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Ethical Issues Related to the Inclusion of Women of Childbearing Age in Clinical Trials

Jonathan D. Moreno

In this brief paper I will discuss the ethical issues associated with the enrollment of women of reproductive potential in clinical trials. I should say at the outset that I believe that women in the referenced population should not be excluded as a class from participation in clinical trials or studies. In the policy I recommend, the exclusion of individual members would have to satisfy the burden of argument that risks are intolerable. In other words, I favor reversing the traditional presumption from exclusion to inclusion.

Without prejudicing the question of recruiting pregnant women as subjects, it should be appreciated that the historic basis for our largely exclusionary policy has been concern about fetal protection.1 The extension of protectionism from pregnant women to all women of reproductive potential was, I believe, the result of intellectual lassitude, defensive legalism, and a misplaced sense of obligation.2 While it might be argued that the prospect of increased research costs has also been a factor, I do not believe that such estimates were attempted until quite recently, when the prospect of a policy change became serious.

There are a number of considerations that support the reform of current policy toward a presumption of inclusion of women of reproductive potential as research subjects. These considerations can be related to three ethical principles that have been viewed as the appropriate analytic framework for questions concerning the morality of clinical trials: respect for persons, beneficence, and justice.3

The most powerful (if not persuasive) argument one could make against exposing women and their possible offspring to the risks of research participation is that we should not expose anyone to unnecessary risk in the name of science.



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Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume 2 - Workshop and Commissioned Papers Ethical Issues Related to the Inclusion of Women of Childbearing Age in Clinical Trials Jonathan D. Moreno In this brief paper I will discuss the ethical issues associated with the enrollment of women of reproductive potential in clinical trials. I should say at the outset that I believe that women in the referenced population should not be excluded as a class from participation in clinical trials or studies. In the policy I recommend, the exclusion of individual members would have to satisfy the burden of argument that risks are intolerable. In other words, I favor reversing the traditional presumption from exclusion to inclusion. Without prejudicing the question of recruiting pregnant women as subjects, it should be appreciated that the historic basis for our largely exclusionary policy has been concern about fetal protection.1 The extension of protectionism from pregnant women to all women of reproductive potential was, I believe, the result of intellectual lassitude, defensive legalism, and a misplaced sense of obligation.2 While it might be argued that the prospect of increased research costs has also been a factor, I do not believe that such estimates were attempted until quite recently, when the prospect of a policy change became serious. There are a number of considerations that support the reform of current policy toward a presumption of inclusion of women of reproductive potential as research subjects. These considerations can be related to three ethical principles that have been viewed as the appropriate analytic framework for questions concerning the morality of clinical trials: respect for persons, beneficence, and justice.3 The most powerful (if not persuasive) argument one could make against exposing women and their possible offspring to the risks of research participation is that we should not expose anyone to unnecessary risk in the name of science.

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Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume 2 - Workshop and Commissioned Papers But in our society we have in effect concluded that research involving human subjects should go forward when participation is voluntary, the risk appears to be minimal, and the foreseeable benefits to others, if not in all cases the subject, are substantial.4 What seems to have distinguished policies concerning research involving women of reproductive potential from research involving other kinds of subjects is the prospect of harm to possible children. Legal issues aside, I can think of three moral grounds for such policies: that possible children cannot consent, that the interests of later generations should be protected by earlier ones, and that biologically mediated risks to future human beings are uniquely unacceptable. The primary purpose of consent policies has been the protection of research subjects. The prospective subject in the studies in question is the woman, not the possible child. In the case of research involving young children, parents have been regarded as the most appropriate sources of permission for research participation. There is also a special class of potential children or fetuses (as against possible children, who are those prior to conception or individuation or ''brain birth" or viability), who could be affected by a woman's participation in research. Consonant with policies concerning children as subjects, when research involving pregnant women has been permitted, potential parents have been regarded as the appropriate decision makers concerning the acceptability of fetal risk, except when a risk-benefit analysis applied to the woman fetus pair is patently unfavorable. Future generations will include women as well as children. Thus the interests of future generations include improved treatment of diseases affecting women. Even if there was reason to think that clinical trials create a serious conflict between the interests of future women and future children (interests which must surely be seen as complementary), the interests of the former could not a priori be dismissed in favor of those of the latter. Finally, one might claim that there is something "worse" about biologically mediated risks as compared to other risks that social action creates for future generations. I do not know what sense to give such a claim, and I do not think that it can be defended without mystifying biological, as against social, relations. I will now turn to arguments on behalf of permitting the class of women of reproductive potential to participate in clinical trials, drawing on the ethical principles mentioned above. The first is an argument from justice: the class of men of reproductive potential has never been excluded, although there is evidence that various substances from occupational and pharmaceutical sources affect the male reproductive system. Male-mediated mutagens may include lead, morphine, thalidomide, caffeine, ethanol, and anesthetic gases.5 Advances in human genetics will surely provide further information about chemical interaction with germ cells in men as well as women. Consistency would therefore require that the class of male subjects of reproductive potential also be rejected. Unless

