The National Research Act of 19741 created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.2 The act charged the commission with identifying the “basic ethical principles which should underlie the conduct of biomedical and behavioral research involving human subjects” and with developing associated guidelines for the ethical conduct of research.3 The resulting Belmont Report, issued in 1978, drew a sharp distinction between research, defined as “an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge,” and practice, or “interventions…designed solely to enhance the wellbeing of an individual patient or client.”4 In addition, and most important, the report articulated three basic principles that provide the ethical foundation for the conduct of research involving human subjects (see Box 9-1).
Respect for persons involves two ethical considerations: (1) individuals are and should be treated as autonomous agents and (2) individuals with diminished autonomy, due to youth, illness, mental disability, or restricted liberty (e.g., prisoners) should receive additional protections. The principle of respect for persons means recognizing the authority of an individual’s preferences and choices about his or her life. In the context of research, the principle of respect for persons is expressed primarily in the use of informed consent, which requires
1See National Research Service Award Act of 1974. Pub. L. No. 93-348 (2014).
2The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was succeeded by the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. An independent entity established by Congress under Public Law 95-622 in 1978, the latter commission operated from January 1980 to March 1983.
3See Commission Duties, Pub. L. No. 93-348 § 202.1a (1974).
4National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research (Bethesda, MD: 1978), available at: http://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/.
that, as a general rule, individuals be afforded the opportunity to choose whether or not to be involved in research. It is incumbent upon investigators to disclose information about a study in language that is comprehensible to potential subjects so that they can provide meaningful and voluntary informed consent. These disclosures typically include the purpose of the research, the research procedures, risks, anticipated benefits (if any) to the subject, the opportunity to ask questions and receive satisfactory responses, and a statement that participation is voluntary and that the subject has the right to withdraw from the study at any time, for any reason.
Beneficence involves two considerations: (1) the maximization of possible benefits for society and subjects; and (2) the minimization of possible harm to subjects. The principle of beneficence presents obligations that are woven throughout the research enterprise. Investigators, institutions, and sponsors must always endeavor to design and conduct research studies so that these obligations are met. Defining the optimum balance between the obligation to maximize benefit and minimize harm is often challenging. Notably, although the principle of beneficence refers to maximizing benefits for society, the Belmont Report does not expand upon this requirement.
Justice is articulated in the Belmont Report as “fairness in distribution” of research benefits and burdens.5 Questions of justice and equal treatment in the research context are critical in the selection of subjects. The application of justice means that investigators must not offer potentially beneficial research only to some groups, nor select only some accessible, vulnerable, or disadvantaged groups for research that involves high risk or little prospect of direct benefit.
Nature of Concern
The core principles of respect for persons, beneficence, and justice remain central to the protection of human research subjects. However, in the nearly four decades since publication of the Belmont Report, the biomedical and sociobehavioral research enterprises have grown enormously and witnessed profound changes in knowledge, technologies, methodologies, and capabilities, as well as in the potential implications of research findings for individual subjects and society. These continuing changes in research contexts and capabilities, in turn, raise questions as to the proper application and balancing6 of the Belmont principles.
There is, for example, disagreement regarding how best to balance the Belmont principles in the context of clinical trials that compare the effectiveness of widely used interventions for given disorders to determine whether one approach may in fact have a better outcome than the other.7 Questions about application of these principles also arise in research involving deidentified human biospecimens or genomic data, community-based participatory research, clinical trials conducted in emergency settings, study designs that incorporate randomization at the unit (cluster) rather than the individual level, and observational research involving large-scale databases.8 Furthermore, while the Belmont Report did not explicitly articulate an obligation to participate in research, some believe that as all are potential beneficiaries of biomedical and sociobehavioral research, all have a responsibility, when opportunities arise and risks are minimal, to participate in research, as broad participation contributes to a greater understanding of human health, disease, and the effectiveness of proposed therapies across a broader spectrum of society, thus providing benefits to the entire population. Thus, research involving human subjects poses profound and unanswered questions about our status as both potential participants in and beneficiaries of the knowledge gained from biomedical and behavioral studies and about our rights and responsibilities as individuals versus our obligations as members of society.
