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The Exclusion of Pregnant, Pregnable, and Once-Pregnable People (a.k.a. Women) from Biomedical Research

Published online by Cambridge University Press:  24 February 2021

Vanessa Merton
Vanessa Merton*
Affiliation:
Pace University School of Law; Radcliffe College, N.Y.U. School of Law
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Abstract

The barriers to women's participation as subjects in biomedical research are currently being challenged as a matter of legislative policy, medicine, and law. This Article catalogs the ways in which women have been disadvantaged by their exclusion and recent developments to redress them, and goes on to dissect the underlying rationales for excluding women from clincial trials. The author reveals the ‘fundamental misconception’ behind exclusionary rationales, and argues that research sponsors in fact have more to fear in the way of potential liability from the exclusion of women, even pregnant women and women of child-bearing capacity, than from their inclusion. Finally, the Article suggests strategies for achieving reform of these exclusionary practices.

Type
Articles
Information
American Journal of Law & Medicine , Volume 19 , Issue 4 , 1993 , pp. 369 - 451
Copyright
Copyright © American Society of Law, Medicine and Ethics and Boston University 1993

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Footnotes

†

This title is of course a tribute to the Supreme Court's astute distinction between pregnant and nonpregnant persons in , Geduldig v. Aiello, 417 U.S. 484 (1974). , See infra notes 237, 252 and accompanying text.

This article is dedicated to the memory of Carol H. Lefcourt, founding partner of Lefcourt, Kraft and Arber, the first all-woman law firm in New York; General Counsel to the New York State Division of Women; co-founder, Coalition on Women's Legal Issues; editor, WOMEN and THE LAW (1984), named “Best Law Book of 1984” by the American Association of Publishers; recipient in 1990 of the Susan B. Anthony Award of the National Organization for Women. Carol died from breast cancer on August 25, 1991, at the age of 47.

References

1 Gina Kolata, In Medical Research, Equal Opportunity Doesn 't Always Apply, N.Y. Times, Mar. 10, 1991, at E16.

2 Hubbard, Ruth, Science, Facts and Feminism, in Feminism and Science 119, 128 (Nancy Tuana ed., 1989)Google Scholar.

3 Risa Denenberg, Treatment and Trials, in Women, AIDS, and Activism 68 (The Act UP/ New York Women and AIDS Book Group ed., 1990).

4 Kirschstein, Ruth L., Research on Women's Health, 81 Am. J. Pub. Health 291, 293 (1991)Google Scholar.

5 See U.S. General Accounting Office, Gao/Hrd-93-17, Women's Health: Fda Needs to Ensure More Study of Gender Differences in Prescription Drug Testing (October 1992). This Gao survey of drug manufacturers that obtained FDA approval of new drugs from January 1988 through June 1991 concluded that gender-related differences in response do exist for many drugs; that women are generally under-represented in clinical trials; and that even when women are included in drug trials, the investigators donot analyze trial results to detect genderrelated differences.

See also U.S. Dep't Health & Human Servs., Pub. no. (PHS) 88-50206, Report of Public Health Service Task Force on Women's Health Issues, Vol. II (October 1985); Mark V. Nadel, General Accounting Office Gao/T-Hrd-90-38, National Institutes of Health: Problems in Implementing Policy on Women in Study Populations (1990) (Testimony before the House Subcommittee on Health and the Environment, June 18, 1990); Society for the Advancement of Women's Health Research, Toward A Women's Health Research Agenda: Findings of the Scientific Advisory Committee (1991); and the collected testimony at the public hearings before the NIH Task Force on Opportunities for Research on Women's Health on June 12-13, 1991 of more than sixty witnesses (transcripts of the testimony of forty-six witnesses are on file with the author); Cotton, Paul, Is There Still Too Much Extrapolation from Data on Middle-Aged White Men?, 263 JAMA 1049 (1990)Google Scholar; Gurwitz, Jerry H. et al., The Exclusion of the Elderly and Women from Clinical Trials in Acute Myocardial Infarction, 268 JAMA 1417 (1992)Google Scholar; Hooper, Celia, Some Drug Trials Show Gender Bias, 2 J. Nih Res. 47 (1990)Google Scholar; Kinney, Evlin L. et al., Underrepresentation of Women in New Drug Trials, 95 Annals Internal Med. 495 (1981)Google Scholar; Kolata, supra note 1, at E16; Earl Lane, The Gender Gap in Medical Research, Newsday, June 25, 1991, at 63 (citing as examples the Physicians’ Health study of aspirin prophylaxis for myocardial infarction in 22,071 men, no women; dietary study of recovery from heart attack in 2033 men, no women; study of behavioral link with heart disease in 3154 men, no women); Mary Lake Polan, Medical Researchers, Heal Thyselves of Gender Bias, LA. Times, Feb. 24, 1991, at M2; Shigeko Segawa, Clinical Trials: It's Still a Man's World, 345 Nature 754 (1990).

With respect to mental health and developmental research, the picture is much the same. “The study of adolescence has been the study of males,” noted psychologist Carol Gilligan in reference to the ongoing work of the Harvard University Project on the Psychology of Women and the Development of Girls. Lindsay Van Gelder, The Importance of Being Eleven: Carol Gilligan Takes On Adolescence, Ms., July-Aug. 1990, at 77; see also U.S. Dep't Health & Hum. Servs., Pub. Health Serv., Alcohol, Drug Abuse, and Mental Health Admin., Pub. No. (ADM) 86-1447, Women and Drugs: A New Era for Research V (Barbara Ray & Monique Braude eds., 1986) (“The history of drug abuse research shares with other sciences a relative paucity of knowledge about females in particular and about gender effects in general. This bias in knowledge stems from the tradition of using male subjects for animal and human experiments and an unexamined assumption that gender is not an important experimental variable.“); Chris Raymond, Recognition of the Gender Differences in Mental Illness and Its Treatment Prompts a Call for More Health Research on Problems Specific to Women, Chron. Higher Educ, June 12, 1991, at A5.

Like so many other issues of clinical research, this phenomenon has been particularly remarked upon in the context of the AIDS pandemic. See Jeannette R. Ickovics & Judith Rodin, Women and AIDS in the United States — Epidemiology, Natural History, and Mediating Mechanisms, 11 Health Psychol., Jan. 1992, at 1 (although women represent more than one-third of all cases of AIDS globally and die significantly sooner after diagnosis than men with AIDS, and despite important gender differences in all phases of the disease process, from prevention and exposure to diagnosis and treatment, women are still excluded from most biomedical and psychosocial research); Institute of Medicine, Expanding Access to Investigational Therapies for Hiv Infection and AIDS 64 (1991) (white males predominate in almost all clinical AIDS trials); Mayer, Kenneth & Carpenter, Charles, Women and AIDS, 266 Sci. AM. 118 (1992)Google Scholar (marked underrepresentation of women in HIV-related clinical research); Gina Kolata, AIDS Research on New Drugs Bypasses Addicts and Women, N.Y. Times, Jan. 5, 1988, at C1, C7. That this was no oversight is well-documented in Gena Corea, the Invisible Epidemic: the Story of Women and AIDS (1992) (recounting the heroic, but unsuccessful, efforts of leading epidemiologist Dr. Zena Stein to get funding from NIH and the American Foundation for AIDS Research to study the disease in women).

The problem of exclusion is not confined to United States research. See Robert Walker, Heart Studies Ignore Women, Calgary Herald, Oct. 19, 1991, at B2 (report on presentations at the annual meeting of the Canadian Cardiovascular Association); Caroline Mallan, Mds Assume Men Need Better Care, Toronto Star, July 26, 1991, at A26 (Canadian men over the age of 45 more than twice as likely as women with similar heart disease to undergo diagnostic angiography and three times as likely to have bypass surgery; doctors don't offer heart surgery to women because they may believe that women don't need to return to work after heart attacks).

6 See attached Toward A Women's Health Agenda, Appendix A. This still quite incomplete list was generated from the written testimony offered by witnesses at the NIH Hearing on the Task Force on Opportunities for Research on Women's Health (June 12-13, 1991); of reports created by the new Society for the Advancement of Women's Health Research; and of legislative committee reports on the proposed Women's Health Equity Act. A more definitive list may be found in the recent National Institutes of Health, U.S. Dep't Health & Hum. Servs., Pub. NO. 92- 3457A, Report of the National Institutes of Health: Opportunities for Research on Women's Health (1992). See also National Women's Health Network, Research To Improve Women's Health: An Agenda for Equity (Dec. 1991) (on file with author).

7 Philip J. Hilts, N.I.H. Starts Women's Health Office, N.Y. TIMES, Sept. 11, 1990, at C9. In March 1993 the Office held two days of public hearings on issues in the recruitment and retention of women in clinical trials. See 58 Fed. Reg. 12,366-67 (Mar. 4, 1993). The National Institutes of Health Revitalization Act of 1993 codifies the creation of this office and defines its mandate as promoting research on women's health. 42 U.S.C.A. § 201d (West Supp. 1993); see infra notes 11, 276.

8 The report entitled Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies (on file with author) was issued as this article went to press.

9 Georgetown University Medical Center, Conference on the Inclusion of Women and Minorities in Clinical Research (June 28-29, 1993) (brochure on file with author).

10 U.S. Health Study to Involve 160,000 Women at 16 Centers, N.Y. Times, Mar. 31, 1993, at A21; Sandra Freidland, A Medical Study on Older Women, N.Y. Times, Apr. 4, 1993, at NJ1, NJ16.

11 The National Insitutes of Health Revitalization Act of 1993, 42 U.S.C.A. § 201 (West Supp. 1993); see infra note 276.

12 Guideline for the Study & Evaluation of Gender Differences in Clinical Evaluation of Drugs, 58 Fed. Reg. 39,406 (July 22, 1993).

13 See infra notes 97-128, 276-287 and accompanying text.

14 All the women in the WHI will be post-menopausal: between the ages of 50 and 79. See Freidland, supra, note 10. While there is some scientific logic to the age range, in that the study is trying to identify causal factors of heart disease, cancer, and osteoporosis, which usually become manifest during those years, many suspect that once again, women of child-bearing potential are being systematically excluded.

15 In the eloquent phrase of Representative Patricia Schroeder, the Congressional leader who has perhaps done more than anyone else to make this issue visible, “[Y]ou fund what you fear. When you have a male-dominated group of researchers, they are more worried about prostate cancer than breast cancer.” Ellen Goodman, A Health-Research Bias, Boston Globe, June 21, 1990, at 15. This widely distributed column was, I believe, the first to make the point that even basic animal research is generally conducted with male white rats. One particularly graphic exhibit attached to the NIH Task Force on Opportunities for Research on Women's Health testimony of the Interstitial Cystitis Association of America, Inc., compared NIH expenditures on male and female urological research. NIH Task Force on Opportunities for Research on Women's Health (exhibit to testimony of the Interstitial Cystitis Ass'n of America, Inc.). The annual expenditure of NIH research dollars on predominantly male urologic disease was $6.49 per person affected; the comparable expenditure on predominantly female urologic disease was $.35 per person affected. (Appendix A, attached.)

More women than ever have entered the profession of medicine. Female first-year medical school enrollment has steadily grown, from 4% in 1930, to 9% in 1969, to over 40% in 1990. But women remain under-represented in the ranks of academic medicine, the major locus of training and nurturing of clinical investigators. See Healy, Bernadine, Women in Science: from Panes to Ceiling, 255 SCIENCE 1333 (1992)Google Scholar. One dean of an American medical school is female. Three per cent of all department chairs are female. Women comprise about 22% of medical school faculty, but they are clustered in the lower ranks; on average, male faculty are promoted twice as fast as women. See Feminist Majority Foundation and American Medical Women's Association, Empowering Women in Medicine 2 (1991); Ama Council on Ethical and Judicial Affairs, Gender Discrimination in the Medical Profession, 4 Women's Health Issues 1 (1994). Although in 1987 women earned 35% of all doctorates in life sciences, and 17% in physical sciences, a recent blue-ribbon panel on the crisis in funding of research projects strongly recommended creation of more programs to encourage more women and minorities to pursue careers in health sciences and academic medicine. See Report of the Committee on Policies for Allocating Health Sciences Research Funds of the Institute of Medicine, in Funding Health Sciences Research (Floyd E. Bloom & Mark A. Randolph eds., 1990) at 13, 123.

Women who do seek careers in research experience the same obstacles as women in other non-traditionally-female career paths. See, e.g., Garb, Maggie, U.S. Health Institutes Face Sex Discrimination Suits, 24 Am. Med. News 4 (1991)Google Scholar; Rorie Sherman, Claims of Bias at NIH Bolstered, Nat'llj., Dec. 9, 1991, at 3, 35 ($225,000 verdict against NIH for sex discrimination against senior scientist; three other sex discrimination cases pending against NIH). The NIH, in particular, has an abysmal record in this regard. In 1986, a GAO report found that NIH takes longer than any other Public Health Service agency to resolve discrimination complaints and did not comply with four of eight Equal Employment Opportunity Commission requirements. See Alisa Solomon, Snake Pit, Mirabella, Apr. 1993, at 140-44. The draft report of an internal task force convened in 1991 “to assess the career development and status of intermural women scientists at NIH” found that women make up only 18% of the tenured scientists, although they constituted 30% of the last decade's post-docs (the traditional track to senior status). Extensive reports by female scientists of anti-woman bias at NIH range from denial of lab time and other resources, rejection of project proposals, and less desirable assignments, to display of degrading images of women in the office and the use of terms like “wicked witch,” “dragon lady,” and “booby lady” to refer to women researchers. In 1992, a Washington, D.C. television station ran a six-part investigative report that featured dozens of female NIH researchers alleging discriminatory treatment. See id.; Scott Greenberger, Science Friction: The Struggle of Female Researchers at NIH, Wash. Post, July 11, 1993, at C3; NIH, Under Increased Scrutiny for Sex Discrimination, Seeks to Ban Researcher from Campus, CORP. Crime Reporter, Oct. 26, 1992, at 8, 16; and Interview with MargaretJensvold, M.D., Director, Institute for Research on Women's Health, CORP. Crime Rep., Oct. 26, 1992, at 8, 16. On April 1, 1994, a female researcher won the first jury verdict ever against the National Institutes of Mental Health for denial of opportunities afforded her male counterparts and retaliation for filing an Eeoc complaint. Lack of Mentoring for Female Physician Considered Sex Bias by Federal fury, 1994 Daily Lab. Rep. (BNA) No. 64, at D-11 (April 5, 1994). Recall also the case of Dr. Frances Conley, the prominent neurosurgeon who resigned her tenured position at Stanford University Medical School to protest the administration's failure to curb the relentless sexism and harassment she and other women professionals had experienced in that institution. See generally the Outer Circle: Women in the Scientific Community (Harriet Zuckerman et al. eds., 1991).

16 Thus, in the popular press one finds still ubiquitous references to the “woman firefighter” or “woman sportscaster” or, for that matter, the woman doctor or lawyer, while the gender of men in the same roles is never mentioned. In medical school, to pick a more salient example, students learn the anatomy and physiology of the “70-kilogram man:” what his urine output is, what dosages of medication he should get. A study reviewing eight major anatomy texts used in medical schools found that identifiably male bodies and body parts constitute 64% of the illustrations, while female bodies were used only for 11 % of the illustrations (the gender of the balance was indeterminate) — except, of course, in the chapter on reproductive anatomy. Carol Tavris, the Mismeasure of Women 96-98 (1992); see also Kay Weiss, What Medical Students Learn About Women, in Seizing Our Bodies: the Politics of Women's Health 212 (Claudia Dreifus ed., 1978), for a collection of extraordinary excerpts from standard contemporary gynecology texts.

[Predominantly male … researchers, policy makers, and practitioners … have typically dealt with differences among types of clients by placing everyone, except White middleaged … men, in special population categories [cit. omit.]… . This special population approach provides a way to incorporate data and experience that is inconsistent with general expectations …, but reduces the need to examine and revise the fundamental assumptions that define the standard for normal … services.

Reed, , Developing Women-sensitive Drug Dependence Treatment Services: Why So Difficult?, 19 J. Psychoactive Drugs 151, 152-53 (1987)Google Scholar; see also Rebecca Dresser, Wanted: Single, White Male for Medical Research, 22 Hastings Center rep. 24, 28 (Jan.-Feb. 1992) (biomedical researchers define “the white male as the normal, representative human being“).

17 See Judith D. Auerbach, Ph.D., Testimony on behalf of the Consortium of Social Science Associations before the Task Force on Opportunities for Research on Women's Health of the Advisory Committee to the Director of National Institutes of Health 4-5 (June 12, 1991) (on file with author).

18 “Women make up more than half the world's population, yet perform two thirds of its work, receive one tenth of its income and own less than one hundredth of its property.” United Nations, Office of Public Information, United Nations Decade for Women 1976-1985, Really Only a ‘Beginning', 22 un Chron., July-Aug. 1985, at ii. In the United States, the tiresome truth remains that college-educated women on average have lower annual income than men with high school diplomas. Depression Affects Productivity, Causes Workplace Accidents, Experts Say, Daily Lab. Rep. (BNA) No. 141, at A-3 (July 23, 1991), and that women employed outside the home make 74¢ for every dollar of salary paid men. Louis S. Richman, The Truth About the Rich and the Poor, FORTUNE, Sept. 21, 1992, at 135; Earnings Increased 3.3 Percent for Wage, Salary Workers, Daily Lab. Rep. (BNA) No. 24, at B-4 (Feb. 5, 1992) (median earnings of full-time paid women workers 74.2 percent of full-time male workers).

19 Andrea Savage-Abramowitz et al., Serving Women: The Impact of Program Structure and Resources, in 1 Drug Dependence and Alcoholism 849 (Arnold J. Schechter ed., 1981); Carmen, Elaine et al., Inequality and Women's Mental Health: An Overview, 138 Am. J. Psychiatry 1319, 1328 (1981)Google Scholar; iff also Kathleen Teltsch, In Detroit, A Drug Recovery Center That Welcomes the Pregnant Addict, N.Y. Times, Mar. 20, 1990, at A14.

20 Jay Katz Et Al., Experimentation with Human Beings (1972).

21 IRB: A Review of Human Subjects Research, published by the Hastings Center and now in its fifteenth volume.

22 The major ethical codes for research scientists speak only to requiring informed consent and ensuring the freedom to refuse to serve as a subject. See, e.g., the Nuremberg Code, Rule 1 (1949); World Medical Association, Declaration of Helsinki: Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects, § III, Rule 3b (1975). Both are reprinted in Robert J. Levine, Ethics and Regulation of Clinical Research 425, 427 (2d ed. 1988) [hereinafter Levine, Ethics and Regulation].

