently become available, less than a year after the conference was held, that the drug may have major potential for use as a postcoital contraceptive.’ This last use accentuates the debate on the introduction of antiprogestin drugs into the United States and raises the possibility of this popularly described “abortion drug” being used contraceptively to prevent unwanted pregnancy and thereby to reduce the incidence of ab0rtion.l The use of RU 486 to prevent abortion rather than to cause it challenges both proponents and opponents of availability of the drug, because its postcoital contraceptive use would serve a significantly greater number of women than its use for abortion. Many opponents of abortion choice do not oppose availability of contraceptive drugs, and supporters of choice favor prevention of unwanted pregnancy and of the associated demand for abortion. Opening this symposium presentation of papers inspired by the conference is the contribution by EtienneEmile Baulieu on updating RU 486 developments. Often described as the father of RU 486, Dr. Baulieu refers only in passing to the discovery and development of RU 486, and draws on the experience of the use of the drug in France and Britain to describe its employment and availability. The drug is currently licensed for use for abortion in these two countries and an application for approval has just been accepted in Sweden. It was approved in China in 1988. In France, over IOO,OOO women have chosen RU

The antiprogestin drug mifepristone, popularly known as RU 486, provides women with the choice of abortion by nonsurgical means. Nonsurgical abortion is coming to be described as medical abortion, in contrast to surgical abortion. For the overwhelming majority of women for whom the drug is suitable and available, the choice it offers is between surgical and non-surgical abortion, and not between having and not having an abortion. The drug is therefore relevant to the issue of abortion technique rather than to the legality, morality or ethics of abortion itself. It would be na‘ive, however, to claim that availability of RU 486 as an abortifacient can be separated from the whirlwind of issues surrounding abortion. Acrimonious debate concerning induced abortion often appears to present a seamless web of issues, each connected to other issues to reinforce arguments that advance individual agendas. Nevertheless, it is possible to isolate a particular area for examination and debate. In this spirit, the American Society of Law and Medicine held its conference in December, 1991, entitled Antiprogestin Drugs: Ethical, Legal and Medical Issues. The conference was designed to address the availability and use of antiprogestin drugs in the United States, taking account of medical, legal, ethical, feminist, theological and related perspectives. The conference faculty numbered 48, and additional participants had opportunities to present information and views, contributing to a rich and varied consideration of issues surrounding the suitability and availability of antiprogestin drugs for termination of pregnancy and for a variety of other uses. The conference did not specifically address the legality or morality of abortion itself, but even within its specific focus, opposing views were expressed about the desirability, effects and symbolic implication of nonsurgical abortion. ‘49

Volume 20: 3, Fall 1992 486 for abortion since 1988, when the then French Minister of Health, Claude Evin, described it in an historic phrase as “the moral property of women.” Dr. Baulieu’s writings make clear not only that RU 486 has a complex biological operation, but also that it will not induce abortion within acceptable levels of efficacy and safety simply by a woman “popping a pill.” This imagery, derived perhaps from the simplicity of taking a contraceptive drug, is deceptive, since antiprogestin abortion is possible only at a paricular period in gestation, and for the foreseeable future will require the administraion of a subsequent prostaglandin drug and medical supervision extending over a 48 hour period, with a later check-up. Indeed, an argument in favor of licensing medical use of RU 486 is the fear that, under prohibiton, an illicit market in antiprogestin drugs would open up that would expose women to the risk of considerable harm from unskilled medical management. On the other hand, excessive caution in skilled use, such as reserving a hospital bed in case of necessity, would negate the health service benefits of nonsurgical abortion. Dr. Marc Bygdeman and his co-author, Dr. MarjaLiisa Swahn, describe their pioneering contribution to the use of RU 486 as an abortifacient. Their work in Sweden, initially published in 1984, showed that the administration of RU 486 with subsequent use of a prostaglandin made RU 486 significantly more effective. They also explain their work determining the acceptability of the drug to women, and their finding that it ... seems unlikely that a medical abortion method with a limited duration of applicaton will influence any significant number of indecisive women to perform an abortion which they would later regret.

