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Conflicts of Interest in Human Subject Research: The Insufficiency of U.S. and International Standards

Published online by Cambridge University Press:  06 January 2021

Marc A. Rodwin
Marc A. Rodwin*
Affiliation:
Suffolk University Law School and IMERA Institute, Aix-Marseille University, Marseille France; Brown University; Oxford University; University of Virginia Law School; Brandeis University Heller School
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Abstract

Researchers, as well as individuals and institutions that oversee their conduct, sometimes have conflicts of interest that weaken or render ineffective efforts to protect human research subjects. This article analyzes United States and international standards used to address conflicts of interest and reviews evidence regarding compliance. It finds current standards are insufficient and recommends that the federal government and international organizations adopt stronger legal standards that require resolving most significant conflicts of interest and specifying how to manage conflicts of interest not resolved.

Type
Articles
Information
American Journal of Law & Medicine , Volume 45 , Issue 4 , November 2019 , pp. 303 - 330
Copyright
Copyright © American Society of Law, Medicine and Ethics and Boston University 2019

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References

This article draws on Marc A. Rodwin Conflicts of interest in Human Subject Research: Best Practices, International Standards, and Challenges in Implementing US Regulations, in Ulf Schmidt, Andreas Frewer, and Dominique Sprumont (eds) Human Research Ethics and the Declaration of Helsinki (Oxford University Press, forthcoming, 2020).

1 See, e.g., Norbert, Steinkamp et al., Regulation of Healthcare Ethics Committees in Europe, 10 Med. Health Care & Philos. 461, 462-75 (2007)Google Scholar (summarizing the regulation of healthcare ethics committees in eight European countries).

2 The idea of conflict of interest emerged from the law of trusts and agency and then spread. Initially, conflicts of interest were understood as a means to address the problem in a class of legal relationships known as fiduciary relations, in which one party has a defined legal obligation to serve the interests of another designated party. Courts and legislatures designated certain relationships as fiduciary based on whether they met certain characteristics. However, today, conflicts of interest rules apply to relations that are not legally defined as fiduciary relations. See Marc A. Rodwin, Medicine, Money, and Morals: Physicians' Conflicts of Interests 181 (1993) [hereinafter Rodwin, Medicine]. See generally Marc A. Rodwin, Conflicts of Interest and the Future of Medicine: The United States, France and Japan (2011).

3 For a discussion of competing definitions, see Marc, A. Rodwin, Attempts to Redefine Conflicts of Interest, 25 Accountability Res. 67, 68 (2018)Google Scholar [hereinafter Rodwin, Attempts to Redefine Conflicts]. See generally Marc, A. Rodwin, Conflicts of Interest in Medicine: Should We Contract, Conserve, or Expand the Traditional Definition and Scope of Regulation, 21 J. Health Care L. & Pol'y 157 (2018)Google Scholar [hereinafter Rodwin, Conflict of Interest in Medicine].

4 See Rodwin, Attempts to Redefine Conflicts, supra note 3, at 70; Rodwin, Conflicts of Interest in Medicine, supra note 3, at 163.

5 Individuals with authority sometimes have the power to act in ways that benefit the interests of their family or friends. The law considers that individual to have a conflict of interest. Rodwin, Conflicts of Interest in Medicine, supra note 3, at 163.

6 See id. at 163-165.

7 However, the law sometimes prohibits public officials from entering into situations that create conflicts of interest to reduce the risk that they will breach their obligations, particularly where a fiduciary has a duty of loyalty. See id. at 164.

8 Conflicts of interest undermine the trustworthiness of conflicted actors and public trust in individuals and institutions. See Bradford, H. Gray, Trust and Trustworthy Care in the Managed Care Era, 16 Health Aff. 34, 36 (1997)Google Scholar . See generally Conflict of Interest in Medical Research, Education, and Practice (Bernard Lo & Marilyn Field eds., 2009) [hereinafter Conflict of Interest]; Clinical Practice Guidelines We Can Trust (Robin Graham et al. eds., 2011).

9 See Karine, Morin et al., Managing Conflicts of Interest in the Conduct of Clinical Research, 287 J. Am. Med. Ass'n 78, 79 (2002)Google Scholar . For a discussion of rights of patients and research subjects as human rights, see generally George J. Annas, Human Rights and Health—The Universal Declaration of Human Rights at 50, 339 New. Eng. J. Med. 1778 (1998).

10 Conflict of Interest, supra note 8, at 102-03.

11 See, e.g., Morin et al., supra note 9, at 80-81; Christopher, C. Muth, Conflict of Interest in Medicine, 317 J. Am. Med. Ass'n 1812, 1812 (2017)Google Scholar.

12 See Am. Med. Ass'n Council on Ethical and Judicial Affairs. AMA Code of Medical Ethics' Opinions on Clinical Research, 17 AMA J. Ethics 1136, 1136-37 (2017).