23 E.g., Bernard Barber et al., Research On Human Subjects: Problems of Social Control in Medical Experimentation (1973); Henry K. Beecher, Research and the Individual (1970); Renee C. Fox, Experiment Perilous (1959); Paul Freund, Experimentation on Human Subjects (1970); Charles Fried, Medical Experimentation: Personal Integrity and Social Policy (1974); Feinstein, Alvan R., Medical Ethics and the Architecture of Clinical Research, 15 Clinical Pharmacology & Therapeutics 316 (1974)Google Scholar; Jonas, Hans, Philosophical Reflections on Experimenting with Human Subjects, 98 Daedalus 219 (1969)Google Scholar; LeRoy Walters, Some Ethical Issues in Research Involving Human Subjects, 20 Persp. Biology & Med. 193 (Winter 1977); see also President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Implementing Human Research Regulations (1983); President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Protecting Human Subjects (1981). But see Robert J. Levine, Appropriate Guidelines for the Selection of Human Subjects for Participation in Biomedical and Behavioral Research, in the National Commission for the Protection of Human Subjects of Biomedical and behavioral Research, the Belmont Report: Ethical Principles and Guidelines FOR the Protection of Human Subjects of Research, Dhew Pub. No. (OS) 78-0013, Appendix I (1978) [hereinafter, the Belmont Report Appendix I]; Levine, Robert J. & Lebacqz, Karen, Ethical Considerations in Clinical Trials, 25 Clinical Pharmacology and Therapeutics 728 (1979)Google Scholar. Levine early on identified the potential benefit to subjects, not of the innovation on trial, but of the quality of care in the research environment.

24 Probably universally recognized as the premier comprehensive treatment is Levine, Ethics and Regulation, supra note 22. As noted above, Levine is one of the few ethicists to comment on this issue, although his discussion in this text is not extensive. See id. at 89-90.

25 National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, dep't Health, Educ. & Welfare, Pub. NO. 78-0012, Ethical Principles and Guidelines for the Protection of Human Subjects Research (1978) [hereinafter Belmont Report].

26 Id. at 18 (emphasis added). The Belmont Report goes on to point out:

Injustice may appear in the selection of subjects, even if individual subjects are selected fairly by investigators and treated fairly in the course of the research. This injustice arises from social, racial, sexual, and cultural biases institutionalized in society. Thus, even if individual researchers are treating their research subjects fairly, and even if IRBs are taking care to assure that subjects are selected fairly within a particular institution, unjust social patterns may nevertheless appear in the overall distribution of the burdens and benefits of research. Although individual institutions or investigators may not be able to resolve a problem that is pervasive in their social setting, they can consider distributive justice in selecting research subjects.

Id. at 19 (emphasis added). It is fair to conclude that the authors of the Belmont Report may have meant by the emphasized phrase more the ultimate knowledge derived from the research than any immediate advantage from the experience of participation; nonetheless, the provocative, and still unusual, focus of the Belmont Report on the need to consider patterns of subject selection when evaluating the ethics of research design bears repetition and reflection today.

27 See, e.g., Harold Edgar & David J. Rothman, New Rules for New Drugs: The Challenge of AIDS to the Regulatory Process, in A Disease of Society: Cultural and Institutional Responses to AIDS 84, 94-98 (Dorothy Nelkin et al. eds., 1991); Eigo, James J., Expedited Drug Approval Procedures: Perspective from an AIDS Activist, 45 Food Drug Cosm. LJ. 377 (1990)Google Scholar.

28 In clinical trials, one group of subjects receives the intervention on trial — a drug, procedure, or device — while another similar group (“the control group“) does not. The health outcomes of both groups are analyzed to detect statistically significant differences — that is, differences that are highly unlikely to be the product of chance or coincidence. Traditionally, clinical trials have been considered ethically permissible if and only if at the inception of a trial, no one, especially the scientist-investigator, knows whether the intervention to be tested is better, worse, or the same as whatever will be received by the control group (placebo, standard therapy, alternative experimental therapy, no intervention). In other words, the tested intervention must be in “clinical equipoise” with the placebo or standard therapy or alternative experimental therapy. Based on the information available at the outset, the control group should be as likely to benefit as the subjects receiving the innovative therapy. See Freedman, Benjamin, Equipoise and The Ethics of Clinical Research, 317 New Eng. J. Med. 141 (1987)Google Scholar.

Likewise, the “null hypothesis” standard for clinical trials dictates that the hypothesis on trial — that a given drug will reduce blood pressure, for example — must be as likely to be false as it is true. See Passamani, Eugene, Clinical Trials — Are They Ethical?, 324 New Eng. J. Med. 1589, 1591 (1991)Google Scholar. In reality, of course, many investigators begin trials with a strong suspicion that the tested intervention will prove efficacious, whether or not they feel comfortable saying so. Despite the ritual disclaimers of informed consent, few subjects, especially sick subjects, believe that their devoted physicians would subject them to experimentation unless the doctors “knew” it would help them. See Hellman, Samuel & Hellman, Deborah S., Of Mice But Not Men: Problems of the Randomized Clinical Trial, 324 New Eng. J. Med. 1585 (1991)Google Scholar; Levine, Robert J., Clinical Trials and Physicians as Double Agents, 65 Yale J. Biology & Med. 65 (1992)Google Scholar. Here, as in the law, the lines between “hope,” “intend,” and “desire,” on the one hand, and “believe” and “know,” on the other, are often tenuous.

29 Because of the uncertainty, presumed or real, about the safety or efficacy of an experimental intervention, trials have typically been defined as non-beneficial and not intended to provide treatment; rather, they are pure vehicles of data-gathering and information acquisition.

30 All these terms denote exceptions to the general rule that a drug not approved for marketing in the United States cannot be provided to patients, other than those enrolled in a protocol. “Compassionate use” is an FDA-approved administration of a nonstandard therapy, whether or not it is under investigation, to an individual patient, and requires agency review on a case-by-case basis. Treatment INDs (“Investigational New Drug“) are limited to drugs intended to treat an “immediately life-threatening” disease and which are already well along the drug development pipeline. See 21 C.F.R. §§ 312.34(a) & 314.35 (1993). “Parallel track” is a means for people with life-threatening diseases who are unable to tolerate or benefit from standard approved therapies, and who cannot, for reasons of exclusionary criteria or geographic inconvenience, enroll in protocol, to gain early access to promising, but non-approved, agents. See Expanded Availability of Investigational New Drugs Through a Parallel Track Mechanism for People with AIDS and other HIV-Related Diseases, 57 Fed. Reg. 13,250 (April 15, 1992); Expanded Availability of Investigational New Drugs Through a Parallel Track Mechanism for People with AIDS and other HIV-Related Diseases, 55 Fed. Reg. 20,856 (April 2, 1990). See generally Lansdale, Bret L., Essay, A Procedural Due Process Attack on Fda Regulations: Getting New Drugs to People with AIDS, 18 Hastings Const. L.Q. 417 (1991)Google Scholar; Young, Frank E. et al., The Fda's New Procedures for the Use of Investigational Drugs in Treatment, 259 JAMA 2267 (1988)Google Scholar. “Buyer's clubs” are organizations of patients, primarily people living with AIDS, who pool knowledge and resources to import pharmaceuticals approved elsewhere but not yet available in the United States, which is permitted so long as the imported substance is for personal use only. See Philip J. Hilts, U.S. Issues Rules on Medicine Clubs, N.Y. Times, May 26, 1993, at A18. While these mechanisms may permit earlier access to an unproven drug, they do not provide the care and other benefits associated with participation in a clinical trial. See infra part I.B.

31 My comment with respect to the average American is even more apt for the average non- American. For a brief reference to this notion in the international context, see Gostin, Laurence, Ethical Principles for the Conduct of Human Subjects Research: Population-Based Research and Ethics, 19 L., Med. & Health Care 191, 196 (Fall-Winter 1991)Google Scholar.

32 Pharmaceutical companies may charge “cost” for drugs used in Treatment Inds and parallel track; it is not yet clear whether “cost” will be interpreted to include R&D, not just production. Public and private insurers generally do not cover “experimental” therapies, even if the drug is licensed for use for a different indication. See generally Griffin, Mary, AIDS, Drugs and the Pharmaceutical Industry: A Need for Reform, 17 Am. J.L. & Med. 363 (1991)Google Scholar; Monaco, Grace Powers & Gottlieb, M. Gail, Treatment Inds: Research for Hire?, 258 JAMA 3296 (1987)Google Scholar.

33 Gina Kolata, Patients Paying to Be Subjects in Brain Study, N.Y. Times, May 24, 1992, at 1; see also E. Haavi Morreim, Patient-Funded Research: Paying the Piper or Protecting the Patient?, Irb: Rev. Hum. Subjects Res., May-June 1991, at 1.

34 See discussion of “the therapeutic misconception” in Paul S. Appelbaum et al., False Hopes and Best Data: Consent to Research and the Therapeutic Misconception, Hastings Center ReP., Apr. 1987, at 20.

35 For an example, see physician and ethicist Kathleen Nolan's comment with respect to HIV-infected children:

AZT and other treatments should be widely available as “standard therapy.” Unfortunately programs to care for children with AIDS remain poorly funded, and it is tragically true that only “participation in investigational treatment programs ensures that a child will receive state-of-the-art care for all symptoms and any complicating illness in addition to HIV disease, thus reducing morbidity and improving quality of life.”

Nolan, Kathleen, AIDS and Pediatric Research, 14 Evaluation Rev. 464, 477 (1990)Google Scholar (citing Dep't of Health & Human Servs., Secretary's Work Group on Pediatric Hiv Infection and Disease: Final Report 24 (1988)).

36 See infra notes 39-77 and accompanying text.

37 Novick, Alvin, Noncompliance in Clinical Trials: I. Subjects, 5 AIDS & Pub. POL'Y 94, 94 (1990)Google Scholar; see also Barbara Brotman, Any Volunteers? Being a Human Guinea Pig Has Its Risks and Its Rewards, Chi. Trib., May 19, 1992, at C1 (most people become research subjects to obtain free medical care; in cancer medicine, clinical trials regarded as best care available).

38 Frank L. Iber et al., Conducting Clinical Trials 110-111, 121 (1987). This text actually has a table of “Advantages to the Subject in Research Participation:”

Possible therapeutic advantage

Better outcome of disease

Closer monitoring than in routine practice

Getting attention for other ailments

Better physical and laboratory health check

Superior physicians, labs, and testing

More contact with the providers

Access to contacts for future health information

Remuneration

The opportunity to make new friends

Contributions to society

Id. at Table 13. The text goes on to describe “Techniques that Enhance Recruitment and Retention of Patients,” including, inter alia, training of all receptionists, technicians, and telephone personnel to provide “friendly, informed contacts that reflect the importance and uniqueness of the patient[!]“; locating and recruiting former research subjects to talk with and reassure potential new subjects; noting in the chart specific information about the subject (e.g., new grandchild, new job, gardening, cooking) so that the subject can be asked about them at the next visit, to “demonstrate to each patient his uniqueness“; and if anxiety is detected about an unrelated health problem, prompt evaluation of symptoms by the principal investigator. Id. at 120-21 (emphasis added). How often do we expect such tender treatment from an ordinary health care provider?

39 Gurwitz, supra note 5, at 1421; Wenger, Nanette K., Exclusion of the Elderly and Women From Coronary Trials — Is Their Quality of Care Compromised?, 268 JAMA 1460 (1992)Google Scholar (editorial). “For many if not most drugs on the market, no one really knows whether they behave any differently in women. Nobody really knows what their role is or should be in pregnancy.” Drug Testing on Men Only, Wash. Post, Dec. 8, 1992, at Z14 (quoting Nancy Buc, former General Counsel at Food and Drug Administration).

40 Pharmacokinetics refers to the concentration over time of an ingested substance in body tissues and blood, i.e. the “bioavailability” of the substance as it is absorbed, metabolized, and excreted. See Merkatz, Ruth B. et al., Women in Clinical Trials of New Drugs: A Change in Food and Drug Administration Policy, 329 New Eng. J. Med. 292, 292 (1993)Google Scholar.

41 Pharmacodynamics means the body's response to a particular concentration of ingested substance. Id. at 293.

42 Id. at 293 and references cited therein.

43 Id. at 293.

44 Fda, Guideline for the Format and Content of the Clinical and Statistical Sections of New Drug Applications, 53 Fed. Reg. 39,524 (1988).

45 Merkatz, supra note 40, at 294.

46 Id. This is not exactly a vigorous enforcement stance. On the disappointing lack of teeth in the proposed new Fda guideline, see infra notes 116-128 and accompanying text.

47 The Belmont Report Appendix I, supra note 23, at 4-65 & 4-66 (emphasis added).

48 Throughout this paper, I use the term “researcher” generically, to include both the investigator scientist and the institutional/corporate sponsor. When it is useful to differentiate the two, I will.

49 See infra notes 139-97 and accompanying text.

50 See infra notes 140-46 and accompanying text.

51 Cotton, Paul, Examples Abound of Gaps in Medical Knowledge Because of Groups Excluded from Scientific Study, 263 JAMA 1051, 1055 (1990)Google Scholar; Marguerite Holloway & Philip Yam, Reflecting Differences: Health Care Begins to Address Needs of Women and Minorities, Sci. AM., Mar. 1992, at 13; Laurence Altman, Study Finds Heart Treatment Differs for Men and Women, N.Y. Times, NOV. 13, 1991, at 18; see also Toward Healthy Women, N.Y. Times, Sept. 9, 1991, at A14.

52 Council on Ethical and Judicial Affairs, Ama, Gender Disparities in Clinical Decision Making, 266 JAMA 559, 559 (1991); see also Kjellstrand, Carl M., Age, Sex and Race Inequality in Renal Transplantation, 148 Archives Internal Med. 1305 (1988)Google Scholar.

53 Council on Ethical and Judicial Affairs, supra note 52, at 559.

54 Id. at 562.

55 Rimm, Eric B. et al., Prospective Study of Alcohol Consumption and Risk of Coronary Disease in Men, 338 Lancet 464, 467 (1991)Google Scholar. Harvard School of Public Health researchers found that men who have up to two drinks per day enjoy a 26% reduction in risk for heart disease compared with those who drink little or not at all. It may be that the risk is also reduced by about 40% in men who have two or three drinks per day, but the sample at that level is too small to permit confidence. Id. at 465-68.

56 Richard Saltus, Study Affirms Alcohol Curbs Heart Ills, Boston Globe, Aug. 23, 1991, at 1, 16.

57 Schnall, Peter L. et al., An Analysis of the HDFP Trial: Evidence of Adverse Effects of Antihypertensive Treatment on White Women with Moderate and Severe Hypertension, 84 N.Y. St. J. Med. 299 (1984)Google Scholar. The article reported that this large study included women, but failed to analyze the data indicating that 168% more of the European-American women aged thirty to sixty-nine with diastolic blood pressure > 105 died on treatment than on control. Interestingly, the critical article that performed this data analysis was turned down by the New England Journal of Medicine, the Journal of American Medical Association, and the Lancet, allegedly because it was too “hot,” and was ultimately accepted by the New York Stale Journal of Medicine only after review by twice the usual number of readers. See Barbara Berney, In Research, Women Don't Matter, the Progressive, Oct. 1990, at 24.

58 Hamilton, Jean & Parry, Barbara, Sex-Related Differences in Clinical Drug Response: Implications for Women's Health, 38 J. Am. Med. Women's Ass'n 126 (1983)Google Scholar.

59 See Annette Kornblum, Are Women Being Ignored?, N.Y. Newsday, Jan. 16, 1990, Discovery Section, at 5.

60 Rosser, Sue V., Is There Androcentric Bias in Psychiatric Diagnosis?, 17 J. Med. & Phil. 223 (1992)Google Scholar.

61 Leon, Andrew C. et al., Continuing Female Predominance in Depressive Illness, 83 Am. J. Pub. Health 754 (1993)Google Scholar; the Women's Health Data Book: A Profile of Women's Health in the United States 63 (Jacqueline A. Horton ed., 1992).

62 Patricia Anstett, Medical Groups and Congress Are Facing Elusive Issues, Chi. Trib., June 23, 1991, at 12 (Interview with Margaret Jensvold, M.D., Director of the Institute for Research on Women's Health).

63 Id.

64 Jeannette R. Ickovics & Elissa S. Epel, Women's Health Research: Policy and Practice, Irb: Rev. Hum. Subjects Res., July-Aug. 1993, at 1, 3.

65 For a careful analysis of this claim, see Levine, Carol & Stein, Gary L., What's In A Name? The Policy Implications of the CDC Definition of AIDS, 19 L., Med. & Health Care 278, 280-82 (Fall- Winter 1991)Google Scholar; see also Office Of Technology Assessment, Pub. no. OTA-BP-H-89, the CDC's Definition of AIDS: Implications OF the Proposed Revisions (1992). As of September 1991, only 6.9% of the 15,563 patients enrolled in AIDS Clinical Trial Group protocols were adult women. By comparison, almost 20% of the enrollees in the Community Programs for Clinical Research on AIDS protocols were women — indicating that it is hardly impossible to recruit and retain female subjects in AIDS protocols. As of February 1992, women constituted 11% of the AIDS cases in the United States, even diagnosed under the male-based definition. See Centers for Disease Control, HIV/AIDS Surveillance, 12 (Feb. 1992). Eighty-five per cent of women with AIDS are diagnosed during childbearing years (age 15-44 years). Ellerbrock, Tedd V. et al., Epidemiology of Women with AIDS in the United States, 1981 through 1990, 265 JAMA 2971 (1991)Google Scholar.

66 56 Fed. Reg. 65,702, 65,703 (1991).

67 See S.P. v. Sullivan, No. 90 Civ. 6294 MJC (S.D.N.Y. filed Oct. 1, 1990) (class action brought by MFY Legal Services and the Lambda Legal Defense and Education Fund).

68 See 56 Fed. Reg. 65,702 (1991).

69 See Office of Technology Assessment, supra note 65, at 4-5, 31-48.

70 Centers for Disease Control, U.S. Dep't of Health & Human Serv., Guidelines for Prophylaxis Against Pneumocystis Carinii Pneumonia for Persons Infected with Human Immunodeficiency Virus, Mortality & Morbidity Rep.: Recommendations & Rep. (NO. S-5), June 16, 1989, at 1, 6.

71 Allen, Machelle Harris, Primary Care of Women Infected with the Human Immunodeficiency Virus, 17 Obstetrics & Gynecology Clinics N. Am. 557, 558 (1990)Google Scholar.

