Women and Health Research Ethical and Legal Issues of Including Women in Clinical Studies: Volume 2: Workshop and Commissioned Papers (1994) / Chapter Skim
Currently Skimming:
11 Impact of Current Federal Regulations on the Inclusion of Female Subjects in Clinical Studies
11 Impact of Current Federal Regulations on the Inclusion of Female Subjects in Clinical Studies
Pages 65-83
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 65... ...
Regulations that Appear to Limit Women's Participation in Clinical Research [1) A Definition of "Childbearing Potential" and Required Prior Reproductive Studies Research protocols commonly contain the exclusionary criterion "pregnant and lactating women and women of childbearing potential," language apparently derived from the Food and Drug Administration's Guidelines for researchers.2 While the Guidelines are not legally binding, research conducted in accordance win the Guidelines qualifies for FDA consideration in a New Drug Application,3 and most investigators take the Guidelines seriously.
|
From page 66... ...
,8 but the FDA does not appear ever to have required such studies to precede Phase III trials.9 There is no practical way for me to research this, but I would bet that "as appropriate" has never been interpreted to require animal studies that would elicit adverse reproductive effects mediated through the male animal.~° What this boils down to is that pharmaceutical companies can choose to market drugs with no information about their reproductive impact, so long as the label makes this clear, and that the animal studies which the FDA defines as a necessary precursor to large-scale clinical Dials with female subjects may never be conducted at all or may be done only in parallel with, not in advance of, clinical testing. To compound ~is, the [DA, and Gus clinical investigators, define the Guidelines' key phrase "of childbearing potential" in a way that, as I have written in another context, envisions all women as "constantly poised for reproductive activity": A woman of childbearing potential is defined as a premenopausal female capable of becoming pregnant.
|
From page 67... ...
are willing to use an effective form of contraception dunag the study, or have been evaluated by a fertility expert and have been found to be infertile, and have been so for greater than five years," to quote one research manual's interpretation.l4 The FDA Guidelines do, however, expressly recognize an exception to the animal reproductive study requirement that gives researchers substantial latitude: testing of a drug anticipated to be a lifesaving or life-prolonging measure.~5 "Life-prolonging" seems a quite elastic phrase that could cover many situations of clinical research. Under the Guidelines, so long as the lack of reproduction studies is pointed out during the informed consent process, and she is tested for pregnancy and advised of contraceptive measures, the woman of childbearing potential may participate in clinical trials of a potentially life-prolonging intervention, even during Phase I
|
From page 68... ...
the fetus will be placed at minimal risk or at risk to the minimum extent necessary to meet the woman's health needs.2' So how significant a barrier for the pregnant woman are these regulations? To begin, let us consider the first requirement: completion of "appropriate" studies in animals and nonpregn~nt people (but presumably, under the Guidelines, not studies in women of childbearing potential)
|
From page 69... ...
Beginning with the debacle of MEA/29, the Richardson-Merrell anticholesterol product that blinded many people because the company failed to pursue ocular abnormalities in test animals,32 courts have penalized companies that do not conduct reasonable testing to determine the potential adverse reactions of their products, even if the testing involved was not required by the FDA.33 In terms of the regulations, however, He question is, what do He pbtases "~e and well-con~lled investigations" and "data demoing substantial effectiveness" mean? For the purposes of this discussion, one significant clue is He FDA's regulation on the labeling of drugs: "Evidence is .
|
From page 70... ...
The results of medical research on men are generalized to women without sufficient evidence of applicability to women."38 The Council went on to recommend: "Research on health problems that affect both sexes should include male and female subjects. Sound medical and scientific reasons should be required for excluding women from medical tests and studies, such as that the proposed research does not or would not affect the health of women."39 Arguably, then, the FDA regulations should be read to require adequate testing, meaning sample sizes and/or stratified analyses sufficient to detect highbackground adverse reactions, in a female population, unless the drug label reveals the paucity of data in women and cautions against undue extrapolation from testing in men.40 DHHS Regulations on Research with Children One of the issues frequently raised in the course of discussing the enrollment of female subjects in clinical trials is the research sponsor's concern about liability to their offspring.4~ In Cat context, it is sometimes said that this concern cannot be resolved by any sort of "waiver" or "assumption of risk" by parent-subjects on behalf of Weir offspring, because while parents can consent to their children's participation in all manner of fairly dangerous and nonbeneficial activities outside the medical arena, generally they can consent to medical intervention for their children only if the intervention is intended and expected to be beneficial to the individual child.42 The traditional view,
|
From page 71... ...