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Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume 2 - Workshop and Commissioned Papers such a "reform" is instituted, debarring the class of women is not only inequitable, it is simply irrational. One of the defining conditions of a Phase III study is the possibility of benefit for the subject. Thus the exclusion of a class of subjects from clinical trials is a violation of the principle of beneficence toward the potential subjects. On the assumption that information concerning the reaction of women in this age group to a study drug will be beneficial to them, it is also a violation of beneficence toward other women who are not among the subjects. Worse, therapies are in fact applied to women in this age group in the clinical setting without reliable information concerning hypothetically differential metabolism in this population. Perhaps draconian laws could be established that would discourage such uses of medication by physicians, but this seems both unlikely and impractical. Therefore, exclusionary research policies applied under currently prevailing conditions not only fail to provide some degree of benefit to women of reproductive potential, they are also a source of risk to women. These considerations establish a prima facie case in favor of participation in clinical trials, especially in light of the failure of opposing arguments. I have already alluded to an opposing argument that applies specifically to nonpregnant women, namely, the possibility that they will become pregnant in the course of a trial. As stated, current policies recognize the authority of parents with regard to risks that might be incurred by potential children (fetuses). Therefore I should think that, at most, the same policies would apply with regard to risks that might be incurred with regard to possible children. This argument does not authorize the prospective subject to accept any and all risk, whether a woman of reproductive potential or a member of any other class. Compounds that do not offer a subject the reasonable prospect of benefits that would offset foreseeable risks should not be brought to a clinical trial. In this context, consider the following scenario: a drug offers a small chance of minor benefit to a subject, but includes a high risk of damage to germ cells. Should such a drug be brought to a clinical trial? I would argue that the harm involved (compromised reproductive well-being) is a harm to the subject (male or female), and that the risk—benefit ratio does not justify a clinical trial. Similarly, participation in Phase I and Phase II studies should be based on an assessment of potential harms to the subject, including damage to her or his reproductive system. Of course, unlike clinical trials, potential benefits to the subject might not be part of such an assessment. However, the presumption of inclusion would place the burden of proof on the argument that the hypothetical risk is unacceptable. Therefore all of the arguments on behalf of participation in clinical trials also apply to studies, except that those that refer to foreseeable benefits to the subject probably would not apply to Phase I studies of toxicity. On its face, beneficence seems to require the exclusion of women who could become pregnant, but an analysis casts doubt on this inference. Conditions