72 The director of infection control for the University Hospital at Stony-Brook in New York, Dr. William Greene, was quoted as recommending this exclusion at a conference on HIV-infected health care providers. See Lambda Legal Defense and Education Fund, Inc., 4 AIDS Update 25 (1991). In a conversation with me on May 28, 1992, Dr. Greene indicated that his reluctance was generated in part by uncertainty about the efficacy of AZT for post-exposure prophylaxis in the general population (by which I gather he meant men and infertile women), as well as by some concern about potential liability to offspring. However, it was based primarily on the absence of safety and efficacy data for pregnant women. Now that several hundred HIV-positive women have used AZT (in the perinatal transmission trial) without evidence of gross anatomical anomalies in their children, Dr. Greene suggested that he would be substantially more comfortable with the participation of pregnant women in a prophylaxis protocol.

73 Levine, Carol, Women and HIV/AIDS Research, 14 Evaluation Rev. 447, 448 (1990)Google Scholar. Erythropoietin is on the market with the usual warning for drugs never tested in pregnant women: “There are no adequate and well-controlled studies in pregnant women. [Erythropoietin] should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.” Physicians’ Desk Reference 593 (3d ed. 1992).

74 Minkoff, Howard L. & Moreno, Jonathan D., Drug Prophylaxis for Human Immunodeficiency Virus- infected Pregnant Women: Ethical Considerations, 163 Am. J. Obstetrics & Gynecology 1111, 1113 (1990)Google Scholar. Fortunately, some physicians like Dr. Minkoff recognize “the mother's rightful primacy both as fetal champion and as the focus of her physician's concern.” Id. at 1113.

75 See Levine, supra note 73, at 457.

76 See, e.g., Sabath, Leon D. et al., Ethics and the Use of Drugs During Pregnancy, 202 Science 540, 540 (1978)Google Scholar (pregnant physician who was prescribed ampicillin for her bronchitis, with no resulting therapeutic effect, measured her blood level of the drug and found it lower than the predicted level; when she later conducted a small study, in pregnant women who were planning elective abortions, of the absorption of erythromycin and clindamycin by measuring levels in recovered fetal tissue, she was indicted under an 1814 Massachusetts grave-robbing statute).

At a presentation on treatment of pregnant women suffering from hypertension, a very knowledgeable expert reviewed the broad spectrum of drugs available to treat this serious condition: peripheral alpha-one blockers, beta blockers, calcium channel blockers, hydralazine, labetalol, and the drugs of choice for hypertension-associated heart failure, sodium nitroprusside and diazoxide. Again and again the expert had to say that she could find no data on the safety and efficacy of these drugs in pregnant women, although they necessarily are used in that population. Patricia A. Howard, Pharm. D., Pharmacotherapy of Hypertension in Pregnancy, Presentation at St. Louis University School of Medicine, (Oct. 13, 1993) (distributed materials on file with the author). Dr. Howard also described the horrible experience with ACE-inhibitors (angiotensin- converting-enzyme inhibitors), which a vigilant practitioner had found produced fatal neonatal renal malfunction after the FDA had approved the drugs for marketing and they had been widely used by, among others, pregnant women. Id.; see also Merkatz, supra note 40, at 295.

77 Mirkin, Bernard L., Drug Therapy and the Developing Human: Who Cares?, 23 Clinical Res. 106, 110 (1975)Google Scholar; see also Mirkin, Bernard L., Impact of Public Policy on the Development of Drugs for Pregnant Women and Children, 23 Clinical Res. 233 (1975)Google Scholar. On the paucity of information about the activity of approved drugs in pregnant women, see Kinney, supra note 5, at 495, 496.

78 The historical “protection” of women by the law, which has meant upholding the legality of their exclusion from occupations and legal functions such as estate administration, and their loss of jobs, seniority, and vital benefits because of pregnancy and forced maternity leave, has always been justified by the “unique” status and role of childbearer. See, e.g., Muller v. Oregon, 208 U.S. 412 (1908) (citing reproductive health concerns in allowing women to work a maximum of 10 hours per day); Bradwell v. Illinois, 83 U.S. 130, 141 (1873) (“The natural and proper timidity and delicacy which belongs to the female sex evidently unfits it for many of the occupations of civil life.“).

79 For expanded discussion, see Vanessa Merton, Ethical Obstacles to the Participation of Women in Biomedical Research, in Feminism and Bioethics: Beyond Reproduction (Susan Wolf ed., 1994) [hereinafter Merton, Ethical Obstacles].

80 For a discussion of the function of Institutional Review Boards, see infra notes 255-62 and accompanying text.

81 Parallel arguments were identified by a planning panel of the Institute of Medicine of the National Academy of Sciences. See National Academy of Sciences, Planning Panel of the Institute of Medicine, Division of Health Sciences Policy, Issues in the Inclusion of Women in Clinical Trials 4 (1991) (on file with author).

82 Some readers may ask why I do not aspire instead to an “objective” or “human” perspective. The short answer is that I do not believe it possible, for me or for anyone else in this so heavily engendered society, to analyze problems that have different impact on women and men “objectively” — if by that is meant an absolute, determinable reality independent of the multitude of forces that shape and qualify human perception. For a useful discussion of the “objectivist illusion,” see Keller, Evelyn Fox, Feminism and Science, in Sex and Sci. Inquiry 233, 233-46 (Sandra Harding & Jean O'Barr eds., 1987)Google Scholar. Keller includes an excerpt from Jean Piaget's The Child's Conception of the World that offers a different definition of objectivity:

Objectivity consists in so fully realizing the countless intrusions of the self in everyday thought and the countless illusions which result — illusions of sense, language, point of view, value, etc. — that the preliminary step to every judgement is the effort to exclude the intrusive self. Realism, on the contrary, consists in ignoring the existence of self and thence regarding one's own perspective as immediately objective and absolute. Realism is thus anthropocentric [and, I would add in this context, androcentric] illusion, finality — in short, all those illusions which teem in the history of science.

Keller, supra, at 238 (quoting Jean Piaget, the Child's Conception of the World 1972). Or, as biologist Ruth Hubbard put it:

After all, facts aren't just out there. Every fact has a factor, a maker. The interesting question is: as people move through the world, how do we sort those aspects of it that we permit to become facts from those that we relegate to being fiction — untrue, imagined, imaginary, or figments of the imagination — and from those that, worse yet, we do not even notice and that therefore do not become fact, fiction, or figment? In other words, what criteria and mechanisms of selection do scientists use in the making of facts?

Hubbard, supra note 2 at 119.

83 I find some corroboration in the medical adage cited and commented on by British physician Sue Roberts. See Sue Roberts, All Women Are Pregnant Until Proved Otherwise, Lancet, July 8, 1978, at 89 (physicians’ tendency to focus on female biological roles both of women colleagues and women patients; role-conflict of inadequate helpmate/sexual object and competent doctor and decision-maker).

84 Not to mention the behavior of, for example, employers whose policies exclude all non-sterile females aged 5 [sic] to 63 from certain jobs in the name of “fetal protection.” See Wright v. Olin Corp., 697 F.2d 1172, 1182 (4th Cir, 1982); discussion infra note 248.

85 The ethical underpinnings of this asserted right are discussed at some length in Merton, Ethical Obstacles, supra note 79. See infra notes 249-50 and accompanying text and part II.B. 1; Halbreich, Uriel & Carson, Stanley, Drug Studies in Women of Child Bearing Age: Ethical and Methodological Considerations, 9 J. Clinical Psycholopharmacology 328, 331 (1989)Google Scholar; see also supra pp. 39-40.

86 Merton, Ethical Obstacles, supra note 79.

87 See infra notes 203-32 and accompanying text.

88 For an interesting recent exposition of this argument, see Benjamin Wittes & Janet Wittes, Group Therapy, New Republic, Apr. 5, 1993, at 15.

89 For a more extensive discussion of this argument, see Merton, Ethical Obstacles, supra note 79.

90 A particularly potent confounder is the usage of other medication by subjects, especially the use of the medication on trial by members of the control or comparison group. This phenomenon has been acknowledged as rampant in the field of AIDS research. See, e.g., PEter S. Arno & Karyn L. Feiden, Against the Odds: the Story of AIDS Drug Development, Politics, and Profits (1992); Gold, Jay A., Is There A Right to Experimental Treatment? 5 Bioethics Bull. 1, 3 (1992)Google Scholar. However, there is no basis for believing that it occurs only in that context.

91 See 42 U.S.C. § 300a-7(d) (1992). Again, this point is elaborated in Merton, Ethical Obstacles, supra note 79.

92 See Lasagna, Louis, Congress, the FDA, and New Drug Development: Before and After 1962, 32 Perspectives in Biology & Med. 322, 322-23 (1989)CrossRefGoogle Scholar.

93 45C.F.R. 46 (1974).

94 56 Fed. Reg. 28,002 (1991); see also Joan Porter, The Federal Policy for the Protection of Human Subjects, Irb: Rev. Hum. Subjects Res., Sept.-Oct. 1991, at 8.

95 Technically, this section applies only to research conducted or supported in whole or in part with HHS funds. Most nongovernmental researchers, however, generally adhere to HHS rules even when they are not applicable.

96 See infra note 269.

97 See Notice of Proposed Guidelines for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs, 58 Fed. Reg. 39,406 (July 22, 1993) [hereinafter Proposed FDA Guideline].

98 FDA, Pub. NO. 77-3040, General Considerations for the Clinical Evaluation of Drugs (1977) [hereinafter FDA Guidelines].

99 21 C.F.R. § 10.90(b) (1993) (research conducted in good faith pursuant to Guidelines will be accepted by FDA for review). “A person may rely upon a guideline with assurance that it is acceptable to FDA.” Id. at § 10.90(b)(l)(i); see also 21 C.F.R. § 312.145 (1993).

100 Obviously the entire discussion in this section bears only on research intended to obtain approval for a new drug or a new indication for an approved drug.

101 Knowing its visceral impact, I prefer to avoid using the word “malpractice” in a paper that I hope will be read by health professionals, but this reference should be explained for those unfamiliar with the phrase “standard of care“: a patient or a client in a professional relationship who seeks to hold the professional responsible for a bad outcome must prove, among other things, that the harm would not have occurred had the professional not breached a professional “standard of care“; that is, did not provide care within the broad range of choices that a competent professional might reasonably consider under the circumstances. Protocols and standards issued by professional organizations and governmental agencies sometimes are utilized as sources of the “standard of care.” See, e.g., STeven E. Pegalis & Harvey F. Wachsman, American Law of Medical Malpractice § 3:1 - § 3:13 (2d ed. 1992).

In this paper I have not taken on the question whether the “trials as treatment” theory expounded above has any implications for professional liability, in the sense of transforming the duties of researcher to subject into something more analogous to those of a physician for a patient — an interesting issue, but one not different for male and female subjects, and thus not germane. See discussion supra notes 37-38 and accompanying text.

102 The FDA has never published a protocol for the Animal Reproduction Studies referenced in the Guidelines, but after several telephone calls to FDA sources, I was sent a copy of a document identified as the pertinent standard. See William D'Aguanno, Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use (undated) (on file with the author). Segment I covers gonadal function, effects of estrous cycles/mating behavior, and early gestation; segment II, teratogenesis; and segment III, the drug's effect on late fetal development, labor and delivery, lactation, and newborn health. In a switch from the typical toxicology studies, conducted primarily in male animals, here most of the testing, and all of it pertaining to intergenerational effects, is done exclusively in females. The interest in male animals is confined to the impact on their fertility.

103 FDA, 1977 Guidelines, supra note 98, at 10. For a good description of the Phase I-Phase II-Phase III categories, see Kessler, David, The Regulation of Investigational Drugs, 320 New Eng. J. Med. 281, 282-83 (1989)Google Scholar. Phase I, the first set of clinical studies, is supposed to use fewer than 100 healthy volunteers to detect gross safety problems and establish the parameters for proper dosages to be tested. Phase II, typically done in a couple of hundred patients, begins to evaluate efficacy and identify side effects, if any. Phase III studies may be conducted in thousands of patients and should be designed to elaborate on therapeutic value and elicit longer-term adverse effects. It is important to note that since Phase I is when dosage parameters are set, and safety issues are defined, the data generated in Phase I is critical to the design — the doses to be tested and the variables to be monitored — in Phase II and Phase III. See 21 C.F.R. § 312.21 (1993) (“During Phase I sufficient information about the drug's pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid Phase II studies.“).

104 Some texts and treatises seem to assume that this testing is necessary for a New Drug Application. See, e.g., Donald E. Vinson & Alexander H. Slaughter, Products Liability: Pharmaceutical Drug Cases § 5.04 (1988 & Supp. 1991). However, nothing in the language of the regulations or the FDA Guidelines is couched in mandatory rather than precatory terms.

105 21 C.F.R. § 314.50(d)(2)(iii) (1991) (emphasis added).

106 Dr. Robert Temple, Director of the Office on Drug Evaluation of the Food and Drug Administration, has stated that no one at the FDA is responsible for determining whether animal reproduction studies are actually conducted. Response to question at Institute of Medicine seminar on inclusion of women in clinical trials, June 23, 1992.

107 The Guidelines do suggest that when testicular or spermatogenetic abnormalities have been observed in animals (which is not to say animal studies to evoke these responses must be done), or when chromosomal abnormalities are anticipated, the inclusion of males in all three Phases of trials depends on a constellation of factors: the nature of the abnormalities, the “importance” of the drug, etc. Compare this textured, case-by-case, only-if-reason-for-concern-hasbeen- demonstrated, approach to the categorical language of the rule about women of child-bearing potential. There is also no mention of a need to discuss contraception with male subjects in these circumstances. See infra notes 267-68 and accompanying text.

108 21 C.F.R. § 201.57 (1991), which governs labeling of human prescription drugs, requires a statement of critical information, if known, but does not create any independent duty to acquire the information. For example, under subsection (f)(5), the label must specify whether “adequate and well-controlled studies in pregnant women” have or have not demonstrated a risk to the fetus, and describe the results of animal reproduction studies, if available. But it is perfectly acceptable to label a drug Pregnancy Category C, in the event that there are no animal reproduction studies and no studies in humans, and state that “It is also not known whether (name of drug) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. (Name of drug) should be given to a pregnant woman only if clearly needed.” Even under the category of nonteratogenic effects, there is no requirement to provide either information, or a warning of the absence of information, about the drug's reproductive impact in men. Compare subsection (f)(7), which requires a clear statement of the absence of data about effects on childbirth, and subsection (f)(8), which requires a clear statement if it is not known whether a particular drug is contained in the milk of nursing mothers.

109 Merton, Vanessa, Community-Based AIDS Research, 14 Evaluation Rev. 502, 519 (1990)Google Scholar [hereinafter Merton, Community-Based].

110 FDA, 1977 Guidelines, supra note 98.

111 See discussion supra notes 83-86 and accompanying text.

112 Iber et al., supra note 38, at 179.

113 FDA, 1977 Guidelines, supra note 98, at 10.

114 Id. at 11.

115 Id.

116 Diane Rehm, Is There Gender Bias in Drug Testing?, FDA Consumer, Apr. 1991, at 8 (Interview with Robert Temple and Margaret Jens void); see also Levine, supra note 73, at 455.

117 In a confidential 1991 survey of 33 major pharmaceutical houses, conducted by the Pharmaceutical Manufacturers Association, 79% reported that FDA reviewers had required them to exclude women of child-bearing potential from their protocols. Lionel D. Edwards, Design and Conduct of Research in Women: To Include or Exclude: A Pharmaceutical Industry Physician's Perspective 17 (Feb. 1992) (unpublished manuscript on file with author).

118 Proposed FDA Guideline, supra note 97, at 39,408.

119 It also, of course, has no effect whatsoever on the substantial body of research, behavioral and otherwise, that is not governed or influenced by FDA standards. But this limitation of any FDA action is inescapable.

120 The Proposed Guideline “urges” that “reasonable numbers” (not defined precisely) of women be included in studies of new drugs. It expresses the agency's “expectation” that women will be included in numbers sufficient to allow for differential data analysis. It “stresses the importance” of assessing potential pharmacokinetic differences. In light of its recognition that the failure to include women in early (Phase I and Phase II) trials may negatively affect the design and dose selection of “the pivotal controlled trials [Phase III]”, see 21 C.F.R. § 312.21(a)(1) (1993), the FDA “encourages” the inclusion of women of all ages in early trials. Merkatz, supra note 40, at 294; Proposed FDA Guideline, supra note 97, passim.

While admitting that “in some cases, there may be a basis for requiring participation of women in early studies,” and that “under these circumstances, clinical protocols should not place unwarranted restrictions on the participation of women,” Proposed FDA Guideline, supra note 97, at 39,409, the Proposed Guideline never translates these observations into an unambiguous condition for FDA approval.

121 Id. at 39,408.

122 The agency recognizes that this change in FDA's policy will not, by itself, cause drug companies or IRB's to alter restrictions that they might impose on the participation of women of childbearing potential. We do not at this time perceive a regulatory basis for requiring routinely that women of childbearing potential be included in particular trials. Proposed FDA Guideline, supra note 97, at 39,408.

The FDA has previously demonstrated the “regulatory authority” to prescribe in fulsome detail every jot and tittle of protocols to be submitted for its approval. Its statutory duty to ensure “adequate and well-controlled investigations … on the basis of which it could … be concluded … that the drug will have the effect it purports … to have” prior to drug approval offers plenty of room to define “adequate” to include testing in women when women will be consumers of the drug. 21 C.F.R. § 314.126 (1988); see 21 U.S.C. § 355 (1972 & Supp. 1993). The FDA's inability to “perceive” its own power when it comes to protecting the rights and interests of women suggests that it may be more of a captive agency than some of us had thought and most of us had hoped.

123 See discussion infra notes 140-46 and accompanying text.

124 Sponsors are required to provide clinical investigators with brochures that describe, inter alia, “the pharmacological and toxicological effects of the drug in animals … .” 21 C.F.R. § 312.23(5)(ii) (1993).

125 A New Drug Application must contain “adequate information about pharmacological and toxicological studies of the drug involving laboratory animals … .” Id. at § 312.23(8). Depending on the nature of the drug and the phase of the investigation, the description is to include the “results of … tests of the drug's effects on reproduction and the developing fetus.” Id. at § 312.23(8)(ii).

126 See also 21 C.F.R. § 312.32(a) (defining adverse experiences that must be reported to the FDA to include “any experience suggesting a significant risk for human [not only female] subjects, including any finding of mutagenicity, teratogenicity, or carcinogenicity.“).

