6
Legal Considerations

Legal considerations governing research on human subjects issue both from federal and state laws and from the institutional framework of sponsor agencies and research organizations that interpret and implement these laws. At the federal level, Congress has passed statutes and various federal agencies have promulgated regulations and guidelines to govern research on human subjects, including policies directly pertinent to the participation of women in clinical studies. The extent to which the individuals and organizations involved in the conduct of research must adhere to these policies depends on the type of policy: statutes and regulations must be followed by public and private entities, while guidelines are recommendations. Guidelines lack the force of law, but nevertheless have been quite effective in eliciting the desired behavior. Guidelines are also highly influential in setting standards for appropriate conduct.

The U.S. Constitution, with its protections of individual rights and provisions for equal protection under the law, provides further constraints on the behavior of public organizations and the private individuals and entities who work for them. Those involved in the conduct of human research also are governed by state constitutions, statutes, regulations, and liability decisions. Developed primarily through state appellate court decisions, the record of liability decisions is known as the law of torts. State tort liability rules are relevant to both the inclusion of women in, and the exclusion of women from, clinical studies. The greatest fears about liability for inclusion stem



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--> 6 Legal Considerations Legal considerations governing research on human subjects issue both from federal and state laws and from the institutional framework of sponsor agencies and research organizations that interpret and implement these laws. At the federal level, Congress has passed statutes and various federal agencies have promulgated regulations and guidelines to govern research on human subjects, including policies directly pertinent to the participation of women in clinical studies. The extent to which the individuals and organizations involved in the conduct of research must adhere to these policies depends on the type of policy: statutes and regulations must be followed by public and private entities, while guidelines are recommendations. Guidelines lack the force of law, but nevertheless have been quite effective in eliciting the desired behavior. Guidelines are also highly influential in setting standards for appropriate conduct. The U.S. Constitution, with its protections of individual rights and provisions for equal protection under the law, provides further constraints on the behavior of public organizations and the private individuals and entities who work for them. Those involved in the conduct of human research also are governed by state constitutions, statutes, regulations, and liability decisions. Developed primarily through state appellate court decisions, the record of liability decisions is known as the law of torts. State tort liability rules are relevant to both the inclusion of women in, and the exclusion of women from, clinical studies. The greatest fears about liability for inclusion stem

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--> mainly from the possibility of injury to offspring resulting from women's participation in clinical drug trials. INSTITUTIONAL FRAMEWORK Health-related research and development in the United States is supported by the federal government (predominantly through the National Institutes of Health [NIH]), the pharmaceutical industry, and private foundations. This institutional structure can affect the conduct of research because it is the source not only of funding, but also of procedures for reviewing the ethics of scientific research-including whether a proposed plan for selecting research participants is just-and of the legal requirements applicable to research. NIH, located within the Public Health Service (PHS) of the Department of Health and Human Services (DHHS), is the single largest supporter of biomedical and behavioral research and development (health R&D) in the world. NIH underwrites approximately 73 percent of all health R&D supported by the U.S. federal government, and about 30 percent of all health R&D in the United States. In fiscal year 1992 the projected NIH health R&D budget was $8.4 billion (NIH, 1992). NIH is an extraordinarily complex organization. It includes a federation of 16 institutes, the National Library of Medicine, two divisions, and four centers. All of these components are coordinated by the Office of the Director. NIH policies have a profound effect on other organizations that have health-related missions, including other federal agencies, awardee institutions, and private foundations and corporations that support or conduct health R&D. Many institutions simply adopt NIH policies and procedures. Other organizations, both public and private, adapt NIH policies to suit their own structures and needs. Most NIH funding components have a twofold structure. Extramural programs support health R&D projects carried out by research institutions throughout the United States and in at least 80 nations worldwide. Intramural programs, operated by federal employees, conduct research on the NIH campus in Bethesda, Maryland, and at a number of other locations throughout the country (Maryland, North Carolina, Colorado, Florida, and other states). Approximately 88 percent of the NIH research budget is disbursed to nonfederal institutions through grants-in-aid, contracts, and cooperative agreements (NIH, 1992). Awards are made by NIH funding components operating with the advice of a large and carefully regulated peer review system. Grant applications submitted to NIH by extramural institutions are typically reviewed by initial review groups (IRGs), commonly called study sections, that conduct scientific merit review and assign a priority score to each application that it recommends for funding. Approximately 20 percent

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--> of applications recommended for funding are actually funded in any given fiscal year. In addition to their responsibilities for assessing scientific merit, IRGs also are asked to identify ethical concerns associated with proposed research in relation to the rights and welfare of human research subjects, care and use of laboratory animals, and scientific misconduct. If an IRG or an NIH staff person raises an ethics concern, a bar to funding is entered into the computerized grant-tracking system. No award can be made in support of a barred project until and unless the concern has been resolved. Most grant applications also are reviewed by a national advisory council or board that considers program relevance and the public importance of the application. Boards and councils also have authority to raise ethical concerns that place a bar to funding. Ethics concerns raised by IRGs are reviewed and resolved by national advisory boards or councils. Contract proposals and cooperative agreements for biomedical and behavioral research are reviewed in a manner similar to that utilized to review grant applications. Technical Evaluation Groups (TEGs) carry out assessment of the proposal in a manner analogous to that of IRGs. As is the case for IRGs, TEGs are expected to identify any ethics concerns associated with proposals for contracts or cooperative agreements. No contract or cooperative agreement can be finalized until and unless ethics concerns have been resolved. In making awards, NIH and other PHS agencies operate under the general authority of the Public Health Service Act, which requires the secretary of DHHS to operate a wide variety of health-related regulatory, research, demonstration, and service programs. Responsibility for these programs is delegated by the secretary, or in some cases directly by the Congress, to the agencies and program directors throughout PHS. Regulatory responsibility for protecting the rights and welfare of human research subjects has been delegated to the Office for Protection from Research Risks (OPRR). Although that office is located within NIH for organizational purposes, it acts on behalf of the secretary of DHHS. The primary instrument that OPRR uses in meeting its responsibility is the promulgation and implementation of regulations codified in the Code of Federal Regulations (C.F.R.) for the protection of human subjects. Those regulations require that, before awardee institutions are permitted to carry out research involving human subjects, they must provide adequate assurance to OPRR that they will comply with the regulations. The primary requirement of the regulations is that before work is begun and at intervals of no more than one year during the conduct of research involving human subjects, each research project shall be reviewed and approved by an institutional review board (IRB). The U.S. Food and Drug Administration (FDA) has also issued regulations at 21 C.F.R. 50 & 56 that include congruent require-

