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6 Legal Considerations
Pages 128-174

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From page 128...
... 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 128
From page 129...
... 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)
From page 130...
... 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)
From page 131...
... 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.
From page 132...
... 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)
From page 133...
... 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; 2. the August 1990 policy notice entitled "NIH/ADAMHA Policy Concerning Inclusion of Women in Study Populations," applicable to extramural research; 3.
From page 134...
... 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.
From page 135...
... 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.
From page 136...
... 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.
From page 137...
... 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.
From page 138...
... 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 riskbenefit 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, 19771.
From page 139...
... This guideline modifies and revises the section of the 1977 version concerning inclusion of women of childbearing potential in clinical trials. The introduction to this guideline indicates that the broad principles that are outlined for the inclusion of women in the early phases of clinical trials will also be applied to FDA approval processes for biological products and medical devices.
From page 140...
... This enables the early identification of possible variations in dosing regimens that can be built into the larger clinical trials. Emphasis is placed on the heightened importance of early pharmacokinetic studies for drugs with a narrow therapeutic range (drugs that have a small range of concentration between the point of effectiveness and the point of toxicity)
From page 141...
... Once again, the importance of such additional studies increases should the early studies indicate a gender-related difference in response to a drug with a narrow therapeutic range. Precautions in clinical trials including women of childbearing potential FDA will rely on the informed consent document and the investigator's brochure to advise participants of the need to take precautions to prevent the inadvertent exposure of a fetus to potentially toxic drugs.
From page 142...
... , and the Department of Veterans Affairs has a policy generally promoting the inclusion of women in clinical studies (Department of Veterans Affairs, 19924. The Department of Energy explicitly recommends that the guidance provided in Subpart B of the DHHS regulations be followed if the proposed research involves pregnant women (Department of Energy, 19921.
From page 143...
... The Fourteenth Amendment's express protections against laws that deny "equal protection" and "life, liberty, and property" are particularly relevant to questions of participation in clinical research. The Fourteenth Amendment, and the Bill of Rights generally, have been interpreted by the Supreme Court to require equal access to government health benefits, along with a high degree of personal liberty in matters affecting health care.
From page 144...
... Fetal Protection Objections to women's participation in clinical studies are often premised on an interest in doing what is best for women's own health and wellbeing; but in some instances they are also based on an interest in fetal and
From page 145...
... Casey also invalidated provisions of a Pennsylvania statute requiring that pregnant women attest to having notified their spouses of plans to abort.2 The Court saw no legally enforceable role for third-party notification and consent in the procreative decisionmaking of adult pregnant women. This is the strongest constitutional basis for an argument that husbands and fathers also have no legally enforceable role in deciding whether a pregnant woman may expose herself and a fetus to research-related health risks, even in the therapeutic context.
From page 146...
... The equal protection clause prohibits the federal government including its regulatory agencies and research units from engaging in certain forms of discriminatory disparate treatment. The Supreme Court has yet to decide a challenge to a demographic restriction on access to clinical studies, but legal experts maintain that research policies that result in the exclusion of women as a class, whether on their face (with explicit exclusionary language)
From page 147...
... recommended the exclusion of women of childbearing potential from early phase drug trials; the regulations governing research on human subjects require that IRBs approve research on pregnant women only if it involves treatment for the mother or fetus and minimal risk to the fetus (45 C.F.R.
From page 148...
... The Supreme Court held that the equal protection clause was not violated by California when it excluded pregnancy-related disability from coverage under the state's disability insurance program. The Court found that the classification in California's program was not between men and women but between pregnant and nonpregnant persons; despite the argument that only women can be pregnant, the Court found that this policy was not on its face treating women differently.
From page 149...
... Similarly, it can be argued that such policies are unconstitutionally underinclusive where they exclude only women of childbearing potential, ignoring fertile men whose reproductive capacities and offspring may be affected by the substance under study (see Chapter 71. Again, any policy that restricts the research participation of women of childbearing potential will also be questionable under the decision in Johnson Controls, in which the Court struck down an exclusion policy that applied to fertile women as well as to pregnant women.
From page 150...
... Rather, the focus of liability concerns is on possible injury to offspring when pregnant women and women of childbearing potential are included in clinical drug trials. Although recent evidence may indicate that exposure of the father to some chemicals may cause harm to a developing fetus (see Chapter 7)
From page 151...
