8
Implementation

Policies requiring the inclusion of women and racial and ethnic groups in clinical studies are already in place. These policies are proactive in that they seek to bring the conduct of clinical studies into line with some general principles of inclusion of diverse population groups as research subjects. The policies assume that the current activities of publicly and privately funded scientists can be viewed as a collective national research enterprise in which there is mutual accountability for the overall extent to which various health problems and population groups are studied. These policies also assume (but do not assure) that processes can be established whereby the desired level of inclusiveness will be achieved. By bringing the force of law to bear upon the research enterprise, the authors of these mandates Congress, the National Institutes of Health (NIH), and the Food and Drug Administration (FDA)-also imply that the desired levels of inclusiveness do not now exist and would probably not develop spontaneously.

The present emphasis placed by NIH on the recruitment of diverse population groups into clinical research is a strong initial step in the pursuit of equity in clinical studies. Where earlier versions of the current NIH policy on inclusion of women in clinical studies simply encouraged investigators to include women in study populations, more recent policy statements require that "clear and compelling" rationales be given for the exclusion of women from proposed studies. More important, efforts to disseminate the policy statement to investigators and reviewers have been bolstered. NIH has conducted a review of the impact of the revised (1991) policy and,



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--> 8 Implementation Policies requiring the inclusion of women and racial and ethnic groups in clinical studies are already in place. These policies are proactive in that they seek to bring the conduct of clinical studies into line with some general principles of inclusion of diverse population groups as research subjects. The policies assume that the current activities of publicly and privately funded scientists can be viewed as a collective national research enterprise in which there is mutual accountability for the overall extent to which various health problems and population groups are studied. These policies also assume (but do not assure) that processes can be established whereby the desired level of inclusiveness will be achieved. By bringing the force of law to bear upon the research enterprise, the authors of these mandates Congress, the National Institutes of Health (NIH), and the Food and Drug Administration (FDA)-also imply that the desired levels of inclusiveness do not now exist and would probably not develop spontaneously. The present emphasis placed by NIH on the recruitment of diverse population groups into clinical research is a strong initial step in the pursuit of equity in clinical studies. Where earlier versions of the current NIH policy on inclusion of women in clinical studies simply encouraged investigators to include women in study populations, more recent policy statements require that "clear and compelling" rationales be given for the exclusion of women from proposed studies. More important, efforts to disseminate the policy statement to investigators and reviewers have been bolstered. NIH has conducted a review of the impact of the revised (1991) policy and,

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--> while the results are not yet available, it is expected that the level of women's participation in clinical studies will be significant. The challenge for those involved in clinical research is how to achieve full implementation of these policies in a way that enhances the overall research enterprise, while simultaneously dealing with the apparent theoretical, methodological, and regulatory complications they pose for investigators, sponsors, peer review and regulatory bodies, and research participants. Of particular relevance to this report is the challenge of anticipating and resolving the social, ethical, and legal dilemmas that may arise in the attempt to achieve equity in our pluralistic society. For example, both the revised guidelines from NIH on the inclusion of subpopulations in research studies and the provisions of the NIH Revitalization Act of 1993 (the "Act") requiring that each NIH-funded study include representative samples of subpopulations unless their absence is justified, have caused concern among many people, including the members of this committee, about the feasibility and cost of conducting clinical studies in accordance with these new mandates. An important consequence of implementing the demands of justice in the context of clinical research is the improvement of scientific knowledge and the ability to address the health problems of all peoples. The Act clearly is intended to promote this goal by changing the prevailing presumption to one of inclusion. The Act requires investigators to both justify any gender or racial or ethnic exclusions and identify and analyze gender differences. The committee fully endorses the spirit of these requirements. Investigators should be obligated to be inclusive in their recruitment practices and to justify any departure in the composition of their study populations from what might be expected given the characteristics of the problem under investigation. The committee is concerned, however, that if the act is too rigidly interpreted, it will make costly and undue demands on the scientific research process and impede the implementation of its noble goal. The committee has offered specific recommendations intended to ensure that questions of justice and inclusion are a top priority at every level of the research process. The committee does not believe that the interests of justice in advancing the health of all people are best served by a requirement that every clinical trial be large enough to conduct valid analyses of every relevant subgroup comparison. As reflected in the committee's guiding principles I and 2, (see Chapter 3), the ultimate burden for achieving justice falls on the national research agenda as a whole and cannot be implemented by a mechanical approach to the selection of subjects on a study-by-study basis. The preceding chapters have laid out the rationale and guiding principles for including greater numbers of women in clinical studies; they also identified the considerations-ethical, scientific, social, and legal-that might impede the achievement of this goal. In the process of presenting this mate-