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--> ments for IRB review of studies involving experimental drugs, devices, and biologics (see below). IRBs are administrative bodies established to protect the rights and welfare of human research subjects recruited to participate in research activities conducted under the auspices of their affiliated institutions. Each IRB has authority to approve, require modifications in, or disapprove all research activities that fall within its jurisdiction. The FDA, another PHS agency, functions under the Food, Drug and Cosmetic Act (FDCA). The FDCA provides the commissioner of FDA with authority and responsibility to regulate (among other articles) the testing and marketing of drugs, biologics, and medical devices involved in interstate commerce. The commissioner also is subject to policies and regulations issued by or under the authority of the secretary of DHHS and by many of the provisions of the PHS Act. In those rare instances when the FDA conducts clinical research, that research is subject to DHHS regulations. When NIH conducts or supports clinical studies involving the testing of investigational drugs, biologics, or devices, NIH and NIH awardee institutions are subject to FDA regulations governing such items. Institutions that conduct clinical studies funded by NIH or another PHS agency involving drugs, biologics, or medical devices are subject to all applicable policies and regulations of both NIH and FDA. Institutions conducting research on drugs, biologics, and medical devices without any public funding, including research conducted by scientists in the employ of pharmaceutical companies and research conducted by academic scientists and others supported by the pharmaceutical industry or private foundations, are subject only to federal policies promulgated by FDA. According to the Pharmaceutical Manufacturers Association (PMA), the pharmaceutical industry contributes just over half of total health research dollars-$10.9 billion in 1992 (PMA, 1992). Industry research is carried out by pharmaceutical companies without federal funding either onsite or at universities. Privately funded pharmaceutical research carried out in a university setting, however, may be subject to DHHS regulations, because individual institutional policies frequently require investigators to conform to DHHS policy, independent of the funding source of a particular study. Private foundations (such as the Pew Foundation) and professional organizations (e.g., the American Lung Association) underwrite a much smaller, but not insignificant, percentage of health research. Such privately funded, nonpharmaceutical research would technically not be subject to any federal policies, but again, if conducted at an institution that receives federal funds, it would likely be subject to DHHS policy.

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--> CURRENT FEDERAL POLICIES Current federal policies that affect equity in clinical studies take the form of statutes, regulations, and agency guidelines and memoranda. These policies govern research funded, conducted, or otherwise regulated by the federal government, its agencies, and departments. The policies vary: some appear to promote inclusion of both genders, others refer to inclusion of women and minorities, and still others specify conditions applicable to women of childbearing potential and pregnant women. Application of a particular policy may depend on funding origin (e.g., NIH, Department of Veterans Affairs, Department of the Army, private funding, and the like), type of research (e.g., drug development or observational study), nature of condition studied (e.g., life-threatening), or fertility status of the proposed study participant (e.g., postmenopausal women, pregnant women, women of childbearing potential, men). Particularly in the area of drug development, clinical studies that receive federal funding or are performed at institutions supported by federal funding may be subject to a number of policies prior to a drug's entrance into the market. Recently such policies have become more consistent. These sometimes overlapping policies are perhaps best understood through evaluation on an agency-by-agency basis. We will begin with a discussion of the policies of or affecting DHHS-funded research, focusing particularly on NIH and FDA policies. This will be followed by a discussion of relevant policies of other federal agencies and departments. Because many policies have been revised since 1990, the rationale for revising the earlier policy will be noted where relevant and available. In addition, the type of study, the condition studied, and any provisions to encourage the performance of scientific analyses to identify gender differences will be highlighted. Finally, where relevant, provisions applicable to fertile women will be contrasted with policies applicable to fertile men. National Institutes of Health As of this writing, NIH policy on study population composition of intramural and extramural research is in transition. The future policy is reflected in Section 131 of the recent NIH reauthorization legislation, the National Institutes of Health Revitalization Act of 1993 (P.L. 103-43, 107 Stat. 133 to be codified at 42 U.S.C. 289a-2). This provision of the law mandates the inclusion of women and racial and ethnic groups in NIH intramural and extramural research. It is to be implemented in fiscal year 1995 through NIH guidelines scheduled to be published in December 1993; draft versions of these guidelines were not available to the committee. The NIH policy on study population composition currently in effect is

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--> expected to be revised for implementation during the transition to the legislatively mandated policy (J. LaRosa, deputy director of the NIH Office of Research on Women's Health, personal communication, October 1993). The policy in effect as of this writing was introduced in 1990 and consists of five components: the August 1, 1990, NIH policy memorandum on inclusion of women and minorities applicable to intramural research; the August 1990 policy notice entitled "NIH/ADAMHA Policy Concerning Inclusion of Women in Study Populations," applicable to extramural research;   the September 1990 policy notice entitled "NIH/ADAMHA Policy Concerning Inclusion of Minorities in Study Populations," applicable to extramural research; an explanatory memorandum entitled "NIH Instruction and Information Memorandum OER 90-5" describing the application of the two policy notices applicable to extramural research; the recently instituted requirements in PHS grant applications and continuation applications to identify proposed and recruited study populations by gender and minority composition. The legislative mandate and its implementing guidelines will likely supersede at least the first four components of the current policy. It is possible that the PHS grant application will be modified as well, to accommodate the policy changes. The current NIH policy, which became effective in February 1991 (referred to collectively here as the "1991 NIH Policy") will only be briefly described, while the new legislative mandate (referred to here as the "Act") will be discussed in detail below, highlighting areas of known controversy. The 1991 NIH Policy Following the issuance of the 1990 GAO report, NIH promulgated a strengthened policy to govern the awarding of federal research grants. The new policy applies to a wide variety of extramural clinical research projects, including: Human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. Standard language articulating the extramural policy now appears in all requests for proposals (RFPs) announced in the NIH Guide for Grants and Contracts:

