Introduction and Overview
The National Bioethics Advisory Commission (NBAC) has identified research involving human biological materials as an increasingly important component of biomedical research and an area in which there is need to enhance the protection of human subjects involved in research. In August, 1999 NBAC issued a report titled Research Involving Human Biological Materials: Ethical Issues and Policy Guidance. The report offers 23 recommendations directed at researchers, institutions, Institutional Review Boards (IRBs), federal agencies and/or other components of the biomedical research and human subject protection enterprises. NBAC has requested that the Department of Health and Human Services (DHHS) review and provide a response to its report. To this end, the Office of Science Policy of the Office of the Assistant Secretary for Planning and Evaluation convened a multi-agency Working Group to analyze the appropriateness, feasibility and practical implications of implementing NBAC’s recommendations and to develop a set of proposed DHHS activities to enhance the protection of human subjects in research involving human biological materials.
The Working Group commends NBAC for its careful analysis and far-reaching recommendations. NBAC’s report will undoubtedly inform DHHS policy regarding human subject protection over the next several years and beyond. The Working Group concurs with a significant majority of NBAC’s recommendations, either in principle or precisely as stated. In a few instances, detailed in this document, the Working Group foresaw some practical problems in implementation of specific recommendations. With a few appropriate exceptions, the Working Group developed proposed actions for each of NBAC’s recommendations.
The Working Group recognizes that, until such time as federal regulations are revised through legislation or rulemaking, any enhancements to federal oversight of human subject protection must be carried out within existing regulations. The Working Group looks forward to NBAC’s forthcoming report on Ethical and Policy Issues in Research Involving Human Participants, which is expected to make recommendations for broad changes in regulations. While the nature and extent of regulatory changes, if any, are not predictable, the Working Group believes that a number of important NBAC recommendations should be implemented as soon as possible. Therefore, for certain of NBAC’s recommendations, the Working Group considered not only what enhancements could be made under current regulations but also what changes could be implemented by investigators and institutions on a voluntary basis.
Several of NBAC’s recommendations address disclosure of research results to subjects. While NBAC has circumscribed the instances in which an investigator may disclose research findings to study subjects, the recently issued Health Insurance Portability and Accountability Act (HIPAA) privacy regulation established the rights of subjects to access information about themselves, including research results. Because some aspects of NBAC’s recommendations are not compatible with the HIPAA privacy regulation, this issue requires further analysis.
The Working Group also recognizes that an increasing amount of human biological materials research involves genetic testing or genetic information1. Such research may or may not result in more than minimal risk to the human subjects who provide the materials but is often assumed to be of high risk by virtue of being a genetic study. The Working Group suggests that Institutional Review Boards (IRBs) review such research against specific criteria and not assume that genetic studies intrinsically pose more than minimal risk.
Brief summaries are provided below of the Working Group’s analysis and proposed actions for each of NBAC’s recommendations. The recommendations have also been summarized and are organized in clusters identical to the groups in NBAC’s report.
Recommendations Regarding Interpretation of the Existing Federal Regulations
Summary of Recommendations and Discussion: Recommendations 1 and 2 address the circumstances under which research conducted with human biological materials should be considered human subjects research and when such research is exempt from current federal regulations. In Recommendation 1, NBAC proposes that (a) research conducted with unidentified samples not be considered human subjects research, (b) research conducted with anonymized samples be considered human subjects research that may be exempt from regulations, and (c) research conducted with identified or identifiable samples be considered human subjects research that could be exempt from regulations only under specific conditions. While the Working Group agrees with substantial portions of Recommendation 1, analysis revealed significant impediments to practical applications of parts of this recommendation. In Recommendation 2, NBAC suggests, and the Working Group concurs, that the purpose for which human biological materials were originally collected, i.e., whether for research or for clinical purposes, should not determine whether research using such samples is eligible for expedited review by IRBs.
Summary of Proposed Actions: In response to Recommendation 1, the Working Group proposes that the Office for Human Research Protections2 (OHRP), in consultation with FDA, (1) reinforce existing guidance that holds institutions, not investigators, responsible for determining whether or not research is subject to Regulations3, (2) ensure that institutions have policies and procedures for making such determinations and (3) broadly disseminate current guidance that is applicable to determining whether research involving coded human biological materials meets the definition of human subjects research. In response to Recommendation 2, the Working Group proposes that DHHS implement NBAC’s suggestion through publication of a federal register notice stating that research using human biological materials originally collected for research purposes may be eligible for expedited review if the newly proposed research poses no more than minimal risk to study participants.