6T. L. Beauchamp and J. F. Childress, Principles of Biomedical Ethics, 7th ed. (New York: Oxford University Press, 2013): 459.
7See, e.g., R. Platt, N. E. Kass, and D. McGraw, “Ethics, Regulations, and Comparative Effectiveness,” JAMA, vol. 311, no. 15 (2014): 1497–1498.
8See, e.g., E. W. Clayton et al., “Confronting Real Time Ethical, Legal, and Social Issues in eMERGE Consortium,” Genetics in Medicine 10 (2010): 616–620; E. Bromley et al., “From Subject to Participant: Ethics and the Evolving Role of Community in Health Research.” American Journal of Public Health, vol. 105, no. 5 (2015): 900–908.; M. Mitka, “Aiding Emergency Research Aim of Report on Exceptions to Informed Consent,” JAMA, vol. 298, no. 22 (2007): 2608–2609; C. Weijer et al., “The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials,” PLOS Medicine, vol. 9, no. 11 (2012): 1–9; and M. A. Rothstein, et al., “Ethical Issues in Big Data Health Research,” Journal of Law, Medicine, and Ethics, vol. 43, no. 2 (2015): 425–429.
Moreover, the scope of regulations for the protection of human subjects in research, as guided by the Belmont principles, is the focus of considerable discussion.9 In medical settings, the boundaries and distinctions between research involving human subjects and activities designed to assure and improve the quality of care (i.e., in clinical practice) can, at times, be difficult to judge with confidence. Furthermore, the optimal application of regulations, developed primarily in the context of biomedical research, to the entire spectrum of sociobehavioral research has been contested for decades10 and remains unresolved.
Given these formidable questions about the application and scope of the Belmont principles, it is necessary to broadly reconsider the legal and regulatory frameworks governing human subjects research, including the optimal locus of regulatory authority within the executive branch. Should oversight reside within each executive branch agency that funds human research, as is currently the case, or within a single independent federal agency that oversees and regulates all federally funded human research?
Currently, there are tremendous opportunities to improve human health, behavior, and well-being, as exemplified by recent federal initiatives to advance our understanding of the pathobiology, diagnosis, and treatment of cancer,11 treat Alzheimer’s disease,12 and advance precision medicine.13 However, pro-
9See, e.g., Institute of Medicine, Responsible Research: A Systems Approach to Protecting Research Participants (Washington, DC: The National Academies Press, 2002) and Institute of Medicine, Preserving Public Trust: Accreditation and Human Research Participant Protection Programs (Washington, DC: The National Academies Press, 2001).
10See, e.g., National Research Council, Proposed Revisions to the Common Rule for the Protection of Human Subjects in the Behavioral and Social Sciences (Washington, DC: The National Academies Press, 2014) and C. K. Gunsalus et al., “Mission Creep in the IRB World.” Science, vol. 312, no. 5779 (2006): 1441.
11In February 2016, the Obama Administration launched the “National Cancer Moonshot with a $1 billion initiative to provide the funding necessary for researchers to accelerate the development of new cancer detection and treatments.” See White House Office of the Press Secretary, “FACT SHEET: Investing in the National Cancer Moonshot,” February 1, 2016, https://www.whitehouse.gov/the-press-office/2016/02/01/fact-sheetinvesting-national-cancer-moonshot.
12“The National Alzheimer’s Project Act (Public Law 111-375), passed unanimously by Congress in December 2010 and signed into law by President Barack Obama in January 2011, required the creation of a national strategic plan to address the rapidly escalating Alzheimer’s disease crisis and the coordination of Alzheimer’s disease efforts across the federal government.” See Alzheimer’s Association, “The National Alzheimer’s Project Act (NAPA),” http://napa.alz.org/national-alzheimers-project-act-background.
13In January 2015, the Obama Administration launched a $215 million “Precision Medicine Initiative” to “pioneer a new model of patient-powered research that promises to accelerate biomedical discoveries and provide clinicians with new tools, knowledge,
gress and success hinge upon an expansion of research involving human subjects. At the same time, there are persistent and varied questions about the sufficiency of the current regulatory framework. The rapidly changing circumstances surrounding research involving human subjects have led many to ask how the protections of human subjects articulated by the Belmont principles can best be maintained given new research capabilities, the accumulation and accessibility of large amounts of personal information, including health data, and the size and reach of the research enterprise. Addressing these challenges, which the framers of the Belmont Report and Common Rule could not have envisioned, will require judicious and creative thinking about how to balance our societal obligation to protect human subjects in research with the goal of maximizing the benefits to human well-being of society’s investments in biomedical and sociobehavioral research.
