Outsourcing Ethical Obligations: Should the Revised Common Rule Address the Responsibilities of Investigators and Sponsors?

The “Common Rule,” found at 45 C.F.R. 46, Subpart A, is a set of federal regulations for protecting human subjects in research that were codified by 15 agencies and departments in 1991.

Danis M. Largent E. et al., Research Ethics Consultation: A Casebook (New York: Oxford University Press, 2012): At 44–47.

Id., at 97–99.

Id., at 125–128.

Here I am using the term “sponsors” as a general term to refer to institutions that fund and support research. The ethical obligations of sponsors (separate from those of investigators) are discussed infra.

Koski G. , “Human Subjects Research and Conflicts of Interest: Research, Regulations, and Responsibility: Confronting the Compliance Myth – A Reaction to Professor Gatter,” Emory Law Journal 52 (2003): 403–416, at 410 (expressing the importance of moving from “a culture of compliance to a culture of conscience” in the conduct of research with human subjects).

Presidential Commission, Moral Science: Protecting Participants in Human Subjects Research (December 2011): At 10.

Id., at 10, 73. The Commission explicitly noted that including language about investigator obligations would help harmonize the Common Rule with the FDA's guidelines (21 CFR Section 312.60), but it would also help harmonize the regulations with research regulations from other countries. See, e.g., SA Health Info, “Ethics in Health Research,” available at <http://www.sahealthinfo.org/ethics/ethicsassesment.htm> (last visited April 24, 2013).

Department of Health and Human Services (DHHS), “Advance Notice of Public Rule-Making (ANPRM): Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators,” Federal Register 76, no. 143 (2011): 44512–44531 (“The proposal for changes described in sections (a) through (c) above would eliminate the current practice of not allowing researchers to begin conducting such minimal risk studies until a reviewer has determined the study does indeed meet the criteria for being exempt. Such delay is not currently required by the Common Rule, and appears to slow research without adding significant protection to subjects. Instead, under the plan being considered, researchers would file with their institution or IRB a brief registration form (about one page long) that provides essential information about the study, including, for example, information about who will be the principal investigator, and the purpose of the study. The researchers would then be authorized to begin conducting the study after the filing (unless the institution chose to review that filing and determined that the research did not qualify as Excused).”).

45 C.F.R. 46, Subpart A (2009). The Common Rule only mentions investigators in the description of what research is exempt, the definitions of “human subject” and “intervention,” the sections on obtaining and documenting informed consent, and the descriptions of who should receive notice from the IRB about its decision. Although Subpart C, which provides additional protections for prisoners involved in research, does discuss investigators' responsibilities with regard to fair subject selection, this Subpart is not part of the Common Rule. The Common Rule has more to say about sponsors, and recognizes that “[e]ach institution engaged in research which is covered by this policy and which is conducted or supported by a federal department or agency shall provide written assurance satisfactory to the department or agency head that it will comply with the requirements set forth in this policy.” It goes beyond compliance to some degree, however, by indicating that all institutions have to prepare “[a] statement of principles governing the institution in the discharge of its responsibilities for protecting the rights and welfare of human subjects of research conducted at or sponsored by the institution.” Finally, the Common Rule indicates that both sponsors and investigators cannot use exculpatory language in informed consent documents that would constitute a waiver of the rights of individual subjects.

45 C.F.R. 46.116 (2009).

45 C.F.R. 46.111(a)(1) (2009). Similarly, the regulations note that “[i]n evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research).” See 45 C.F.R. 46.111(a)(2) (2009).

45 C.F.R. 46.103 (2009).

45 C.F.R. 46.116 (2009).

See DHHS, supra note 9.

Id.

Saleem T. Khalid U. , “Institutional Review Boards – A Mixed Blessing,” International Archives of Medicine 4, no. 19 (2011): 19–25, at 20 (Explaining that IRBs “represent an intrusion of bureaucracy and excessive red tape into medicine to the extent of being ‘frustrating’, ‘consternating’ and ‘paternalistic’ for the researchers.”).

Heimer C. A. Petty J. , “Bureaucratic Ethics: IRBs and the Legal Regulation of Human Subjects Research,” Annual Review of Law and Social Science 6 (2010): 601–626, at 605–606, 622 (“[M]uch of the literature on human subjects regulation asserts that IRBs have failed at the task of regulating human subjects research.”).