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--> rial, the committee has stated a number of its conclusions and recommendations with regard to the broad shape and general direction of this process. In this final chapter, many of these broad recommendations are tied to the specific actors and actions needed to achieve a collective national research effort that-in both practice and perception-will equitably address the health concerns of the diverse populations that make up our society. Some of these actions involve short-term strategies that can be implemented almost immediately; others involve the strengthening of existing mechanisms or institutions; still others depend upon processes that do not yet exist and may take considerable time to establish. The overall long-term goal of these activities is to improve our scientific knowledge and ability to address the health problems of all peoples. The committee believes that this will require the active involvement of all sectors of the research community. While these recommendations concentrate on the NIH research structure, the committee also recognizes the vital contributions of pharmaceutical companies and other nonfederal sponsors to the overall research enterprise. Therefore, the committee recommends that the spirit of the recommendations in this chapter be appropriately modified and applied by private and nonprofit sponsors in their research context. Furthermore, enhanced efforts to coordinate federal, private, and nonprofit research efforts are encouraged. The committee believes that everyone involved in the conduct of research-project investigators, institutional review boards (IRBs), initial review groups (IRGs), technical evaluation groups (TEGs) (together, IRGs and TEGs are commonly known as study sections), scientific advisory councils, and NIH management-must participate in this process. Therefore, while the recommendations are made to NIH, they specifically address each step in the process, from the conception of the research project by the investigator, to the review process of IRBs, to the scientific review boards, IRGs and TEGs (study sections), the implementation of the overall research agenda by the NIH advisory councils, and finally to the overall assurance of accomplishing the research mission by NIH. The ultimate criteria for judging the success of a public policy to achieve justice and promote inclusion will be changes in research policy and clinical practice, and ultimately improvements in health status indicators, particularly in areas where unjustifiable disparities currently exist. Specific objectives include the following: Establish accountability for implementation at every level of the research enterprise, including levels well above that of the individual investigator; Provide the necessary database to shape adherence and identify gaps in knowledge;

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--> Establish a system for monitoring compliance with specific inclusion-based requirements and evaluating the extent to which fairness is being achieved; Use the preceding processes and data bases to educate, inform, and promote discussion among policy makers, bureaucrats, investigators, IRBs, IRGs, TEGs, and the general public. RECOMMENDATIONS The committee has divided its recommendations into two categories: those that can be implemented immediately and maintained over the long term; and those that will depend on preparatory steps and should be implemented as soon as feasible. Recommendations to address objectives of accountability, for example, can and should be implemented immediately. Recommendations for the development of new databases, however, cannot be fully implemented until consistent changes in data collection have been achieved. NIH already requires reporting of the composition of study populations, which keeps investigators aware of the need to involve diverse populations. Additional resources, supports, and monitoring strengthen this effort by providing numerous opportunities at each level within the review process for the evaluation, referral, and revision of protocols. The committee strongly endorses the principle that tracking the study population composition and topics of funded studies and providing this information on a regular basis to all those involved in the research process will in and of itself raise the level of awareness and activity concerning the issues of both study composition and attention to women's health concerns. The assessment of accumulated research is the most comprehensive mechanism for monitoring the implementation of the policy of inclusion. The protocol review suggested here, however, increases the likelihood that questionable protocols will be recognized early and handled effectively. The Investigator Immediate Actions The committee believes that tracking both the composition of study populations and topics of funded studies, and providing this information on a regular basis to all those involved in the research process, will, in and of itself, raise the level of awareness and activity concerning the issues of both study composition and attention to women's health concerns. NIH already requires investigators to report the composition of study populations, which