127 See Proposed FDA Guideline, supra note 97, at 39,411. Note that this concern appears to be limited to fetal toxicity and women subjects.

128 For a more detailed analysis of the shortcomings of the Proposed Guideline, see HIV Law Project & Now Legal Defense and Education Fund, Memorandum on the FDA's Proposed Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs (Oct. 18, 1993) (on file with author) [hereinafter Memorandum on FDA's Proposed Guideline]. Another troubling example of recognizing the problem but doing nothing to rectify it is the recently completed International Ethical Guidelines for Biomedical Research Involving Human Subjects of the Council of International Organizations of Medical Sciences and the World Health Organization (on file with the author). Guideline 11 acknowledges that:

Women in most societies have been discriminated against with regard to their involvement in research. Women who are biologically capable of becoming pregnant have been customarily excluded from formal clinical trials … owing to concern about undetermined risks to the fetus. Consequently, relatively little is known about the safety and efficacy of most drugs, vaccines, or devices for such women, and this lack of knowledge can be dangerous… .

A general policy of excluding from such clinical trials women biologically capable of becoming pregnant is unjust in that it deprives women as a class of persons of the benefits of the new knowledge derived from the trials. Further, it is an affront to their right of self-determination… .

Premenopausal women have also been excluded from participation in many research activities … in case the physiological data associated with various phases of the menstrual cycle would complicate interpretation of research data. Consequently, much less is known of women's than of men's normal physiological processes. This, too, is unjust in that it deprives women as a class of persons of the benefits of such knowledge.

Id. at 33-34. Despite its recognition of these injustices, Guideline 11 categorically excludes pregnant or nursing women from protocols, unless the research carries no more than minimal risk for the fetus or infant, its objective is new knowledge about pregnancy or lactation, and women who are not pregnant or nursing would not be suitable subjects. It utterly ignores the right of women to make their own risk-benefit calculus. The International Ethical Guidelines impose no such restrictions on fertile and reproductively active male subjects.

129 45 C.F.R. § 46.206(a)(1) (1975). Other conditions, intended to ensure that no inducements or pressures to terminate the pregnancy are part of the research design, are also enumerated in this section.

130 45 C.F.R. § 46.207(a) (1992). Section 46.205 imposes various special obligations, mostly pertaining to informed consent, on IRBs that review protocols involving pregnant women and fetuses. All these provisions may be waived or modified by the Secretary of Health and Human Services on request of a researcher, 45 C.F.R. § 46.211, but virtually no requests have been made, possibly because since 1980 an indispensable participant in the waiver process, an Ethical Advisory Board within HHS, has not been funded or appointed. See Levine, Ethics and Regulation, supra note 22, at 319-20.

131 See 45 C.F.R. § 46.207(b). A pregnant woman is not yet a mother, and her impregnator is not yet a father. See Solomon, Renee, Note, Future Fear: Prenatal Duties Imposed by Private Parties, 17 Am.J.L. & Med. 411, 417 n.37 (1991)Google Scholar.

132 Given the recent Supreme Court decision in Planned Parenthood of Southeastern Pa. et al. v. Casey, 112 S. Ct. 2791 (1992), it is hard to see how this paternal consent condition, if ever applied, could be upheld against constitutional challenge. The only one of the set of anti-choice state restrictions struck down in Casey was the husband notification provision, because “[i]t is an inescapable biological fact that state regulation with respect to the child a woman is carrying will have a far greater impact on the mother's liberty than on the father's.” Id. at 2830. If paternal notification cannot be required for an abortion that will kill the fetus, the constitutionality of requiring paternal consent for a much lesser risk to the fetus is dubious.

The other exceptions to this requirement also might be applicable to many pregnant research subjects: when the father cannot be identified or found, or the pregnancy resulted from rape.

133 See discussion infra notes 278-80 and accompanying text.

134 Levine, Ethics and Regulation, supra note 22, at 8-10, 298.

135 See discussion supra notes 27-79 and accompanying text.

136 See John C. Fletcher & Joseph D. Schulman, Fetal Research: The State of the Question, Hastings Center Rep., Apr. 1985, at 6 and Karen Lebacqz, Fetal Research: A Commissioner's Reflection, Irb: Rev. Hum. Subjects Res., May 1979, at 7, for varied approaches to assessing risk in this context. “Minimal risk” is defined elsewhere in the regulations to mean that the danger anticipated from the research is not greater, considering both probability and magnitude, than the danger of ordinary daily life or routine physical or psychological tests. 58 Fed. Reg. 28,002, 28,013-14 (June 18, 1981). For a fetus, isn't an amniocentesis, with its half-percent chance of miscarriage, now a routine test? What about chorionic villi sampling? Ultrasound? Wouldn't the risk of ordinary daily life include the risk of a mother or father who smokes or who works where smoking is permitted? Drinks socially? Eats food containing additives? Disregards the prenatal care provider's advice? See Kentucky v. Welch, 864 S.W.2d 280, 283 (Ky. 1993) (“What if a pregnant woman drives over the speed limit, or … does not wear the prescription lenses she knows she needs to see the dangers of the road?“).

On the latter point, see Barbara K. Rothman, When a Pregnant Woman Endangers Her Fetus, Hastings Center Rep., Feb. 1986, at 25, describing what a typical “fetal abuse” case of twentyfive years ago might have sounded like:

[The pregnant woman], a diabetic, refused her DES treatment, prescribed as especially important in the prevention of miscarriage among diabetics. Further, although she was eleven pounds overweight at the time of conception, she refused to limit her weight gain over the course of the pregnancy to under thirteen pounds. She compounded the problem by not taking the diuretics prescribed, and twice refused to show up for scheduled X-rays, citing a distrust of medications and radiation. Her irrational refusal to comply with her doctor's advice, plus her unwillingness or inability to limit her weight gain, indicate fetal abuse.

See Merton, Ethical Obstacles, supra note 79.

137 The subject of “maternal-fetal conflict,” and the fallacious and invidious premises packed into that term, are ably dissected in Johnsen, Dawn, Shared Interests: Promoting Healthy Births without Sacrificing Women's Liberty, 43 HASTINGS L.J. 569 (1992)Google Scholar. Surprisingly, the American College of Obstetricians and Gynecologists (hardly a radical feminist outfit), while buying into the “conflict” paradigm, has recognized that “Obstetricians should refrain from performing procedures that are unwanted by a pregnant woman. The use of judicial authority to implement treatment regimens in order to protect the fetus violates the pregnant woman's autonomy.” Opinion from the Committee on Ethics, American College of Obstetricians and Gynecologists, Opinion No. 55, “Patient Choice: Maternal-Fetal Conflict” (1987); see also Ama Board of Trustees Report, Legal Interventions During Pregnancy, 264 JAMA 2663 (1990).

138 See Nat'l Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Dep't Health Education and Welfare, Pub. No. (OS) 76-127, Research on the Fetus 65 (1975):

Therapeutic research directed toward the pregnant woman may expose the fetus to risk for the benefit of another subject and thus is at first glance more problematic. Recognizing the woman's priority regarding her own health care, however, the Commission concludes that such research is ethically acceptable provided that the woman has been fully informed of the possible impact on the fetus and that other general requirements have been met. Protection for the fetus is further provided by requiring that research put the fetus at minimum risk consistent with the provision of health care for the woman. Moreover, therapeutic research directed toward the pregnant woman frequently benefits the fetus, though it need not necessarily do so. In view of the woman's right to privacy regarding her own health care, the Commission concludes that the informed consent of the woman is both necessary and sufficient.

In general, the Commission concludes that therapeutic research directed toward the health condition of either the fetus or the pregnant woman is, in principle, ethical. Such research benefits not only the individual woman or fetus but also women and fetuses as a class, and should therefore be encouraged actively.

Id.

139 The usually unstated but logically necessary final step of the argument is that such accountability and responsibility would be wrong and unjust. For a discussion of the thesis that it may be precisely the just outcome, see infra notes 198-202 and accompanying text.

140 One of the most frequently cited compilations on this subject is Lester F. Soyka & Justin M. Joffee, Male Mediated Drug Effects on Offspring, in Drug and Chemical Risks to the Fetus and Newborn 49 (Richard Schwartz & Sumner Yaffe eds., 1980). Literature reviews have focused on occupational exposures. See, eg., Haas, Joanna & Schottenfeld, David, Risks to the Offspring from Parental Occupational Exposures, 21 J. Occupational Med. 607 (1979)Google Scholar (chromosomal aberrations in men exposed to vinyl chloride and benzene); Savitz, David & Chen, Joanna, Parental Occupation and Childhood Cancer: Review of Epidemiologic Studies, 88 Envtl. Health Persp. 325 (1990)Google Scholar (in review of 24 case-control studies, no specific parental occupational exposure established as cause of childhood cancer, but several paternal occupations associated with childhood leukemias and nervous system tumors); see also Children's Cancer Tied to British A-Plant Workers, N.Y. Times, Feb. 18, 1990, at 27, reporting six-fold elevated risk of leukemia in offspring of male workers at nuclear plant. “The main finding was of a raised risk for those children whose fathers worked at Sellafield, in particular fathers with the highest recorded exposures to external ionizing radiation before their child's conception.” Id. (emphasis added); see also Gardner, M.J. et al., Results of Case-control Study of Leukaemia and Lymphoma Among Young People Near Sellafield Nuclear Plant in West Cumbria, 300 Brit. Med. J. 423 (1990)Google Scholar.

Male toxic exposures ranging from lead and other heavy metals to dibromochloropropane (DBCP) and chlordecone (Kepone) also have been demonstrated to affect the likelihood both of conception and of spontaneous abortion. See Michael Castleman, Toxics and Male Infertility, Sierra Club Bull., Mar.-Apr. 1985, at 49; Hemminki, Kari et al., Spontaneous Abortions in an Industrialized Community in Finland, 73 Am. J. Pub. Health 32 (1983)Google Scholar; Whorton, M. Donald, Adverse Reproductive Outcomes: The Occupational Health Issue of the 1980's, 73 Am. J. Pub. Health 15 (1983)Google Scholar (editorial).

141 See the announcement in The Nation's Health, May-June, 1992, at 17; Bulletin of the Conference on Male-Mediated Developmental Toxicity (Sept. 1992) (on file with the author).

142 Olshan, Andrew et al., Paternal Occupation and Congenital Anomalies in Offspring, 20 Am. J. Indus. Med. 447 (1991)Google Scholar.

143 An earlier study from the same group, controlling for maternal age, found elevated relative risk of Down syndrome in the offspring of fathers employed as janitors, mechanics, metalworkers, and sawmill workers. Olshan, Andrew et al., Paternal Occupational Exposures and the Risk of Down Syndrome, 44 Am. J. Hum. Genetics 646, 649 (1989)Google Scholar. The children of male anesthesiologists also experience increased congenital abnormalities. Spence, Alastair A. et al., Occupational Hazards for Operating Room-based Physicians: Analysis of Data From the United States and United Kingdom, 238 JAMA 955 (1977)Google Scholar. Carbon disulfide and ionizing radiation have repeatedly been linked to malformations in the children of exposed men. See Joan Bertin, Reproductive Hazards in the Workplace, in Reproductive Laws for the 1990's 277-305 (Sherrill Cohen & Nadine Taub eds., 1989); Elaine Draper, Risky Business 69 (1991). Dr. Ellen Silbergeld, a toxicologist at the University of Maryland, found defects in the brain development of the offspring of male rats exposed to lead at levels equivalent to those experienced by many factory workers. One form of retinoblastoma, Wilm's tumor, and Prader Willi syndrome all have been associated with paternal exposure or spermal mutation. Sandra Blakeslee, Research on Birth Defects Shifts to Flaws in Sperm, N.Y. Times, Jan. 1, 1991, at Al, C36. “Researchers have found several childhood cancers that primarily arise from new mutations traced to sperm, never to eggs.” Id. at 36. Reduced body weight, delayed maturation, and learning and behavioral problems have been observed through four generations of paternal exposure of rodents to opioids and nitrous oxide. Friedler, Gladys, Behavioral Effects in Offspring of Male Mice Injected with Opioids Prior to Mating, 11 Pharmacology & Biochemical Behav. 23 (1979)Google Scholar; Friedler, Gladys, Effect of Limited Paternal Exposure to Xenobiotic Agents on the Development of Progeny, 7 Neurobehavioral Toxicology & Teratology 739 (1985)Google Scholar.

144 See Miller, Susan Katz, Warning: Smoking May Damage Your Sperm, 136 New Scientist 13 (1992)Google Scholar (even sperm with gross abnormalities may have same chance as healthy sperm of reaching and penetrating ovum; men should be encouraged to abstain from alcohol and tobacco and avoid other chemical exposures prior to reproduction); Merewood, Anne, Sperm Under Siege: More Than We Ever Guessed, Having a Healthy Baby May Depend on Dad, 23 Health 53 (1991)Google Scholar (children of fathers who smoke close to time of conception 20% more likely to develop brain cancer, lymphoma, and leukemia); Jane E. Brody, Possible Links Between Babies’ Health and Fathers’ Habits and Working Conditions, N.Y. Times, Dec. 25, 1991, at 64; Devra L. Davis, Fathers and Fetuses, N.Y. Times, Mar. 1, 1991, at A27; see also Adams, Perry M. et al., Male-transmitted Developmental and Neurobehavioral Deficits, 4 Teratogenesis Carcinogenesis Mutagenesis 149 (1984)Google Scholar; Little, Ruth E. & Sing, Charles F., Association of Father's Drinking and Infant's Birth Weight, 314 New Eng.J. Med. 1644 (1986)Google Scholar (association between paternal preconceptual alcohol consumption and birthweight); J. Makin et al., A Comparison of Active and Passive Smoking During Pregnancy: Long-term Effects, Neurotoxicology & Teratology, Jan. 1991, at 5.

145 Olshan, supra note 142, at 448. Cocaine and methadone have been found in semen; see Yazigi, Ricardo A. et al., Demonstration of Specific Binding of Cocaine to Human Spermatozoa, 266 JAMA 1956 (1991)Google Scholar.

146 See Davis, Devra et al., Male-mediated Teratogenesis and Other Reproductive Effects: Biologic and Epidemiologic Findings and A Plea for Clinical Research, 6 Reproductive Toxicology 289 (1992)Google Scholar (more than 60 different compounds identified as increasing risk to offspring from male-mediated exposures; lack of extensive human evidence a deficiency in research, not absence of effect); Hales, Barbara et al., Increased Postimplantation Loss and Malformations among the F2 Progeny of Male Rats Chronically Treated With Cyclophosphamide, 45 Teratology 671 (1992)Google Scholar (edema, syndactyly, gigantism and dwarfism observed in second-generation offspring of exposed male rats); Miller Susan Katz, Can Children Be Damaged by Fathers’ Cancer Therapy?, 135 New Scientist 5 (1992) (male cancer patients advised against using semen collected after start of chemotherapy because of “potentially drastic mutagenic effect“); Researchers Find Pre-Developmenl of Cancer Could Start Before Birth, Cancer Wkly, July 20, 1992, at 10 (National Cancer Institute study confirms that exposure of sperm to carcinogens can make offspring more susceptible to cancers); iff also Sins of the Fathers, 318 Economist 87 (1991); Blakeslee, Sandra, Father Figures: the Male Link to Birth Defects, 10 Am. Health 54 (1991)Google Scholar. See generally Gladys Friedler, Developmental Toxicology: Male-mediated Effects, in Occupational and Environmental Reproductive Hazards: A Guide for Clinicians 52-59 (Maureen Paul ed., 1993).

147 There is one oblique reference to the need for special study if animal data indicates a risk of decreased sperm production, and a general reference to risk-benefit calculation when people (presumably meaning men) of reproductive age participate in a study of a drug that has demonstrated reproductive toxicity, but the emphasis remains on harm to offspring of female, not male, subjects. Proposed FDA Guideline, supra note 97, at 39,411.

148 A similar dynamic led to the “fetal protection” policies barring non-sterile women from lucrative though possibly fetotoxic jobs in many industries. See Mark, Valerie, The Flip Side of Fetal Protection Policies: Compensating Children Injured through Parental Exposure to Reproductive Hazards in the Workplace, 22 Golden Gate U. L. Rev. 673, 674-75 (1992)Google Scholar. It is noteworthy that the one reported decision on employer liability to employee offspring for toxic workplace exposure involved the developmentally disabled son of a man exposed to mercury on the job. See Skelly v. Firestone Tire & Rubber Co., 20 O.S.H. Rep. (BNA) 1040 (1990). But see Widera v. Ettco Wire and Cable Corp., 1994 WL 167738 (N.Y. App. Div. 1994) (no common law or OSHA cause of action against father's employer for infant prenatally injured by father's toxic exposure on the job).

149 Solomon, supra note 131, at 413 & n.6.

150 See Roland F. Chase, Annotation, Liability for Prenatal Injuries, 40 A.L.R.3d 1222 (1971); W. Page Keeton et al., Prosser & Keeton on Torts § 55, at 367 (5th ed. 1984 & Supp. 1988). Almost a half-century ago the District of Columbia became the first jurisdiction to recognize a civil right of action for prenatal injury. Bonbrest v. Kotz, 65 F. Supp. 138 (D.D.C. 1946).

151 Robertson, Horace B., Jr., Toward Rational Boundaries of Tort Liability for Injury to the Unborn: Prenatal Injuries, Preconception Injuries, and Wrongful Life, 1978 Duke L.J. 1401, 1412 (1978)Google Scholar.

152 E.g.,in New York the leading decisions of New York's highest court in Enright v. Eli Lilly & Co., 570 N.E.2d 198 (N.Y.), cert, denied 112 S. Ct. 197 (1991) (no cause of action for “third generation” DES effects, i.e. cerebral palsy attributable to premature birth caused by mother's DES-caused defective reproductive organs); Albala v. City of New York, 429 N.E.2d 786 (N.Y. 1981) (no cause of action for child's injury due to negligently perforated uterus prior to conception); Catherwood v. American Sterilizer Co., 498 N.Y.S.2d 703 (Sup. Ct. 1986) (no cause of action for child's Down's syndrome attributed to maternal preconceptual exposure on the j ob to ethylene oxide), afd, 511 N.Y.S.2d 807 (App. Div.), appeal dismissed, 515 N.E.2d 908 (N.Y. 1987); see also Becker v. Schwartz, 386 N.E.2d 807, 814 (N.Y. 1978), overruling Park v. Chessin, 387 N.Y.S.2d 204 (Sup. Ct. 1976) (negligent advice to mother of child with polycystic kidneys that congenital defect would not recur led her to become pregnant and bear second polycystic child who died).