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--> Applications for grants and cooperative agreements that involve human subjects are required to include minorities and both genders in study populations so that the research findings can be of benefit to all persons at risk of the disease, disorder, or condition under study. The applicant must describe the proposed study population composition and provide a "compelling" justification for gender or racial and ethnic group exclusion. The investigator must also address gender and racial and ethnic issues "in developing a research design and sample size appropriate for scientific objectives of the study." The NIH Policy Notice further explains that the inclusion of women and racial and ethnic groups in study populations will be considered a matter of scientific and technical merit in peer review. What constitutes a "compelling" reason for exclusion has generated debate both within the scientific community and within Congress (Wittes and Wittes, 1993). The explanatory memorandum to NIH staff and peer advisory groups directs them to consider sufficient only "strong scientific or practical reasons" for the exclusion of women or racial and ethnic groups from clinical research. Some of the potentially "acceptable" justifications listed include: research on a "predominantly or exclusively a male condition'' (e.g., prostate cancer); research that presents an "unacceptable risk for women of childbearing age"; certain pilot and feasibility studies in which "gender differences may not be germane"; research in an area that "has already been extensively studied in women"; and in certain instances, studies that would be "prohibitively expensive" (NIH, 1990). Monitoring of study populations is accomplished through reporting requirements specified in PHS grant and continuation applications. These applications require awardees to identify annually proposed and actually enrolled study populations according to gender and the five designated racial and ethnic categories (American Indian/Alaskan Native, Asian/Pacific Islander, Black [not of Hispanic origin], Hispanic, and White [not of Hispanic origin]). A summary of study population composition during the first full year of the policy's implementation is expected to be issued by NIH soon. Most of the NIH intramural research program is subject to a different, less restrictive policy that requires only that gender-based exclusions be indicated and a "clear rationale" be provided. It currently reads, in its entirety: The inclusion of women must be considered in the study populations for all clinical research efforts. Exceptions would be studies of diseases which exclusively affect men or where involvement of pregnant women may expose the fetus to undue risks. Gender differences should be noted and evaluated. If women are not to be included, a clear rationale should be provided for their exclusion.

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--> In order to provide more precise information to the medical community, it is recommended that publications resulting from NIH- or ADAMHA-conducted research specify, in the abstract or summary, the gender(s) of the research subjects or patients [Rall, 1990]. Large-scale intramural projects that are implemented through contracts are not subject to the foregoing policy, but rather are considered part of the extramural program for policy purposes. The Act The NIH Revitalization Act of 1993 became law on June 10, 1993. The Act requires that women and ethnic and racial groups be included as subjects in each intramural and extramural clinical research project supported by NIH. It further requires that a clinical trial that includes women and racial and ethnic minorities as participants be designed and carried out to provide for valid analysis of whether the variables being studied affect these subpopulations differently than other participants. Furthermore, NIH is instructed to conduct or support outreach programs for recruitment and retention of women and racial and ethnic group participants in clinical research projects. The law allows for exemptions in cases of research that are inappropriate with respect to the health of the subjects, the purpose of the research, or other circumstances determined by NIH. NIH is required to promulgate implementing guidelines by December 7, 1993. These guidelines are to specify when the inclusion of women and members of racial and ethnic groups as subjects in clinical research is inappropriate; how clinical trials must be designed to have adequate representation of subpopulations to distinguish whether a treatment affects a subpopulation differently than the other members of a research project; and the operation of outreach programs. The Act includes express instructions for the NIH guidelines. For example, it specifically prohibits cost considerations as a reason for determining that the inclusion of women and racial and ethnic groups is inappropriate for a clinical trial. In other clinical research projects, however, an exception from the prohibition on cost considerations is allowed when the data that would be obtained by the research project is or will be obtained through other means that provide data of comparable quality. An example of where NIH may allow the exclusion of certain subpopulations on cost grounds is where a body of research on those groups exists and will be analyzed for differential response through other means, such as meta-analysis. Another exception from the prohibition of cost considerations involves cases where there is already a substantial body of scientific data demonstrating that there is no significant difference between subpopulations in the effects of the variable being studied. This prohibition on the consideration of cost differs from the 1991 NIH Policy, which allows cost to be an acceptable rationale for women's exclusion from certain clinical trials.

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--> NIH has been provided with some degree of latitude in the development of their guidelines. For example, the act requires that clinical trials be designed and performed to enable a valid analysis of whether women or racial and ethnic groups respond differently than other subjects in the research. Concern has been expressed about the interpretation and implications of this clause. (IOM, 1993; Wittes and Wittes, 1993). The language of the report suggests the intent of Congress: Although the Committee has given the Director of NIH the general authority to define [valid analysis]. . . the Committee intends for that definition to include an analysis of not only whether differences among study populations exist statistically, but an analysis of what those differences are as well as their relative importance for various population subgroups in the study. This would indicate that women and racial and ethnic groups are to be enrolled in clinical research projects in numbers large enough to provide statistical significance, and that the analysis of such research is to include distinctions among and between the various population groups, including women. These concerns have already been discussed in Chapter 4. The NIH policy does not automatically require that study designs provide statistical power to perform gender analysis except "whenever there are scientific reasons to anticipate differences between men and women." Those who favor the language in the Act over that in the NIH policy contend that the scientific literature on gender-mediated effects is sufficiently sparse that one will not always be able to "anticipate" such differences (S. Wood, scientific director of the Congressional Caucus for Women's Issues, personal communication, May 1993). Other provisions of the Act require NIH to establish internal and external committees to advise it on issues in women's health research, including gender differences in clinical drug trials and disease etiology, course, and treatment. The Act also requires NIH to determine the extent of women's representation as senior physicians and scientists in the institutes and to carry out activities to increase the extent of such representation. Finally, the Act mandates the creation of a national data system and clearinghouse on research for women's health (see Chapter 2). The NIH Revitalization Act directs NIH to define the terms "minority group" and "subpopulations." The Act does not clarify the extent of required inclusion of racial and ethnic groups in clinical research projects. The reasons for the unequal legislative specificity between women and minority groups is discussed in the House Committee on Energy and Commerce report accompanying the bill: the committee explained that representative inclusion of minority groups poses a complex problem because not only are there variations between Caucasians and people of color, but there