13 Cf. Morin et al., supra note 9, at 80; Abby, R. Rosenberg, ‘Get the Consent’—Nonfinancial Conflict of Interest in Academic Clinical Research, 35 J. Clin. Oncol. 11, 12 (2017)Google Scholar (discussing how task-oriented approaches to obtaining consent may “be associated with a failure meet the overarching best interests of the patient”).

14 This kind of conflict of interest can occur when a physician receives compensation for recruiting his patients to be a human subject in research conducted by another researcher. See Trudo, Lemmens & Paul, B. Miller, Regulating the Market in Human Research Participants, 3 PLOS Med. 1237, 1237 (2006)Google Scholar; see also James, A. Christensen & James, P. Orlowski, Bounty-Hunting and Finder's Fees, 27 IRB: Ethics & Human Res. 16, 16 (2005)Google Scholar; Mark, A. Hall et al., Per Capita Payments in Clinical Trials: Reasonable Costs Versus Bounty Hunting, 85 Acad. Med. 1554, 1554-56 (2010)Google Scholar; Trudo, Lemmens & Paul, B. Miller, The Human Subjects Trade: Ethical and Legal Issues Surrounding Recruitment Incentives, 31 J.L. Med. & Ethics 398, 398 (2003)Google Scholar; James, Raftery et al., Payment to Healthcare Professionals for Patient Recruitment to Trials: Systematic Review and Qualitative Study, 12 Health Tech. Assessment 1, 57 (2008)Google Scholar.

15 Robert Whitaker, Lure of Riches Fuels Testing, Boston Globe, Nov. 17, 1998; Kurt Eichenwald & Gina Kolata, A Doctor's Drug Studies Turn Into Fraud, N.Y. Times, May 17, 1999 at A1 [hereinafter Eichenwald & Kolata, Drug Studies Turn Into Fraud]; Kurt Eichenwald & Gina Kolata, Drug Trials Hide Conflicts for Doctors, N.Y. Times, May 16, 1999, §1, at 1 [hereinafter Eichenwald & Kolata, Drug Trials]. In recent years these practices have been infrequently used.

16 Eichenwald & Kolata, Drug Trials, supra note 15, §1, at 1.

17 See, e.g., Eichenwald & Kolata, Drug Studies Turn Into Fraud, supra note 15, at A1.

18 Bayh-Dole Act, Pub. L. No. 96-517, 94 Stat. 3015 (1980) (codified as amended 35 U.S.C. §§ 200-211 (2012)).

19 Peter G. Gosselin, Flawed Study Helps Doctors Profit on Drug, Boston Globe, Oct. 19, 1988, at 1 [hereinafter Gosselin, Flawed Study]

20 Id. at 17.

21 There were some irregularities in the research. The researchers changed research protocols without receiving permission from the institutional review board (IRB). Id. at 16.

22 Peter G. Gosselin, The System Failed in Drug Research Probe, Boston Globe, Dec. 5, 1988, at 29.

23 Gosselin, Flawed Study, supra note 19, at 17.

24 See, e.g., 21 U.S.C. § 355 (2012).

25 Marc, A. Rodwin, Independent Drug Testing to Ensure Drug Safety and Efficacy, 18 J. Health Care L. & Pol'y 45, 47 (2015)Google Scholar [hereinafter Rodwin, Independent Drug Testing]; see also Marc, A. Rodwin, Independent Clinical Trials to Test Drugs: The Neglected Reform, 6 St. Louis U.J. Health L. & Pol'y 113, 163 (2012)Google Scholar.

26 Rodwin, Independent Drug Testing, supra note 25, at 47.

27 Richard, A. Davidson, Source of Funding and Outcome of Clinical Trials, 1 J. Gen. Internal Med. 155, 156-57 (1986)Google Scholar; Joel, Lexchin et al., Pharmaceutical Industry Sponsorship and Research Outcome and Quality: Systematic Review, 326 BMJ 1167 1168-70 (2003)Google Scholar; Sergio, Sismondo, Pharmaceutical Company Funding and its Consequences: A Qualitative Systematic Review, 29 Contemp. Clinical Trials 109, 109-13 (2008)Google Scholar.

28 Cf. Conflict of Interest, supra note 8, at 157-59 (discussing recommendations on how to address conflicts of interest that arise from gifts, grants, employment in medical education).

29 Id. at 158-59; see also Marc, A. Rodwin, Conflict of Interest in the Pharmaceutical Sector: A Guide for Public Management, 21 Depaul J. Health Care L. 1, 10 (2019)Google Scholar [hereinafter Rodwin, Conflict of Interest in the Pharmaceutical Sector].

30 See Michelle, M. Mello et al., Academic Medical Centers' Standards for Clinical-Trial Agreements with Industry, 352 New. Eng. J. Med. 2202, 2204-08 (2005)Google Scholar; Thomas, Bodenheimer, Uneasy Alliance: Clinical Investigators and the Pharmaceutical Industry, 342 New. Eng. J. Med. 1539, 1539, 1541-42 (2000)Google Scholar.