Other decisions that have rejected preconceptual tort liability include Sorrells v. Eli Lilly & Co., 737 F. Supp. 678 (D.D.C. 1990) (applying Maryland law)(dismissal of third-generation DES claim); Hegyes v. Unjian Enterprises, Inc., 286 Cal. Rptr. 85 (Cal. Ct. App. 1991) (dismissal of claim for premature delivery necessitated by mother's lumbo-peritoneal shunt, resulting from automobile collision caused by defendant), reh'gdenied, No. B047481, 1991 Cal. App. Lexis 1220 (Cal. Ct. App. Oct. 10, 1991), review denied, No. S023723, 1992 Cal. Lexis 264 (Cal. Jan. 16, 1992); McAuley v. Wills, 303 S.E.2d 258 (Ga. 1983) (dismissal of claim for child's postpartum death caused by mother's paraplegia, resulting from automobile collision caused by defendant); McNulty v. McDowell, 613 N.E.2d 904, 907 (Ma. 1993) (summary judgment for defendant granted because “mere fact that most women of child-bearing age are … capable of becoming pregnant does not impose duty of care on their physicians to any later-conceived children“); Loerch v. Abbott Labs., 445 N.W.2d 560 (Minn. 1989) (en banc) (upholding lower-court dismissal of third-generation DES claim by split vote); Grover v. Eli Lilly and Co., 591 N.E.2d 696 (Ohio 1992) (dismissal of third-generation DES claim).

153 It is unquestionably possible for a child or its parents to recover for injuries to the child, once born alive, resulting from pre-conceptual negligent or intentional conduct. See, e.g., Bergstresser v. Mitchell, 577 F.2d 22 (8th Cir. 1978) (applying Missouri law) (action permitted on claim that uterine rupture caused by negligent prior Caesarean section resulted in premature birth and hypoxia to second child); Jorgensen v. Meade Johnson Laboratories, Inc., 483 F.2d 237 (10th Cir. 1973) (applying Oklahoma law) (strict liability action permitted on claim that preconception use of oral contraceptives caused chromosomal damage resulting in birth of Down's Syndrome twins); Renslow v. Mennonite Hospital, 367 N.E.2d 1250 (111. 1977) (action permitted on claim for child's permanent injury resulting from negligent pre-conceptual transfusion of Rhnegative blood into Rh-positive mother); Monusko v. Postle, 437 N.W.2d 367 (Mich. App.), Iv. app. denied, 433 Mich. 869 (1989) (action permitted on claim for failure to test rubella status of mother and immunize her prior to conception of injured child); Lazevnick v. General Hospital of Monroe Country, 499 F. Supp. 146 (M.D. Pa. 1980) (applying Pennsylvania law) (action permitted for error in blood test record during first pregnancy that resulted in paralysis and brain damage of second child), apparently overruling Morgan v. U.S., 143 F. Supp. 580 (D.C.N.J. 1956) (applying Pennsylviania law) (dismissing claim that transfusion to woman two years prior to birth of child caused harm to child); Harbeson v. Parke-Davis, Inc., 656 P.2d 483 (Wash. 1983) (action permitted on claim for pre-conceptual failure to inform mother of risks of taking Dilantin during pregnancy).

One lower Philadelphia court, in an unreported decision, permitted a “third generation” DES case to proceed, but will require the plaintiff to prove that defendant manufacturers knew of the risk of the injury to the reproductive systems of the second generation, in order to establish the foreseeability of harm to the third generation — a formidable burden. Rorie Sherman, New DES Front, Nat'l L.J., Mar. 12, 1990, at 1, 27. See also Pitre v. Opelousas Gen. Hosp., 530 So. 2d 1151 (La. 1988) (no liability to child for negligent tubal ligation resulting in child's birth with congenital albinism, but dictum left open possibility of child's pre-conceptual claim on showing of foreseeability of specific defect).

Note that Bergstresser and Renslow both represent the speculation of the federal courts as to how state courts would construe their law. Renslow and Bergstresser also have been roundly criticized for their reliance on prenatal precedent, in particular the overruled New York decision in Park v. Chessin, 387 N.Y.S.2d 204 (Sup. Ct. 1976), to support their recognition of pre-conceptual liability. See supra note 152; Hegyes v. Unjian Enterprises, Inc., 286 Cal. Rptr. 85, 94 (Cal. Ct. App. 1991), review denied, Jan. 16, 1992.

Not considered here are the so-called “wronglful pregnancy” or “wrongful conception” cases where parents seek compensation for the birth of a healthy child after a negligently performed sterilization. See generally Donaldson, Russell G., Annotation, Recoverability of Cost of Raising Normal, Healthy Child Bom as Result of Physician's Negligence or Breach of Contract or Warranty, 89 A.L.R.4th 632 (1991)Google Scholar. Although obviously the harm alleged is the result of pre-conceptual tortious conduct, a failed sterilization is in no way analogous to the conduct of biomedical researchers.

Two other distinct categories of claim have given rise to pre-conceptual tort liability, but are hardly instructive as to the potential of such liability for researchers. One group, the Rh-factor cases, all arise from a physician's failure to detect or treat the Rh-negative status of a woman during her care for one pregnancy, with the result that children born subsequently are severly damaged or die because of the “sensitization” of the mother and her production of antibodies lethal to the fetus. These decisions emphasize the extraordinary factors tilting toward liability in Rh-negative cases: not just the routine nature of the blood-typing procedure, but the fact that failure to treat an Rh-negative woman is malpractice per se, and that the resulting hemolytic disease and death of the child is “overwhelmingly preventable.” Graham v. Keuchel, 847 P.2d 342, 364 (Okla. 1993).

As the courts determining these claims reiterate, the whole focus of the information or treatment not provided is protection of “those who, although unconceived at the time of [the woman's] treatment, are anticipated and foreseeable.” Id. at 365. “The same duty is owed both the mother and her unconceived child — i.e., the duty to prevent the mother's sensitization … .” Id. at 365 n.130. See also Yeager v. Bloomington Obstetrics and Gynecology, Inc., 585 N.E.2d 696 (Ind. App.), aff'd, 604 N.E.2d 598 (Ind. 1992); Walker v. Rinck, 604 N.E.2d 59 (Ind. 1992) (in both cases, action permitted on claim for failure to determine Rh-negative status of mother during prior pregnancy); accord. Empire Casualty Co. v. St. Paul Fire and Marine Insurance Co., 764 P.2d 1191 (Colo. 1988); Lough v. Rolla Women's Clinic, Inc., 866 S.W.2d 851 (Mo. 1993).

The second distinctive category of pre-conceptual injury are claims resulting from negligent genetic investigation and counseling following the birth of a child with serious anomalies. In these cases, physicians reassured the parents that they had no genetic defects and could safely conceive other children, only to discover after the birth of a similarly damaged sibling that their reassurances were wrong, and negligently so. Again, the courts have permitted these preconceptual claims to stand, but the defendants in these cases bear no resemblance to medical researchers, unless the latter provide their subjects with undue reassurances. E.g., Gallegher v. Duke University, 852 F.2d 773 (4th Cir. 1988) (applying North Carolina law); Lininger v. Eisenbaum, 764 P.2d 1202 (Colo. 1988); Rush v. Lloyd, 616 So.2d 415 (Fla. 1993). But see Bruggeman v. Schimke, 718 P.2d 635 (Kan. 1986) (although court found that physician provided negligent genetic counseling, and that a physician consulted about the possible hereditary defects owes duty of care not only to parents, but to unconceived children, child's “wrongful life” claim rejected as a matter of law).

154 Speaking of the causation issue, and citing more than a score of lengthy law review articles on the subject, Prosser says: “There is perhaps nothing in the entire field of law which has called forth more disagreement, or upon which the opinions are in such a welter of confusion.” KEETON ET AL., supra note 150, at § 41.

155 To achieve the same outcome, courts also use the terms “duty,” “foreseeability,” and “negligence,” all of which turn out to be inextricably intertwined with the analysis of proximate cause.

“Proximate cause,” in short, has been an extraordinarily changeable concept. “Having no integrated meaning of its own, its chameleon quality permits it to be substituted for any one of the elements of a negligence case when decision on that element becomes difficult… . No other formula … so nearly does the work of Aladdin's lamp.“

Keeton et al., supra note 150, at § 42, quoting, Green, Leon, Proximate Cause in Texas Negligence Law, 28 Tex. L. Rev. 471 (1950)Google Scholar.

156 303 S.E.2d 258 (Ga. 1983).

157 Id. at 260.

158 Hegyes, 286 Cal. Rptr. at 99. But see Walker v. Rinck, 604 N.E.2d 59 (Ind. 1992). In a 3-2 decision, Walker reversed an intermediate appellate court's determination that a parent's decision to conceive more children, after having been informed that her physician had negligently failed to ascertain and appropriately medicate her Rh-negative condition, was an intervening cause of the harm to her subsequently born children. Id. at 596. The majority ruled that the later pregnancies were “totally foreseeable” and that the very purpose of the physician's care had been “to protect future fetuses.” Id. at 595. The court was at pains, however, to avoid recognizing “a duty … [that] might lead physicians to forego treatment that might benefit the mother but pose a risk to later children,” thus placing them “in a direct conflict between their moral duty to patients and the proposed legal duty to … hypothetical future generations.” Id. at 595 (quoting Albala v. City of New York, 429 N.E.2d 786 (N.Y. 1981)). It found that administration of the proper medication for Rh-negative blood “neither benefits nor harms the mother; It is given only to protect potential fetuses not yet conceived.” Id. In the research context, the court's analysis of causation, which was strongly criticized by its to dissenters, id. at 598, has limited utility.

159 See, e.g., Monusko v. Postle, 437 N.W.2d 367, 369 (Mich. App.), Iv. app. denied, 433 Mich. 869 (1989).

160 Renslow v. Mennonite Hosp., 367 N.E.2d 1250, 1254 (111. 1977)(child injured by preconception transfusions to mother).

161 Hegyes, 286 Cal. Rptr. at 103.

162 Catherwood v. American Sterilizer Co., 498 N.Y.S.2d 703, 706 (Sup. Ct. 1986), aff’d, 511 N.Y.S.2d 805 (App. Div.), appeal dismissed, 515 N.E.2d 908 (1987).

163 See, e.g., Turpin v. Sortini, 643 P.2d 954 (Cal. 1982) (negligent failure to diagnose sibling's hereditary defect); Curlender v. Bio-Science Labs., 165 Cal. Rptr. 477 (Cal. Ct. App. 1980) (negligent testing for gene for Tay-Sachs disease). But see Smith v. Cote, 513 A.2d 341, 351-55 (N.H. 1986) (refusing to recognize “wrongful life” claim of child prenatally injured by negligent failure to test mother for rubella) and cases discussed therein.

164 437 N.W.2d 367 (Mich. App.), lv. app. denied, 433 Mich. 869 (1989).

165 286 Cal. Rptr. 85 (Cal. Ct. App. 1991).

166 Id. at 86-87.

167 “A duty is easily recognized where … the parents consulted the physician for the express purpose of determining whether to conceive a child or to terminate an existing pregnancy … [when] a medical professional's conduct… is directly and intentionally related to whether a child is conceived or born.” Id. at 100-01.

168 Id. at 89 n.4; see discussion of strict liability law, infra notes 178-88, 204-34 and accompanying text.

169 367 N.E.2d 1250 (111. 1977).

170 Id. at 1258.

171 Id.

172 Id. at 1255 (emphasis added).

173 Id.

174 Id. at 1262 (Ryan, J., dissenting) (quoting William L. Prosser, Pabgraf Revisited, 52 Mich. L. Rev. 1, 27 (1953)).

175 Cf. Graham v. Keuchel, 847 P.2d 342 (Okla. 1993). One of the negligent Rh-negative senitization cases, Graham reversed a verdict because the court did not direct the jury to find a defense of supervening cause only if the mother's conception of the injured child had been intentional or in reckless disregard of her awarenewss of the risk to the child. Id. at 354, n.55. However, it also determined that if a woman knew of her Rh-sensitive status, had been adequately warned of the dangers of conception in that condition, and completely understood the medical risk, then the “forces set in motion by the doctors’ failure to give her [the treatment] may be said to have become passive … . If she undertook unreasonable risks by becoming pregnant in her sensitized condition, the harm … is not attributable to the doctors, but to the normal risks of pregnancy for a woman who has been sensitized.” Id. at 352-53. “The doctors … would not be held accountable for foreseeing that an adult female patient, who is sui juris, would willfully conceive in the face of substantial risk of known and appeciated danger of severe disability or death to the child.” Id. at 351.

176 If a researcher does breach a duty to a subject, either by concealing information or misreading tests or departing from the protocol, and harm ensues to the subject's children — whether they are unconceived, conceived, born, or grown-up — all bets are off. The researcher may be responsible for that harm — as, I would hope, everyone would agree is only fair. That, however, has no bearing on the quite different question whether the researcher's inclusion of a subject, without any negligence, could in and of itself subject the researcher to liability to the subject's future offspring for unavoidable harm.

177 For a very similar conclusion with respect to employer liability for harm to workers’ offspring, based on an intervening causation analysis, see Mark, supra note 148, at 695-97.

178 483 F.2d 237 (10th Cir. 1973).

179 Id. at 238, 240.

180 Id. at 240.

181 There is also definitely some question as to whether a subject's assumption of the risk (or in some circumstances, contributory negligence) in proceeding with the protocol would be imputed to and binding on the as-yet-unborn or unconceived child. This issue is discussed more extensively below under the question of waiver of liability. See infra note 302.

182 Keeton et al., supra note 150, § 102 (emphasis added).

183 Different issues arise when the subject is a minor limited in capacity to consent to anything, including medical treatment. This topic deserves its own monograph and cannot be addressed here. However, it should be noted that those whom the law calls “mature minors” or “emancipated minors” — because of their actual independence from their parents, through employment, marriage, or parenthood — do not fall into this category, because they can generally consent both to medical treatment and to research participation. See James M. Morrissey et al., Consent and Confidentiality in the Health Care of Children and Adolescents 90-92 (1986).

184 Compare Solomon, supra note 131, at 427:

The first problem is fear of medical malpractice liability, should the fetus develop into a damaged baby. Since few physicians have a clear understanding of malpractice law, this concern is very real to them. Nevertheless, there is a simple response. The doctrine of informed consent, based on the constitutional right to refuse medical treatment, requires that the physician disclose the risks and benefits of any medical procedure to the patient for her decision. Far from forcing or coercing the patient to act in accordance with the physician's orders, the law requires the patient to have the final say. The woman, not the fetus, selects and employs her doctor. Therefore, the physician discharges his legal duty by providing the woman with the required information.

185 Keeton et al., supra note 150, at § 122.

186 In 1980, in a plain effort to permit recovery against the mother's insurer, Michigan became the first state to sustain a claim against a child's mother for injuries resulting from her negligent conduct during the pregnancy. Grodin v. Grodin, 301 N.W.2d 869, 871 (Mich. 1980) (action permitted against mother for damage to son's teeth caused by use of tetracycline during pregnancy; must establish whether choice was “reasonable exercise of parental discretion“); see also Bonte v. Bonte, 616 A.2d 464 (N.H. 1992). One other state court considered such a claim and rejected it, at least with respect to unintentional harm, to avoid “State scrutiny [of] all the decisions a mother must make in attempting to carry a pregnancy to term” and the creation of an adversarial relationship between the pregnant woman and fetus from the moment of conception until birth. Stallman v. Youngquist, 531 N.E.2d 355, 355, 360 (111. 1988) (child born with intestinal injuries, apparently resulting from automobile collision while mother was five months pregnant). However, one writer believes that at least thirty U.S. jurisdictions have demonstrated their receptiveness to recognition of a woman's duty to her embryo-fetus. See Beal, Ron, “Can I Sue Mommy?” An Analysis of a Woman's Tort Liability for Prenatal Injuries to Her Child Born Alive, 21 San Diego L. Rev. 325, 357 (1984)Google Scholar. See generally Thomas M. Fleming, Right of Child to Action Against Mother for Infliction of Prenatal Injuries, 78 A.L.R.4th 1082, 1088 (1990) (suggesting that “recognition … of a mother's liability for injuring her unborn child might involve a duty on her part to properly care for her own body throughout her fertile years, regardless of pregnancy or her knowledge thereof, and render admissible evidence of such self-injurious conduct before conception as heavy drinking or drug use“).

Many commentators enthusiastically support the notion of maternal prenatal civil liability. See Joseph S. Badger, Note, Stallman v. Youngquist: Wo, You Can't Sue Mommy In Illinois;’ The Illinois Supreme Court Rejects Maternal Prenatal Civil Liability, 11 N. Ill. U. L. Rev. 409, 433 n.169 (1991). One even suggests that women should be held liable for perinatal transmission of the human immunodeficiency virus — a concept that stands out, even among academic law reviews, for its stunning remoteness from the real world as well as for its condemnatory attitude toward people living with AIDS. Curley, Martha M., Note, Establishing Relief for the Most Innocent of All AIDS Victims: Liability for Perinatal Transmission of AIDS, 28 J. Fam. L. 271 (1990)Google Scholar. No one on this long list of commentators, however, seems to have considered the possibility of paternal liability to a child for prenatal or preconceptual injury.

187 The only contrary analysis that I have found is a footnote in a student note, David S. Steefel, Note, Preconception Torts: Foreseeing the Unconceived, 48 U. Colo. L. Rev. 621, 636 n.81 (1977). The author relies on the black-letter language of Section 89 of the Restatement (Second) of Torts (and other rules) that “normal” and “foreseeable” intervening causes do not supersede a defendant's liability. See Keeton et al., supra note 150, at § 44. He errs, in my judgment, by focusing on the conception of offspring as the superseding “event;” my argument is, rather, that it is the informed consent of the male or female subject which supersedes the defendant's duty. As Prosser says,

Sometimes the defendant will be free to assume that when a third person becomes aware of the danger, and is in a position to deal with it, the third person will act reasonably. It is only where misconduct is to be anticipated, and taking the risk of it was unreasonable, that liability will be imposed for consequences to which such intervening acts contributed.

Id. Without more, the choice to participate in a protocol should not be characterized as “misconduct.“

188 See Enright v. Eli Lilly & Co., 570 N.E.2d 198 (1991) (no cause of action for “third generation” DES effects, in part because of “dangers of overdeterrence — the possibility that research will be discouraged or that beneficial drugs will be withheld from the market“).

