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Bridging the gap between gene discovery and our ability to use genetic information to benefit health requires population-based knowledge about the contribution of common gene variants and gene-environment interactions to the risk of disease. The risks and benefits associated with population-based research involving genetics, especially lower penetrance gene variants, can differ in nature from those associated with family-based research. In response to the urgent need for appropriate guidelines, the Centers for Disease Control and Prevention formed a multidisciplinary group to develop an informed consent approach for integrating genetic variation into population-based research. The group used expert opinion as well as federal regulations, the National Bioethics Advisory Commission’s report on research involving human biological materials, existing consent forms, and literature on informed consent to create suggested language for informed consent documents and a supplemental brochure. This language reflects the premise that the probability and magnitude of harm--as well as possible personal benefits--are directly related to the meaning of the results for the health of the participant, and that appropriate disclosures and processes for obtaining consent should be based on an assessment at the outset of the likelihood that the results will generate information that could lead directly to an evidence-based intervention. This informed consent approach is proposed to promote discussion about how best to enable potential participants to make informed decisions about population-based research involving genetics and to suggest issues to consider for research sponsors, institutional review boards, and investigators.
The Human Genome Project has produced an explosion of genetic information. Unfortunately, the gap is immense between gene discovery and our ability to use genetic information to improve health and prevent disease. Bridging this gap with population-based knowledge about the contribution of gene variants and gene-environment interactions to disease requires that genetics be integrated into the public health research agenda. The likely outcome of this research will be more effective and targeted medical and public health interventions. A significant challenge in pursuing these scientific aims is satisfying the basic ethical principles of respect for persons, beneficence, and justice [1]. How these principles are best applied depends on the nature of the risks and potential benefits of a particular study. Genetic research is typically considered sensitive because much of it has been directed toward the investigation of highly predictive mutations in families with a heavy burden of disease. Investigating BRCA1/2 mutations among families that have multiple members affected with breast or ovarian cancer, for example, arouses grave concerns about the psychological and social harms that could result from uncovering information that has significant implications for the health of family members. These concerns are intensified when only limited or unproven interventions are available. Thus, recommendations for the protection of genetic research participants typically call for close scrutiny by an Institutional Review Board (IRB), detailed informed consent procedures, and professional genetic counseling, sometimes both pre- and post-test [2]. Some highly penetrant gene variants should ideally also be studied in a population-based setting. Although BRCA1/2 mutations are thought to account for less than 5% of all breast cancers [3], ascertaining their impact in the general population could help scientists understand the risks and biological mechanisms of breast cancer in general. Nevertheless, the most important contribution of population-based research involving genetics will be to elucidate the interactions between lower penetrance gene variants and environmental factors that increase the risk of disease. The interaction between genes and one’s chemical, physical, infectious, nutritional, social, and behavioral environment plays a role in many, if not all, diseases, including the common chronic diseases of public health interest. Fulfilling the ultimate promise of the Human Genome Project--benefiting human health--requires population-based data concerning the prevalence of gene variants, their associations with disease, and their interactions with modifiable risk factors [4]. Although much has been written about ethical issues in epidemiology [5,6], ethical, legal, and social issues in genetic testing [7,8], and informed consent for genetic research [2,9], there is little or no guidance available specifically for population-based studies of low-penetrance gene variants. Recommendations developed for family-based research are not well suited to most population-based research because they generally fail to distinguish between studies expected to reveal clinically relevant information about participants and studies expected to have meaningful public health implications but involving few physical, psychological, or social risks for individual participants. Uniform application of these recommendations to all genetic research could make some otherwise beneficial population-based studies difficult or impossible to conduct. As noted by Clayton et al. [10], the risks involved in identifying high-risk mutations must be distinguished from the risks of identifying "common alleles that are neither necessary nor sufficient for the development of disease." In response to the urgent need for appropriate guidelines, the Centers for Disease Control and Prevention (CDC) formed a multidisciplinary group to develop an informed consent approach for integrating genetic variation into population-based research. This approach highlights similarities with other population-based research; indeed, many argue that genetic information is fundamentally similar to other kinds of health information [11]. However, society currently invests enormous power in the concept of genetics and, considering the history of eugenics and other research abuses in the United States and around the world, clarifying the obligations of investigators to participants in population-based research involving genetics is important. We propose this approach to stimulate discussion about how best to enable individuals to make informed decisions about participation in population-based research involving genetics and to suggest issues to consider for research sponsors, IRBs, and investigators.