Recommendation Regarding Special Concerns About the Use of Unlinked Samples
Summary of Recommendation and Discussion: In Recommendation 3, NBAC focuses on the conditions that must be met by an investigator proposing to anonymize samples that are already in his or her control before his/her research can be recognized as exempt from the Regulations. NBAC proposes, and the Working Group agrees, that before research using such samples is deemed exempt from human subject protection regulations, institutions must ensure that the process used to anonymize samples is effective. NBAC also addresses the concern that research with anonymized samples may “unnecessarily reduce the value”4 of the research. While the Working Group shares NBAC’s concern on this issue, analysis identified practical obstacles to implementation of Recommendation 3(b).
Summary of Proposed Action: The Working Group proposes that DHHS explore the feasibility of collaborating with appropriate professional and scientific societies to develop educational materials on methods for anonymization of human biological materials.
Recommendations Regarding Requirements for Investigators Using Coded or Identified Samples
Summary of Recommendations and Discussion: The Working Group concurs with both Recommendations 4 and 5, which address the need to protect the identity of individuals who are sources of human biological materials used in research. Recommendation 4 highlights the role and responsibilities of repositories, and Recommendation 5 describes information that IRBs should require from investigators before approving research with human biological materials that are or can be linked to human subjects.
Summary of Proposed Actions: In response to Recommendation 4, the Working Group proposes that OHRP, in consultation with FDA, review the adequacy of existing guidance and disseminate that which remains current to repositories that are subject to the Regulations, and undertake outreach to encourage repositories not subject to federal oversight to adopt this guidance. While Recommendation 5 does not require specific DHHS action, the Working Group proposes that OHRP, in consultation with FDA, work to increase awareness of relevant guidance and other educational materials that are useful in the preparation and review of research proposals.
Recommendations Regarding Obtaining Informed Consent
Summary of Recommendations and Discussion: Recommendations 6 through 9 address the process of obtaining informed consent for the research use of human biological materials. The Working Group concurs with Recommendation 6, which addresses the need for separating consent for research from consent for clinical procedures. The Working Group agrees with Recommendation 7 regarding an individual’s right to decline to participate in research and with Recommendation 8 regarding interpretation of existing consents with respect to research that was not foreseen at the time the original consent was obtained. For Recommendations 7 and 8 the Working Group identified issues that should be considered with a view toward assuring that implementation of NBAC’s recommendations enhances human subject protection and biomedical research. Finally, the Working Group concurs with Recommendation 9, which addresses the consent options that could be offered to potential research subjects with respect to use of their human biological materials in research.
Summary of Proposed actions: In response to Recommendation 6, the Working Group proposes that OHRP, in conjunction with NIH, FDA, CDC and other appropriate DHHS agencies, sponsor a workshop on informed consent to assist in determining what additional studies are needed and what additional guidance might be developed by OHRP in conjunction with other appropriate agencies. In response to Recommendation 7, the Working Group proposes that OHRP, in consultation with FDA, reinforce the need for appropriate training of individuals who are responsible for obtaining informed consent, as well as the need to ensure that the right to decline to participate in research is clearly stated in consent forms. In response to Recommendation 8, the Working Group proposes that OHRP, in consultation with FDA, take the lead in developing guidance on evaluating the adequacy of extant consent documents. In response to Recommendation 9, the Working Group proposes that DHHS continue to fund studies in this area and disseminate the results of such studies.
Recommendations Regarding the Criteria for Waiver of Consent
Summary of Recommendations and Discussion: Recommendations 10 through 13 address four criteria in federal regulations that govern waiver of consent. Each of these recommendations is tied to one of four criteria, all of which must be satisfied before a waiver of consent may be granted. These criteria require the researcher to demonstrate that (1) the research poses minimal risk to subjects, (2) there is no adverse effect on subjects’ rights and welfare, (3) it would be impracticable to obtain consent, and (4) subjects will be provided, whenever appropriate, with additional pertinent information after completion of the study. The Working Group concurs with NBAC’s four recommendations for application of these criteria to research involving human biological materials. However, the Working Group notes that, for research regulated by the FDA, rules governing waiver of consent are more restrictive. The Working Group also considered some practical issues that must be addressed with respect to whether and how findings from a study conducted under a waiver of consent may be shared with a study subject. Finally, the Working Group identifies some issues that would not be resolved by implementing Recommendation 12 at a specific point in time.
Summary of Proposed Action: The Working Group proposes that OHRP, in consultation with FDA, prepare and disseminate guidance to support implementation of Recommendations 10-13.