Schmeizer M. , “Institutional Review Boards: Friend, Not Foe,” Gastroenterology Nursing 29, no. 1 (2006): 80–81, at 80.

Keith-Spiegel P. Koocher G. P. , “The IRB Paradox: Could the Protectors Also Encourage Deceit?” Ethics & Behavior 15, no. 4 (2004): 339–349, at 343.

De Vries R. DeBruin D. A. Goodgame A. , “Ethics Review of Social, Behavioral, and Economic Research: Where Should We Go from Here?” Ethics & Behavior 14, no. 4 (2004): 351–368, at 352.

Azar B. , “Ethics at the Cost of Research?” American Psychological Association Monitor 33, no. 2 (2002): 38–40, at 38.

See Koski , supra note 6, at 409.

Rushton H. G. , “Institutional Review Board Approval – More Red Tape or a Step in the Right Direction?” Journal of Urology 180, no. 3 (2008): 804–805, at 804.

Levine R. J. , “Institutional Review Boards: A Crisis in Confidence,” Annals of Internal Medicine 134, no. 2 (2001): 161–163, at 161.

See De Vries , supra note 17, at 352.

See Azar , supra note 17, at 38 (quoting a researcher who “viewed the IRB more as a hurdle to get over rather than a way of helping me improve my research.”).

Douglas J. D. , “Living Morality Versus Bureaucratic Fiat,” in Klockars C. B. O'Connor F. W. , eds., Sage Annual Review of Studies in Deviance: Vol. 3: Deviance and Decency (Beverly Hills, CA: Sage, 1979): 13–34, at 32, available at <http://www.educ.ttu.edu/uploadedFiles/personnel-folder/lee-duemer/epsy-6304/documents/Living%20morality%20versus%20bureaucratic%20fiat.pdf> (last visited March 4, 2013).

Kahn J. P. Mastroianni A. C. , “Moving From Compliance to Conscience: Why We Can and Should Improve on the Ethics of Clinical Research,” Archives of Internal Medicine 161, no. 7 (2001): 925–928, at 925.

Id.

See Heimer , supra note 17, at 610.

Id., at 622.

See Presidential Commission, supra note 7, at 9.

Id., at 9.

Fanelli D. , “How Many Scientists Fabricate and Falsify Research? A Systematic Review and Meta-Analysis of Survey Data,” PLoS One 4, no. 5 (2009): e5738.

Id.

Fang F. C. Ferric C. Steen R. G. Casadevall A. , “Misconduct Accounts for the Majority of Retracted Scientific Publications,” Proceedings of the National Academy of Sciences 109, no. 42 (2012): 17028–17033, at 17028.

Steen R. G. , “Retractions in the Scientific Literature: Is the Incidence of Research Fraud Increasing?” Journal of Medical Ethics 37, no. 4 (2011): 249–253, at 250.

See Steen , supra note 31, at 250.

Editorial, “Promoting Research Integrity: A New Global Effort,” The Lancet 380, no. 9852 (2012): 1445–1445, at 1445.

Beecher H. K. , “Ethics and Clinical Research: From the Anaesthesia Laboratory of the Harvard Medical School at the Massachusetts General Hospital,” New England Journal of Medicine 274, no. 24 (1966): 1354–1360, at 1360.

See 45 C.F.R. 46.109(e) (“An IRB shall conduct continuing review of research covered by this policy at intervals appropriate to the degree of risk, but not less than once per year, and shall have authority to observe or have a third party observe the consent process and the research.”).

DuBois J. M. , “Is Compliance a Professional Virtue of Researchers? Reflections on Promoting the Responsible Conduct of Research,” Ethics & Behavior 14, no. 4 (2004): 383–395, at 390 (“Our current oversight system, based on the use of IRBs, is hardly capable of ensuring that people use the IRB system or ensuring that people follow their approved protocols.”). Note that the Food and Drug Administration (FDA) has proposed new rules that encourage IRBs to monitor research more closely in certain cases.

See FDA, “Guidance for IRBs, Clinical Investigators and Sponsors,” available at <http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM328855.pdf> (last visited April 25, 2013) (“The IRB may also elect to observe, or have a third party observe, the consent process and the research (21 CFR 56.109(f)), particularly if any concerns remain about the investigator's qualifications or experience.”).