A prior Institute of Medicine report called for the formation of an independent committee to reassess the adequacy of the federal regulatory system for overseeing human research.14 The authors of that report noted that the “the language of the Common Rule deserves a careful and comprehensive reassessment for clarity and relevancy” and recommended that Congress “authorize and appropriate funding for a standing independent, multidisciplinary, nonpartisan expert Committee on Human Research Participant Protections whose membership would include the perspective of the research participant.”15 That committee was not created.
In 2011, the Department of Health and Human Services (HHS) issued an Advance Notice of Proposed Rulemaking as part of an effort to update the Common Rule governing human subjects research. HHS subsequently issued a Notice of Proposed Rule Making (NPRM)16 in September 2015.17 Both notices elicited many comment letters describing the deficiencies of the proposals and the risks they pose to the conduct of important research.18
and therapies to select which treatments will work best for which patients.” See White House Office of the Press Secretary, “FACT SHEET: President Obama’s Precision Medicine Initiative,” January 30, 2016, https://www.whitehouse.gov/the-press-office/2015/01/30/fact-sheet-president-obama-s-precision-medicine-initiative.
14See, e.g., Institute of Medicine, Responsible Research: A Systems Approach to Protecting Research Participants, (Washington, DC: The National Academies Press, 2002).
15Ibid, pp. 198-199.
16Federal Policy for the Protection of Human Subjects,” Federal Register 80, no. 173 (September 8, 2015): 53933, https://www.gpo.gov/fdsys/pkg/FR-2015-09-08/pdf/201521756.pdf.
18See, e.g., letters from the Association of American Medical Colleges, available at: https://www.aamc.org/download/451896/data/aamcsubmitscommentstohhsonthecommonrulenprm.pdf; the Council on Governmental Relations, available at: http://cogr.edu/COGR/files/ccLibraryFiles/Filename/000000000257/NPRMCommonRuleCOGRResponse12-8-15%20(2).pdf; the Association of American Universities and the Association of Public and Land-grant Universities, https://www.aau.edu/WorkArea/DownloadAsset.aspx?id=16885;
Several provisions of the proposed regulations have been identified as problematic. These include: (1) proposed changes relating to the definition and handling of biospecimens; (2) how determinations are made regarding whether certain types of research may be excluded from administrative or institutional review board consideration; (3) inconsistencies amongst the proposed changes; and (4) an absence of specifics for key deliverables.
Both the significant number of comments and the concerns expressed in response to the proposed rule highlight a need to address numerous issues that have emerged since publication of the Belmont Report. Indeed, the regulations governing human subject research merit regular examination and updating. As will be demonstrated below, the current regulatory atmosphere indicates that our nation would benefit from a standing independent national advisory commission tasked with regularly examining and updating regulations governing all federally funded human subjects research and charged with addressing difficult and precedent-setting cases as well as matters of general policy.
During a presentation at a recent meeting of the Secretary’s Advisory Committee on Human Research Protections,19 Lauren Hartsmith of the HHS Office of Human Research Protections (OHRP)20 provided an analysis of the public comments on the September 2015 NPRM. She noted that:
“There was concern about the overall complexity and the length of the NPRM. Concern about the lack of availability of some of the key deliverables in the NPRM. Specifically, those were the exemption determination tool, the broad consent template, and the Secretary’s list of privacy safeguards.”21
and Public Responsibility in Medicine and Research, available at: http://www.primr.org/WorkArea/DownloadAsset.aspx?id=10166.
19The Secretary’s Advisory Committee on Human Research Protections (SACHRP) “provides expert advice and recommendations to the Secretary of HHS on issues pertaining to the protection of human subjects in research.” See http://www.hhs.gov/ohrp/sachrp-committee/. The committee is charged with advising “the Secretary on how to improve the quality of the system of human research protection programs, including the responsibilities of investigators, institutional review boards (IRBs), administrators, and institutional officials, and the role of the Office for Human Research Protections and other offices within the Department of Health and Human Services.” See SACHRP Charter, available at: http://www.hhs.gov/ohrp/sachrp-committee/charter/index.html.