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--> are also variations among variations (or subpopulations) of the same racial or ethnic group. The report emphasized the importance of identifying such variations in clinical studies, but explains that this statutory language was chosen to prevent quotas or numerical goals for participation in clinical research projects (U.S. Congress, 1993). Food and Drug Administration Policies FDA policies concerning the inclusion of women in clinical studies are reflected in guidelines. It is important to note that guidelines do not have the force of law or regulation, and they do not have to go through the same public comment procedures as regulations. Guidelines are not binding on the agency, nor do they create or confer any rights, privileges, or benefits for or on any person. They are provided as an aid to organizations involved in the evaluation of new drugs for FDA approval who wish to market such drugs. FDA guidelines are used to specify the information that data reviewers of such applications will expect in the research that supports the safety and efficacy of a drug. There are three FDA guidelines that are particularly relevant to inclusion of women in clinical trials. Two of these are discussed in detail; discussion of a 1988 guideline is incorporated into the discussion of the 1993 guideline, where its content has been reiterated. 1977 Guidelines In 1977 the FDA issued guidelines for drug development: "General Considerations for the Clinical Evaluation of Drugs." The 1977 guidelines specifically stated that pregnant women and "women who are at risk of becoming pregnant" should be excluded from Phase I studies. They further recommended that a "woman of childbearing potential" be excluded from "large-scale clinical trials" (i.e., Phase III studies) until all three segments of the FDA Animal Reproduction Guidelines have been completed. The guidelines further provided that ''if adequate information on efficacy and relative safety has been amassed during Phase II, women of childbearing potential may be included in further studies provided Segment II and the female part of Segment I of the animal reproductive studies have been completed" (FDA, 1977:10). Segment I animal testing covers fertility and reproductive performance; Segment II covers teratogenesis; and Segment III covers perinatal and postnatal effects. Women of childbearing potential, however, could receive investigational drugs in the absence of adequate animal reproduction studies when: (1) the drug was considered to be a life-saving or life-prolonging measure (e.g., cancer therapy), (2) the drug belonged to a class of compounds for

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--> which teratogenic potential had already been established in animals, or (3) the woman had been "institutionalized" for a period of time adequate to verify that she was not pregnant. When, under this exception, an investigational drug is used to treat a serious disease, the guidelines recommend that the investigator point out the lack of reproduction studies during the informed consent process, test the woman for pregnancy, and advise her of contraceptive measures. As Merton (1994) notes, the guidelines do not mandate the performance of reproduction studies at any time, and, further, do not mention how the results of such studies should affect the inclusion of women. Lactating women are specifically mentioned in the guidelines, with the recommendation that excretion of the drug or its metabolites should be determined when feasible prior to their usage of the drug. If a woman becomes pregnant during the trial, the guidelines recommend fetal follow-up. The guidelines broadly defined a woman of childbearing potential as a "premenopausal female capable of becoming pregnant" (FDA, 1977). Included in the definition were women on oral, injectable, or mechanical contraception; women who were "single"; and women whose partners had been vasectomized or were using mechanical contraception. This exclusion was based on a concern that women might become pregnant during the course of a clinical trial and a judgment that the potential risks of exposing a fetus to an experimental drug of unknown fetal toxicity were greater than the potential benefits of the information that would be gathered by including women of childbearing potential in these early trials. Critics of the 1977 FDA guidelines had questioned for years whether the guidelines reflected gender stereotyping (e.g., female susceptibility and male invulnerability) more than concerns about good science (see Kinney et al., 1981). At a recent conference evaluating the issues concerning the inclusion of women in clinical trials, cosponsored by FDA and the Food and Drug Law Institute, critics claimed that an asymmetry existed in the risk-benefit analyses for research on men of reproductive potential and women of reproductive potential.  They noted that according to the guidelines, research involving agents thought to cause reproductive harm in male animals could be conducted in men depending on "the nature of the abnormalities, the dosage at which they occurred, the disease being treated, the importance of the drug, and the duration of drug administration" (FDA, 1977). In practice this meant that even a drug known to have teratogenic effects in animals could be tested in men if they were simply informed of the risks and advised not to conceive while participating in the trial. The 1977 guidelines would have excluded women of reproductive potential from such trials based on the fact that potential offspring might be harmed. The background paper accompanying recently issued FDA guidelines explains that the 1977 guidelines may have discouraged participation of

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--> particular research protocol outweigh the risks for any class of potential participants, the IRB could be liable for approving a protocol that permits participation of pregnant women where there is no benefit to the woman and some risk to the fetus. At least one commentator has noted that there may be settings where third parties are not entitled to rely on even fully informed consent of the woman to guard against liability, particularly if the protocol poses serious risks to the fetus while offering little benefit to the woman (Clayton, 1994). Yet another commentator noted that there is no precedent for imposing liability on a researcher who has properly obtained informed consent for harm to a participant's offspring. Because the harm is done by the woman's choice to participate in a research protocol, with full knowledge that it might have damaging consequences, the woman's negligent choice is an intervening cause in the injury (Merton, 1992). There is considerable disagreement over whether a court would find a mother legally liable for injury to offspring resulting from her participation in a clinical trial, but some agreement about the remote likelihood of successful legal action by an injured offspring against a pharmaceutical manufacturer who has obtained valid informed consent from the mother (Reisman, 1992; R. Blumberg, FDA Office of the General Counsel, personal communication, August 1993; Flannery and Greenberg, 1994). Consent of the father9 As mentioned above, there may also be risks to offspring when fertile men participate in trials of drugs that may cause damage to germ cells. The issue here, however, is whether the father's consent is necessary to avoid liability for injury to the offspring when the mother participates in a clinical trial of little or no benefit to her and with risk of harm to the fetus. There is no explicit policy or case law, but analogies from related areas may apply. For medical treatment of minors, one parent's informed consent is sufficient (Holder, 1985); DHHS regulations for research on children also require the consent of only one parent. Because the concern is with harm to a fetus rather than a child, federal regulations with respect to fetal tissue research may also be relevant; where such research is permitted, it requires informed consent of both father and mother, unless the father's identity and location cannot reasonably be ascertained, the father is not reasonably available, or the pregnancy resulted from rape (45 C.F.R. § 46.209-210). This committee is concerned with the participation of women in clinical research, however, and thus the case law on abortion, where a woman chooses for her own benefit to undergo a medical procedure, may be more applicable. An earlier section of this chapter discusses how the Supreme Court has invalidated state laws requiring a woman to obtain spousal consent or give spousal notification before obtaining an abortion. Based on these examples, it is unlikely the father's consent could