The authors describe their research on the use of combined RU 486/prostaglandin therapy for second trimester abortion, explaining that their initial findings show greater efficacy and decreased side effects and pain. Finally, they explain that their preliminary findings indicate that the use of RU 486 as a contraceptive administered after ovulation on a monthly basis may prove to be an attractive alternative to present contraceptive methods. The article by Forrest Greenslade, Judith Winkler and Ann Leonard moves beyond the RU 48 G/prostaglandin method itself, often referred to as the “hardware,” to the service delivery aspects needed to promote patient satisfaction, the “software” considerations. They explain that the process of therapeutic innovation is an evolution through the stages of clinical research and product development to the introduction and incorporation of the refined method into a health care setting. They provide a framework to consider how best to maximize the overall quality of abortion services and reproductive health care by the introduction of new biotechnology such as RU 48 b/prostaglandin.

Renee Holt explores considerations for appropriate use of the RU 486/prostaglandin treatment for pregnancy terminations in low resource settings. She stresses the need to explore ways to simplify the procedure without compromising safety. They include minimizing side effects and maximizing acceptability, developing one drug that combines RU 486 with prostaglandin, decreasing the dose of RU 486, which would also decrease the cost, preventing or decreasing any illicit and improper uses, and interpreting or changing the law to facilitate its introduction. Steve Heilig presents results of his survey of obstetricians and gynecologists in California showing that the majority think that the drug should be made available for clinical use and additional research. Significantly, 2 2 percent of those surveyed who do not currently perform abortions reported that they would do so by the RU 486/ prostaglandin technique. Since these physicians understood that this medical method of abortion did not necessarily improve upon the safety and efficacy of surgical abortion, it may be speculated that they were attracted by the avoidance of surgery and the greater acceptability to women that the technique could offer. There are four papers addressing the complex and diverse issues surrounding patient perspectives. Historically, the introduction of new medical techniques was not based on a factual understanding of their acceptability to women. As a result, the introduction of such new methods of contraception as the IUD met with significant discontinuation rates, because women found them unacceptable. Seen in that historical perspective, the research that these papers describe is significant not only for what it discloses, but for the fact that it was and is being conducted. Henry David explains that measuring acceptability of an abortion technique presents a difficult challenge, because greater understanding of and agreement on relevant indicators of acceptability are needed. Indicators include attitudinal indicators (expressed opinions) and behavioral indicators (actual choices). The author explains that in the case of behavioral indicators, many women for countless generations have accepted whatever abortion method has been available regardless of emotional stress, physical pain, health risks and financial costs. To facilitate research on acceptability, the article outlines some possible definitions to help classification of perceptions. These definitions are applied in a small California study on acceptability the author helped to design and undertake. The article concludes by contrasting the results of the California study with other studies that have been undertaken or are ongoing in other parts of the world. The article by Beverly Winikoff and her colleagues explains the finding of a collaborative research project in India and Cuba. The object of the research is to “understand the motivations, reactions and preferences of women, eligible for both, but undergoing, by choice, either surgical

Law, Medicine 6 Health Care or medical abortion regimens.” Ninety percent of the women interviewed said they would choose medical abortion again if faced with a choice between surgical and medical abortion. This research project also addresses the issue of feasibility: “Is it feasible to introduce this technology in medical settings different from the ones where it is currently being used?” The authors explain that feasibility of use depends on many factors including costs, clinic facilities, procedures to control the supply of the drug and, €or example, the training necessary for the delivery of the treatment regimen. This research is relevant not only to developing countries, but also to certain locations in developed countries such as some inner cities and rural areas. Marge Berer analyzes the information available from France on women’s perspectives on their use of RU 486/ prostaglandin in comparison with vacuum aspiration. The latter part of the article calls for further exploration of women’s perspectives on using this method and suggests that the information from such research would provide a basis for resolving disagreement among reproductive health professionals and activists and a better idea of what women think the future of abortion technology should be. The author cautions that in spite of the widespread agreement that acceptability studies are central to the development of new reproductive techniques and procedures, the research on what women find acceptable and how they expereience treatments remains at an early stage. There was much discussion at the December 1991 conference, for example, of whether women might favor medical abortion because it puts them in charge of the process, while surgical abortion leaves them the passive subjects of bodily intrusions. In responding to the question whether adolescents are good candidates for RU 486 as an abortion method, Judith Senderowitz explains that there is little experience and no known documentation of adolescents’ use of RU 486. Given that over one million pregnancies occur annually in adolescent women in the U.S., the author urges that this knowledge gap be closed. She examines what is known about adolescent use of family planning and abortion services and reviews some of the developmental and behavioral issues. She describes factors that may explain why adolescents fail to use contraceptives, including their capacity for denial that limits their ability to recognize that they are pregnant. They may therefore tend to undergo abortion at later and riskier times than they would with better understanding of how their bodies function. Such adolescent behavior will have to be addressed, because as is well known, the current RU 486/prostaglandin regimen requires that it be used within either 49 or 63 days of the last missed period, as is the case in France and the U.K. respectively. In this symposium issue, the articles fall along a continuum ranging from empirical work on the scientific safety and efficacy of antiprogestins to normative work