20The Office for Human Research Protections “provides leadership in the protection of the rights, welfare, and wellbeing of subjects involved in research conducted or supported by the U.S. Department of Health and Human Services.” See “About OHRP,” available at: http://www.hhs.gov/ohrp/about-ohrp/index.html.
21L. Hartsmith. HHS Office of Human Research Protections (OHRP). NPRM Update: Summary of Public Comments. Presentation to the Secretary’s Advisory Committee on Human Research Protections (SACHRP), May 18, 2016.
Video of the SACHRP meeting and Hartsmith’s presentationare available at: https://videocast.nih.gov/summary.asp?Live=19186&bhcp=1.
With regard to the “exemption determination tool,” the NPRM proposes that federal departments and agencies develop a voluntary research exemption determination tool. Based on information input by a researcher, the web-based tool would determine whether research is exempt from the human subjects regulations.22
Regarding the broad consent template, the NPRM proposes the development of a template for acquiring consent from an individual for the storage or maintenance of biospecimens for use in future research.23 Templates are expected to contain all required consent elements (such as a description of the research material covered, the option to consent, and the ability to withdraw consent). The NPRM indicates that at least two broad consent templates will be developed: (1) for information and biospecimens originally collected in the research context; and (2) for information and biospecimens originally collected in a non-research context. The templates will be issued for public comment at a later date.
A third key deliverable, the Secretary’s “list of privacy safeguards,” is also unavailable. This list is to be developed following public comment on the types of safeguards that would be appropriate.24 These safeguards would be designed to protect the privacy of human participants in research by protecting the confidentiality of personal information. Other laws or regulations that currently mandate the protection of human research participants would need to be examined as a part of the development of the envisioned safeguards.
The omission of specifics on key tools and guidelines like the exemption determination tool, consent templates, and list of privacy safeguards is problematic; because the items are undefined at present, it is impossible to comment on their merit or utility prior to the issuance of the final rule. Furthermore, it is not possible to provide an accurate estimation of regulatory impact without a clear understanding of what compliance will involve.
Uncertainty may also lead to an increased regulatory burden as institutions, in an effort to comply with vague or fragmentary regulations, implement speculative procedures which may ultimately be unwarranted. Institutions may also elect to reject, delay, or halt research in areas of regulatory vagueness.
In her presentation to SACHRP, Hartsmith also noted that there is “concern about some of the proposals being internally inconsistent and concern about
22See “Federal Policy for the Protection of Human Subjects,” Federal Register 80, no. 173 (September 8, 2015): 54009. The NPRM states that, “Under the proposed rule, unless otherwise required by law, exemption determinations may be made by (1) an individual who is knowledgeable about the exemption categories and who has access to sufficient information to make an informed and reasonable determination, or (2) the investigator who accurately inputs information into the federally created web-based decision tool.”
23Ibid, p. 53969.
24The NPRM states that “For the purposes of informing the development of…privacy safeguards, comment is sought on what types of safeguards would be appropriate. There are additional statutes or acts that mandate the protection of privacy and confidentiality of identifiable private information that may be reasonable to include.” Ibid, p. 53979.
proposals giving investigators too much leeway to determine if their research falls under the rule.” The latter concern “was specifically around the proposed concept of exclusions in the NPRM.”25
With regard to exclusions, the NPRM identifies eleven types of research that fall outside the scope of the proposed regulations. Some of this research is also “exempt” under current Common Rule regulations. As envisioned by the NPRM, excluded research is not subject to administrative or IRB review. Instead, investigators have the responsibility to make determinations as to whether the research should be subject to external review. Examples of excluded research include: “collection and analysis of data, biospecimens, or records by or for a criminal justice agency for activities authorized by law or court order solely for criminal justice or criminal investigative purposes;” “quality assurance or improvement activities involving the implementation of an accepted practice to improve the delivery or quality of care or services;” and “public health surveillance activities, including the collection and testing of biospecimens, conducted, supported, requested, ordered, required, or authorized by a public health authority and limited to those necessary to allow the public health authority to identify, monitor, assess, or investigate potential public health signals or the onset of a disease outbreak.”26
In assessing the proposed exclusions, one researcher observed that some exclusions “will likely be widely welcomed, such as…[an] explicit exclusion of journalism, oral history, biography, and historical scholarship activities.” However, there is “worry that the exclusion of certain activities…could lead to a weakening of subject protections.” “The proposed rule does not…offer insight into how determinations about whether the disclosure of information would reasonably place subjects at risk will be made.”27 Further, the NPRM does not sufficiently describe how the proposed exclusions will be implemented to ensure adequate protection of human research participants.