Our informed consent approach is based on federal policy for the protection of human research participants, as codified at Title 45, Part 46, of the Code of Federal Regulations (45 CFR 46). The approach follows closely the document, Consent for CDC Research: A Reference for Developing Consent Forms and Oral Scripts [12]. We also considered literature on informed consent for human tissue research [10,13,14,15,16], particularly the report of the National Bioethics Advisory Commission (NBAC) [17]. In addition, we studied 10 existing consent forms for population-based research involving genetics from CDC and other major studies outside CDC. Although these forms were developed in the absence of specific guidance, they received IRB approval and thus provided useful ideas for appropriate wording and disclosures. Our purpose was not to critique or compare these documents, however, so we do not cite them here. Using these and other resources, one of us (L.B.) created an informed consent template containing suggested language for the collection of new, coded specimens in population-based studies, a supplemental informational brochure to accompany consent documents, and a draft of this manuscript. Following internal and external discussions, the CDC Office of Genomics and Disease Prevention formed an ad hoc group of non-federal experts to review these materials. Members were invited based on their (1) expertise in genetics and/or research ethics; (2) representation of diverse backgrounds, including genetics, medicine, public health, epidemiology, law, ethics, and consumers; and (3) broad understanding of public health research. Draft versions of the template, brochure, and manuscript were circulated to group members electronically, providing a foundation for detailed comments and expert input via an extensive email forum. Group members posed a number of questions for discussion and resolution and documents were revised approximately 10 times in response to comments from group members and JAMA peer reviewers. Group members reviewed all new versions of the documents and final versions were accomplished over an approximate 12 month period.
The informed consent template contains suggested language for informed consent required by ethical considerations and federal regulations. The supplemental brochure provides additional general information to prospective participants about population-based research involving genetics. The content and rationale for selected sections of the template are described below. Why is this study being done? Investigators must explain to prospective participants the purposes of their research (45 CFR 46.116(a)(1)). None of the 10 existing consent forms we reviewed explicitly identified the genes to be examined. For some broad, exploratory studies, the exact genes may not be known and for still others, numerous genes and gene-environment interactions will be under investigation. Specifying certain genes may limit researchers to the study of only those genes even though others may be related to the same disease and, conversely, naming one disease that will be studied (e.g., heart disease) could be misleading if a gene under investigation is also linked to other diseases (e.g., Alzheimer disease) [18]. Focus group research could provide useful insight into the level of detail that has an impact on prospective participants’ decision making. In any event, researchers should be prepared to answer all questions about the genes under investigation to the extent such information is known.
What is involved in this study? In addition to obtaining biological material, population-based research involving genetics often requires gathering information about participants’ exposures to environmental factors and their health outcomes, for example through questionnaires or interviews. Investigators and IRBs must consider the problems raised if information about family history will be elicited, including the potential need to obtain consent from all identifiable individuals [19]. This section of the consent form can also be used to notify participants that investigators would like to store remaining biological material for future testing if the material will be unlinked (or "anonymized") [12]. Unlinking biological materials makes identifying the source difficult, if not impossible, and the potential for harm effectively disappears [17]. If stored materials will be coded or directly identified, a separate section is needed to describe such plans; see below, "What will happen to my sample after the study is over?"
How will information about me be kept private? One of the core ethical considerations of genetic research is the privacy of biological materials and any information derived from them [20,21]. Consent documents should affirm that participants’ privacy will be protected, as well as provide details about security measures and any legal protections that are available (e.g., a Certificate of Confidentiality).
What are the risks of the study? The investigator’s charge is to neither understate nor overstate the risks involved so that prospective participants can make informed choices about entering the study [12]. The risk of harm in genetic research is primarily related to the disclosure of information that could lead to insurance or employment discrimination, social stigmatization, familial disruption, or psychological distress. However, one important factor in assessing the probability and magnitude of these harms is the potential clinical relevance of the results. NBAC states that "most research using human biological materials is likely to be considered of minimal risk because much of it focuses on research that is not clinically relevant to the sample source" [pg. 67]. Similarly, much population-based research involving genetics likely poses minimal risk because it focuses on questions expected to have meaningful public health implications but few clinical implications for individual participants. NBAC presents 4 questions for assessing the extent to which a source could be harmed [pg. 67], which may be useful for IRBs and investigators to consider when describing risks:
Another potential risk is that of group harms [22]. Population-based research involving genetics may focus on particular groups because of differences in disease prevalence. When these groups are socially defined (e.g., by race or ethnicity), research on genetic susceptibilities could perpetuate discrimination against or stigmatization of the group as a whole, even when the increase in disease risk for the individual is small. Current regulations for protecting research participants address risks and benefits to identifiable individuals. IRBs may consider group harms, and should consider consulting group members about cultural and other issues that may be raised by the research. However, the burden of considering group implications falls primarily on the participants themselves, and reasonably foreseeable risks to groups should be disclosed in consent documents.