31 Mello et al., supra note 30, at 2208.

32 Lori Andrews & Julie B. Chronis, A Pound of Flesh: Patient Legal Action for Human Research Protections in the Biotech Age, in Patients as Policy Actors: A Century of Changing Markets and Missions, 83-108 (Beatrix Hoffmann et al. eds., 2011).

33 Id. at 99-100.

34 See id. at 83-84.

35 Id. at 84.

36 See Mark, Barnes & Patrik, S. Florencio, Financial Conflicts of Interest in Human Subjects Research: The Problem of Institutional Conflicts, 30 J.L. Med. & Ethics 390, 390 (2002)Google Scholar [hereinafter Barnes & Florencio, Financial Conflicts of Interest]; Mark, Barnes & Patrik, S. Florencio, Investigator, IRB and Institutional Financial Conflicts of Interest in Human-Subjects Research: Past, Present and Future, 32 Seton Hall L. Rev. 525, 525-28 (2001)Google Scholar; Ezekiel, J. Emanuel & Daniel, Steiner, Institutional Conflict of Interest, 332 New Eng. J. Med. 262, 262-63 (1995)Google Scholar.

37 Some writers hold that when an institution's senior official has financial interests that can affect the institutional policies, this situation also creates an institutional conflict of interest. See Ass'n Am. Univs., Report on Individual and Institutional Financial Conflict of Interest, at i, ii (2001); Conflict of Interest, supra note 8, at 218. However, the financial interests of senior officials in an organization reflect their own conflicts of interest, so there is no need to define these as institutional conflict.

38 See Sheldon Krimsky, Science in the Private Interest: Has the Lure of Profits Corrupted Biomedical Research? 27-56 (2004).

39 Timothy Caulfield & Ubaka Ogbogu, The Commercialization of University-Based Research: Balancing Risks and Benefits, 70 BMC Med. Ethics, Oct. 2015, at 1, 2; see also U.S. Gov't Accountability Office, GAO-04-31, University Research: Most Federal Agencies Need to Better Protect Against Financial Conflicts of Interest 4-6 (2003) [hereinafter U.S. Gov't Accountability Office, GAO-04-31].

40 These arrangements can also cause institutional corruption. See Marc, A. Rodwin, Conflicts of Interest, Institutional Corruption, and Pharma: An Agenda for Reform, 41 J.L. Med. & Ethics 511, 511-19 (2013)Google Scholar; Marc, A. Rodwin, Rooting Out Institutional Corruption to Manage Inappropriate Off-Label Drug Use, 41 J.L. Med. & Ethics 544, 654-64 (2013)Google Scholar.

41 See Carl, Elliott, Institutional Pathology and the Death of Dan Markingson, 24 Accountability in Res. 65, 70 (2017)Google Scholar.

42 See id. at 65-79; U.S. Gov't Accountability Office, GAO-02-89, Biomedical Research: HHS Direction Needed to Address Financial Conflicts of Interest (2001) (discussing the need for further oversight of institutional conflicts of interest) [hereinafter U.S. Gov't Accountability Office, GAO-02-89].

43 The National Research Act of 1974, codified at 42 U.S.C. §232 (2012). Federal involvement began in 1966, when the National Institutes of Health (NIH) developed guidelines for research involving human subjects.

44 The initial guidelines followed the U.S. Surgeon General policy statement “Clinical research and investigation involving human beings.” The regulations were issued in title 45, section 46.111 of the Code of Federal Regulations. 45 C.F.R. § 46.111 (2018).

45 45 C.F.R. § 46 (2018).

46 45 C.F.R. § 46.109 (2018).

47 45 C.F.R. § 46.108 (2018).

48 45 C.F.R. § 46 (2018).

49 45 C.F.R. § 46.107(d) (2018). The prohibition dates from the 1981 regulation.

50 The revised Common Rule with explanations and replies to comments on the proposed rule can be found at Federal Policy for the Protection of Human Subjects, 82 Fed. Reg. 7149, 7150 (Jan. 19, 2017) (codified at 45 C.F.R. pt. 46). For commentaries on the most recent revised rule, see Barbara, E. Bierer, Mark, Barnes & Holly, F. Lynch, Revised ‘Common Rule’ Shapes Protections For Research Participants, 36 Health Aff. 784, 784-88 (2017)Google Scholar; Ezekiel, J. Emanuel & Jerry, Menikoff, Reforming the Regulations Governing Research with Human Subjects, 365 New Eng. J. Med. 1145, 1145-49 (2011)Google Scholar (discussing the advanced notice of proposed rulemaking for revisions to the Common Rule); Lisa Nichols et al., What Do Revised U.S. Rules Mean for Human Research?, Science, Aug.18, 2017, at 650.