Finally, Hartsmith presented the following comment as illustrative of the regulated community and public’s comments on the NPRM. She prefaced the comment by stating, “This is…a sample quotation from one of the commenters. It is a good summary of the concerns that were expressed about the overall document.”:
The urgency to approve a final revised Common Rule prior to the end of the 2016 is deeply concerning and has resulted in a premature, rushed
25L. Hartsmith. HHS Office of Human Research Protections (OHRP). NPRM Update: Summary of Public Comments. Presentation to the Secretary’s Advisory Committee on Human Research Protections (SACHRP), May 18, 2016.
26See “Federal Policy for the Protection of Human Subjects,” Federal Register 80, no. 173 (September 8, 2015): 53948-53949.
27E. A. Hurley, “Unpacking the NPRM: A New Category of Exclusions,” Ampersand, October 13, 2015, available at: http://blog.primr.org/unpacking-the-nprm-a-new-categoryof-exclusions/.
document that is replete with deficiencies, contradictions, areas of conflict or overlap with other federal requirements, undefined processes, categories or lists and yet to be developed forms and templates. The lack of availability of these items at this late stage in the rule making process makes commentary particularly challenging.28
During the SACHRP meeting, there was significant discussion about the process of moving from an NPRM to a final rule. An agency is not permitted to base its final rule on the number of comments in support of the rule over those in opposition to it. Rather, the agency must base its reasoning and conclusions on the rulemaking record, consisting of the comments, scientific data, expert opinions, and facts accumulated during the pre-rule and proposed rule stages.29 At the meeting, OHRP Director Jerry Menikoff reiterated that a final rule “should be a logical outgrowth of what was originally presented or something that was appropriately discussed as part of the comments in the public comment process.”30
The comments and issues highlighted in Hartsmith’s presentation to SACHRP align with the results of an analysis of public comments by the Council on Governmental Relations and the Association of Public and Land-grant Universities (see Box 9-2). They also align with the assessment of members of the leadership of the nonprofit Public Responsibility in Medicine and Research (PRIM&R) in a letter to the New England Journal of Medicine:
The NPRM is a troublingly incomplete product: internally inconsistent, dependent on untested assumptions, and too inchoate to be ready for promulgation with just some minor editing. The document, which had largely been crafted behind closed doors, invited public response to 88 unresolved policy questions in addition to comments on the proposed rules themselves. It introduces new regulatory mandates when less rigid solutions would offer sensible alternatives and permit adjustment in light of experience.31
28L. Hartsmith. HHS Office of Human Research Protections (OHRP). NPRM Update: Summary of Public Comments. Presentation to the Secretary’s Advisory Committee on Human Research Protections (SACHRP), May 18, 2016.
The source for this statement is a comment letter from Emma A. Meagher, Senior Associate Dean, Clinical Research and Associate Vice Provost, Human Research and Dawn Bonnell, Vice Provost for Research, University of Pennsylvania. The letter is available at: https://www.regulations.gov/#!documentDetail;D=HHS-OPHS-2015-0008-0579.
29See Office of the Federal Register, “A Guide to the Rulemaking Process,” available at: https://www.federalregister.gov/uploads/2011/01/the_rulemaking_process.pdf.
30J. Menikoff, HHS Office of Human Research Protections at May 18-19, 2016 SACHRP Meeting.
Video of the SACHRP meeting is available at: https://videocast.nih.gov/summary.asp?Live=19186&bhcp=1.