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--> be required in order for a pregnant woman to participate in a clinical trial, or that the addition of the father's consent would shield a manufacturer from liability. Is Johnson Controls Relevant? Some commentators have suggested that the language of the recent decision by the Supreme Court in Johnson Controls, discussed in the foregoing section on constitutional issues, might be influential in future case decisions in other contexts. While certainly not decisive, it may be pertinent in decisions relating to liability for injuries to offspring from clinical research. The company argued that fear of tort liability justified its policy of excluding women from jobs with potentially high lead exposure. The Court rejected this argument noting that "if, under general tort principles, Title VII bans sex-specific fetal protection policies, the employer fully informs the woman of the risk, and the employer has not acted negligently, the basis for holding an employer liable seems remote at best." Since Johnson Controls was a case of employment discrimination, this comment on the unlikelihood of liability is not to be interpreted as definitive, but it may provide support for persons who assert that adequate informed consent from the woman would be sufficient protection against liability. Liability for Exclusion Liability for excluding women from clinical trials may be a serious risk, particularly for pharmaceutical manufacturers and, indirectly, for physicians. Manufacturers' liability results when, after a drug is on the market, evidence emerges that the drug is more dangerous or less effective in women (Flannery and Greenberg, 1994). For example, a woman may have an adverse reaction from one of her prescriptions and discover that the drug was never tested in women. Her injury is not a research injury as this term has been used thus far. In this example it is the woman's exclusion from clinical research, not her inclusion, that caused the injury. Increased awareness on the part of women that they are not always represented in the populations tested may contribute to an increasing number of legal actions for exclusion. Under strict liability principles, manufacturers may be held liable for the defective design of a product, and a drug that has not been adequately tested may be found to be defectively designed (Flannery and Greenberg, 1994). In addition, manufacturers must warn about not only the known risks, but also foreseeable risks that should have been known if "reasonable, developed human skill and foresight" had been applied (Flannery and Greenberg, 1994, quoting ALI, 1977).

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--> The duty to warn about foreseeable risks requires that pharmaceutical manufacturers apply state-of-the-art testing methods to their products. With all of the recent publicity about physiological differences between men and women with regard to drug efficacy, dosing, and adverse reactions, it would be difficult to argue that all-male studies of drugs that may be used by women represent state-of-the-art testing methods (Flannery and Greenberg, 1994). In states with a case-by-case determination of the application of comment k (which protects pharmaceutical manufacturers against strict liability-see above), manufacturers will have a difficult time arguing that a drug is "unavoidably" unsafe if they fail to test the drug in a population that might foreseeably use it (Bowles, 1992). Also, if the courts find that the manufacturer deliberately avoided learning about whether a risk was associated with its drug, the manufacturer could be liable for punitive damages as well (Flannery and Greenberg, 1994). In contrast to the lack of reported legal cases of injury from inclusion in research, there are a number of cases in which damages were awarded to plaintiffs, in part because of inadequate testing of the drug before it was released into the market. Courts have no qualms about scrutinizing the research design of a clinical trial and criticizing research sponsors, not only for unreliable technique and sloppy data handling but also for a lack of response to actual market conditions (Merton, 1992, citing Tinnerholm v. Parke, Davis & Co). In one such case, West v. Johnson & Johnson Products, Inc., a woman who claimed that she had suffered from toxic shock syndrome resulting from use of a tampon marketed by Johnson & Johnson Products was awarded damages. The court found that the company had failed to study the basic microbiology of the human vagina, to test for vaginal infections, and to include women with a history of vaginitis in their human studies (Merton, 1992). In Taylor v. Wyeth Laboratories, the court found that a prudent manufacturer, once aware that women with type A blood experience a disproportionate number of pulmonary embolisms, would have looked at the relationship between blood type and blood-clotting risk in women taking oral contraceptives (Merton, 1992). Courts have also awarded damages to injured plaintiffs on the grounds of inadequate testing for adverse effects, even in cases where the FDA did not require further testing (Merton, 1992, citing Barson v. E.R. Squibb & Sons, Inc.). In legal actions where the plaintiff claims inadequacy of premarket testing, however, plaintiffs may face some difficulty in proving that their injuries were caused by a failure to test for foreseeable risks. In Jones v. Ortho Pharmaceutical Corp., the plaintiff sought to hold Ortho liable for her carcinoma in situ, claiming that they failed to conduct clinical trials that would have established whether the oral contraceptive she took caused cancer. Because a tort action must prove that the defendant's behavior caused the injury, the plaintiff attempted to persuade the court that because Ortho

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--> did not conduct the proper clinical trials, which would have enabled her to show the causal link between the contraceptive and her cancer, the company was presumptively liable. The California intermediate appellate court would not allow the plaintiff to presume causation from a lack of premarket testing (Merton, 1992). Thus, although there is a general lack of case law on liability for injuries to research participants, there is some precedent for liability for exclusion from research. The case law suggests that if a drug was found to cause injuries to women, and yet women had been excluded from clinical trials of the drug, the pharmaceutical manufacturer might be held liable for failing to test the drug in women. For some drugs, however, the potential for teratogenic or mutagenic effects is low or the negative effects are manifested after a long latent period. For these drugs, even adequate testing in all relevant populations may not reveal their potential to cause harm. At least one commentator has noted that establishing surveillance systems, or requiring companies to keep track of and report adverse drug reactions, may provide plaintiffs with a source of evidence that a company knew or should have known that a particular drug or dose level was potentially dangerous and required further testing or a more adequate warning label (Gibbs and Mackler, 1987). For physicians, liability resulting from exclusion of women from drug trials arises in the form of negligent drug prescription. For example, the physician could be liable for prescribing a drug to a woman: (1) for a different purpose than that for which it was initially designed and tested or (2) in disregard of the drug's label that it has not been tested in women. With regard to liability for offspring injury resulting from exclusion of women (or men) from drug trials, information about testing for reproductive and developmental effects is often not available for all drugs for which such testing would be appropriate. CONCLUSIONS AND RECOMMENDATIONS The many federal regulations governing research on human subjects do not provide investigators and IRBs with clear answers on issues concerning the inclusion of women and racial and ethnic groups in clinical studies. Recent changes in policies, however, have made them more consistent. All of the recent changes have been implemented to promote the inclusion rather than exclusion of women. Consistency and, where possible, congruence among these policies is important to promote compliance and prevent confusion. Policies and regulations issued by the FDA or other PHS agencies must be harmonized with those of NIH. At the very least, policies and regulations issued by NIH and those issued by FDA must not be contradictory. The