51 45 C.F.R. § 46.107(d) (2018).

52 Leslie, E. Wolf, & Jolanta, Zandecki, Conflicts of Interest in Research: “How IRBs Address Their Own Conflicts”, 29 IRB: Ethics & Hum. Res. 6, 8 (2007)Google Scholar.

53 Eric, G. Campbell et al., Financial Relationships Between Institutional Review Board Members and Industry, 355 New Eng. J. Med. 2321, 2321, 2327 (2006)Google Scholar.

54 Id. at 2324-25.

55 Christine, Vogeli et al., Policies and Management of Conflicts of Interest Within Medical Research Institutional Review Boards: Results of a National Study, 84 Acad. Med. 488, 490-91 (2009)Google Scholar.

56 Id. at 492-93.

57 See, e.g., Bernard, Lo, Leslie, E. Wolf & Abiona, Berkeley, Conflict-of-Interest Policies for Investigators in Clinical Trials, 343 New Eng. J. Med. 1616, 1616-20 (2000)Google Scholar.

58 See, e.g., AAMC Task Force on Fin. Conflicts of Interest in Clinical Res., Protecting Subjects, Preserving Trust, Promoting Progress II: Principles and Recommendations for Oversight of an Institution's Financial Interests in Human Subjects' Research, 78 Acad. Med. 225, 239-44 (2003) [hereinafter AAMC]; Susan, H. Ehringhaus et al., Responses of Medical Schools to Institutional Conflicts of Interest, 299 JAMA 665, 665-71 (2008)Google Scholar; David Korn, Financial Conflicts of Interest in Academic Medicine: Whence They Came, Where They Went, 8 Ind. Health L. Rev. 3, 13-42 (2011).

59 AMA Council on Ethical & Jud. Aff., Conflicts of Interest: Update (June 18-22, 1989), in AMA Proceedings of the House of Delegates 138th Annual Meeting: Chicago, Illinois 188-89 (1989).

60 For a review of ethics law and literature in 1980s and early 1990s, see generally Rodwin, Medicine, supra note 2.

61 21 C.F.R. § 54.4 (1998); 42 C.F.R. § 50.604 (1995).

62 Morin et al., supra note 9, at 80-83.

63 AAMC supra note 58, at 232-34.

64 Id. at 229-30.

65 Ass'n Am. Med. Ctr., Protecting Patients, Preserving Integrity, Advancing Health: Accelerating the Implementation of COI Policies in Human Subjects Research, at viii (2008) [hereinafter Ass'n Am. Med. Ctr., Protecting Patients]

66 See Conflict of Interest, supra note 8, at 9-10 (discussing Recommendation 4.1).

67 Id. at 184-88 (discussing Recommendation 6.1 and Recommendation 6.2).

68 Id. at 157-58 (discussing Recommendation 5.1).

69 Id. at 226-28 (discussing Recommendation 8.1).

70 Office of the Inspector Gen., U.S. Dep't of Health & Human Servs., OEI-01-97-00195, Recruiting Human Subjects: Pressures in Industry-Sponsored Clinical Research 26 (2000).

71 Id.

72 Am. Med. Ass'n Principles of Med. Ethics, Opinions on Financing and Delivery of Health Care, Fee Spilling (2016).

73 Leslie E. Wolf, IRB Policies Regarding Finder's Fees and Role Conflicts in Recruiting Research Participants, IRB: Ethics & Human Res., Jan.-Feb. 2009, at 15 (“[Twenty-six IRBs] (22%) mentioned the issue of physicians recruiting their patients.”).

74 Id. at 15-16.

75 Robert Kitzman, “Members of the Same Club”: Challenges and Decisions Faced by US IRBs in Identifying and Managing Conflicts of Interest. PLOS One, July 2011, at 2-7; see also Robert Klitzman, The Ethics Police? The Struggle to Make Human research Safe 361 (2015).

76 Evidence-based Synthesis Program Ctr., Maintaining Research Integrity: A Systematic Review of the Role of the Institutional Review Board in Managing Conflict of Interest 29 (2012).

77 Kevin, P. Weinfurt et al., Policies of Academic Medical Centers for Disclosing Conflicts of Interest to Potential Research Participants, 81 Acad. Med. 113, 114 (2006)Google Scholar.

78 Id. at 116; see also David, B. Resnik, Disclosing Conflicts of Interest to Research Subjects: An Ethical and Legal Analysis, 11 Accountability Res. 141, 141-59 (2004)Google Scholar; Marc, A. Rodwin, Physicians' Conflicts of Interest: The Limitations of Disclosure, 321 New Eng. J. Med. 1405, 1407 (1989)Google Scholar.

79 Cf. Office of the Inspector Gen., U.S. Dep't of Health & Human Servs., OIG-01-97-00193, Institutional Review Boards: A Time for Reform 7 (1998) (noting the pressures on IRBs to “accommodate institutional financial interests.”) [hereinafter Office of the Inspector Gen., OIG-01-97-00193].