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--> keeps investigators aware of the need to involve diverse populations. It is important that individual investigators be aware of both the state of the science and the state of clinical practice with respect to gender and other subgroup differences in their areas of research. In designing studies, investigators should conduct literature reviews to determine (1) the extent to which an evidentiary base exists for suspecting gender-specific and subgroup effect, and (2) the extent to which women and other groups have served as participants in relevantly similar research. If there is a plausible basis for suspecting gender differences, investigators should make every effort to recruit sufficient participants of both genders to conduct analyses to detect these differences. In the absence of such an evidentiary base, investigators should recruit participants of both genders. Where sample size is large enough, investigators also should conduct analysis of gender differences in these studies. Investigators should strive to collect sufficient data on gender-related variables to permit a refined interpretation of any observed gender differences (e.g., potential confounders or mechanistic variables such as hormonal status of women, weight, and adiposity) and to reveal trends or suggest hypotheses. As Soon as Feasible Investigators should draw on the expertise available in the social science community to improve the ways in which the variables of gender, race, and ethnicity are conceptualized, operationalized, and measured in their studies. Such collegial exchanges will enable investigators to tailor their study designs, recruitment and retention efforts, and informed consent procedures to the study population selected, to avoid unwarranted exclusions of potential participants, and to be prepared to collect sufficient data on gender-related and subgroup variables to analyze for confounding effects. Investigators clearly need broad-based support from the other actors within the research process in order to carry out their part of a comprehensive agenda. The committee recommends that IRBs, IRGs, TEGs, scientific advisory councils, and NIH management become more directly involved with investigators in activities that promote development of more inclusive study designs. Measures recommended by the committee, such as IRB review of protocols for study population composition and NIH provision of opportunities for investigator training and access to needed databases, facilitate investigator efforts to realize the goal of greater inclusion.

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--> The IRB Immediate Actions As part of the IRBs' responsibility for ensuring the just selection of persons to be participants in research, IRBs should require investigators to provide the proposed gender, racial, and ethnic composition for each study, as well as information about the distribution of the condition under study in the population at large and the composition of subjects in previous relevant research. It is the IRBs' responsibility to make a determination that the composition of the proposed study is equitable. As Soon as Feasible IRBs, in concert with NIH, should engage in educational efforts that will ensure awareness among investigators of gender and racial and ethnic biases. Research organizations could draw upon the expertise of social scientists experienced in the conceptualization, operationalization, measurement, and analysis of variables relevant to these issues to assist investigators. The committee believes that providing feedback to IRBs concerning the characteristics of the study populations and research topics it has approved will serve to raise the level of awareness of IRBs to issues of justice and inclusion. The NIH Office of Protection from Research Risks (OPRR) should require IRBs to collect data on study population composition and research topics of all studies subject to IRB review. OPRR could monitor study population composition through, for example, a representative sample of general assurance IRBs. IRGs and TEGs Immediate Actions Once NIH policies for inclusion of gender, racial, and ethnic groups are finalized, it is anticipated that IRGs and TEGs will have significant responsibility for monitoring their implementation. As with any new policy, it is expected that in the initial stages of implementation guidance will be needed. NIH should develop a mechanism for monitoring the actions taken by IRGs and TEGs in implementing policies for inclusion of gender, racial, and ethnic groups, and provide feedback to the IRGs and TEGs in order to ensure consistent and appropriate interpretation of these policies. Among other tools for evaluation, NIH might consider taking a ran-

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--> dom sample of justifications for exclusions. Central review and evaluation can standardize the implementation of the policy, and it will correct both unnecessarily strict and overly lenient policy interpretations by the peer review system. It will also provide illustrative material for education of IRG and TEG members as recommended below. As Soon as Feasible Each IRG and TEG should recruit members with expertise in the area of gender, racial, and ethnic differences or persons sensitive to gender and racial and ethnic concerns. Furthermore, every member of IRGs and TEGs should receive training and education on evaluation of study population composition and gender, racial, and ethnic differences. The very presence of qualified males and females from different racial and ethnic backgrounds is one way of increasing the likelihood that the relevant questions and appropriate conceptualizations are considered by investigators. A rough measure of sensitivity could be based on professional activities, such as research agenda, participation in committees of professional associations, publications, and service at one's institution. Scientific Advisory Councils As Soon as Feasible Mechanisms should be developed for ensuring that principles of justice are central considerations in the setting of the nation's research agenda. Because clinical research carries both benefits and burdens, justice requires that no one group-gender, racial, ethnic or socioeconomic-receive disproportionate benefits or bear disproportionate burdens of research. For the overall biomedical research agenda to comply with the requirements of justice, studies must not only include women as well as men, but also women and men from different age cohorts and different racial and ethnic groups. In addition, the health needs of all women and men should receive their fair share of research resources and attention. Scientific advisory councils have the ultimate responsibility for determining priorities in the research agenda for the subject matter area they cover. These decisions should move toward establishing equity in U.S. research efforts for all populations over time. Databases compiled by NIH can be used by scientific advisory councils in making decisions about research priorities within the available funding and in determining what areas require requests for proposals (RFPs) or requests for applications (RFAs) to improve the balance of research across diseases and subgroups. The heads of the councils should confer periodically to assess the application of principles of justice across research areas.