189 The only tort claims against a researcher for damage to subject's offspring ever brought have been the intentional tort — not negligence — claims against the University of Chicago and Eli Lilly & Co. for their conduct of the DES trial in which female subjects were deliberately misinformed and misled. See Wetherill v. University of Chicago, 570 F. Supp. 1124 (N.D. 111. 1983); Mink v. University of Chicago, 460 F. Supp. 713 (N.D. 111. 1978).

190 If the subject was not paying to participate in the protocol or for the drug administered, quaere whether strict liability for non-negligent conduct, which is limited to those engaged in the business of selling a product, would be applicable. If the research subject is analogized to a “professional tester,” it would appear that transfer of products that are still in a testing stage and have not yet “entered the stream of commerce” will not be held to the strict liability standard. See Marshall Shapo, the Law of Products Liability § 12-34 & § 12-35 (1987). It is quite clear that physicians and other providers of health care are not strictly liable for defects in products that they dispense or prescribe. See, e.g., Magrine v. Spector, 241 A.2d 637 (N.J. 1968), aff'd 250 A.2d 129 (N.J. 1969).

191 “Loss of consortium” is the legal term for the harm of losing the “society and affection” or in the case of a child, the “society, guidance, attention and care” of a family member who is injured or killed. It is an item of damages separate from physical injury, medical expenses, pain and suffering, or financial loss. In the last decade, children have been permitted to sue for loss of parental consortium in several states. Keeton et al., supra note 150, at § 125.

192 See, e.g., Levine, Ethics and Regulation, supra note 22, at 95-153.

193 In light of developing knowledge of the male contribution to birth defects, such risks are no longer “unforeseeable” and therefore exempt from the product manufacturer's duty to warn. See discussion supra notes 140-46 and accompanying text.

194 See infra notes 255-65 and accompanying text.

195 For example, if the subject were paid. The vast majority of Phase I subjects — the “normal healthy volunteers” — are paid. Although often characterized as independent contractors, researchers certainly could choose instead to establish an employee-employer relationship. It is noteworthy that the greatest resistance to female subject inclusion seems to focus on Phase I, and the dire risks associated with utterly untried interventions, often when animal data is still quite incomplete. Yet, as Robert Levine recounts, when years ago insurance companies were solicited to give estimates for workers’ compensation coverage of a large Phase I testing facility, their per capita cost estimates for insuring the Phase I subjects was about the same as for insuring the facility's secretaries: very low. Workshop on Research Involving Human Subjects, Annual Meeting of the American Society of Law, Medicine and Ethics, October 23, 1993. Study of Phase I subjects in prison found 58 adverse medical events (using a very broad definition) and no deaths or permanent disability in the course of almost 18 billion subject-days of Phase I exposure. Levine, Ethics and Regulation, supra note 22, at 39-40.

196 Bell v. Macy's California, 261 Cal. Rptr. 447 (Ct. App. 1989), review denied, 1989 Cal. LEXIS 4637 (Cal. Nov. 16, 1989); see also Witty v. American Gen. Capital Distribs., Inc., 697 S.W.2d 636 (Tex. Ct. App. 1985), afd in part, rev'd in part on other grounds, 727 S.W.2d 503 (Tex. 1987) (both wrongful death and emotional distress claims of employee whose fetus was killed in work accident barred by workers’ compensation). But in the jurisdiction of Louisiana, where the fetus has been statutorily declared a juridical human being with all the rights of any child, the employer may be liable in a civil tort action, not merely in workers’ compensation, for negligence that causes the death of an employee's fetus. Adams v. Denny's Inc., 464 So. 2d 876 (La. Ct. App.), cert, denied, 467 So. 2d 530 (La. 1985); see also Namislo v. Akzo Chemicals, Inc., 620 So. 2d 573 (Ala. 1993); Dillon v. S.S. Kresge Co., 192 N.W. 2d 661 (Mich. Ct. App. 1971). See generally, Eggen, Jean M., Toxic Reproductive and Genetic Hazards in the Workplace: Challenging the Myths of the Tort and Workers’ Compensation Systems, 60 Fordham L. Rev. 843, 879-84 (1992)Google Scholar; Mark, supra note 148.

197 Contra, Jarvis v. Providence Hosp., 444 N.W.2d 236 (Mich. Ct. App. 1989). But note that In Jarvis, not only did the employer hospital omit to give gamma globulin to the pregnant lab technician exposed to hepatitis, the supervising physician affirmatively misled the woman by telling her that the sample to which she had been exposed had tested negative for hepatitis and that there was no need for concern. Id. at 238. Also, for whatever reason, the employer's attorney failed to raise the defense of exclusivity of remedy with respect to the woman's survivors’ action. Id. at 242 n.5. The court in fact engaged in the kind of “causal intervention” analysis that I predict courts will, and found that the woman's intervening conduct — failure to report the exposure for two days and to seek health care elsewhere — did not constitute a proximate cause of the fetal death.

198 Some will argue that the analogy to workplace fetal protection policies falls apart in the face of the differences between employment and participation in research. Getting and keeping a job is seen as an unalloyed benefit, while serving as a subject is if anything a sacrifice. This perspective, grounded in the traditional notions of “the null hypothesis” and “clinical equipoise,” and the much-touted distinction between research and treatment, is at best partial. See supra note 28. Employment has its burdens too, and, as the prior discussion reveals, research can offer distinct benefits to its subjects. See discussion supra notes 29-79 and accompanying text.

199 Int'l Union, United Auto., Aerospace and Agric. Implement Workers of Am., Uaw, v. Johnson Controls, Inc., 499 U.S. 187 (1991). See discussion supra notes 140-46 and accompanying text.

200 “It is no more appropriate for the courts than it is for individual employers to decide whether a woman's reproductive role is more important to herself and her family than her economic role. Congress has left this choice to the woman as hers to make.” Id. at 211.

201 See Moore v. Regents of Univ. of Cal., 793 P.2d 479 (Cal. 1990), cert, denied, 499 U.S. 936 (1991) (researchers refuse to share with patient profit from “immortal” cell line cultured from his spleen without his knowledge or consent). By “success” I do not necessarily mean an exciting breakthrough on a particular protocol or development of a particular drug; as with other enterprises, over time those engaged in research have to expect to absorb costs associated with experiments that don't work. and, of course, the trial that fails to disprove a null hypothesis may well be publishable or otherwise translatable into tangible benefit for the researcher.

202 Some may turn around the arguments advanced above about the benefits of being a research subject, and say that those benefits transform the subject into a true joint venturer who, having made a conscious decision to proceed despite (let us assume) awareness of possible if unquantifiable risks to offspring, should bear sole and absolute responsibility for whatever ensues. Rarely, I think, will the incidental advantages of being a subject approach the overall gain of the researcher from the research.

203 See discussion supra notes 140-46 and accompanying text.

204 Restatement (Second) of Torts § 402A (1965) [hereinafter Restatement]. A “Restatement” is an authoritative source of general legal rules and principles, not tied to the law of any particular state. In the field of products liability, each state also has its own body of judicial precedent and statutes controlling commercial transactions.

205 It has occasionally been suggested that strict liability would not apply to providers of investigational drugs because usually the drugs are not “sold,” i.e., transferred for value, to the consumer-subjects. At least one court rejected this contention summarily, pointing out that the manufacturer testing the drug was “in the business of selling drugs,” and that its ultimate goal was the commercially profitable sale of the drug. Gaston v. Hunter, 588 P.2d 326, 338-39 (Ariz. Ct. App. 1978). This defense is particularly problematic because claims of strict liability sound in tort, not contract, and may be maintained by family members, employees, guests, or donees of an original purchaser. See infra note 206. The only other avenue would be statutory or common-law definition of the provision of investigational drugs as a “medical service,” rather than distribution of a product, as occurred with respect to processors and providers of blood and blood components. See, e.g.. Doe v. Travenol Labs., Inc., 698 F. Supp. 780 (D. Minn. 1988) and authorities reviewed therein.

206 “Privity” is a relationship between two legal actors that gives rise to legal consequences, such as seller-buyer. The concept originally limited the reach of strict liability to those consumers or users who had actually purchased the defective goods, as opposed to their friends or relatives. With some infrequent exceptions, it no longer is significant in the law of strict liability. See Restatement § 402A, cmt. 1; Prosser, William L., The Fall of the Citadel, 50 Minn. L. Rev. 791 (1966)Google Scholar.

207 Brochu v. Ortho Pharmaceutical Corp., 642 F.2d 652, 655 (1st Cir. 1981).

208 E.g. Basko v. Sterling Drug, Inc., 416 F.2d 417, 426 (2d Cir. 1969); Sterling Drug, Inc. v. Cornish, 370 F.2d 82, 85 (8th Cir. 1966); Grundberg v. Upjohn Co., 813 P.2d 89,97 (Utah 1991).

209 see. e.g., Ezagui v. Dow Chem. Co., 598 F.2d 727 (2d Cir. 1979).

210 Some courts have deemed all prescription drugs, by definition, in this category. See, e.g., Brown v. Superior Court San Francisco County, 751 P.2d 470 (Cal. 1988). Other courts believe that this assessment should be made on a case-by-case basis, considering the real value of and need for marketing of the drug. See, e.g., Hill v. Searle Labs., 884 F.2d 1064 (8th Cir. 1989); Kociemba v. G.D. Searle & Co., 695 F. Supp. 432 (D. Minn. 1988); Collins v. Eli Lilly & Co., 342 N.W.2d 37, 52 (Wis.), cert, denied, 469 U.S. 826 (1984).

211 See, e.g., Givens v. Lederle, 556 F.2d 1341 (5th Cir. 1977) (strict liability imposed for failure to warn pediatrician of risk of vaccine-induced polio); Niemiera v. Schneider, 555 A.2d 1112 (N.J. 1989) (sufficient to warn physician of risk of convulsions from DPT vaccine). Compare Davis v. Wyeth Labs., Inc., 399 F.2d 121 (9th Cir. 1968) (necessary to warn consumers of risk because drug administered in a mass vaccination program without the “learned intermediary” of the physician); accord Reyes v. Wyeth Labs., Inc., 498 F.2d 1264 (5th Cir.), cert, denied, 419 U.S. 1096 (1974).

212 See, e.g., Cobbs v. Grant, 502 P.2d 1 (Cal. 1972).

213 See, e.g., Sterling Drug, Inc. v. Yarrow, 408 F.2d 978 (8th Cir. 1969) (unreasonable to fail to instruct “detail men” (sales representatives) who regularly saw prescribing physicians to warn them about drug risks).

214 See, e.g., Doe v. Miles Labs., Inc., 927 F.2d 187, 194-95 (4th Cir. 1991); O'Hare v. Merck & Co., 381 F.2d 286 (8th Cir. 1967).

215 Singer v. Sterling Drug, Inc., 461 F.2d 288 (7th Cir.), cert, denied, 409 U.S. 878 (1972).

216 See, e.g.. Chambers v. G.D. Searle & Co., 441 F. Supp. 377, 383 (D. Md. 1975), aff'd, 567 F.2d 269 (4th Cir. 1977) (per curiam).

217 See, e.g., Salmon v. Parke, Davis & Co., 520 F.2d 1359, 1362, 1364 (4th Cir. 1975); Mazur v. Merck & Co., Inc., 742 F. Supp. 239 (E.D. Pa. 1990); In re Tetracycline Cases, 747 F. Supp 543, 550 (W.D. Mo. 1989); Shanks v. Upjohn Co., 835 P.2d 1189, 1197-98 (Alaska 1992); see also Cipollone v. Liggett Group, Inc., 112 S.Ct. 2608 (1992) (not all failure-to-warn and design defect claims against tobacco manufacturers preempted by federal statutes regulating cigarette advertising and promotion); Silkwood v. Kerr-McGee Corp., 464 U.S. 238, 251 (1984) (federal nuclear safety regulations do not preempt state punitive damage awards).

218 21 U.S.C. § 355(b)(1)(A) (1988).

219 21 C.F.R. § 314.50(d)(5)(v) (1993).

220 Toole v. Richardson-Merrell, Inc., 60 Cal. Rptr. 398 (Ct. App. 1967).

221 Barson v. E.R. Squibb & Sons, Inc., 682 P.2d 832 (Utah 1984) (manufacturer negligent in not testing for teratogenic effects of injected progestational hormone); see also West v. Johnson & Johnson Prods., Inc., 220 Cal. Rptr. 437, 448 (Ct. App. 1985) (failure of tampon manufacturer to study the basic microbiology of the human vagina, to test for vaginal infections, and — of particular interest — to include women with a history of vaginitis in the human studies), cert, denied, 479 U.S. 824 (1986).

222 See, e.g., Wooderson v. Ortho Pharmaceutical Corp., 681 P.2d 1038, 1063-64 (Kan. 1984), cert, denied, 469 U.S. 965 (1984) (sustaining award of punitive damages to victim of hemolytic uremic syndrome from oral contraceptive because of Ortho's failure to do further animal research after independent researcher reported finding lesions in vessel walls of autopsied women taking oral contraceptives).

223 Taylor v. Wyeth Labs., 362 N.W.2d 293, 296-97 (Mich. App. 1984) (even absent any study, prudent manufacturer would have explored relationship between blood type and blood clotting risk in women taking oral contraceptives, once aware that women with type A blood experience disproportionate number of pulmonary embolisms).

224 2 Marden G. Dixon & Frank C. Woodside III, Drug Product Liability 14-68 (1991).

225 Hoffman v. Sterling Drug, Inc., 485 F.2d 132, 140-41 (3d Cir. 1973).

226 See, e.g., Tinnerholm v. Parke, Davis & Co., 285 F. Supp. 432, 448 (S.D.N.Y. 1968), modified on other grounds, 411 F.2d 48 (2d Cir. 1969) (upholding negligence claim of child catastrophically injured by Quadrigen vaccine [subsequently withdrawn by the manufacturer] because vaccine “rushed to commercialization” without testing under market conditions).

227 21 C.F.R. § 314.50(5)(v) (1993).

228 21 C.F.R. § 201.57(c)(3)(i) (1993).

229 I was pleased to find that Ellen Flannery, partner in Covington and Burling in Washington, D.C., and a leader of the private pharmaceutical and medical device bar, concurs in this assessment of possible liability risk. “Drug manufacturers will likely find it increasingly difficult to prove that all-male studies of many drug products constitute state-of-the-art testing. There is growing recognition that the physiological differences between men and women make it scientifically inadequate in many instances to conduct clinical tests or epidemiological studies using only male subjects.” Ellen Flannery & Sanford N. Greenberg, Liability Exposure for Exclusion and Inclusion of Women as Subjects in Clinical Studies 9 (Mar. 11, 1993) (unpublished paper on file with author).

230 Dalehite v. United States, 346 U.S. 15, 51-52 (1953) (Jackson, J., dissenting).

231 209 Cal. Rptr. 456 (Ct. App. 1985).

232 This concept was derived from an accepted principle of tort law, enunciated in Haft v. Lone Palm Hotel, 478 P.2d 465 (Cal. App. 1970): when there is a substantial probability that a defendant's negligence caused plaintiffs injury, and when that negligence makes it impossible as a practical matter for the plaintiff to prove causation (in Haft, it was the hotel's failure to provide a lifeguard at its pool, which meant there were no witnesses to the plaintiffs decedent's drowning), it is appropriate to shift the burden of proof from the plaintiff to establish causation to the defendant to disprove it.

233 Once a product is on the market and being prescribed, all testing can stop. To detect statistically rare outcomes, we rely entirely on the voluntary submission of Adverse Drug Experience Reports from physicians. Unfortunately, clinicians have nothing to gain but altruistic satisfaction from submitting these reports. They have to lose, at minimum, the time spent shuffling paper. At worst, they, as well as the pharmaceutical houses, may be implicated in a medical negligence action. The post-marketing surveillance program has been notoriously lax and spotty.

234 The Supreme Court did not establish this proposition with respect to gender until 1971. See Reed v. Reed, 404 U.S. 71 (1971). Five years later, it formulated the test for legitimate government differentiation on the basis of gender: “[Classifications by gender must serve important governmental objectives and must be substantially related to the achievement of those objectives.” Craig v. Boren, 429 U.S. 190, 197 (1976). More recently, the test was reformulated to require “exceedingly persuasive justification” for the differentiation. Mississippi Univ. for Women v. Hogan, 458 U.S. 718, 724 (1982). But see Personnel Admin. Mass. v. Feeney, 442 U.S. 256 (1979) (if government action gender-neutral on its face, despite discriminatory results of its application, must demonstrate that discrimination is intentional to find Constitutional violation).

Many state constitutions also include Equal Protection provisions that may be interpreted more broadly than the federal clause. See, e.g., People v. Davis, 537 N.Y.S.2d 430, 434 (Sup. Ct. 1988).

235 42 U.S.C. § 2000e(k) (1978). Outside the realm of Title VII, however, some courts have found that differential treatment of women because of their capacity to become pregnant is not an impermissible gender-based classification. See, e.g., Michael M. v. Superior Court, 450 U.S. 464 (1981) (upholding statutory rape statute applicable only to males because of state interest in limiting illegitimate pregnancies); Toomey v. Clark, 876 F.2d 1433 (9th Cir. 1989) (no violation of Equal Protection by state juvenile court's consideration of defendant's pregnancy in decision to waive jurisdiction and permit prosecution as an adult); United States v. Flores, 540 F.2d 432, 438 (9th Cir. 1976) (court may consider pregnancy in sentencing). It may be worthy of note that all these decisions involve criminal law and prosecution.

236 If we are talking about a nonpublic entity not subject to Constitutional standards, then only “employers” according to the statutory definition — employing more than a certain number of people, for example — would be covered.

237 Pregnancy discrimination in employment may also be covered by state anti-discrimination statutes. See, e.g., New York City Transit Auth. v. State Div. of Human Rights, 577 N.E.2d 40 (N.Y. 1991). Outside the employment context, discrimination based on pregnancy may not be deemed gender discrimination that violates the Equal Protection clause. Geduldig v. Aiello, 417 U.S. 484, 497 n.20 (1974) (permitting insurance system to distinguish between pregnant women and “nonpregnant persons“). Within the employment arena, courts must accept as defenses that may defeat discrimination claims, “bona fide occupational qualification” and “business necessity.” Without elaborating on these complex legal doctrines, both permit differential treatment of men and women in the workplace upon a convincing argument that it is “necessary.” E.g., Dothard v. Rawlinson, 433 U.S. 321 (1977).