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Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume 2 - Workshop and Commissioned Papers on participation that hinge on a homosexual lifestyle, a promise to avoid pregnancy, or documented sterility would raise daunting problems of verification, would erect decisive obstacles to many worthwhile protocols, and would in many cases have to be applied to men as well as women. Inequitable practices already characterize this area: in trials of a drug (Proscar) that had been found to cause defects in the offspring of male laboratory animals, men were asked only to pledge that they would use "mechanical contraception."6 The human male's notorious unreliability with respect to such guarantees does not require comment. I have argued that studies that pose a patently unfavorable balance of risks and benefits should not be offered to women of reproductive age, as they would not be offered to any human subjects; studies that pose no foreseeable risk to the reproductive system should routinely include both male and female subjects. In all other cases, respect for persons implies that individual women of reproductive potential should be the ultimate decision makers with respect to the question whether the risks of participation are acceptable or not. The same ethical principle also requires that subjects understand what they are getting into. Bearing in mind that a consent form should merely document, and not replace, an educational process between the investigator and the candidate, care should be given to ensuring that there is such understanding. Vigorous subject education efforts are indicated when the proposed trial presents a known risk to the reproductive system, in spite of foreseeable benefits to the subject. The intensive "pregnancy prevention program" undertaken by Hoffman-LaRoche, Inc., in connection with the clinical use of Accutane, serves as an example of such initiatives. In the consent form itself I would recommend language of the following sort: It is possible that this treatment will cause damage to children if you choose to have them. You have already been told what is known about this possibility, and you are encouraged to ask further questions. (Include when appropriate: We urge you not to become pregnant while you are part of this study.) You may want to discuss this with others before you agree to take part in this study. If you wish, we will arrange for a doctor, nurse or counselor who is not part of this study to discuss this possibility with you and anyone else you want to have present. This recommendation is consistent with current federal regulations, which require disclosure to subjects of risks that may be incurred by the subject or by the embryo or fetus "if the subject is or may become pregnant. . . ."7 However, by adopting this language the quoted regulation overlooks male-mediated mutagenesis. When such risks are known prospective male subjects should be engaged in a consent process similar to that described above. Finally, in our time and in our society, exclusion of a class from

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Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume 2 - Workshop and Commissioned Papers participation in a clinical trial has consequences beyond the denial of the specific treatment opportunity.8 For example, in the area of HIV research there are tangible advantages attached to participation as a research subject for members of the population likely to be at risk, advantages such as improved access to care. In some cases treatment modalities for those who have "failed" with standard medications have only been available within protocol. In citing these advantages of participation in research for a specific subgroup of women of reproductive age, I open myself to the charge that I am inviting race, sex, and class-based exploitation. Yet it is a canon of research ethics that the benefits as well as the burdens of research should be equitably distributed. Further, the practical implications of exclusion of younger women from clinical trials help to highlight the import of my more general claim, that the class of women of reproductive potential should not be excluded from participation as subjects in research. Here, then, is a summary of my conclusions: The class of women of reproductive age should be presumed as eligible for enrollment in research. The burden of argument in particular cases should rest on showing that the balance of risks and benefits is patently unacceptable, including harm to the subject's reproductive system without offsetting benefits to the subject. In all other cases the informed consent process should enable the woman to be the ultimate decision maker concerning the acceptability of risks.9 An important by-product of these considerations could be a more cautious approach to the investigation and use of drugs in males of reproductive potential. NOTES 1.   Levine, C. 1993. Women as research subjects: New priorities, new questions. In: Emerging Issues in Biomedical Policy: An Annual Review, R.H. Blank and A.L. Bonnicksen, eds. New York: Columbia University Press. 2.   Dresser R. Wanted: Single, white male for medical research. Hastings Center Report 22(1):24–29. 3.   National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. 1979. The Belmont Report. Federal Register 44(76):23192–23197. 4.   Levine R. 1986. Ethics and the Regulation of Clinical Research. New Haven: Yale University Press. 5.   Soyka, L.F., and Joffe, J.M. 1980. Male-mediated drug effects on offspring. In: Drug and Chemical Risks in the Fetus and Newborn, R.H. Schwartz and S.J. Yaffe, eds. New York: Alan R. Liss. Uzych, L. 1985. Teratogenesis and mutagenesis associated with the exposure of human males to lead: A review. Yale Journal of Biology

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Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume 2 - Workshop and Commissioned Papers     and Medicine 58:9–17. 6.   Comment by Dr. Bonnie Goldmann (Senior Director, Regulatory Affairs, Merck Research Laboratories), Food and Drug Law Institute Conference on Clinical Trials, Washington, D.C., October 5, 1992. Also reported in Debrovner, D. 1993. Of mice and men. American Druggist January:30. 7.   Department of Health and Human Services. 1983. 45CFR 46.116(b) (1); 21 CFR 50.25(b) (1). 8.   Minkoff, H., Moreno, J., and Powderly, P. 1992. Fetal protection and women's access to clinical trials. Journal of Women's Health 1:37–41. 9.   For their comments on an earlier draft, the author expresses his gratitude to his colleagues in the Division of Humanities in Medicine, and also to Howard Minkoff, M.D., and Richard H. Schwartz, M.D., all of the SUNY Health Science Center at Brooklyn.