on frameworks for the evaluation of the drug in ethical terms and legal rules regulating its introduction, distribution and use. There are five papers that consider various ethical and legal aspects. Ruth Macklin provides a framework for ethical analysis, and begins by explaining that good ethics begins with sound facts. She brings sound facts to bear on exploring the following ethical questions: Would introduction of RU 486 into the U.S. produce more benefits than harms? Would introduction enhance the autonomy of women? Would introduction afford women the prospect of greater privacy? Would RU 486 increase access for women in the U.S. to a means of terminating unwanted pregnancy? In noting the lack of access of U.S. women to the benefits of this drug, she explains that [a]n ironic twist of distributive justice is that women in countries such as China and India now have access to RU 486, at least through enrolment in clinical trials, while access is not open to women in the U.S. because of political opposition and moral cowardice. While Bruce Meinstein’s paper provides an ethical framework for analyzing the question whether pharmacists in particular have a right to refuse to fill prescriptions for abortifacient drugs, his discussion will be useful to many other health professionals struggling with the moral aspects of abortion. The author explains that the answer to the question can turn on the professional model of the physician-pharmacist-client relationship that one applies. If one believes that the pharmacist has a contractual relationship with the client through the libertarian model of professionalism, then the pharmacist can freely negotiate, and has no moral obligation to fill a prescription. If, however, the pharmacist is bound by what is called a guild model of professionalism, then the pharmacist can refuse only if the profession makes allowances for conscientious objection. In the third model, the pharmaceutical technician model, the pharmacist is the technician of the physician, and is bound to fill the prescription the physician writes. Finally, in the societal model, the refusals a pharmacist can express are only those authorized by society. Nancy Buc examines some of the legal issues surrounding the introduction of RU 486 and goes on to separate legal from political considerations. She concludes that the legal problems are minimal and that the political problems are paramount. She explains that, given the research and publication to date in peer reviewed journals on the use of RU 486/prostaglandin, it is unlikely that the regimen would fail the legal criteria demonstrating safety and efficacy. In examining whether product liability issues

Volume 20: 3, Fall 1992

for contraceptive and abortifacient drugs are different from those for other drugs, she points out that the question has to be seen in the context of how women’s health concerns are generally addressed and “the overly protective and sexist approach” taken to drugs for women’s conditions, diseases and disabilities. She concludes that the real problem is that there is no willing sponsor of the drug in the U.S. and recommends the establishment of a drug company called “Feminist Pharmaceuticals.” Reed Boland contrasts the role of governments and companies in the introduction of RU 486 in France and the U.K. with that of the company empowered to request introduction in the U.S., Hoechst-Roussel, and the U.S. government. He describes how the French and British companies and governments were willing players, and how Hoechst-Roussel in the U.S. is reluctant to market and the U.S. government has not encouraged research on this method. He examines how the provisions of the French, U.K., and U.S. patent laws have been and could be used to require the company to apply to market the drug. Commonly known as “use it or lose it” patent provisions, sections of the patent legislation generally enable governments to move a patent or a license for a therapeutic product from a holder that fails or refuses to market to a sponsor that will make it available to consumers. The provisions are based on the theory that in providing a monopoly to a company to develop and market a drug, a government is entitled to ensure the public benefits from the monopoly in return. Reed Boland explains how this theory is applied differently by the laws of France, the U.K. and the U.S. William Hayhurst, in his article on the patenting and supply of therapeutic products, explains how the “use it or lose it” patent provision in the Canadian law might be applied to require the Canadian subsidiary of the company controlling RU 486 to introduce it into Canada. Boland puts the issue starkly: does a drug company have a moral responsibility to facilitate access to a drug or processes that have been unequivocally shown to have significant benefits to public health and have the potential of making even greater contributions if more fully studied and exploited? Further, does not such a company become morally accountable for any suffering that results from its refusal to work its patent? He explains that many countries have answered these questions in the affirmative and concludes by showing how U.S. case law on compulsory licensing could be used to require Hoechst-Roussel to market RU 486 in the U.S. William Hayhurst’s complementary legal analysis explores means by which Canadian patent law might be employed to provide a bridgehead for abortifacient use of RU 486 in North America, and locations where U.S.