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--> closer the congruence between FDA and NIH regulations and policies, the more likely that a regulated institution will understand precisely what is required and be motivated to comply. When NIH updated its policy concerning inclusion of women in 1991, and added the sanction of possible reduction in the project's priority score for noncompliance, many in the research community came to believe that FDA and NIH policies were contradictory. Now that the FDA has updated its 1977 policy, and NIH is in the process of updating its 1991 policy, there is an opportunity to achieve congruence between the positions of the two agencies. The committee recommends that NIH work closely with the FDA and with other PHS agencies to make regulations and policies on inclusion of women and racial and ethnic groups consistent with one another and, wherever possible, to make them congruent. If the policies of the two agencies are harmonized, there will still remain the task of educating the research community concerning what is required, and motivating that community to comply. Enunciation of sound and congruent policies, in conjunction with a comprehensive educational program, will ensure that policies and the rationales for the policies are properly understood by the research community. The committee recommends that NIH, in cooperation with FDA, should institute a comprehensive education program directed at investigators, institutions and IRBs on policies concerning the inclusion of women and racial and ethnic groups in clinical studies. It is impossible to quantify the risk of tort liability from the inclusion of women in clinical studies at this time, because: (1) there is no complete compendium of unreported cases involving settlements and (2) women have not been included in some major studies in the past. Difficulties of prediction are compounded because tort law is governed by the individual states, with many variations on issues such as whether a woman's informed consent will serve to bar an independent action by a child injured as a fetus during such research. Analysis of existing legal rules and principles seems to indicate that the likelihood of successful damage actions is limited. Nevertheless, broadening the research population to include those groups previously excluded may also generate additional legal actions that will test existing legal doctrine. A special set of concerns in the research area stems from the differing bases for liability according to which party is a defendant. A pharmaceutical company, for example, might be sued on the basis of strict liability, while a researcher ordinarily would be sued only on the basis of negligence.

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--> With regard to the latter, the new federal policies calling for inclusion of women in clinical studies will help establish new standards that will be relevant to legal actions. Many of the concerns voiced about liability in the context of research including women are the same as those with regard to the tort system in general. For example, expert scientific testimony is necessary to establish that a particular drug caused an injury. There are inherent difficulties in assuring the unbiased nature of such testimony in what are often highly technical cases. The committee recommends that current and future initiatives toward general tort reform include attention to issues of research-related injury, including issues of proof of causation. The question of whether there should be a special compensation scheme for injuries sustained by children as a result of a parent's participation in a clinical study is similar to that raised in the context of research subjects in general. The committee does not recommend adoption-at this time-of a special compensation scheme limited to coverage of children injured prenatally or preconceptually. Any new compensation scheme focusing only on such injuries poses especially difficult problems with regard to establishing causation and averting large numbers of questionable recoveries. Appendix D discusses several existing compensation schemes dealing with children and illustrates these and other difficulties. The committee recommends that NIH thoroughly review the area of compensation for research injury in general and that consideration of implementation of any compensation scheme include attention to prenatal and preconceptual injuries to children resulting from a parent's participation in a clinical study. Our current health care reimbursement system does not include coverage for medical care resulting from injuries sustained during research. This could be accomplished through a system of universal access with adequate coverage. The committee recommends that health care reform efforts include considerations of medical care for research-related injury. The committee recognizes that, regardless of their basis or justification, fears about liability are real. On balance, however, the committee concludes that liability concerns should not represent an impediment to implementation of public policies that favor the broader inclusion of women in clinical studies.

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--> NOTES 1.   Department of Agriculture, Department of Energy, National Aeronautics and Space Administration, Department of Commerce, Consumer Product Safety Commission, International Development Cooperating Agency, Agency for International Development, Department of Housing and Urban Development, Department of Justice, Department of Defense, Department of Education, Department of Veterans Affairs, Environmental Protection Agency, Department of Health and Human Services, National Science Foundation, Department of Transportation. 2.   Previously, in Planned Parenthood of Central Missouri v. Danforth, the Supreme Court invalidated a state law requiring a woman to obtain consent of her spouse before obtaining an abortion. The Court stated that ''Inasmuch as it is the woman who physically bears the child and who is the more directly and immediately affected by the pregnancy, as between the two, the balance weighs in her favor." 3.   One notable exception is In re A.C., where the appellate court overturned the decision of the trial court to force a woman to undergo a caesarean in order to save her baby. The court held that "in virtually all cases the question of what is to be done is to be decided by the patient—the pregnant woman-on behalf of herself and the fetus" (In re A.C.). 4.   See the paper by Professor Debra DeBruin in Volume 2 of this report for further analysis of whether women are owed affirmative action measures as a result of past discrimination in research. 5.   In the one case in which NIH was the defendant, which the general counsel's office believes was dismissed, a prisoner claimed he was due credit for good behavior for participating in a study. In the other two, an NIH grantee institution was the defendant. In one, a prisoner claimed participation an NIH-funded study as defense to murder (he received a defective batch of experimental human growth hormone as a child); in the second, the plaintiff, who had a suicidal history, sued for improper care and monitoring after he jumped out of the window while on an experimental epilepsy drug (personal communication, S. Sherman, Associate General Counsel, NIH, June 1993). 6.   At least one attorney for a pharmaceutical company has commented that it may not be the reality of the liability but the perception of legal risk that causes many drug companies to take defensive action to avoid possible involvement in a legal proceeding (IOM, 1991b). 7.   The Supreme Court recently rejected the long-standing Frye rule, which set the standard for the acceptability of scientific evidence in legal proceedings. The Frye rule required that any proposed scientific testimony must have received general acceptance of its reliability by the relevant scientific community before the court would admit it into evidence. In Daubert