80 See Adam, Hedgecoe et al., Research Ethics Committees in Europe: Implementing the Directive, Respecting Diversity, 32 J. Med. Ethics 483 (2006)Google Scholar.

81 Richard, A. Rettig, The Industrialization of Clinical Research, 19 Health Aff. 129, 137-40 (2000)Google Scholar.

82 Office of the Inspector Gen., OIG-01-97-00193, supra note 79.

83 Office of the Inspector Gen., U.S. Dep't of Health & Human Servs., OEI-03-07-00700, How Grantees Manage Financial Conflicts of Interest in Research Funded by the National Institutes of Health 3-5 (2009) [hereinafter Office of the Inspector Gen., OEI-03-07-00700]

84 Id. at 8-18.

85 Office of the Inspector Gen., Dep't of Health & Human Servs., OEI-03-09-00480, Institutional Conflicts of Interest at NIH Grantees 1-3 (2011).

86 Id. at 9, 12.

87 Id. at 17.

88 Conflict of Interest, supra note 8, at 22, 228 (discussing Recommendation 8.2).

89 42 C.F.R. § 50.601 (2011).

90 Responsibility of Applicants for Promoting Objectivity in Research for which Public Health Service Funding is Sought and Responsible Prospective Contractors, 76 Fed. Reg. 53,256, 53,256-57 (Aug. 25, 2011) (codified at 42 C.F.R. pt. 50).

91 42 C.F.R. §§ 50.604-605 (2018). Significant financial interest is defined as those of the investigator, or investigator's spouse and dependent children that appears related to the investor's responsibilities. It includes remuneration in the previous 12 months, equity interests and other payments valued at more than $5,000. 42 C.F.R § 50.603 (2018).

92 42 C.F.R. § 50.605(b)(3)(vii)(C).

93 U.S. Gov't Accountability Office, GAO-02-89, supra note 42, at 4.

94 42 C.F.R. § 50.605(a) (2011).

95 Office of the Inspector Gen., OEI-03-07-00700, supra note 83, at ii-iii.

96 Id. at iii.

97 Id. at ii; see also U.S. Gov't Accountability Office, GAO-04-31, supra note 39, at5-6.

98 See Office of the Inspector Gen., Dep't of Health & Human Servs., OEI-01-08-00510, Challenges to FDA's Ability to Monitor and Inspect Foreign Clinical Trials, at i-ii (2010).

99 Protection of Human Subjects, 21 C.F.R. § 50.1 (1980). The FDA regulation requires that researchers obtain the consent of research subjects and that an IRB approves the research protocol. About 80 percent of new drug applications rely in part on clinical trials performed outside the United States and for these, the FDA has alternative requirements that are set forth in 21 C.F.R. § 312.120. They must meet the standard of Good Clinical Practices (GCPs) promulgated by the ICH, which require that an ethics committee or IRB approve the research protocol, that researchers obtain the consent of research subjects, and that the research complies with certain other standards. 21 C.F.R. § 50 (2019); 21 C.F.R. § 56 (2019). Until 2008, the FDA required that foreign studies comply with the Declaration of Helsinki rather than the ICH Good Clinical Practices. Pharmaceutical firms that want to use studies conducted outside the United States to support an application to market a drug in the United States must meet FDA standards. As a result, pharmaceutical and medical device firms have encouraged foreign nations to develop a human subject research rules that meets FDA standards.

100 21 C.F.R. § 54.4(a)(3) (2019); 45 C.F.R. § 46 (2018); Financial Relationships and Interests in Research Involving Human Subjects: Guidance for Human Subject Protection, 69 Fed. Reg. 26,393 (May 12, 2004).

101 21 C.F.R. § 54.1 (2019).

102 Id.

103 Id.

104 21 C.F.R. § 54.5(c) (2019).

105 Moore v. Regents of Univ. of Cal., 793 P.2d 479, 485 (Cal. 1990). For decisions suggesting that there is no duty for a physician-researcher to disclose their economic interests, see Greenberg v. Miami Children's Hosp. Research Inst., 264 F. Supp. 2d 1064, 1073-74 (S.D. Fla. 2003).

106 Moore, 793 P.2d at 481.

107 Id. at 485.

108 Robin, Fretwell Wilson, The Death of Jesse Gelsinger: New Evidence of the Influence of Money and Prestige in Human Research, 36 Am. J. L. & Med. 295, 301-02 (2010)Google Scholar.

109 Id. at 308.

110 Id. at 308 (citing Memorandum from Kathleen A. Denis, Dir., Ctr. for Tech. Transfer, to Neil Nathanson, Chair, Conflict of Interest Standing Comm. (Dec. 15, 1994)).