women would have access. Such women would tend to be more affluent. Their access would repeat the historic inequity of access to abortion services since opposition to abortion has always borne disproportionately on poor, less educated and younger women in societies. Rachaei Pine provides a case note on Benten v. Kesster, in which she and her colleagues at the New York-based Center for Reproductive Law and Policy were involved as attorneys representing Ms. Benten and her companions. The case was brought in July 1992 to challenge the exclusion of RU 486 from the provision in the Food and Drug Administration regulations allowing the importation of unapproved drugs for personal use on a discretionary basis. The note explains that while Ms. Benten was not successful in importing RU 486 for her personal use, she and her companions did secure a strongly worded condemnation of the import ban from the U.S. District Court in New York, and some insightful comments from Justice Stevens dissenting in the Supreme Court’s decision on the government’s successful appeal. It may be pointed out that Hoechst-Roussel, in refusing to submit an application to the FDA for approval to market RU 486, has gained free publicity that a drug company would usually covet. Hoechst-Roussel may be acting as its own worst enemy, however, in striving to keep RU 486 unavailable to U.S. women. Its policy will probably cause other challenges to be made and intensify the controversy surrounding abortion that this company says it is trying to avoid. For instance, the Comptroller of the City of New York, Elizabeth Holtzman, has circulated a letter, dated June 25, 1992, asking the New York City Health and Hospitals Corporation (HHC) to refuse to purchase drugs from the Roussel affiliates for which adequate substitutes are available until Roussel takes the steps necessary to petition the FDA for full marketing and testing of RU 486 in the U.S. and advises HHC that it has done so.

In bringing together scientific information about the present and potential uses of antiprogestin drugs and ethical thought regarding their availability and the integrity of the legal regulation of medical techniques, the ASLM conference addressed the challenge of resolving conflicts between medical advances and political ideology. Relevant idealogies ranged from fundamentalist anti-choice convictions to feminist concerns about the use of new drugs. Speculation about governmental approval of employment of abortifacient drugs was coupled with questions about whether pharmaceutical companies would or should seek approval of products that are politically contentious and socially divisive. It became relevant to inquire, for instance, whether methotrexate, the first chemotherapy to offer a nonsurgical treatment of cancer without radiation, which also induces abortion, would be approved for use in the

Law. Medicine ei. Health Care U.S. in the present climate. The need to balance the claimed benefits to women against perceived detriments to values, ideologies and more pragmatic interests was a Pervasive theme of the conference and underscores the cumulative significance of the resulting papers.

References I . A. Glasier, K.J. Thong, M. Dewar, et al., “Comparison of Mifepristone (Ru 486) and High Dose Estrogen-Progestogen for Emergency Postcoital Contraception,” New England lournal of MeJiicine 1992, forthcoming: 2. D.A. Grimes and R.J. Cook [editorial] “Mifepristone (RU 486): An Abortifacient to Prevent Induced Abortion?” New England Journal of Medicine I 992, forthcoming.

Antiprogestin drugs: ethical, legal and medical issues.

RU 486 allows women the choice of a medical rather than a surgical abortion, and, for most women, the choice is one of procedure, not of whether to ha...
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