Susan H. Ehringhaus Association of American Medical Colleges PRIMR, May 3, 2004

1. Conflicts of Interest and the Research Enterprise: Are Protection of Human Subjects and Research Integrity on the Line? Susan H. Ehringhaus Association of American Medical Colleges PRIMR, May 3, 2004

2. U.S. Medical School Revenuesas a percentage of total revenues

3. Medical School Revenues, 2002Public Research-Intensive Schools Median Total Revenues = $781.9 million (N =7) Source: LCME Part I-A Annual Financial Questionnaire

4. Medical School Revenues, 2002Private Research-Intensive Schools Median Total Revenues = $850.5 million (N =13) Source: LCME Part I-A Annual Financial Questionnaire

5. Private Grants for Research at U.S. Medical Schools 1996-2002 $ in millions Current $ Constant $ Fiscal Year Source: LCME Part I-A Annual Financial Questionnaire

7. What’s at Stake • Potential for harm • Record of harm • Achievements of immense social value • Universities must be articulate with rest of society, including industry • Question is how to assure that the essence of the university isn’t compromised at the connections with industry

8. What’s at Stake, cont’d. • Not a new phenomenon • Not about dollars • Value of social good to universities, faculties, students far greater than $ values • Strong, effective, though inevitably imperfect, management of risks • Benefits outweigh likely losses to society from avoidance of relations with industry

9. AAUP Declaration of Principles (1915) “All true universities, whether public or private, are public trusts…. “Their independence is essential because the university provides knowledge not only to its students, but also to the public agency in need of expert guidance and the general society in need of greater knowledge; and… These latter clients have a sake in disinterested professional opinion, stated without fear or favor, which the institution is morally required to respect.”

10. Historic View, Stanford, 1968 • Stanford “assumes that [faculty] will be alert to the possibility that outside . . . financial interests . . . can affect the objectivity of their decisions.” • “If those assumptions are valid . . . then no codes or monitoring devices are needed; if they are not valid, then none will suffice.”

11. Research and Self-Regulation • Peer review • Replication • Publication • Experience has taught that institutions can’t rely on individuals to assess their own situations in relation to interface with industry • Rules and hierarchies of risky situations, behaviors • Transparent and depersonalized systems of assessment and risk adjustment/avoidance

12. Research and Government Regulation • Regulation of expenditure of government research funds: accounting standards, allowable costs heavily regulated and enforced, e.g., effort reporting • Regulation of actual conduct of research and behaviors of researchers: remarkably light-handed approach, deference to university autonomy and self governance

13. Research and Government Regulation, cont’d. • Federal-Academic partnership in basic research • Oversight through “assurances” • Protection of human subjects • Research misconduct • Conflicts of interest

14. Research and Government Regulation, cont’d. • Stanford v. Sullivan: “This Court will not…subject to government censorship the publications of institutions of higher learning and others engaged in legitimate research…. [Stanford will be allowed] to use its own judgment on when and what to publish, notwithstanding that its research is supported by federal funds.”

15. Changes in the “Ecology” of Biomedical Research • Huge progress of biomedical science, making research results attractive for commercial development and clinical application • Invention of recombinant DNA technology, spawning the biotech industry and its linkages to academe (1980 patent)

16. Changes in the Ecology of Biomedical Research, cont’d. • 1980 Supreme Court decision in Diamond v. Chakrabarty holding that “anything under the sun” invented by man is patentable • Bayh-Dole Act • Silicon Valley, Route 128, Research Triangle: impacts on local, state, and federal policies and politics, especially re commercialization of university research

17. Cracks in the Foundation • Several highly publicized, some tragic cases in 1980s, 1990s, continuing to present • Debut of research misconduct and conflict of interest together in the public consciousness • Question: are financial self-interests in biomedical research inevitably problematic?

18. Federal Commentary:GAO Report to Senator Frist, Senate Subcommittee on HELP: “Financial Conflicts in Biomedical Research” • November 2001 • Wide variations in policies • Absence of formal linkages between COI evaluation and IRBs • Absence of guidance on institutional COI

19. Federal Commentary:NIH Draft Guidance, March 31, 2003 • Offers “Issues for Consideration”, including: • types of financial interests that should be considered • methods of responding to COIs • methods of evaluation of COIs • operations of IRBs • review by IRBs • responsibilities of investigators • Institutional COI

20. Federal Commentary:NIH Draft Guidance, March 31, 2003, cont’d. • Affirms institutional self-regulation • Eschews “one size fits all” approach • Affirms acceptability of policy variations based on individual and institutional circumstances

21. Recent Commentary Bekelman, Li, Gross – JAMA 1/03 • Financial relationships among industry, investigators, and academic institutions are widespread. • COIs arising from these relationships can influence biomedical research in important ways.

22. Recent Commentary Johns et al. – JAMA 2/03 • Calls for complete divestiture by all institutional officials of research-related FIs. • Institutions could maintain their FIs in research under conditions (separation and independent review panel).

23. Recent Commentary • Blumenthal, NEJM, 12/18/03 • “There remain many uncertainties on the road to the realization of this vision of a voluntary, private-sector solution to the problems associated with the academic-industrial relationship in clinical research.”

24. Recent Commentary, cont’d. • “Nevertheless, private-sector initiatives, government pressure, and the ever-looming threat of scandal appear to have launched the university community on a path toward increased disclosure and closer management and monitoring of academic-industrial relationships in clinical research. In non-clinical research, however, there is no comparable prospect.”