Are any costs or payment involved? Some genetic studies may have the potential to result in a product with commercial value. When this possibility exists, it should be disclosed along with a statement about whether participants would share in any profits.
How will I find out about the results of the study? According to NBAC [pg. 72], disclosure of research results to participants should be an exceptional circumstance and occur only when all of the following apply: (1) the findings are scientifically valid and confirmed; (2) the findings have significant implications for the participant’s health concerns; and (3) a course of action to ameliorate or treat these concerns is readily available. The consent documents presented here reflect a policy of not disclosing individual research results to participants. The justification for this policy is discussed in the following section.
What will happen to my sample after the study is over? Storing remaining biological material in a coded or directly identified form may enhance its research value in terms of the ability to link it with other clinical and epidemiologic data but raises issues that should be addressed in a separate section of the consent form [12]. This section should clarify who, or at least what types of individuals, will have access to research samples [20,23] and whether third parties (e.g., outside investigators) will have access to the "key" that links coded samples to identifying information. As noted above, the ease of identifying the source of a biological sample is an important part of assessing overall risk. Thus, any arrangements that either facilitate or block identification of participants should be disclosed in the consent form. To assist collection, storage, and appropriate use of biological materials and to help prospective participants understand the decision they are being asked to make, NBAC recommends that consent forms be developed that provide a number of options, such as [pg. 64]:
In some situations, offering this number of relatively imprecise options may be prohibitively complex. Our consent documents suggest an alternative, which is to state that investigators would like to store remaining biological material for future research, describe plans for such research to the extent they are known, and offer participants the option of consenting or refusing. Storing biological materials for future research is essentially a separate project, and consent forms should expressly state the right to refuse to have one’s material stored irrespective of the decision to participate in the immediate project [12].
Much of the language in our consent materials is based on the distinction between genetic research expected to reveal clinically relevant information about individual participants and genetic research that is not. The probability and magnitude of harm--as well as possible personal benefits--arising from genetic research are directly related to the meaning of the results for the health of the participant and her family. When the meaning of the results is not known or when they have only a small impact on the probability of disease, the risks are reduced. Much population-based research involving genetics will not be expected to reveal clinically relevant information. We are in the infancy of the "genetic revolution" and much is unknown. Establishing associations between genes and disease in the general population begins with quantifying statistical relations, and even those that appear to be significant cannot be applied with any precision to particular individuals. As in other epidemiologic research, the interpretation of such data requires a chain of evidence substantiating the validity of the association and supporting a considered judgment as to cause and effect. Building this chain is neither simple nor straightforward, and any single study is but one component. In addition, many population-based genetic studies will focus on lower-penetrance gene variants. Family-based studies provide a unique framework for investigating highly penetrant gene variants, i.e., those that lead to disease expression a majority of the time and thus, through inheritance, produce familial aggregation. Lower-penetrance gene variants by definition lead to smaller increases in relative risk for disease and a corresponding decrease in the probability of harms stemming from misuse of the information. Research on lower-penetrance gene variants may, however, allow better understanding of underlying disease mechanisms and the role of environmental exposures on a population level, providing significant opportunities for public health intervention. There will be population-based studies for which the approach suggested here is not appropriate. At some point, the weight of existing evidence for a gene-disease association or gene-environment interaction will mean that the next generation of epidemiologic studies will be confirmatory rather than exploratory. Furthermore, not all population-based studies will involve lower-penetrance gene variants, and in any event, drawing a dividing line between low and high penetrance would be difficult. When the risks identified in the study are both valid and associated with a proven intervention for risk reduction, disclosure may be appropriate. Thus, the decision to use the approach suggested here should be based on an assessment at the outset of the likelihood that research results will generate information that could lead directly to an evidence-based intervention. Our approach is intended for studies where such results are not expected, as is currently typical of most population-based research involving genetics. This is the basis for our recommendation that individual results not be reported to participants, and therefore merits further discussion: Some IRBs have held that investigators are obligated to offer participants in genetic research their individual results. This stance, perhaps based in part on justifiable concerns arising in the context of family-based research, can create serious problems when applied to most population-based studies. First, at this time, the objective of much population-based research involving genetics is to help establish clinical validity by characterizing gene-disease associations [8]. Until a chain of evidence regarding risk associations has been established, the results of such research will have no clinical interpretation or significance. Second, without independent confirmation, the analytic validity of individual results may be in question. Federal regulations require that results given to patients be performed in a laboratory certified under the Clinical Laboratory Improvement Amendments (CLIA), which establish criteria for quality assurance. Many research laboratories are not certified, as CLIA contains an exemption for "research laboratories that test human specimens but do not report patient specific results for the