31D. H. Strauss, E. A. Hurley, and A. M. Capron, “Reform of Clinical Research Regulations,” New England Journal of Medicine, no. 374 (2016): 1693-1694.
It is instructive to examine a key item in the NPRM that raised particular concern, as such a consideration illustrates the problems of moving the NPRM to a final rule.
The NPRM proposes an expansion of the definition of human subject to include deidentified, excess, or residual biospecimens. This expansion would require that individuals provide written “broad” consent for the use of such biospecimens in research—a significant departure from current practice. This would permit patients undergoing tissue excisions to grant permission for future unspecified uses of their de-identified biospecimens. It is important to understand that biospecimens, properly preserved, can last for generations. Such specimens have proved helpful in addressing unanticipated medical issues using technologies that did not exist at the time of excision or collection. The inability to envision future opportunities for research that could advance knowledge raises questions about the meaning and ethical sufficiency of “broad consent.” If, for example, waivers were unavailable for the clinical use of biospecimens for which no research use was intended at the time of excision or collection, critical post facto correlations, for example, between the Zika virus and microcephaly, may go unrecognized.
Redefining research with de-identified biospecimens as human subjects research would impose significant burdens and limitations on research institutions and the ability of research institutions to obtain specimens from health institutions that do not have the infrastructure or resources to comply with the proposed revisions to the Common Rule. As a result, research samples may not be as broadly representative of the population as they have been and research findings may no longer be so generalizable. Such limitations will likely imperil the conduct of
long-established and remarkably fruitful areas of research.32 Research on excess or residual biospecimens has contributed enormously to the growth of medical knowledge for nearly a century and a half, improving human health with little evidence of harm to individuals whose biospecimens were used in this way.33 That some find the implications of broad consent for future research troubling34 is another compelling example of the need for thoughtful deliberation about how best to protect individual human research subjects while continuing to advance medical knowledge that will benefit many—including, potentially, subjects themselves and their loved ones. Further, there is little evidence that individuals understand exactly what they are being asked to consent to. Nor can patients or their caregivers credibly envision what the future might hold.
In addition, as envisioned by the NPRM, broad consent would expand informed consent practices to nonresearch settings where the individual’s priority is exclusively clinical care, and it would involve institutional personnel unfamiliar with research or with the principles guiding human subjects research.35 Thus, whether the elements of informed consent laid out in the Belmont Report (information, comprehension, and voluntariness) can be achieved by broad consent as envisioned by the NPRM is debatable.36
As the example of biospecimens demonstrates, a new assessment is needed to determine whether current measures adequately protect human subjects in contemporary biomedical research without unjustifiably impeding the conduct of well-designed research that contributes to human well-being. Put differently,
32See, e.g., the joint statement issued on May 6, 2016, the Association of American Universities, the Association of Public and Land-grant Universities, and the Council on Governmental Relations. In the statement, the organizations state that, “There is broad consensus that the proposed regulations regarding biospecimens, as written, would be damaging to science, medicine, and human health and would not improve participant safety and autonomy.” See http://www.cogr.edu/COGR/files/ccLibraryFiles/Filename/000000000347/050916prCommonRuleFinal.pdf.
33Under current regulations, requests for discarded specimens are reviewed when specimens are: (1) identifiable or (2) de-identified but collected specifically for a particular research project. If specimens do not have identifiers, they are exempt from institutional review board (IRB) review. In instances where IRB review is required, investigators must affirm to the IRB that identifiers will not be retained and provide information about the procedures that will be used to ensure that the specimens will be de-identified. Under the proposed regulations, a waiver of consent would be difficult to obtain, and the ability of an IRB to follow the current practice of review of discarded specimens for use in research would essentially be eliminated.
34See, e.g., D. H. Strauss, E. A. Hurley, and A. M. Capron. “Reform of Clinical Research Regulations.” New England Journal of Medicine, no. 374 (2016): 1693–1694.
35See, e.g., N. E. Kass et al., “The Research-treatment Distinction: A Problematic Approach for Determining Which Activities Should Have Ethical Oversight,” Hasting Center Report, vol. 43, no. S1 (2013): S4–S15.