111 Id. at 300, 305.

112 See Arnold, S. Relman, Dealing with Conflicts of Interest, 310 New Eng. J. Med. 1182, 1183 (1984)Google Scholar (“[we] suggest to our authors that they routinely acknowledge in a footnote all funding sources supporting their submitted work”).

113 Arnold, S. Relman, New “Information for Authors“ and Readers, 323 New Eng. J. Med. 56, 56 (1990)Google Scholar.

114 Marcia, Angell & Jerome, P. Kassirer, Editorials and Conflicts of Interest, 335 New Eng. J. Med. 1055, 1056 (1996)Google Scholar.

115 Jeffrey, M. Drazen & Gregory, D. Curfmam, Financial Associations of Authors, 346 New Eng. J Med. 1901, 1901-02 (2002)Google Scholar.

116 George, D. Lundberg & Annette, Flanagin, New Requirements for Authors: Signed Statements of Authorship Responsibility and Financial Disclosure, 262 JAMA 2003, 2004 (1989)Google Scholar.

117 See, e.g., Catherine, D. DeAngelis et al., Reporting Financial Conflicts of Interest and Relationships Between Investigators and Research Sponsors, 286 JAMA 89, 90 (2001)Google Scholar; Annette, Flanagin et al., Update on JAMA's Conflict of Interest Policy, 296 JAMA 220, 221 (2006)Google Scholar; Phil, B. Fontanarosa et al., Reporting Conflicts of Interest, Financial Aspects of Research, and Role of Sponsors in Funded Studies, 294 JAMA 110, 110-11 (2005)Google Scholar; Drummond, Rennie et al., Conflicts of Interest in the Publication of Science, 266 JAMA 266, 267 (1991)Google Scholar.

118 See Jeffery, M. Drazen et al., Uniform Format for Disclosure of Competing Interests in ICJME Journals, 361 New Eng. J Med. 1896, 1896-97 (2009)Google Scholar.

119 Sheldon, Krimsky et al., Scientific Journals and Their Authors' Financial Interests: A Pilot Study, 67 Psychotherapy & Psychosomatics 194, 197-200 (1998)Google Scholar; Sheldon, Krimsky et al., Financial Interest of Authors in Scientific Journals: A Pilot Study of 14 Publications, 2 Sci. & Engineering Ethics 395, 402-06 (1996)Google Scholar.

120 Physician Payments Sunshine Act, 42 C.F.R. § 403.904 (2010).

121 Dollars for Docs, ProPublica, https://projects.propublica.org/docdollars (last updated June 28, 2018).

122 See, e.g., Charles Orenstein & Katie Thomas, Memorial Sloan Kettering Leaders Violated Conflict-of-Interest Rules, Report Finds, ProPublica (Apr. 4, 2019, 3:41 PM),.

123 Charles Orenstein & Katie Thomas, Top Official at Memorial Sloan Kettering Resigns After Failing to Disclose Industry Ties, ProPublica (Sept. 13 2018. 8:45 PM),.

124 Katie Thomas & Charles Orenstein, Top Cancer Doctor, Forced Out Over Ties to Drug Makers, Joins Their Ranks, ProPublica (Jan. 7, 2019 6:17 PM),.

125 For an assessment of the effects of the Sunshine Act, see Moya Ball, Shining the Light on Fundamental Flaws in Global Healthcare Sunshine Laws, and a Proposal for Patient-Focused Transparency, Health, June 2016, at 1 (2016); Alison, R. Hwong et al., A Systematic Review of State and Manufacturer Physician Payment Disclosure Websites: Implications for Implementation of the Sunshine Act 42 J. L. Med. & Ethics 208 (2014)Google Scholar; Richard, S. Saver, Shadows Amid Sunshine: Regulating Financial Conflicts in Medical Research, 145 Chest 379 (2014)Google Scholar.

126 See, e.g., 42 C.F.R. §§ 50.604 (2018); 45 C.F.R. § 46.109 (2018).

127 21 C.F.R. § 54.4 (2019).

128 See, e.g., Ass'n Am. Med. C., supra note 65, at 13-2; Fontanarosa et al., supra note 117, at 111.

129 Congress certainly has authority to legislate uniform rules for research used to support applications to market new drugs and medical devices subject to FDA review and for institutions that receive federal funds. Moreover, Congresses' authority to regulate interstate commerce appears to provide grounds to regulate human subject research more generally, because it is now conducted largely by for-profit firms that work nationally and often internationally or by not-for-profit organizations that affect the interstate commerce in medicine.

130 45 C.F.R. § 94.4(a) (2018).

131 The World Medical Association is an international confederation of professional medical associations established in 1947 that in 2018 included 113 national medical associations. About Us, World Med. Ass'n, https://www.wma.net/who-we-are/about-us [https://perma.cc/9MTJ-LUKY].