Recommendations Regarding Reporting Research Results to Subjects
Summary of Recommendations and Discussion: Recommendations 14 through 16 address the disclosure of research results to subjects. The Working Group considered these recommendations with respect to both disclosure initiated by the researcher and disclosure at the request of the subject. Recommendation 14 outlines conditions that should be met before research results may be reported to subjects. The Working Group notes that Recommendation 14 appears to be in conflict with some provisions of the HIPAA privacy regulation which was issued after NBAC completed its report. If such conflict could be resolved, the Working Group agrees that only valid information should be disclosed but is troubled by the remaining two criteria that are to be met before results can be disclosed to subjects. The Working Group concurs with Recommendations 15 and 16, which require researchers to identify the circumstances under which research results warrant disclosure, to develop a plan for managing such disclosure, and to provide appropriate medical advice or referral when disclosure is made.
Summary of Proposed Actions: The Working Group proposes further analysis of Recommendation 14. The Working Group proposes that OHRP, in consultation with FDA, develop and disseminate guidance for implementation of Recommendations 15 and 16.
Recommendations Regarding the Considerations of Potential Harms to Others
Summary of Recommendations and Discussion: Recommendations 17 and 18 address the need to minimize the risk of harm to groups associated with the individuals who are the sources of the human biological materials to be used in research. The Working Group agrees with the suggestion in Recommendation 17 that investigators should plan research to minimize such risks and should, when appropriate, consult with representatives of relevant groups in planning research that could pose such risks. The Working Group is persuaded that further work is needed to identify appropriate methods for consultation with representatives of groups. While it is appropriate for IRBs to consider risk of group harm even for studies conducted with anonymized samples, the current regulations do not provide a mechanism for DHHS to require IRB review of such studies. The Working Group agrees with Recommendation 18, which states that risk of group harm should be disclosed during the process of obtaining informed consent for research.
Summary of Proposed Actions: While awaiting NBAC’s recommendations regarding group harm in its forthcoming report on federal oversight of human subject protection, the Working Group proposes that DHHS encourage studies of strategies, including those suggested in Recommendation 17, to minimize group harm. The Working Group proposes that OHRP, in consultation with FDA, develop guidance for implementation of Recommendation 18.
Recommendations Regarding the Publication and Dissemination of Research Results
Summary of Recommendation and Discussion: Recommendation 19 addresses the risk that dissemination of research results could cause harm to subjects or groups with which subjects are associated. The Working Group agrees that investigators should consider such risks and make efforts to reduce them. The Working Group also agrees with Recommendation 20, which urges journals to adopt a policy that would require published results of research studies to include a statement about whether research was conducted in compliance with federal human subject protection regulations, regardless of whether or not the research was subject to federal regulatory oversight.
Summary of Proposed Actions: No DHHS action is required.
Recommendations Regarding Professional Education and Responsibilities
Summary of Recommendations and Discussion: The Working Group concurs with NBAC’s Recommendations 21 and 22 regarding professional education and responsibilities. Recommendation 21 focuses on the need to continue and expand efforts to train investigators and to identify exemplary practices for protection of human subjects in research involving human biological materials. Recommendation 22 addresses the need for additional resources to ensure protection of human subjects. The Working Group agrees with this recommendation and also underscores the need to ensure appropriate utilization of existing resources.
Summary of Proposed Actions: In response to Recommendation 21, the Working Group proposes that DHHS continue ongoing activities and coordinate such efforts throughout the Department. In response to Recommendation 22, the Working Group proposes that DHHS continue to work with awardee institutions to highlight the importance of adequate support for human subject protection activities.
Recommendation Regarding the Use of Medical Records in Research on Human Biological Materials
Summary of Recommendation and Discussion: Recommendation 23 points out that there are similarities between research using human biological materials and research using medical records and calls upon those drafting medical records privacy laws to harmonize rules governing the two types of research. The Working Group concurs with this recommendation, but calls attention to the fact that there are also important differences between these two areas of research.
Summary of Proposed Action: No DHHS action is required.
1 – Widely varying definitions for “genetic testing” and “genetic information” have been proposed and/or adopted by professional associations and advisory committees, in legislation, and in regulations. The charge to the Working Group did not include a mandate to define these terms.
2 – References to OHRP in this report also refer, whenever applicable, to OHRP’s predecessor organization, the Office for Protection from Research Risks (OPRR).
3 – The Working Group refers to the body of DHHS human subject protection regulations as “the Regulations”.
4 – NBAC Report Research Involving Human Biological Materials: Ethical Issues and Policy Guidance at page 61, Recommendation 3 (b).