36See, e.g., Jocelyn Kaiser, “Researchers Decry Consent Proposal,” Science, vol. 352, no. 6288 (2016): 878–879.
where should the balance points be set among autonomy, beneficence, and justice? The current system may, for example, be better served by explicit sanctions against investigators and institutions seeking to re-identify biospecimen sources by any method, including linkage of genomic sequence data to identifiers, rather than by redefining all research with de-identified biospecimens as human subjects research subject to a revised Common Rule.
Implementation of the proposed rule necessitates maintaining a link between the consent document and the biospecimen. This proposal per se raises substantial risks of re-identification and loss of privacy. Further, the associated financial37 and societal costs will be significant. Many clinical care facilities, such as those serving underserved or rural populations, for example, may not be able to bear these costs, thereby undermining the principles of justice and beneficence by skewing research toward studies and populations that can be accommodated only at large medical centers. As PRIM&R noted in its comment letter in response to the NPRM:
The stated goal of the NPRM is to reduce unnecessary administrative burden associated with regulation, [but] the requirements related to the use of biospecimens in research will likely create new barriers to research participation without advancing subject autonomy. New systems and mechanisms for obtaining and tracking broad consent across all patients entering a facility will need to be developed and implemented. This process will require significant resources on the part of institutions that collect biospecimens; it will be entirely out of reach for small healthcare institutions and community and school-based clinics, and may very well be beyond the capability of some larger and better-resourced institutions. As some facilities decide that they cannot manage the costs (in terms of time, staff, infrastructure, and other resources) of obtaining and tracking broad consent (is the consent still valid? does it impose any limits or requirements regarding the use of an individual’s specimens? etc.), specimens collected for clinical purposes at such facilities will no longer be available for future research. As a result, the populations within the communities those institutions serve may be excluded from such research. This is problematic from the perspectives both of justice and of good science.38
37As calculated by HHS, over the 2016–2025 period, present-value benefits of all proposed changes will be $2.6 billion with annualized benefits of $308 million (as estimated using a 3 percent discount rate). Present-value costs are estimated at $13.3 billion with annualized costs of $1.6 billion (as estimated using a 3 percent discount rate). See “Federal Policy for the Protection of Human Subjects,” Federal Register 80, no. 173 (September 8, 2015): 53933, https://www.gpo.gov/fdsys/pkg/FR-2015-09-08/pdf/2015-21756.pdf. Weill Cornell Medicine, however, estimates that “it could cost [the institution] as much as $4 million annually to comply with the expanded regulations.” See L. H. Glimcher, “How Not to End Cancer in Our Lifetimes,” Wall Street Journal, April 4, 2016.
Research regulations should facilitate innovative ways for institutions to communicate with patients in meaningful and effective ways about participation in activities aimed at improving health care delivery. Such activities, when carried out systematically, are often referred to as quality improvement (QI) research.39 Lack of clarity in the NPRM regarding which quality improvement activities constitute research, and when written consent is required for institutions to conduct such research, may discourage valuable and low-risk efforts to improve patient care.
The NPRM is marred by omissions, the absence of essential elements, and a lack of clarity. In addition, important questions about the overall impact and long-term costs of the proposed regulatory changes are unresolved. In light of these deficiencies, it would be impractical to use the current NPRM as the basis for achieving a meaningful, consistent, and harmonious revision of the regulations governing human subjects research that is optimally responsive to developments that have occurred since the publication of the Belmont Report.
The core principles of respect for persons, beneficence, and justice as articulated in the 1978 Belmont Report are central to the protection of human subjects in research studies.
In the nearly four decades since the publication of the report, however, the biomedical and sociobehavioral research enterprises have grown enormously. This growth, accompanied by the development of a remarkable number of new research capabilities and contexts, raises questions as to the optimum application and balancing of the Belmont principles, as well as whether these principles are, in and of themselves, still sufficient pillars upon which to build human research protection programs and regulations. In addition, the overarching legal and regulatory frameworks and institutional arrangements governing human research subjects require reconsideration and clarification.
Addressing contemporary challenges associated with human subjects research, including new research capabilities and contexts; the profusion, sharing, and accessibility of personal data; and increasing privacy concerns, will require creative and forward-looking legal, regulatory, and institutional frameworks. The important work of addressing these challenges is critical both for enhancing protections for individuals participating in research and for optimizing the federal investment in human research to advance knowledge and improve individual and societal well-being.