... The NIH Office of the General Counsel is only aware of three legal actions for clinical research injuries where NIH was involved in the past 20 years.5 According to the FDA Office of the General Counsel, that agency has never been the subject of a legal action resulting from a clinical trial injury (R. Blumberg, personal communication, August 19931.
From page 152...
... With regard to injuries to offspring, until very recently FDA guidelines discouraged the use of women of childbearing potential in early phases of research; hence the full potential for liability for injuries to offspring may be unrealized. Even though there are few reported cases of research-related injury, fear of liability has played a key role in the exclusion of women in their childbearing years and pregnant women from many clinical studies.
From page 153...
... For example, many states, through their courts and state legislatures, have adopted portions of the Restatement (SecondJ of Torts, the American Law Institute's synthesis of the major principles of contemporary tort law (ALI, 19771. The three legal bases for a legal action for research injury are battery, negligence, and strict liability.
From page 154...
... In some cases, for example, plaintiffs exposed to toxic substances recovered damages for anxiety caused by fear of getting cancer (Reisman, 1992~. Strict liability Pharmaceutical manufacturers, because they are in the busi ness of selling a product, may also be held to the legal principles governing product liability.
From page 155...
... Because nearly all research is conducted after securing consent from participants, most legal actions by participants for research injuries will be based on whether the information given to the participant before securing consent adequately warned of the potential risks (Reisman, 19921. The doctrine of informed consent requires that physicians secure consent from the patient before medical treatment is administered, and this consent must be based on information given to the patient about the risks and benefits of the proposed procedure and the alternatives (Wadlington, 19841.
From page 156...
... to make a decision (Keeton et al., 19841. A recent decision from a North Carolina court indicates that courts may require a higher standard for informed consent in nontherapeutic research injury cases.
From page 157...
... It is possible that this "discretionary function exception" to FTCA may operate to bar a legal action for research injury against a federal agency such as NIH or FDA. In deciding whether a particular employee's actions qualify under the discretionary function exception, the court will examine whether the employee's actions involved an element of choice or judgment and whether this choice was a permissible exercise of policy judgment (Wion, 19891.
From page 158...
... Consequently, legal actions against FDA in connection with NDAs have been dismissed by federal courts under the discretionary function exception (Wion, 19891. But in one case where an injured plaintiff claimed FDA made a decision to release a polio vaccine based on inadequate animal test data, the court held that FDA's assessment of the animal data was a scientific determination, not the exercise of a discretionary function, and thus subject to liability (Griffin v.
From page 159...
... Liability for Injuries to Offspring As mentioned above, the greatest source of concern about liability is the possibility of injury to offspring when women of childbearing potential are included in clinical drug trials. Fear of liability to offspring may be based on a number of factors.
From page 160...
... When the plaintiff is the child, the likelihood of a successful legal action depends in part on the ability of the parents to show they would not have participated in the research had they known about the risks. Damage awards to these children can include pain and suffering and damages to
From page 161...
... If the child is stillborn as a result of a research injury, the parents may bring an action for wrongful death; in states that permit such a cause of action, the damage award is usually relatively small (Clayton, 1 9941. Potential defendants In addition to all of the defendants discussed above, it may be possible for the child to sue a parent for participating in a clinical drug trial, depending on the law of parent-child immunity in the state.
From page 162...
... Sufficiency of informed consent Under the limited case precedent available, the likelihood of a successful legal action for offspring injury has depended on whether obtaining informed consent from the woman is sufficient, in all circumstances, to avoid liability. The committee is aware of emerging data concerning the possibility of male-mediated developmental effects (see Chapter 71; nevertheless, this possibility has not operated to exclude fertile men as a class from clinical drug trials.
From page 163...
... 46.4071. A court may find, however, that these regulations governing research on minors do not apply to offspring injury resulting from a woman's participation in a clinical study.
From page 164...
... 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~.
From page 165...
... 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, 19941.
From page 166...
... 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
From page 167...
... . 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.
From page 168...
... 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.
From page 169...
... 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.
From page 170...
... 7. The Supreme Court recently rejected the long-standing Frye rule, which set the standard for the acceptability of scientific evidence in legal proceedings.
From page 171...
... In: Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume 2, A Mastroianni, R
From page 172...
... In: Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume 2, A Mastroianni, R
From page 173...
... 1994. Ethical issues related to the inclusion of pregnant women in clinical trials (I)
From page 174...
... , 2674 (19764) Federal Employees Liability Reform and Tort Compensation Act of 1988, P.L.


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