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-->     v. Merrell Dow Pharmaceuticals, the Court explained that Frye's general acceptance standard was superseded by the adoption of the Federal Rules of Evidence. Under the Federal Rules, the trial judge makes a flexible determination of whether the evidence rests on a reliable foundation and is relevant to the task at hand. The effect this change in evidentiary rules will have on the liability climate for research injuries is unknown. 8.   See Bergstrasser v. Mitchell (court allowed a child to recover for damages caused by his premature birth, which allegedly resulted  from a previous negligently performed C-section); Renslow v. Mennonite Hospital (court allowed infant to recover for injury caused by a negligent blood transfusion of the mother before conception); Monusko v. Postle; Albala v. City of New York. 9.   "Father" is the term chosen here to include the biological father of the baby, the child's legal guardian, or anyone the law would recognize as having legal responsibility for the welfare of a child. REFERENCES ALI (American Law Institute). 1977. Restatement (Second) of Torts Section 402A. Bordas, L.M. 1984. Note: Tort liability of institutional review boards. West Virginia Law Review 87:137-164. Bowles, L.E. 1992. The disenfranchisement of fertile women in clinical trials: The legal ramifications of and solutions for rectifying the knowledge gap. Vanderbilt Law Review 45(4):877920. Bush, J.K. 1993. Women's participation in clinical research: The industry perspective. Presented at Conference on the Inclusion of Women and Minorities in Clinical Research, Bethesda, Md., June 28, 1993. Caban, C. 1993. Personal communication with T. Johnson. May 7. (Dr. Carlos Caban advises the NIH Office of Research on Women's Health with respect to its policy on the inclusion of women in clinical research.) Campbell, J.E. 1969. Civil Liability for Investigational Drugs: Part II. Temple Law Quarterly 42(4):289-354. Cardon, P.V., Dommel, F.W., Jr., and Trumble, R.R. 1976. Injuries to research subjects: A survey of investigators. New England Journal of Medicine 295:650-654. Charo, R.A. 1994. Constitutional issues raised by the exclusion of women from research trials. In: Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume 2, A. Mastroianni, R. Faden, and D. Federman, eds. Washington, D.C.: National Academy Press. Clayton, E.W. 1994. Liability exposure when offspring are injured because of their parents' participation in clinical trials. In: Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume 2, A. Mastroianni, R. Faden, and D. Federman, eds. Washington, D.C.: National Academy Press. Department of the Army. 1992. Memorandum from Gregory P. Berezuk, Chief, Human Use Review and Regulatory Affairs Office, Office of the Surgeon General, re: Human subjects research review board policy regarding pregnancy testing of research subjects (January 21). Department of Energy. 1992. Protecting Human Research Subjects at the Department of

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--> Energy: Human Subjects Handbook. Washington, D.C.: Office of Health and Environmental Research, Office of Energy Research, Department of Energy. Department of Veterans Affairs. 1992. Inclusion of women and minorities in clinical research. Veterans Health Administration Manual M-3, Part 1, Chapter 14 (July 24). Flannery, E., and Greenberg, S.N. 1994. Liability exposure for exclusion and inclusion of women as subjects in clinical studies. In: Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume 2, A. Mastroianni, R. Faden, and D. Federman, eds. Washington, D.C.: National Academy Press. FDA (Food and Drug Administration). 1993. Guideline for the study and evaluation of gender differences in the clinical evaluation of drugs. Notice. Federal Register 58(139):3940639416. FDA. 1977. General Consideration for the Clinical Evaluation of Drugs. Rockville, Md.: FDA. Gibbs, J.N., and Mackler, B.F. 1987. Food and Drug Administration regulation and products liability: Strong sword, weak shield. Tort and Insurance Law Journal 22(Winter):194243. Green, V. 1993. Doped Up, Knocked Up, and Locked Up?: The Criminal Prosecution of Women Who Use Drugs During Pregnancy. New York: Garland. Harvard Medical Practice Study. 1990. Patients, doctors, and lawyers: Studies of medical injury, malpractice litigation, and patient compensation in New York . Boston: Harvard Medical Practice Study. Holder, A.R. 1985. Legal Issues in Pediatrics and Adolescent Medicine. New Haven: Yale University Press. IOM (Institute of Medicine). 1989. Medical Professional Liability and the Delivery of Obstetrical Care. Washington, D.C.: National Academy Press. IOM. 1991a. Issues in the Inclusion of Women in Clinical Trials. Report of Planning Panel of the Institute of Medicine's Division of Health Sciences Policy. March 1-2. Washington, D.C.: Institute of Medicine. IOM. 1991b. Expanding Access to Investigational Therapies for HIV  Infection and AIDS. Summary of a Conference, March 12-13, 1990. Washington, D.C.: National Academy Press. IOM. 1993. Inclusion of Women in Clinical Trials: Policies for Population Subgroups. Washington, D.C.: National Academy Press. Keeton, W.P., Dobbs, D.B., Keeton, R.E., and Owen, D.G., eds. 1984. Prosser and Keeton on the Law of Torts. St. Paul, Minn.: West. Kinney, E.L., Trautmann, J., Gold, J., Vesell, E.S., and Zelis, R. 1981. Underrepresentation of women in new drug trials. Annals of Internal Medicine 95(4):495-499. Kobasic, D.M. 1988. Institutional review boards in the university setting: Review of pharmaceutical testing protocols, informed consent and ethical concerns. Journal of College and University Law 15(2):185-216. Mariner, W.K. 1994. Compensation for research injury. In: Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume 2, A. Mastroianni, R. Faden, and D. Federman, eds. Washington, D.C.: National Academy Press. Merton, V. 1992. The Exclusion of Pregnant, Pregnable, and Once-Pregnable People a.k.a. women) from Biomedical Research. Unpublished Paper (December 12). Merton, V. 1994. The impact of current relevant federal regulations on the inclusion of female subjects in clinical studies. In: Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume 2, A. Mastroianni, R. Faden, and D. Federman, eds. Washington, D.C.: National Academy Press. NIH (National Institutes of Health). 1990. NIH Instruction and Information Memorandum OER 90-5. December II. NIH, Office of Research on Women's Health. 1991. National Institutes of Health: Opportuni-