The Notice of Proposed Rulemaking on the Federal Policy for the Protection of Human Subjects would impose additional burdens that could be detrimental to areas of important research. The committee believes that the NPRM does not ade-
39See, e.g., D. H. Strauss, E. A. Hurley, and A. M. Capron, “Reform of Clinical Research Regulations,” New England Journal of Medicine, no. 374 (2016): 1693–1694.
quately or effectively address the breadth, depth, and import of unanswered questions; rather, its inadequacies signal a pressing need for a comprehensive review of the nation’s ethical, legal, regulatory, and institutional frameworks for protecting human research subjects.40 At this time, there is no entity that can carry out this review. SACHRP and OHRP perform valuable roles,41 but neither could conduct the type of review that is required. SACHRP, through OHRP, advises the Secretary of HHS, and neither OHRP nor SACHRP engages other departments and agencies. The current complexity of the issues related to human subjects research requires thorough, independent, cross-agency consideration and expert input from a wide range of disciplines and stakeholder groups.
9.1. The committee recommends that Congress authorize, and the President appoint, an independent, free-standing national commission modeled on the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. This commission was authorized by Congress under Public Law 95-622 in 1978, appointed by the President in 1979, and existed outside the structure of federal departments and agencies. The commission had a direct line-item appropriation from Congress, appointed its own staff, and set its own agenda.
Congress should charge the proposed commission with examining and updating as necessary the ethical, legal, and institutional frameworks governing human subjects research. The commission should make recommendations to the President, Congress, and relevant federal agencies regarding how the basic ethical principles governing human subjects research should be applied to unresolved human research questions and novel human research contexts, including but not limited to:
- Research involving anonymous and de-identified human biospecimens;
- Research involving large datasets, for example, research with human genomic, transcriptomic, proteomic, or metabolomic data or associated DNA, RNA, and protein analyses and relevant integrated approaches;
- Research in which the interests of discrete and insular communities are at stake;
- Clinical studies conducted in emergency settings;
- Research involving adults with diminished decision-making capacities;
- Clinical trials where the unit of intervention is a cluster or group;
40The committee notes that the National Research Council report cited earlier recommended the formation of an independent committee or commission to address comparable issues.
41See footnotes 19 and 20 in this chapter.
- Clinical studies comparing the effectiveness of different accepted interventions for a given disorder to determine whether one approach may be preferable to the other;
- Observational research involving large-scale databases;
- The appropriate boundaries of regulation of minimal-risk sociobehavioral research; and
- Research aimed at clinical innovation and quality assurance and improvement.
The commission should have two broad charges:
Recommend to the President and Congress ethically sound regulatory approaches for unresolved questions in human subjects research, including:
- The scope of human research activities that should be covered by federal regulations for human subjects research (including the determination of the types of low-risk research activities, such as some types of sociobehavioral research, that should fall outside the scope of the regulations);
- How regulation should address the increasingly blurred boundaries between research and medical care and the means by which new regulations should distinguish between the two;
- How to incorporate investigator responsibilities into human subjects research regulations; and
- How to balance individual rights, such as the right to privacy, with collective obligations to advance public health and well-being.
Recommend to the President and Congress revisions in the legal and institutional structures for regulating research with human subjects that address such questions as:
- Where in the executive branch should the regulatory authority for human subjects research lie? Should it rest within each agency that conducts or funds such research, as is currently the case, or should there be a single, independent agency that regulates all federally funded human subjects research? Which model best serves the interests of efficiency, harmonization, and the mitigation of conflicts of interests?
- Should the United States have a standing advisory committee on human subjects protections? If so, what types of cases or questions should it address, how should it be structured, whom should it advise, and where should it fit within the agency structure?
9.2. To ensure that the proposed national commission can address the full range of unanswered questions regarding the protection of human subjects in federally funded research, the committee recommends that the executive branch withdraw the Notice of Proposed Rulemaking on the Federal Policy for the Protection of Human Subjects. The committee further recommends that the regulatory structure protecting human research subjects not be revised until the national commission has issued its report and the research community, patient groups, the public, and others have had an opportunity to consider and respond to the commission’s recommendations.