See Danis , supra note 2, at 49–50.

Jessen J. Robinson E. Bigaj S. , “Unreported Clincial Research Fraud and Misconduct,” Journal of Clinical Research Best Practices 3, no. 1 (2007): 1–5, at 2.

Id.

Klitzman R. Appelbaum P. S. , “To Protect Human Subjects, Review What Was Done, Not Proposed,” Science 335, no. 6076 (2012): 1576–1577, 1577.

Id.

Joffe S. Miller F. G. , “Bench to Bedside” Mapping the Moral Terrain of Clinical Research,” Hastings Center Report 38, no. 2 (2008): 30–42, at 37–38.

Id., at 36.

Lie R. K. Emanuel E. J. Grady C. , “The Standard of Care Debate: The Declaration of Helsinki Versus the International Consensus Opinion,” Journal of Medical Ethics 30, no. 2 (2004): 190–193, at 192.

Shah S. K. Dawson L. Dixon D. O. , “Should Sponsors and DSMBs Share Interim Results across Trials?” Journal of the Acquired Immune Deficiency Syndrome 58, no. 5 (2011): 433–435.

Given the state of flux and considerable ethical debate around some ethical obligations, it can be difficult to determine how best to codify them into regulations. The NIH policy on post-trial access to antiretroviral therapy demonstrates one way of incorporating duties that are still somewhat unclear. It requires that investigators plan in advance how they will address post-trial access, and that these plans will be evaluated by an independent body, but it does not rule out research that does not provide access to treatment post-trial. See National Institutes of Health, “Guidance for Addressing the Provision of Antiretroviral Treatment for Trial Participants Following Their Completion of NIH-Funded HIV Antiretroviral Treatment Trials in Developing Countries,” 2005, available at <http://grants.nih.gov/grants/policy/antiretroviral/guidance.doc> (last visited April 25, 2013).

Emanuel E. J. Wendler D. Grady C. , “What Makes Clinical Research Ethical?” JAMA 283, no. 20 (2000): 2701–2711, at 2708.

For example, various obligations to share benefits with communities in multinational research are very controversial. See, e.g., Shah S. K. Wolitz R. Emanuel E. J. , “Refocusing the Responsiveness Requirement,” Bioethics 27, no. 3 (2013): 151–159.

London A. J. Kimmelman J. , “Justice in Translation: From Bench to Bedside in the Developing World,” The Lancet 372, no. 9632 (2008): 82–85.

Wolitz R. Emanuel E. J. Shah S. K. , “Rethinking the Responsiveness Requirement for International Research,” The Lancet 374, no. 9692 (2009): 847–849.

World Medical Association, Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects (2008).

Grady C. , “Ethics of International Research: What Does Responsiveness Mean?” Virtual Mentor, Ethics Journal of the American Medical Association 8, no. 4 (2006): 235–240.

Macklin R. , Double Standards in Medical Research in Developing Countries (Cambridge, UK: Cambridge University Press, 2004): At 3.

Participants in the 2001 Conference on Ethical Aspects of Research in Developing Countries, “Moral Standards for Research in Developing Countries: From ‘Reasonable Availability’ to ‘Fair Benefits,’” Hastings Center Report 34, no. 3 (2004): 17–27.

Council for International Organizations of Medical Sciences (CIOMS), International Ethical Guidelines for Biomedical Research Involving Human Subjects (Geneva, World Health Organization, 2002).

See Lie , supra note 43, at 190.

Schüklenk U. , “The Standard of Care Debate: Against the Myth of an ‘International Consensus Opinion,’” Journal of Medical Ethics 30, no. 2 (2004): 194–197, at 194.

45 CFR Section 46 (2009)

21 CFR Section 50 (1999).

21 CFR Section 312.60 (1999).

21 CFR, Subpart D, Section 312.50 (1999).

South African Medical Research Council, Ethics Guidelines, Book 1, no. 9, available at <http://www.sahealthinfo.org/ethics/ethicsassesment.htm> (last visited April 25, 2013).

Here I am considering penalties that would apply directly to researchers through the Common Rule and that are not mediated through the IRB. IRBs do have authority to disapprove research in advance or terminate ongoing research, but again, these types of penalties rely on compliance with the IRB, and not a recognition of the obligations sponsors and investigators retain independently of the IRB. See 45 C.F.R. §§46.109, 46.113.