diagnosis, prevention or treatment of any disease" (42 CFR 493.3(b)(2)). This may create a quandary for investigators if they are expected to offer results. If a researcher discloses an individual’s result in response to a request under the Privacy Act or other applicable law (see below), that is generally not considered a "report for diagnosis" because it is disclosed in order to comply with the law and not for the medical purposes set out under the exemption. However, the quandary may remain with regard to any routine expectation that individual results be offered when the lab is not CLIA certified. Third, when research involves existing biological materials and consent has been waived, offering results is especially problematic. Genetic information should never be given to a participant who does not want it. Therefore, results should not be returned unless a consent process is in place that includes the opportunity for an informed decision not to receive results. Finally, creating an ethical or legal obligation to provide research results to participants could confuse the role of the researcher, especially if the researcher is not a physician. Physicians have an obligation to act in the best interest of their patients. To the extent that generalizable knowledge is generated and available for consideration of its relevance to the standard of care, the researcher’s "obligation" to participants--to conduct good science and disseminate her findings widely--is satisfied. We believe that a reasonable means of addressing these dilemmas may be to apply the criterion proposed above: an assessment at the beginning of a research project of the likelihood that the results will generate information that could lead directly to an evidence-based intervention. If such an outcome is deemed likely on the basis of existing evidence and the aims of the study, the approach suggested here should not be used. The project should be established in connection with a CLIA-approved lab and participants should be informed about the specific genes to be studied. They should be counseled about the risks and benefits of clinically relevant genetic information and offered the option of receiving their individual results. If such an outcome is deemed unlikely, the approach suggested here (or a derivative version; see "Conclusion" below) may be appropriate, including the statement that individual results will not be provided. Attempting to define certain exceptions under which an after-the-fact determination to offer results might be made could prove problematic. Informing participants about these exceptions would be extremely difficult and researchers, IRBs, and participants are apt to disagree about what constitutes a finding sufficiently certain or significant to merit disclosure. Asking participants to consent after explaining clearly that individual results will not be provided may be the optimal ethical approach at this time to broad, exploratory genetic research. Participants should, however, be given the option to receive an aggregate report of overall study results, for example through a newsletter. In the rare event that results unexpectedly have clinical significance, participants could still receive through this mechanism any recommendation to be tested for a particular trait in a clinical laboratory, without revealing individual results. Participants who consent to storage and use of their biological material for future research should be given the option to receive aggregate reports about studies conducted using samples from the "bank" where their material is stored. One condition of obtaining samples from the bank could be an agreement by investigators to supply information about their studies and the overall results for dissemination to participants. The challenge will be to find ways of presenting research findings in lay language and to be clear about any clinical implications and their meanings in different populations. Our consent approach may need to be modified in certain instances to meet applicable laws. For example, the Privacy Act provides individuals the right to review and get copies of their information (5 USC 552(a)(d)(1)). This Act applies when records are maintained by a federal agency in a "system of records," a term that means a group of records under the control of a federal agency from which information is retrieved by the name of the individual, identifying number, or some other identifying particular. When research is subject to the Privacy Act, informed consent documents need to include the Privacy Act notification statement. In addition, individuals should be informed in advance of their right to see their information. However, while the Privacy Act permits an individual access to her records upon request, it does not command affirmative steps to disclose results absent a request.
Federal regulations for the protection of human participants apply to both behavioral and biomedical research, but their articulation reflects an emphasis on clinical research [24], e.g., clinical trials or other research involving manipulation or intervention. As NBAC noted, "Applied to non-clinical research, the regulatory requirements seem to be either irrelevant or insufficient to provide protection" [24]. Dr. Francis Collins, director of the National Human Genome Research Institute, made a similar observation when he stated, "The IRB Guidebook is dusty and out of date for genetics research" [25]. We attempt here to begin meeting the need for appropriate guidelines for population-based research involving genetics, especially lower penetrance gene variants. Our proposed informed consent approach and recommended issues to consider are not fundamentally different from but an extension of existing guidance for other kinds of population-based research. The materials contain suggested language for use when the likelihood of generating information that is of clinical relevance to individual participants is small, as is currently typical of much population-based research involving genetics. This language must be modified to address the specific issues that arise within any individual study. Further broad-based discussion will be important for refining this informed consent approach, as will focus group research among potential research participants. It will also be important to create alternate versions of these materials, for example, for:
As epidemiologic research in this area evolves, it will be important to continue re-evaluating the optimal approach to obtaining informed consent.
The authors thank Janet McNicholl, Deborah Tress, Karen Steinberg, and Diane Wagener. We also thank CDC scientists who brought attention to these issues. This project was supported in part under a cooperative agreement from CDC through the Association of Teachers of Preventive Medicine.
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This page last modified on October 26, 2004 |