25. Interests at Stake • Primacy of interests of human subjects • Public trust • Integrity of research, researcher, and research institution • Social good • External credibility • Access to clinical trials • Fiscal responsibility

26. “Competing” Interests at Stake • Bayh-Dole • Technology transfer • Competition for talent • Stressed budgets • Economic development

27. The public The university The faculty Research subjects IRBs Research sponsors Federal government Trustees/Regents Donors State legislatures Alumni Peer institutions The Stakeholders

29. Regulation of Conflict of Interest • Self-policing isn’t enough • Experience has taught that institutions can’t rely on individuals to assess their own situations in relation to interface with industry • Can institutions assess their own institutional conflicts? • Rules and hierarchies of risky situations, behaviors • Transparent and depersonalized systems of assessment and risk adjustment/avoidance

30. AAMC Taskforce on Financial COI in Clinical Research • Cracks in the foundations • Wide variability of COI policies across academic research institutions • Federal regulatory gap for human subjects research • Limited to NIH and NSF funded research • No mandate for special scrutiny of financial interests in HSR • Congressional interest in enacting mandates • Necessity to maintain public trust

31. Underlying Assumptions • Prohibiting any financial dealings with industry is not in the public (or institution’s) interests • Permitting unfettered financial dealings undermines academic credibility and invites loss of public trust • Voluntary standards are preferable to government mandates • Public has dual interests: • accelerating advances in prevention, diagnosis and treatment • safeguarding the welfare of human subjects and the integrity of science

32. AAMC Task Force: Goal Create a model for effective and credible institutional self-regulation

33. Overarching framework A “rebuttable presumption” that a significant financial interest precludes conducting human subjects research

34. Rebuttable Presumption • Not an absolute prohibition (but intended to be close to it) • Sets a high standard for prior review by an institutionally authorized group • Rebuttal must demonstrate “compelling circumstances” To wit: the research could not otherwise be conducted as safely or as effectively

35. Considerations in Judging Compelling Circumstances • Nature of science • Nature and magnitude of significant financial interest • How closely interest is related to the research • Degree interest will be affected by the research • Extent interest is amenable to oversight and management

36. If Rebuttal is Successful • Rigorous, disinterested oversight • COI committee determines appropriate monitoring • COI committee documents findings and recommendations • Disclosure required (research subjects, funders, journals, audiences, the public on request) • Transparency

37. Risks to Subjects and Integrity of Research; Potential for Bias and Exploitation • Hierarchies of risks • Calibrations of responses, adjustments, interventions, prohibitions

38. Workable Review Mechanisms 1. Major research contracts over x years from one sponsor 2. Equity in a start-up sponsoring research at the institution 3. Significant consulting relationship with sponsor 4. Patent royalties from licensee who sponsors research 5. Endowment position in licensee of research 6. Major gifts/contracts from research sponsor *Types of Events

39. The AAMC Survey • Designed to measure state of policies at U.S. medical schools on individual financial conflicts of interest in human subjects research • Tracked AAMC recommendations • Launched June 2003; closed February 2004 • 80% response rate from accredited U.S. medical schools (n = 126) • Report expected late Spring 2004

40. Uptake by AAMC Constituents • Response rate • 23 of top 25 NIH medical school award recipients • 44 of top 50 NIH medical school award recipients • 82% response rate to survey • Strong progress in some areas; need for improvement in others • Indicators of changes, differences in types of institutions, benchmarking

41. AAMC Task Force: Epilogue • “The Task Force recognizes that the public’s extraordinary support of academic biomedical research will remain critically dependent upon public confidence and trust that are especially vulnerable in research involving human subjects.”

42. AAMC Task Force: Epilogue, cont’d. • “The Task Force does not believe, and does not intend, that adoption of the recommended policy and guidelines by the academic medical community should interfere with health academic-industry relationships or with the continued robust flow of academic biomedical invention into beneficial products.”

43. AAMC Task Force: Epilogue, cont’d. • “The Task Force does believe that these policies and guidance can help to ensure that the relationships remain principled, protective of research subjects and scientific integrity, and capable of withstanding intense public scrutiny.”

44. Concluding Observations • Extraordinarily generous public investment in biomedical research post WWII has NOT been driven by scientific curiosity or abstract goal of enriching scientific knowledge. • It has been driven by expectation and hope that diseases will be better understood, prevention and therapeutic interventions more effective, suffering reduced, and public health improved.

45. Concluding Observations, cont’d. • The NIH dollar, with few exceptions, stops at discovery. • Health care is an application of science, a form of engineering • It is a source of contribution to its own science base, disengaged from application of science • But the success of academic medical centers attests to the social value of associating discovery and application, institutionally and (to some degrees) functionally

46. Concluding Observations, cont’d. • Partnering to bring biomedical research to market is inevitable. • As long as the practice and development of applications of science in health care are, as elsewhere, a predominantly economically-driven business enterprise, the interaction of science and industry is necessary to advance health care capacity and the social good by by the practical application of discovery

47. Concluding Observations, cont’d. • Commercial development of scientific discoveries is, with exception of the defense industry, almost exclusively dependent on private capital – from venture capitalists, start-ups, biotechnology and pharmaceutical firms, etc. • Robust development pathway of immense social benefit requires not prohibition but effective regulation, education, and enforcement.

48. Concluding Observations, cont’d. “Publicity is justly commended as a remedy for social and industrial diseases. Sunlight is said to be the best of disinfectants; electric light the most efficient policeman.” L. Brandeis, 1913