238 E.g., N.Y. Exec. Law § 296(2)(a) (McKinney 1993):

It shall be an unlawful discriminatory practice for any person, being the owner, lessee, proprietor, manager, superintendent, agent or employee of any place of public accommodation … because of the … sex … of any person, directly or indirectly, to refuse, withhold from or deny to such person any of the accommodations, advantages, facilities, or privileges there of ….

Remarkably, the public accommodations provision of the federal civil rights law, 42 U.S.C. § 2000a, does not apply to discrimination on the basis of gender. Seidenberg v. McSorley's Old Ale House, Inc., 308 F. Supp. 1253 (S.D.N.Y. 1969).

239 The most common recent context of these decisions has been the refusal of some healthcare providers to treat people with HIV infection. See, e.g.. Doe v. Jamaica Hosp., N.Y.L.J., May 6, 1991, at 27 (alleged exclusion of HIV-infected pregnant woman from hospital's high-risk prenatal care unit could violate public accommodation section of New York Human Rights Law); Estate of Campanella v. Hurwitz, New York City Comm'n on Hum. Rights, July 31, 1991 (private dentist's office a place of public accommodation under New York City Human Rights Law). But see In re Sattler, 580 N.Y.S.2d 35 (App. Div.), appeal denied, 610 N.E.2d 388 (N.Y. 1992) (“one-chair” dental practice not a place of public accommodation under New York City Human Rights Law). The clear definition of public accommodation in the Americans with Disabilities Act, may, ironically, support a less expansive interpretation of the less clear provisions of some gender discrimination laws. 42 U.S.C. § 12181(7)(F) (Supp. III 1991).

While a few state statutes do expressly state that places of public accommodation may serve only men or only women if the place “is in its nature reasonably restricted exclusively to individuals of one sex,” e.g., N.J. Stat. Ann. § 10:5-12(f) (West 1992), it is hard to see how research protocols could meet that standard. The controversy over gender discrimination in private clubs has also spawned the concept of a place of apparent public accommodation that is deemed “distinctly private” and therefore exempt from the statute. See, e.g., United States Power Squadrons v. State Human Rights Appeal Bd., 452 N.E.2d 1192, 1204 (N.Y. 1983). But few settings that would be conducting a research protocol would qualify as anything like a private club.

240 See, e.g., Rendell-Baker v. Kohn, 457 U.S. 830, 840-42 (1982); Stanturf v. Sipes, 224 F. Supp. 883, 890 (W.D. Mo. 1963), aff'd, 335 F.2d 224 (8th Cir. 1964), cert, denied, 379 U.S. 977 (1965).

241 Note that the federal statute, Title VI of the Civil Rights Act, does not prohibit gender discrimination in programs and activities receiving federal financial assistance. 42 U.S.C. § 2000d (1988).

242 Of the almost $10 billion devoted to health sciences research and development in the U.S. in fiscal year 1991, 78% was dispensed by the federal agencies NIH and Adamha (Alcohol, Drug Abuse, and Mental Health Administration). Two-thirds of that sum was contracted out to private academic institutions. Funding Health Sciences Research, supra note 15 at 35, 77, 79.

243 Compare West v. Atkins, 487 U.S. 42 (1988) (prison doctors acting under contract to care for inmates are state actors).

244 429 U.S. 190, 197 (1976); see supra note 234 for a description of the test.

245 It should also be noted that many state courts have interpreted their own constitutions to offer greater protection of individual liberty than the United States Constitution offers in view of the present federal bench. See, e.g., Committee to Defend Reprod. Rights v. Myers, 625 P.2d 779, 799 (Cal. 1981) (California Constitution prohibits Medi-Cal exclusion of reimbursement for abortions); In re T.W., 551 So. 2d 1186, 1192-93 (Fla. 1989) (Florida Constitution prohibits requirement of parental consent to minor's abortion); Doe v. Director of Dep't of Social Servs., 468 N.W.2d 862, 869 (Mich. Ct. App. 1991) (Michigan Constitution prohibits Medicaid exclusion of coverage for abortions not necessary to save mother's life), rev'd, 487 N.W.2d 166 (1992).

246 National Institutes of Health Revitalization Act of 1993, 42 U.S.C.A. § 201 (West Supp. 1993); see infra text accompanying note 276.

247 See, e.g., Youngberg v. Romeo, 457 U.S. 307, 323 (1982) (decisions about adequacy of care of developmentally disabled in state institutions “presumptively valid if made by a professional“); Parham v.J.R., 442 U.S. 584 (1979) (no need for due process protections for children committed to mental hospitals by their parents or by the State, since admission decision made by team of mental health professionals).

248 Int'l Union, United Auto., Aerospace and Agric. Implement Workers of Am., v. Johnson Controls, Inc., 499 U.S. 187, 207 (1991). Because of its significance in this area, and because the issuance of this decision from this Supreme Court was frankly amazing to most opponents of gender bias, Johnson Controls merits some extended discussion.

The management policy challenged was quite typical of the fetal protection policies adopted by dozens of major American corporate employers. See Elaine Draper, Risky Business 200 n.13 (1991) (study of 198 large chemical and electronic companies in Massachusetts found nearly one in five — 37 companies — restricted women's work options on the ground of potential fetal risk, while ignoring male reproductive hazards). Johnson Controls had never hired women on its production line before the Civil Rights Act of 1964 outlawed patent sex discrimination. Initially, its policy was to inform women workers about the known risks of lead exposure during pregnancy and to tell parents (of both genders) that they were responsible for the health of their unborn children. In 1982, it revamped its policy to mandate exclusion of all fertile females from jobs that would expose them to certain levels of lead. As a result, at least one female worker was sterilized. She, along with a 50 year-old divorced female employee who had been involuntarily transferred to a lower-paying job, and a male employee who was denied an unpaid leave of absence prior to becoming a father, charged that Johnson Controls had violated Title VII. 499 U.S. at 192.

The Supreme Court found this policy biased against women. Id. at 199-00. To justify “facial” discrimination — a policy that on its face treats women differently from similarly situated men — an employer must show a “bona fide occupational qualification, reasonably necessary to the normal operation of the business or enterprise (BFOQ).” Id. at 200-03. While injury to a potential fetus is a “deep social concern,” the safety of an employee's offspring is not an essential component of that employee's ability to do the job: pregnant women have the same skills and aptitudes for the Johnson Controls jobs as nonpregnant employees. “Decisions about the welfare of future children must be left to the parents who conceive, bear, support and raise them rather than to the employers who hire those parents.” Id. at 206.

The Court was not unmindful of the liability concerns that had been raised by Johnson as a defense. Id. at 208-09. Acknowledging the risk of lawsuits for prenatal injury, the Court majority stated that employers who adhere to Osha standards (provide blood tests, proper ventilation, safety equipment, etc.) should face no liability. Id. In concurrence, Justice White noted that Osha compliance is not always a defense to tort liability; that parents can't waive their children's claims and that parental negligence can't be imputed to children; and that strict liability, rather than negligence, might in fact become the basis for successful legal action in some instances. Id. at 213-14. Nonetheless, he did not deem this possibility of future liability a sufficient counterweight to the protected interest of women in equal treatment, and the majority responded that the incremental cost of hiring women was not so high as to “threaten survival of the employer's business.” Id. at 210-11.

As I try to show here, given the sources of potential liability that remain even if researchers continue to exclude women subjects, the incremental cost of the necessary insurance or self-insurance likewise does not “threaten survival” of the research enterprise.

For a less rosy view of Johnson Controls, and a persuasive argument that it represents a “limited” and perhaps “short-lived” victory for women, see Jennifer Morton, Comment, Pregnancy in the Workplace — Sex-Specific Fetal Protection Policies — U.A.W. v. Johnson Controls, Inc. — A Victory for Women?, 59 Tenn. L. Rev. 617, 634 & passim (1992) (noting that several concurringjustices would uphold sex-specific fetal protection policy based on employer's concern for potential fetus, and/ or (in dicta) extra costs associated with employing women, and Justice Marshall's replacement by Justice Thomas subsequent to this decision).

249 See J.E.B. v. Alabama ex rel. T.B., 1994 WL 132232 (Apr. 19, 1994); Taylor v. Louisiana, 419 U.S. 522 (1973); Strauder v. West Virginia, 100 U.S. 303, 308 (1879); see also Batson v. Kentucky, 476 U.S. 79, 87 (1986); U.S. v. DeGross, 913 F.2d 1417, 1420-23 (9th Cir. 1990).

250 Shurberg Broadcasting of Hartford v. F.C.C., 876 F.2d 902, 917 (D.C. Cir. 1989); see also Levine, Carol, Has AIDS Changed the Ethics of Human Subjects Research?, 16 L. Med. & Health Care 167, 172 (1988)Google Scholar:

[I]f there is a right to be a research subject, and again that is arguable, it is not a general right to enter whatever trial one may choose but the right to be offered an equal opportunity to be considered for all trials that are appropriate, given one's medical condition and other scientifically relevant characteristics.

My partial rejection of Levine's analysis in this piece stems from my inability to muster much confidence in the use of terms such as “appropriate” and “scientifically relevant.“

251 42 U.S.C. § 2000e(k) (1978).

252 417 U.S. 484 (1974). Geduldig's “continuing vitality” has recently been reaffirmed by the Court. Bray v. Alexandria Women's Health Clinic, 113 S. Ct. 753, 760 n.3 (1993).

253 Annas, George, Protecting the Liberty of Pregnant Patients, 316 New Eng. J. Med. 1213, 1214 (1987)Google Scholar. For full development of this contention see Merton, Ethical Obstacles, supra note 79.

254 Elaine W. v. Joint Diseases North General Hosp., Inc., 613 N.E.2d 523, 525 (N.Y. 1993).

255 42 U.S.C. § 2891-3 (1974).

256 See, e.g., N.Y. Pub. Health Law § 2444 (Consol. 1987) (Protection of Human Subjects). This statute largely tracks the National Research Act of 1974, Pub. L. No. 93-348, 88 Stat. 852 (codified as amended in scattered sections of 42 U.S.C), but it does not explicitly require the “human research review committees” it mandates to seek equitable selection of subjects.

257 Initially the National Research Act mandate applied not only to research done with federal funds but to all research conducted at or sponsored by an institution receiving federal funds. 45 C.F.R. § 46.101(a) (1977). The original regulations of the Secretary of the Department of Health, Education and Welfare specifically limited the requirement of IRB review to “activities supported under grants or contracts from Dhew.” 45 C.F.R. § 46.102(a) (1977). The requirement of IRB review now applies to all research “conducted, supported, or otherwise subject to regulation by any federal department or agency” that has adopted the new Federal Policy for the Protection of Human Subjects. 56 Fed. Reg. 28,002, 28,012 (1991). In practice, most institutions that receive any federal funds (and most research institutions do) review all protocols through the same process and generally do not differentiate those that are federally funded. Note, however, that the New York state law, for example, applies to all research conducted in the state, regardless of funding source. N.Y. Pub. Health Law § 2444 (Consol. 1987).

258 See, e.g., 45 C.F.R. § 46.107(b) (1992). See generally Robert A. Greenwald et al., Human Subjects Research: A Handbook for Institutional Review Boards (1982); Levine, Ethics and Regulation, supra note 22, at 321-28. Interestingly enough, the original flat requirement that an IRB could not consist entirely of one gender has been revised to mandate merely “every nondiscriminatory effort to ensure” that no IRB consists entirely of men or women. See 45 C.F.R. § 46.107 (1992). From the perspective of the role IRBs could play in changing exclusionary research practice, this seems an unfortunate and unnecessary regression.

259 Federal regulations have always required IRBs to determine that “selection of subjects is equitable,” taking into account the purposes of the research and the setting in which it will be conducted. See, e.g., 45 C.F.R. § 46.111(a)(3) (1992). A provision added to section 46.111 of the Federal Policy for the Protection of Human Subjects, “Criteria for the Approval of Research,” requires IRBs to be “particularly cognizant of the special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons” and to ensure additional safeguards to protect the rights and welfare of these “subjects … likely to be vulnerable to coercion or undue influence.” See also the parallel provision of the Food and Drug Administration at 56 Fed. Reg. 28,029 (1991).

The good news is that this new provision suggests that pregnant women can be research subjects; the bad news is that it defines them as inherently vulnerable, requiring special protec tions from and raising special “problems” for researchers. This is not the place, but the implications and premises of this provision warrant more examination.

260 National Commission for the Protection of Human Subjects of Biomedical and Be Havioral Research, Report and Recommendations: Institutional Review Boards 82 (1978); see also Greenwald et al., supra note 258, at 25. For a different view, see Angela R. Holder, Liability and the IRB Member: The legal aspects, IRB: Rev. Hum. Subjects Res., June-July 1979, at 7.

261 purCell v. Zimbelman, 500 P.2d 335 (Ariz. 1972); Nielsen v. Regents of the Univ. of Cal., Civ. No. 665-049 (Sup. Ct. Cal. Cty. of San Francisco, Sept. 11, 1973); Bailey v. Mandel, Civ. No. K-74-110 (D.C. M.D. 1974); see also Mason v. Institutional Review Bd. for Human Research, Medical Univ. of S.C., 953 F.2d 638 (4th Cir. 1992) (seeking injunctive relief to compel IRB to continue terminated protocol); Head v. Colloton, 331 N.W.2d 870 (Iowa 1983) (seeking injunctive relief to compel amendment of a protocol, but not with regard to selection of subjects). Recently, a Quebec court held not only the investigator and the hospital, but the hospital's research committee (the functional equivalent of an IRB) responsible for the death of a research subject due to cardiac arrest after fluorescein angiography. Weiss v. Solomon, R.J.Q,. 731 (1989). The court suggested that the Research Committee had failed, among other things, to insist on adequate screening of subjects for the kind of cardiomyopathy that made this subject especially at risk for this procedure.

262 See Robertson, John, The Law of Institutional Review Boards, 26 U.C.L.A. L. Rev. 484, 531 (1978)Google Scholar.

263 See supra note 28.

264 See discussion supra notes 249-50 and accompanying text. See generally, King, Joseph H., Causation, Valuation, and Chance in Personal Injury Torts Involving Preexisting Conditions and Future Consequences, 90 Yale L.J. 1353 (1981)Google Scholar; John D. Hodson, Annotation, Medical Malpractice: Loss of Chance Causality, 54 A.L.R.4th 10 (1987 and Supp. 1990).

265 See, e.g., Evers v. Dollinger, 471 A.2d 405 (N.J. 1984); Herskovits v. Group Health Coop., 664 P.2d 474 (Wash. 1983); see also Falcon v. Memorial Hosp., 462 N.W.2d 44 (Mich. 1990) and authorities cited therein; Perez v. Las Vegas Medical Ctr., 805 P.2d 589 (Nev. 1991). Aware of the besieged sense of many clinicians, I feel obliged to note that these decisions do not stand for the proposition that missing a diagnosis automatically amounts to malpractice. The doctor who merely makes a mistake is not liable — only the doctor whose mistake is attributable to an unexcused departure from a reasonable standard of professional care.

266 See Jean Hamilton, Avoiding Methodological and Policy-Making Biases in Gender-Related Health Research, in U.S. Dep't Health & Human Servs., Pub. No. (PHS) 88-50206, Women's Health: Report of the Public Health Service Task Force on Women's Health Issues IV-54, IV-57-60 (1987).

267 See Nichols, Eve K., Expanding Access to Investigational Therapies for HIV Infection and AIDS, 1991 Inst, of Med. 69-71 (1991)Google Scholar. Unfortunately, the FDA's Proposed Guideline, while acknowledging this problem, is guilty of just this fallacy. See Proposed FDA Guideline, supra note 97, at 39,410 (emphasizing pharmacokinetic rather than pharmacodynamic by-gender analyses because “the number of documented gender-related pharmacodynamic differences of clinical consequence is at this time small“).

268 21 C.F.R. § 50.25(b)(1) (1988).

269 On December 15, 1992, a coalition of the HIV Law Project of the AIDS Service Center of Lower Manhattan, the National Organization for Women Legal Defense and Education Fund, the AIDS Project of the American Civil Liberties Union, and other AIDS-activist organizations petitioned the FDA for just such amendments, pursuant to 21 C.F.R. § 10.30. See Citizen Petition (Dec. 15, 1992) (petition sent to FDA, on file with author). The FDA's response — the Proposed FDA Guideline — is completely inadequate in this regard. See discussion supra notes 118-28 and accompanying text.

270 On the need for careful monitoring of male compliance with such restrictions, see infra note 287.

271 A concomitant of this change would be for FDA regulations to mandate completion of animal reproduction studies prior to human testing. See Citizen Petition, supra note 269, at 6-7; supra note 107-08 and accompanying text.

272 Carol Levine et al.. Building a New Consensus: Ethical Principles and Policies for Clinical Research on HIV/AIDS, IRB: Rev. Hum. Subjects Res., Jan.-Apr. 1991, at 1, 14, 16. The working group that developed this consensus document included prominent clinical AIDS researchers and ethicists, as well as representatives of potential subject populations. Their recommendations depart from mine in continuing to treat pregnant women as different from men engaged in reproductive activity, although they do require that pregnant women be permitted access to Phase II/ III trials or treatment INDs if a drug is potentially life-saving, and would create a rebuttable presumption that pregnant women are eligible for all trials. See id. at 16. While the context of this report is AIDS research, the merit of its analysis is not confined to that.

273 See supra notes 131-32 and accompanying text.

274 In 1986, NIH and ADAMHA promulgated the Policy Concerning Inclusion of Women in Study Populations. NIH, Policy Concerning Inclusion of Women in Study Populations (1991) (hereinafter NIH Policy). “Clinical research findings should be of benefit to all persons at risk of the disease, regardless of gender.” Id. at 1. The Policy requires evaluation of the gender composition of each study proposed for funding, and a statement of reasons for excluding members of one gender or for “a disproportionate representation” of one gender. Gender representation should be “appropriate to the known incidence/prevalence of the disease or condition being studied,” and reasons for exclusion of one gender must be “well explained and justified.” The justification must be “compelling,” but it may consist of “a strong scientific rationale” or “a need to protect the health of the subjects.” Id.

A 1990 Government Accounting Office report concluded, however, that the Policy had virtually no impact because no mechanism of institutional enforcement had been set up. Applicants for NIH grants were not advised about it, and the grant application reviewers did not utilize it as a factor in evaluating the merit of competing proposals. The Policy did not even apply to the NIH's own intramural projects. See National Institutes of Health: Problems in Implementing Policy on Women in Study Populations, Hearings Before Subcommittee on Health and the Environment, House of Representatives, 101st Cong., 2d Sess. 47 (1990) (testimony of Mark V. Nadel, Associate Director, National and Public Health Issues, Human Resource Division). See further discussion of the NIH Policy infra notes 281-87 and accompanying text.