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--> ties for Research on Women's Health. Summary report of a conference held at Hunt Valley, Md., September 4-6. NIH. 1992. NIH Data Book 1992: Basic Data Relating to the National Institutes of Health. Bethesda, Md.: NIH. NIH and ADAMHA (Alcohol, Drug Abuse, and Mental Health Administration). 1990. NIH/ADAMHA Policy Concerning Inclusion of Women in Study Populations. NIH Guide 19(31):18-19. NOW Legal Defense and Education Fund. 1992. Citizens' Petition to the FDA, signed by AIDS Service Center HIV Law Project, NOW Legal Defense and Education Fund, and American Civil Liberties Union, AIDS Project. December 15. NRC (National Research Council). 1989. Biologic Markers in Reproductive Toxicology. Washington, D.C.: National Academy Press. NRC (National Research Council)/IOM. 1990. Developing New Contraceptives: Obstacles and Opportunities. L. Mastroianni, Jr., P.J. Donaldson, and T.P. Kane, eds. Washington, D.C.: National Academy Press. PMA (Pharmaceutical Manufacturers Association). 1992. 1992 survey report: 91 medicines in testing; 3 approved this past year. P. 8 in Development: AIDS Medicines, Drugs and Vaccines. Washington, D.C.: PMA. Rall, J.E. 1990. Memorandum to scientific directors, clinical directors, chiefs, and ICD clinical branches/laboratories from NIH deputy director for intramural research. Policy on the Inclusion of Women in Study Populations: Intramural and Epidemiological (August 1). Bethesda, Md.: National Institutes of Health. Reisman, E.K. 1992. Products liability: What is the current situation and will it change (and how) when more women are included in studies? Presented at the Women in Clinical Trials of FDA-Regulated Products Workshop, Food and Drug Law Institute, Washington, D.C., October 5. Robertson, J.A. 1982. The law of institutional review boards. UCLA Law Review 25:484-549. Robertson, J. 1994. Ethical issues related to the inclusion of pregnant women in clinical trials (1). Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume 2, A. Mastroianni, R. Faden, and D. Federman, eds. Washington, D.C.: National Academy Press. Selwitz, A.S., and Wermeling, D.P. 1992. IRB Policies and Practices: Review of Subject Population. Paper commissioned by the Office of Protection from Research Risks, National Institutes of Health. Sherman, R. 1990. New DES front. The National Law Journal 12(March 12):1, 26-27. Steinbock, B. 1994. Ethical issues related to the inclusion of pregnant women in clinical trials (II). Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume 2, A. Mastroianni, R. Faden, and D. Federman, eds. Washington, D.C.: National Academy Press. Tribe, L.H. 1987. American Constitutional Law. Westbury, N.Y.: Foundation Press. Tribe, L.H. 1991. Abortion: The Clash of Absolutes. New York: W.W. Norton. U.S. Congress. 1993. House Report 103-28:84. Wadlington, W. 1984. Breaking the silence of doctor and patient (review of J. Katz's The Silent World of Doctor and Patient). The Yale Law Journal 93(8):1640-1651. Wion, A.H. 1989. Potential implications of the Supreme Court's decision in Berkovitz v. United States. Food, Drug & Cosmetic Law Journal 44:145-156. Wittes, B., and Wittes, J. 1993. Group therapy. The New Republic April 5:15-17.

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--> STATUTES AND REGULATIONS 45 C.F.R. 46 21 C.F.R. 50 & 56 28 U.S.C. § 1346(b), 2674 (19764) Federal Employees Liability Reform and Tort Compensation Act of 1988, P.L. 15-11 CASE REFERENCES Albala v. City of New York, 445 N.Y.S. 2d 108 (1981) Apicella v. Valley Forge Military Academy and Junior College, 630 F. Supp. 20 (E.D. Pa. 1985) Barson v. E.R. Squibb & Sons, Inc., 682 P.2d 832 (Utah 1984) Bergstrasser v. Mitchell. 448 F. Supp. 10 (D.C. Mo. 1977), aff'd, 577 F.2d 22 (8th Cir. 1978) Bonbrest v. Kotz, 65 F. Supp. 138 (1946) Bonte v. Bonte, 616 A.2d 464 (N.H. 1992) Craig v. Boren, 429 U.S. 190 (1976) Cruzan v. Director, Missouri Department of Health, 497 U.S. 261 (1990) Daubert v. Merrell Dow Pharmaceuticals, 113 S.Ct. 2786 (1993) Enright v. Eli Lilly & Co., 570 N.E.2d 198 (N.Y. 1988) Friter v. IOLAB Corporation, 607 A.2d 1111 (Pa. Super. Ct. 1992) Gaston v. Hunter, 588 P.2d 326 (Ariz. Ct. App. 1978) Geduldig v. Aiello, 417 U.S. 484 (1974) Griffin v. United States, 500 F.2d 1949 (3d Cir. 1974) Grodin v. Grodin, 301 N.W.2d 869 (Mich. Ct. App. 1981) In re A.C., 573 A.2d 1235 (D.C. Ct. App. 1990) International Union, UAW v. Johnson Controls, 111 S. Ct. 1196 (1991) Jones v. Ortho Pharmaceutical Corp., 209 Cal. Rptr. 456 (1985) Monusko v. Postle. 175 Mich. App. 269, 437 N.W. 2d 367 (1989) Newport News Shipping & Dry Dock Co. v. EEOC, 462 U.S. 669 (1983) Personnel Administrator of Massachusetts v. Feeney, 442 U.S. 256 (1979) Planned Parenthood of Central Missouri v. Danforth, 428 U.S. 52 (1976) Planned Parenthood of Southeastern Pennsylvania v. Casey, 112 S.Ct. 2791 (1992) Renslow v. Mennonite Hospital, 67 111.2d 348, 367 N.E. 2d 1250 (1977) Roberts v. Patel, 620 F. Supp. 323 (N.D. Ill. 1985) Roe v. Wade, 410 U.S. 113 (1973) Salgo v. Leland Stanford Jr. University, 317 P.2d 170 (Cal. Ct. App. 1957) Shack v. Holland, 389 N.Y.S.2d 988 (1976) Stallman v. Youngquist, 531 N.E.2d 355 (Ill. 1988) Taylor v. Wyeth Laboratories, 362 N.W.2d 293 (Mich. App. 1984) Tinnerholm v. Parke, Davis & Co., 285 F. Supp. 432 (S.D.N.Y. 1968), modified on other grounds, 411 F.2d 48 (2d Cir. 1969) United States v. Orleans, 425 U.S. 807 (1976) West v. Johnson & Johnson Products, Inc., 220 Cal.Rptr. 437 (1985) Whitlock v. Duke University 637 F. Supp. 1463 (M.D.N.C. 1986), aff'd, 829 F.2d 1340 (4th Cir. 1987)