RECOMMENDED CHANGES IN THE FEDERAL LAW Full inclusion of women in biomedical research would be somewhat easier to implement if there were some revision of current federal regulations. Because these limitations are not statutory in origin, however, such revision would not require congressional action, but could be undertaken by the relevant administrative agencies at any time.46 Amendment of IDA Regulations First, the FDA Guidelines should be redrafted to raise identical concerns about the participation of both male and female subjects of reproductive potential, and to allow women to decide for themselves, as men do, about the relative risks and benefits-for them-of participation in Phase I or early Phase II trials.47 FDA regulations require researchers to inform subjects "when appropriate" that the research may involve "risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant)
|
From page 72... ...
It is inequitable and discriminatory to exclude women, including women of reproductive age, from clinical trials.52 Another component of DHHS regulations that needs revision is Subpart B Here, the best option would be to delete Section 46.207, the provision dealing with "Activities directed toward pregnant women as subjects." Its language is ambiguous and confusing; the subsection requiring paternal consent is surely unconstitutional even under present standards; and given that about all it permits is activity intended to "meet the health needs ofthe mother," depending on one's view of the purposes of clinical research, either it is tautological or it describes a null set.
|
From page 73... ...
The NIlVADAMHA Policy Concerning Inclusion of Women in Study Populations ("NIH Policy") appears to establish a firm presumption that women shall be included in protocols.
|
From page 74... ...
There is an alternative approach: requiring adequate animal studies of adverse reproductive effects in both male and female animals. Such studies would have to test for all potential male routes of prenatal and pre conceptual impact.
|
From page 75... ...
Federal agencies should require that all research be evaluated to determine whether its design will elucidate gender-specific differences and permit systematic analyses of gender-specific variables.58 This requirement cannot be confined to areas of acknowledged gender difference, for example, drugs metabolized through pathways influenced by sex steroid hormones, because the failure to recognize differences may reflect a lack of prior research rather than the right questions having been asked and answered in the negative.s9 At a minimum, phannacokinetic screens of all new drugs should be conducted in both women and men, and animal studies should include female as well as male animals. Whenever animal reproductive studies are conducted, they should seek to determine the incidence of adverse reproductive outcomes through the male parent.
|
From page 76... ...
The new policy also does not compel research sponsors to complete animal reproduction studies in both male and female animals prior to commencement of clinical trials. My own expectation is that absent regulatory compulsion, liability concerns and some of the other factors discussed at the workshop will remain formidable obstacles to the participation of women as subjects in biomedical research.
|
From page 77... ...
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.
|
From page 78... ...
One exception is identical to a precondition for the pregnant woman's participation in research that may pose more than a minimal risk to the fetus: i.e., that the purpose ofthe research be to meet the pregnant woman's health needs. Since any research that poses more than minimal risk is permissible only if its purpose is to meet the pregnant woman's health needs (regardless of progenitor consent)
|
From page 79... ...
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.
|
From page 80... ...
41. This subject is addressed in the companion paper of Professor Ellen Wright Clayton, `'Liability Exposure When Offspring Are Injured as a Result of Parent Participation in Clinical Trials." In my own analysis of the question elsewhere, I have emphasized that researchers have as much cause for concern about liability to the offspring of their male subjects.
|
From page 81... ...
51. A concomitant of this change would be for FDA regulations to mandate completion of animal reproduction studies prior to human testing.
|
From page 82... ...
2, actually requires proper research design, or merely that a stratification analysis of male and female subjects be performed, regardless of the persuasiveness of the results (e.g., even if the female sample size is inadequate)
|
From page 83... ...
IMPACT OF CURRENT FEDERAL REGULATIONS 83 59. See Institute of Medicine, Expanding Access to Investigational Therapies for HIVInfection and AIDS 7.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.