Gatter R. , “Human Subjects Research and Conflicts of Interest: Walking the Talk of Trust in Human Subjects Research: The Challenge of Regulating Financial Conflicts of Interest,” Emory Law Journal 52, no. 1 (2003): 327–340, at 367.

Id., at 362.

Id.

Le Grand J. , “Knights, Knaves, or Pawns? Human Behavior and Social Policy,” Journal of Social Policy 26, no. 2 (1997): 149–169, at 154.

Feldman Y. , “The Expressive Function of Trade Secret Law: Legality, Cost, Intrinsic Motivation, and Consensus,” Journal of Empirical Legal Studies 6, no. 1 (2009): 177–212, at 178–179.

Sunstein C. , “Symposium: Law, Economics, & Norms: On the Expressive Function of Law,” University of Pennsylvania Law Review 144 (1996): 2021–2053, at 2031.

See also McAdams R. H. , “An Attitudinal Theory of Expressive Law,” Oregon Law Review 79 (2000): 339–344, at 339 (arguing that the “law changes behavior by signaling the underlying attitudes of a community or society.”).

See Sunstein , supra note 59, at 2032–2033.

Lessig L. , “Symposium: Law, Economics, & Norms: Social Meaning & Social Norms,” University of Pennsylvania Law Review 144 (1996): 2181–2189, at 2186.

Id.

The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research (1978), at 1, in Emanuel E. J. Crouch R. A. Arras J. D. , eds., Ethical and Regulatory Aspects of Clinical Research (Baltimore: Johns Hopkins University Press, 2003).

Wittlin M. , “Buckling under Pressure: An Empirical Test of the Expressive Effects of Law,” Yale Journal on Regulation 28 (2011): 419–468, at 440–447.

Id.

Kahan D. M. , “Gentle Nudges vs. Hard Shoves: Solving the Sticky Norms Problem,” University of Chicago Law Review 67 (2000): 607–645, at 614.

Id., at 625–26.

See Presidential Commission, supra note 7, at 71.

Id., at 72.

Ariely D. , Predictably Irrational: The Hidden Forces that Shape Our Decisions (New York: HarperCollins, 2008): At 211–214.

Id.

The FDA requires that investigators sign a form in which they make several commitments, such as agreeing to conduct a study according to the protocol and notifying the sponsor of any deviations from the protocol, inform patients about the investigational nature of the drugs used, keep accurate records, and obtain review from a qualified IRB. See <http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM074728.pdf> (last visited April 25, 2013). Notably, these commitments generally relate to ensuring the correct process is followed and do not emphasize the importance of ethical behavior on the part of the investigator. Nevertheless, the general approach used by the FDA could be adapted for investigators presenting their studies for review to IRBs.

Kahan D. M. Posner E. A. , “Shaming White-Collar Criminals: A Proposal for Reform of the Federal Sentencing Guidelines,” Journal of Law & Economics 42 (1999): 365–388, at 366.

See Gatter , supra note 54, at 372–373.

Id., at 392.

See Belmont Report, supra note 63 (“In the case of particular projects, investigators and members of their institutions are obliged to give forethought to the maximization of benefits and the reduction of risk that might occur from the research investigation. … [E]ven if individual researchers are treating their research subjects fairly, and even if IRBs are taking care to assure that subjects are selected fairly within a particular institution, unjust social patterns may nevertheless appear in the overall distribution of the burdens and benefits of research. Although individual institutions or investigators may not be able to resolve a problem that is pervasive in their social setting, they can consider distributive justice in selecting research subjects.”).

National Bioethics Advisory Commission (NBAC), Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries (Bethesda, 2001);

Nuffield Council, Ethics of Research Related to Healthcare in Developing Countries (London, 2002);

South African Medical Research Council, Guidelines on Ethics in Medical Research: General Principles (2005);

World Medical Association, Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects (2008);

Council for International Organizations of Medical Sciences (CIOMS), International Ethical Guidelines for Biomedical Research Involving Human Subjects (Geneva: World Health Organization, 2002).

See Emanuel , supra note 46, at 2707.

See Gatter , supra note 54, at 399 (arguing that with respect to regulating conflicts of interest, disclosure requirements “must be included in a regulatory plan out of respect of the autonomy of would-be human subjects, [but] cannot form the backbone of any such plan”).