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--> In developing research priorities, these councils should give special consideration as to whether the health needs of pregnant women are being adequately addressed by their institutes. NIH Immediate Actions NIH should maintain the current policy emphasis on the inclusion of women in NIH-supported clinical studies. NIH should continue the practice of identifying research concerns of various subgroups (gender, race, ethnicity, socioeconomic status) and offer RFAs and RFPs for such studies. Where new requirements for subgroup analysis result in increases in study size and additional recruitment strategies, supplemental funds (e.g., from the NIH Office of Research on Women's Health) should be made available to meet these funding challenges. NIH should commission studies to determine the present state of scientific knowledge on gender, racial, and ethnic differences to help investigators determine where subgroup analysis would be likely to identify clinically significant differences. These efforts should culminate in the establishment of a database that includes such information as differences in disease incidence and prevalence, as well as relevant physiological and cultural differences in subgroups. Investigators would be able to consult this database in developing strategies to identify and detect gender, racial, and ethnic differences. NIH should require that proposals for clinical studies include in their literature reviews the following: the extent to which an evidentiary base exists for suspecting gender or other subgroup differences relevant to the proposed research; the demographic characteristics of subjects in past similar research; groups for which the proposed study might have special relevance; how the preceding information justifies the population selected for the proposed study; and how that choice will address gaps identified in the literature. This requirement should be incorporated into the guidelines on the grant application (PHS 398 form). NIH should widely disseminate to the scientific community methodological guidance on: (1) compliance with the legislative mandate regarding the inclusion of women and other subgroups in clinical research and (2) considerations for valid subgroup analysis.

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--> As Soon as Feasible NIH should pursue the current dialogue with Congress and the research community on the policy of inclusion and the commitment to justice. The objective is to develop mechanisms that merge public policy goals with scientific advice to promote legislation that is at once socially responsible, practical, and consistent with good science. Such action would extract the scientific community from a current dilemma: if NIH is strictly responsive to the law, clinical studies may become larger and more expensive in order to be in compliance, with no guarantee that this is either the most efficient or effective way to advance the health interests of women or other groups. If this results in an inability to fund an adequate range of biomedical research, it is likely that the health interests of all people will suffer, and thus justice will not be served. As part of the registry of clinical studies it is currently evaluating, NIH should establish a database cross-referenced by: (1) categories of disease and physiological or psychological factors and (2) study population composition of ongoing and published studies. This database should be compiled in a way that ensures easy accessibility to the data included by subgroup classification. Reporting requirements for all studies should be comprehensive and uniform and at a minimum  include: the research questions addressed and the gender, race, ethnicity, socioeconomic status, age and hormonal status (i.e., pregnancy, stage of menstrual cycle) of the study population. To facilitate the collection of data about inclusion and justice from non-federally supported research, NIH should encourage journal publishers to require presentation of data on demographic characteristics. Currently, there is no national norm that compels pharmaceutical manufacturers and other investigators to submit their data to a registry or other data repository. NIH should assist investigators in the effort to detect gender differences by: (1) identifying, developing, and disseminating alternative methods for detecting or formulating hypotheses about gender differences and (2) providing guidance for the use of these methods by investigators, IRGs, and TEGs. The new legislative mandate makes it especially critical that both investigators and review committees clearly understand the interrelationship of sample sizes and the power to draw statistically significant inferences about differences between subgroups. A proactive strategy of development and dissemination would help investigators in complying with regulations. It would also help to prevent the introduction into the literature of analyses based on insufficient data-analyses that could ultimately do a disservice to subgroups by fostering seemingly valid but erroneous conclusions.

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