132 Dominique Sprumont et al., The Helsinki Declaration and the Law: An International and Comparative Analysis, in History and Theory of Human Experimentation: The Declaration of Helsinki and Modern Medical Ethics 223, 248 (Ulf Schmidt & Andreas Frewer eds., 2007); Robert, V. Carlson et. al., The Revision of the Declaration of Helsinki: Past, Present and Future, 57 British J. Clinical Pharmacology 695, 695-99 (2004)Google Scholar (discussing changes in the DoH up to the 2000 revisions). The foundational ethical guideline on research on humans is the Nuremberg Code (1947), developed by the international court that tried Nazi regime physicians for the atrocities/experiments conducted without consent on inmates in concentration camps. It is known for promoting human rights and championing the idea that no research should be conducted on humans without their consent. However, it does not discuss conflicts of interest. See Jay Katz, The Consent Principle of the Nuremberg Code: Its Significance Then and Now, in The Nazi Doctors and the Nuremberg Code: Human Rights in Human Experimentation 227 (George J. Annas & Michael A. Grodin eds., 1996); Jay, Katz, The Nuremberg Code and the Nuremberg Trial: A Reappraisal, 276 JAMA 1662, 1662 (1996)Google Scholar.

133 See Robert, Gatter, Conflicts of Interest in International Human Drug Research and the Insufficiency of International Protections, 32 Am. J. L. & Med. 351, 354 (2006)Google Scholar.

134 The Council for International Organizations of Medical Sciences is an international, non-profit organization established in 1949 by the WHO and UNESCO that represents the biomedical scientific community through its member organizations. CIOMS' mission is to advance public health through guidance on health research including ethics, medical product development and safety. About, Council for Int'l Orgs. of Med. Servs., https://cioms.ch/about [https://perma.cc/C9G4-LNLJ].

135 The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, founded in 1990, is an initiative that brings together regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of pharmaceutical product development and registration. ICH's mission is to achieve greater harmonization worldwide to ensure that safe, effective, and high quality medicines are developed and registered in the most resource-efficient manner. Mission, Int'l Council for Harmonization for Better Health, https://www.ich.org/page/mission [https://perma.cc/64PX-KN4S].

136 Cf. Erin D. Williams, Cong. Research Serv., RL32909, Federal Protection for Human Research Subjects: An Analysis of the Common Rule and Its Interactions with FDA Regulations and the HIPAA Privacy Rule 20-21 (2005) (discussing how past FDA regulations referenced the DoH for the use of foreign clinical trials in support of new drug applications).

137 See Laura Eggertson, Helsinki Doctrine Under Review, 184 CMAJ E827, E827-E828 (2012) (quoting Dr. Michael Carome) (“[W]hile [the Declaration of Helsinki] is frequently cited as an important document … currently it doesn't bind any physician researcher in a legal way.”).

138 Federal Policy for the Protection of Human Subjects, 82 Fed. Reg. 7149, 7159 (Jan. 19, 2017).

139 See Gatter, supra note 133, at 363.

140 See, e.g., Abdullahi v. Pfizer, Inc., 562 F.3d 163, 175 (2d Cir. 2009).

141 Id. at 182-84.

142 Id. at 169.

143 Moore v. Regents of Univ. of Cal., 793 P.2d 479, 485 (Cal. 1990).

144 See generally World Health Org., Guidelines for Good Clinical Practice for Trials on Pharmaceutical Products (1995).

145 Id. § 4.1.

146 The 2002 WHO Handbook for Good Clinical Research Practice Guidance for Implementation states that ethics committee members “should be held to the same standards of disclosure [of conflicts] as scientific and medical research staff” and cites the CIOMS guidelines. Council for Int'l Orgs. of Med. Sciences, International Ethical Guidelines for Biomedical Research Involving Human Subjects, at xii (2002). The handbook seems to merely note other standards rather than set a new WHO standard. Id. The preamble says it “is based on major international guidelines, including … the ICH Good Clinical Practice: Consolidated Guidelines.” Id.

147 See generally U.S. Food & Drug Admin., E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) (2018); European Meds. Agency, Guideline for Good Clinical Practice E6(R2) (2002).

148 See U.S. Food & Drug Admin., supra note 149, at 12-15

149 See, e.g., 21 C.F.R. § 54.4 (1998).

150 Id.

151 2014 O.J. (L 158) 57, at 19.

152 See Carlson et. al., supra note 132, at 703-04. The conflict of interest provisions were not changed in the 2013 revision.

153 World Med. Ass'n, WMA Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects § 22 (Oct. 2013) (“The protocol should include information regarding funding, sponsors, institutional affiliations, potential conflicts of interest.”).

154 Id. § 26. (“In medical research involving human subjects capable of giving informed consent, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest.”).