275 See Women's Health Equity Act, S. 2961, 101st Cong., 2d Sess. (1990); Clinical Trials Fairness Act, S. 2945, 101st Cong., 2d Sess. (1990) and H.R. 2507, 102d Cong., 1st Sess. (1991) (vetoed).

276 42 U.S.C.A. § 201 (West Supp. 1993).

277 Id. at § 131. This is a serious limitation in itself; although NIH supports and conducts a great deal of research, one wonders why the legislation is not at least as broad in scope as the federal regulations discussed above — applicable to all research conducted, funded, or regulated by any federal agency or department. Other bills have been introduced that would require attention to women's health interests in the investigation of all drugs prior to FDA approval. See Pharmaceutical Interaction Safety Act, H.R. 2694, 103d Cong., 1st Sess. (1993); Pharmaceutical Testing Fairness Act, H.R. 2695, 103d Cong., 1st Sess. (1993)

278 Section 131. Requirement of Inclusion in Research Sec 492B.(a).

  1. (1)

    (1) In conducting or supporting clinical research …, The Director of NIH shall, subject to subsection (b), ensure that—

    (A) women are included as subjects in each project of such research; …

  2. (2)

    (2) The Director of NIH … shall conduct or support outreach programs for the recruitment of women … as subjects in projects of clinical research.

    (b) The requirement established in subsection (a) … shall not apply to a project of clinical research if the inclusion, as subjects in the project, of women …

  3. (1)

    (1) is inappropriate with respect to the health of the subjects;

  4. (2)

    (2) is inappropriate with respect to the purpose of the research; or

  5. (3)

    (3) is inappropriate under such circumstances as the Director of NIH may designate.

Id. at § 131. Cost is not to be considered as a factor in defining “inappropriate.” Regulations, intended to explicate “inappropriate,” were issued on March 28, 1994, effective June 1, 1994. NIH, NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research, 59 Fed. Reg. 96598. The regulations address only Phase III clinical trials and require nothing more than a review of existing data to ascertain whether they suggest significant clinical differences between women and men. If so, then the Phase III trial must be designed to elucidate those differences. However, in Subsection VI(c), the Guidelines state that in most studies, approximately equal numbers of men and women should be subjects unless different proportions are “appropriate” because of known epidemiological differences. 59 Fed. Reg. 14508, 14512. Thus, “inappropriate” is somewhat circularly defined as “not appropriate,” but at least it would appear to exclude factors such as risk to offspring. Researchers are not required to indicate how they propose to comply with this legislation until fiscal year 1995. Id. at § 131(d)(2)(A)(i), (e)(1), (2).

279 Scientists who want to find a way around this statute will argue that the homogeneity rationale fits neatly within the “purposes of the research” exception; that concern for that “vulnerable” group, pregnant women, warrants exclusion of those who are or may unwittingly be pregnant “for their health“; and so on. Surely exclusions suggested by FDA Guidelines or apparently required by other federal regulation render contradictory inclusion “inappropriate,” and I am afraid that the Director's regulations, which were to have been issued by December 10, 1993, will declare exactly that.

280 Another example of this ubiquitous vagueness: the one federal statute that currently mandates the inclusion of women as subjects is the National Commission on Acquired Immune Deficiency Syndrome Act, 42 U.S.C. § 300cc-16(a)(3) (1991), the authorization for the Secretary of HHS to distribute grants and contracts for AIDS research: “The Secretary shall ensure that, as appropriate, clinical research programs [for AIDS centers] include as research subjects women, children, hemophiliacs, and minorities.” (emphasis added) As of this writing, no regulations interpreting “as appropriate” have been issued.

281 See supra note 274.

282 Letter from Karen L. Hagberg, Coordinator, Women in Research Task Force, to Ruth L. Kirschstein, M.D., 2 (June 28, 1991) (on file with author).

283 See supra part II.B.

284 Letter from Ruth L. Kirschstein, M.D., Acting Director, Office of Research on Women's Health, to Karen L. Hagberg, Coordinator, Women in Research Task Force 3 (Oct. 23, 1991) (on file with author).

285 See supra notes 137-38 and accompanying text.

286 See supra notes 140-46 and accompanying text.

287 Since it is more difficult to monitor male compliance with protocol restrictions on impregnation than to require routine pregnancy tests, more stringent limitations on the mobility and privacy of male subjects may be necessary for the duration of their study participation, and substantially thereafter, until it is established that their sperm are free of any contamination or mutation.

288 42 U.S.C. § 300aa-ll (1991); see discussion of National Childhood Vaccine Act of 1986 and the California AIDS Vaccine Victims Compensation Fund in Mariner, Wendy & Gallo, Robert, Getting to Market: the Scientific and Legal Climate for Developing an AIDS Vaccine, 15 L., Med. & Health Care 17, 24 (1987)Google Scholar.

289 On the failure of American workers’ compensation systems to enhance safety incentives or to make employers accountable for the cost of hazards in the workplace, see Daniel Berman, Death on the Job 54-73 (1978) (workers’ compensation replaces less than 10% of income lost by victims; e.g., life of a Puerto Rican worker is worth as low as $11.34 per week in compensation system); Hylton, Keith N. & Laymon, Steven E., The Internalization Paradox and Workers’ Compensation, 21 Hofstra L. Rev. 109 (1992)Google Scholar (demonstration of the incomplete internalization of cost); Office of Technology Assessment, Pub. no. OTA-H-256, Preventing Illness and Injury in the WORKPLACE 302, 309 (1985); Glen M. Shor, Workers’ Compensation: Subsidies for Occupational Disease, 1 J. Pub. Health Pol'y 328 (1980).

On the inefficiencies, delay, and consequent harm to claimants, see the Final Report of the State of New York Temporary State Commission on Workers’ Compensation and Disability Benefits 15-19, 29-72, 79-83, 101-03, 121-25 (1986); Kenneth C. Crowe, Workers'Comp: In NY, It's Hurting, Newsday.June 27, 1988, at III-1; Hearings Before the Temporary State Commission on Workers’ Compensation and Disability Benefits, Dec. 10, 1984 (testimony of licensed representative Marilyn S. Brook) (on file with the author); Lawrence White, Workers’ Noncompensation, in Human Debris 74-112 (1983); Lawrence White, Living the Nightmare, in Human Debris 74-112 (1983); Jerry L. Mashaw, Lessons for the Administration of Workers’ Compensation from the Social Security Disability Insurance Program, in New Perspectives in Workers’ Compensation 97 (John F. Burton, Jr. ed., 1988); Viscusi, W. Kip & Moore, Michael J., Workers’ Compensation: Wage Effects, Benefits Inadequacies, and the Value of Health Losses, 69 Rev. Econ. & Stat. 249 (1987)Google Scholar; John F. Burton, Jr., Compensation for Permanent Partial Disabilities, in Safety and the Work Force 18 (John D. Worrall ed., 1983).

On the attitude of industry toward workers’ compensation as protecting their interest, see the following quotation from the physician for a large chemical company: “Industry doesn't worry much about workers’ compensation because those awards are so pitifully small. The lawsuits that frighten them are those that don't have the protection of workers’ compensation.” Quoted in Elaine Draper, Risky Business 148 (1991).

290 See, e.g., Gorenberg, Hayley & White, Amanda, Off the Pedestal and Into the Arena: Toward Including Women in Experimental Protocols, 19 N.Y.U. Rev. L. & Soc. Change 205, 228-29 (1992)Google Scholar; Judith Areen et al., Clinical Research Involving Women as Subjects: Legal Considerations: A Monograph Commissioned by the Office for Protection from Research Risks of the National Institutes of Health 25-26 (1992) (unpublished monograph on file with the author). For years there has been debate about taking biomedical research out of the common law tort liability system. See, e.g., President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Compensating for Research Injuries: the Ethical and Legal Implications OF Programs to Redress Injured Subjects (1982); Adams, Bernard R. & Shea-Stonum, Marilyn, Toward a Theory of Control of Medical Experimentation with Human Subjects: The Role of Compensation, 25 Case W. Res. L. Rev. 604 (1975)Google Scholar. The idea has never become concrete, probably because there have been virtually no legal claims by subjects against researchers — reflecting either that participation in clinical research is extremely safe or that the waiver clauses in informed consent documents are artfully drawn.

291 See Keeton, et al., supra note 150, § 18, § 68. A release or waiver may be subject to attack if it is not “unambiguous and understandable,” or if it fails to make clear that it applies not only to the inherent dangers of the enterprise, but to those harms caused by negligence. See Gross v. Sweet, 400 N.E.2d 306, 309 (N.Y. App. Div. 1979)(waivers of liability strictly scrutinized; “should not compel resort to a magnifying glass and a lexicon“); Boll v. Sharp & Dohme, 120 N.E.2d 836 (N.Y. App. Div. 1954) (blood donor's covenant not to sue construed to permit lawsuit for negligence because it included commitment to use “customary procedures” and did not exonerate defendants from liability for departure from those procedures).

Express waivers, such as those executed at amusement parks and stables, are quite often deemed “contrary to public policy” and not enforceable under certain circumstances, usually when the signer is considered to be in an unequal bargaining position. See, e.g., N.Y. Gen. Oblig. Law §§ 5-321 to 5-326 (McKinney 1989 & Supp. 1993) (liability waivers obtained by landlords, garage-owners, caterers, etc. void). Although the researcher-subject relationship might seem to lend itself to that kind of analysis, to my knowledge express assumption of risk in the medical context has never been voided as a matter of public policy. However, see 21 C.F.R. § 50.20 (1993): “No informed consent, whether oral or written, may include any exculpatory language through which the subject… is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability for negligence.” Waiver and release, of course, are not quite the same as assumption of risk through operation of law. Also, it is not the subject's legal rights that concern researchers.

292 See supra notes 83-85 and accompanying text.

293 For an argument that in the analogous case of work-related harm to offspring, waiver would be unenforceable, see Ashford, Nicholas A. & Caldart, Charles C., The Control of Reproductive Hazards in the Workplace: A Prescription for Prevention, 5 Indus. Rel. L.J. 523, 556 (1983)Google Scholar. Ashford and Caldart believe that the public policy favoring a healthful workplace and the inequality of bargaining power between employer and employee would combine to void a waiver of liability required as a condition of future employment, and argue that just as divorced parents cannot bind their children to a custody agreement or particular level of support without court approval, worker-parents should not be able to waive a future child's right to sue for fetal damage. Id. at n.158. But see, Swinton, Katherine, Regulating Reproductive Hazards in the Workplace: Balancing Equality and Health?, 33 U. Toronto L.J. 45, 67 (1983)Google Scholar (United Kingdom Law Commission recommends, and Parliament adopts, statute making binding mother's contractual waiver of liability and assumption of risk on future child's behalf).

294 See Angela Holder, Legal Issues in Pediatric and Adolescent Medicine 151 (2d ed. 1985). If the research presents only minor risk and does hold out promise of benefit, then one parent may consent. IRBs also may waive the requirement of parental permission. See generally, James M. Morrissey et al., Consent and Confidentiality in the Health Care of Children and Adolescents 22, 90-91 (1986). One sui generis situation that severely strains this precept is the case of a child who needs a bone marrow or kidney transplant that could best be supplied by a minor (or mentally impaired adult) sibling. May the parent consent to the healthy sibling's organ donation? Courts have permitted such procedures on theories of psychological benefit to the sibling or under the rubric of “substituted judgment” — the legal fiction that the child, if able to exercise judgment, would consent to the donation. See, e.g., Hart v. Brown, 289 A.2d 386, 388 (Conn. Super. Ct. 1972); Strunk v. Strunk, 445 S.W.2d 145, 149 (Ky. 1969). Other courts, however, have refused to honor the parents’ wishes. See, e.g.. In re Richardson, 284 So.2d 185, 187 (La. 1973).

295 However, the one attempt to obtain a judicial declaration that parents have no right either to permit or to compel their children's participation in nontherapeutic research did not succeed. Holder, supra note 294, at 153-54, n.16.

296 Holder, supra, note 294, at 170-71. In the second edition, Professor Holder revises this assessment somewhat: “There are numerous precedents for the conclusion that a parent cannot waive a child's rights under law… . If a parent gave permission for research on a child and real damage occurred, the child would not be bound by the waiver signed by the parent.” Id. at 160.

297 Additional Protections for Children Involved as Subjects in Research, 45 C.F.R. § 46.401 (1983).

298 Id. at § 46.406-07. Instead of the term “consent,” the regulations speak of parental permission and the child-subject's assent. IRBs may waive the requirement of parental permission and/or minor assent altogether.

299 It is possible to go overboard. I recall one protocol submitted to the IRB I chaired that contained language amounting to a release of the sponsor from responsibility for intentional physical assault by the investigator. The IRB, I hasten to add, did not approve the protocol.

300 For an intriguing argument that the effect of the federal regulatory scheme and IRB review is legally equivalent to judicial authorization of medical intervention for an incompetent, i.e. an unborn or unconceived child, and therefore would constitute a “consent” that would immunize a researcher, see Sandomire, Hazel, Women in Clinical Trials: Are Sponsors Liable for Fetal Injury?, 21 J. L., Med. & Ethics 217, 221-23 (1993)Google Scholar.

301 Compare 45 C.F.R. § 46.207 with § 46.208.

302 Aside from assumption of risk, another potential defense to researcher liability is contributory negligence: when an injured party “contributes” to his or her own harm through unreasonably risky conduct, the claim against a third person may be either precluded or proportionately reduced. See generally, Keeton et al., supra note 150, at 65. (I will dispense with the full complexity of the comparative negligence system, which in some jurisdictions permits recovery only if the injured party's “contribution” is assessed as less than 50% and in others will permit some recovery even if the contribution amounts to 90% it has no bearing on the present topic.) It would be unusual to find “negligence” on the part of a research subject — perhaps departure from the protocol in taking unauthorized concomitant medications might be an example — but one can imagine the allegation that it was negligent for a prospective parent to participate in a protocol with unknown risks to offspring.

This defense would be of little avail to the researcher, however, because in almost every state, contributory negligence on the part of a parent is not imputed to a child injured in part because of that negligence, and so the child's recovery is not barred or reduced. See Keeton et al., supra note 150, at § 74; Int'l Union, United Auto., Aerospace and Agric. Implement Workers of Am., Uwa, v. Johnson Controls, Inc., 499 U.S. 187, 199 n.3 (1991) and authorities cited therein. Recovery for mental or emotional distress of the parent occasioned by the harm to the child might well be abrogated, but that is not the major element of damages feared by researchers. See, e.g.. City of Louisville v. Stuckenborg, 438 S.W.2d 94 (Ky. Ct. App. 1968); Davila v. Bodelson, 704 P.2d 1119 (N.M. Ct. App. 1985). (In theory, a researcher held liable could also seek indemnification from the negligent subject-parent, but given the financial status of the typical research subject, this is an almost frivolous observation.)

As discussed previously, the real significance of being able to attribute negligence to the research subject-parent in this context is to sever the causal link between the researcher's conduct and the harm to the child by interposing the subject's contributory negligence as a superseding cause. See supra notes 149-89 and accompanying text. As may be evident from what I've said so far, the law of intervening or superseding causation is a true morass, and its application in this context would require another full-scale article, but Prosser provides a useful illustration of how it can work to relieve a putative wrong-doer from responsibility: if someone gives a child something dangerous, like dynamite caps, and the child's parent becomes aware of the danger, but allows the child to retain the dangerous item, “it is at least possible to conclude that from that point forward the responsibility is the parent's rather than the defendant's.” KEETON ET AL., supra note 150, § 44 at 318. Likewise, if the parent-to-be is fully apprised of potential risk, including unknown risk, to future offspring from participation in a research protocol, and enters the protocol anyway, arguably “the responsibility is the parent's” rather than the researcher's. See supra note 175.

303 Novick, Alvin, May a Human Subject Waive the Right to Be Treated as A Human Subject?, 5 AIDS & Pub. Pol'yj. 45, 48 (1990)Google Scholar.

304 Id.

305 In addition to the classic horror stories of Tuskegee, MER/29, DES, Dalkon Shield, and thalidomide, other examples, including the resistance of aspirin manufacturers to labels that would warn of the risk of Reyes’ Syndrome; the failure of Eli Lilly to reveal deaths associated with the arthritis drug Oraflex; the criminal charges against company officials for concealing the liver damage associated with Selacryn, are described in Schwartz, Teresa M., The Role of Federal Safety Regulations in Products Liability Actions, 12 J. Prod. Liab. 305 (1989)Google Scholar. See generally, JOHN Braithwaite, Corporate Crime in the Pharmaceutical Industry (1984).

306 Memorandum on FDA's Proposed Guideline, supra note 128, at 1-2.

307 An excellent summary of the variety of sources of influence within the research community can be found in Mark S. Frankel, Human Experimentation: Social and Professional Control, in Encyclopedia of Bioethics 702 (Warren T. Reich ed. 1982).

308 On the importance of transmission of norms and ideals in the process of professional education, see Katz, Jay, The Education of the Physician-Investigator, 98 Daedalus 480 (1969)Google Scholar; see also, the Student-Physician: Introductory Studies in the Sociology of Medical Education 76-77 (Robert K. Merton et al. eds., 1957).

309 See Governing Council of the Am. Pub. Health Ass'n, Interim Policy Statement LB1, Support for Women's Health Research, 81 Am. J. Pub. Health 260 (1991).

310 See supra note 8.

311 See discussion supra 259 and accompanying text.

312 Merton, Community Based, supra note 109, at 524.

313 A survey of all IRB chairpersons at institutions with NIH approval, conducted in the fall of 1991, found that 80-90% of the 329 responding IRBs had no policy in place with respect to equitable selection of subjects relative to gender; that fewer than half the IRBs routinely ask investigators to justify a proposed exclusion of female subjects; and that 73% routinely require women subjects to use contraception during a trial, while 93% did not have a parallel requirement for male subjects. Surprisingly, several of the IRB chairs indicated that equitable selection of subjects was not a legitimate concern for an IRB. Many more respondents volunteered categorical statements about the requirements of federal regulation, the likelihood of liability, and the supremacy of the value of fetal protection as a value above all others, that reflect the misinformation and inaccurate analysis of these issues criticized throughout this article. Ada Sue Selwitz & Daniel P. Wermeling, IRB Policies and Practices: Review of Subject Population, 20-33 (undated) (unpublished monograph prepared as NIH background paper, on file with author).

314 See discussion supra notes 255-65 and accompanying text.