155 Id. § 36.

156 This is true as a matter of law. For an evaluation of the effect of disclosure on practice see Sheldon Krimsky, Combatting the Funding Effect in Science: What's Beyond Transparency? 21 Stan. L. & Pol'y Rev., 81, 96-102 (2010). For a discussion of ways to manage conflicts of interest see Rodwin, Conflict of Interest in the Pharmaceutical Sector, supra note 29, at 11-27.

157 See Daylian, M. Cain, George, Loewenstein & Don, A. Moore, The Dirt on Coming Clean: Perverse Effects of Disclosing Conflicts of Interest, 34 J. Legal Stud. 1, 1, 18-22 (2005)Google Scholar.

158 See id. at 3-7; Daylian, M. Cain, George, Loewenstein & Don, A. Moore, When Sunlight Fails to Disinfect: Understanding the Perverse Effects of Disclosing Conflicts of Interest, 37 J. Consumer Res. 836, 849-850 (2011)Google Scholar; George, Loewenstein, Daylian, M. Cain & Sunita, Sah, The Limits of Transparency: Pitfalls and Potential of Disclosing Conflicts of Interest, 101 Am. Econ. Rev. 423, 423-24 (2011)Google Scholar.

159 See Council for Int'l Org. of Med. Sci., International Ethical Guidelines for Biomedical Research Involving Human Subjects 27-28 (2002); Council for Int'l Org. of Med. Sci., International Ethical Guidelines for Health-related Research Involving Humans 95-98 (2016) [hereinafter CIOMS, 2016 Guidelines].

160 COIMS, 2016 Guidelines, supra note 159, at 89.

161 Id. at 89, 96-98.

162 Id. at 92 (commentary on Guideline 24).

163 Id. at 97.

164 Id. at 95.

165 Id. at 97.

166 Id. at 89.

167 See, e.g., Moore v. Regents of Univ. of Cal., 793 P.2d 479, 483 (Cal. 1990).. For decisions suggesting that there is no duty for a physician-researcher to disclose their economic interests, see Greenberg v. Miami Children's Hosp. Research Inst., 264 F. Supp. 2d 1064, 1070-71 (S.D. Fla. 2003). See also Wilson, supra note 108, at 301-325.

168 See generally World Health Org., supra note 144.

169 See Gatter, supra note 133, at 354.

170 However, there is only one organization with a standard for disclosure of conflicts by ethics committees and that weakens the ability of ethics committees to enforce its standards of conduct for its members or act as an unconflicted actor.

171 U.S. Gov't Accountability Office, GAO-02-89, supra note 42, at 7-8.

172 See id. at 3-5; U.S. Gov't Accountability Office, GAO-04-31, supra note 39, at 3-4.

173 Robert, Steinbrook, Protecting Research Subjects—The Crisis at Johns Hopkins, 346 New Eng. J. Med. 716, 716 (2002)Google Scholar.

174 U.S. Gov't Accountability Office, supra note 39, at 5

175 Daniel, Carpenter, The Political Economy of FDA Drug Review: Processing, Politics, and Lessons for Policy, 23 Health Aff. 52, 61 (2004)Google Scholar.

176 See Moore v. Regents of Univ. of Cal., 793 P.2d 479, 483-86 (Cal. 1990).

177 42 C.F.R. § 50.602 (2018).

178 See generally CIOMS, 2016 Guidelines, supra note 159; World Health Org., supra note 144; World Med. Ass'n, supra note 153.

179 CIOMS, 2016 Guidelines, supra note 159, at 97; World Med. Ass'n, supra note 153, at § 34.

180 CIOMS, 2016 Guidelines, supra note 159, at 89.

181 Terminating the financial arrangement often resolves the conflict. How most regulations look back several years and include past financial ties as a source of conflicts.

182 See Conflict of Interest, supra note 8, at 224-25.

183 See id. at 88-90.

184 See id. at 84-85 (citing Leslie Z. Benet, Presentation at the Institute of Medicine Committee on Conflict of Interest in Medical Research, Education, and Practice (May 22, 2008)).The GAO and researchers have issued several studies reviewing university policies on conflicts of interest in research. See, e.g., U.S. Gov't Accountability Office, supra note 173; U.S. Gov't Accountability Office, supra note 174; Susan H. Ehringhaus, et al., Responses of Medical Schools to Institutional Conflicts of Interest, 299 JAMA 665 (2008).

185 Joel, Lexchin & Orla, O'Donovan, Prohibiting or ‘Managing’ Conflict of Interest? A Review of Policies and Procedures in Three European Drug Regulation Agencies, 70 Soc. Sci. & Med. 643 (2010)Google Scholar.

186 Id. at 645-46.

187 Id. at 646.

188 Conflict of Interest, supra note 8, at 216-29; Krimsky, supra note 38, at 27-56; Barnes & Florencio, Financial Conflicts of Interest, supra note 36, at 393; Ehringhaus et al., supra note 58, at 665-671; Emanuel & Steiner, supra note 36.

189 See Conflict of Interest, supra note 8, at 117-18.