Presented by: Arthur O. Anderson MD Director Office of Human Use and Ethics, US Army Medical Research Institute of I

1. RCR Lecture at USAISR, San Antonio, TX17 November 2010PR-10-426Conflict of Interest in Military Medical Research:What is it, How to recognize it, & what to do about it? Presented by: Arthur O. Anderson MD Director Office of Human Use and Ethics, US Army Medical Research Institute of Infectious Diseases The opinions presented here are the personal views of the author and are not to be construed as official or as representing the Department of Defense.

2. What credentials do I have to discuss conflict of interest ? • 1962-1966 I had 16 credit hr in philosophy before med school and pathology training • 1962-1974 HQS Human Research Committee • 1974- Questionable Tularemia study • 1975-Appointed chair (OGE-450) • 1993-Research Integrity added to duties • 1999-2005 FCPS ethics panel, faculty COI • 2008-Consultant to a major university to review faculty and institutional COI

3. What is a conflict of interest? • We all have personal interests • Some are financial and some are not (e.g., prestige, desires, career advancement) • An interest is not necessarily a conflict • An interest becomes a conflict when it has the potential (or the appearance of the potential) to affect our judgment • Conflicts may be potential or actual, perceived or real, harmful or insignificant. Adapted from a 2009 PRIM&R Conflict of Interest Presentation by Suzanne M. Rivera, PhD.

4. Conflict of Interest - Concerns • “Conflicts of Interest in Health Care” has emerged as a “hot-button” issue for Congress and the media. • Financial conflicts of interest raise concerns about the objectivity and trustworthiness of research conduct and publications, the prudent management of scientific investigations and other activities in the public interest, and the commitment of health care professionals to the best interests of patients. • Failures of individuals and institutions to disclose andappropriately manage financial ties with industry (including pharmaceutical, medical device, medical supply, and insurance companies) contribute to questions about whether industry has undue influence in research and other activities.

5. Conflict of Interest: Concerns becoming more complex as civilian medicine evolves • As medical research, professional education, health care, and institutional management have become vastly more complex, the task of managing conflicts of interest has become more challenging. • Industry - leading funder of medical research, and research conducted in nonacademic settings. • Industry also funds the “development of evidence reviews” and “practice guidelines” that are intended to help translate research findings into practice. • Such guidelines may shape clinical choices and may even be used to evaluate professional or institutional performance.

6. Federal Conflict of Interest Law • Federal Government employees are prohibited by criminal statute (18 U.S.C. §§ 201-209) from participating personally and substantially in a particular matter as part of official duties which will have a direct and predictable effect on their financial interest or the financial interest of their spouse, minor child, outside employer, or certain others. • Code of Federal Regulations Title 5, Volume 3, Chapter XVI Office of Government Ethics Part 2635 Standards of Ethical Conduct for Employees of the Executive Branch, Subpart D_Conflicting Financial Interests, Sec.2635.402 Disqualifying financial interests

7. Conflict of Interest Regulations • 32 CFR 219, Protection of Human Subjects Paragraph 219.107(e) No IRB Member COI. • AR 70-25, Use of Volunteers as Subjects of Research, Appendix C-7 Conflict of Interest • HRPP Conflict of Interest - Policy/Procedure • 21 CFR 54, Financial Disclosure by Clinical Investigators (1 April 2008) • 42 CFR 50, Subpart F, & 45 CFR 94, (11 July 1995) Responsibility of Applicants for Promoting Objectivity in Research for which PHS Funding is Sought* • *(Revisions & Proposed Rule , comment period ended 21 August 2010)

8. Can We Recognize Our Own Conflicts of Interests? • This biblical quote “And why beholdest thou the mote that is in thy brother's eye, but considerest not the beam that is in thine own eye?” Matthew 7:3-5 • May show how long we have known about our problem with self-perception

10. Federal Conflict of Interest Law in federal court "for conflict of interest and making false statements related to his investments." "Crawford, 68, falsely stated in a 2004 government filing that shares of Sysco Corp. and Kimberly-Clark Corp. had been sold when he and his wife continued to hold them, U.S. Attorney Jeffrey Taylor said in the charging documents. Crawford also failed to disclose income from exercising stock options in Embrex Inc., the documents said." Lester M. Crawford, Commissioner of the U.S. Food and Drug Administration (FDA), was charged October 16, 2006,

11. Three Types of Conflicts • Institutional • Private sponsor is spin-off from institution • Institution holds stock in sponsor • Institution holds patent on test article • IRB Member • Member is a co-investigator on study • Member’s spouse is a member of study team • Member owns or buys stock in sponsor • Investigator • Principal investigator (PI) has personal interest the article under study, product inventor or PI’s prestige is linked to its success • PI financially invested in sponsor company or on payroll • Sponsor rewards PI for meeting study goals Adapted from a 2009 PRIM&R Conflict of Interest Presentation by Suzanne M. Rivera, PhD.

12. Important Considerations • Identify individuals whose interests may result in prohibited conflicts, and what are the reporting thresholds and categories • Have written procedures and criteria for interpreting information about interests • Have a management plan to enable decisions, disclosure requirements, and monitor activities if conflicts of interest are found Adapted from a 2009 PRIM&R Conflict of Interest Presentation by Suzanne M. Rivera, PhD.

13. I.O. is Vulnerable to COI • Institute officials must • Foster research productivity • Balance numerous institutional interests • Support IACUC/HUC/QARCO/IBC etc. – protect and reinforce their authority, freedom and autonomy • Recruit and retain outstanding researchers • Enforce high standards for research integrity • Rake in and distribute the royalties, MIPRs etc • Facilitate product development • Keep institution off front page of newspaper • Pressure to accomplish mission objectives Adapted from a 2009 PRIM&R Conflict of Interest Presentation by Suzanne M. Rivera, PhD.

14. Managing Institutional Conflicts • Not an easy answer within DOD • Presently any institutional or individual COI Management is referred to the JAG office and an attorney issues a legal opinion • Often these opinions fail to deal with ethical issues related to factors other than money • Universities include information about COI in faculty/student handbooks and define conflict of interest pretty clearly. They also define conflict of commitment

15. COI in Educational Institutions

16. Managing IRB Member Conflicts • Recommend member notify the IRB Chair or the IRB office of a COI in advance (use form) • Elicit COI information from members at beginning of IRB meeting (This is a good opportunity to update COI Information if an annual COI form was used) • IRB members with a COI must leave the meeting during deliberation and actions on activities for which the COI exists • Members with COI may answer questions but must be absent during deliberation and voting. • IRB minutes must record the name of the IRB member with the COI, state they were recused and what time they left & returned to the meeting Adapted from a 2009 PRIM&R Conflict of Interest Presentation by Suzanne M. Rivera, PhD.

17. Managing Investigator Conflicts • Disclosure to subjects, funders, journals, audiences • Oversight/monitoring (Who does this?) (Use OGE 450, Separate review of financial disclosures by IRB Subcommittee for relevant holdings, interests, exceeding $10,000 or outside employment (*) • Independent consent process (i.e., someone other than the PI does the consenting) • Recusal from studies (i.e. ,the PI abstains from any involvement with studies linked to his COI) • Divestiture of interests • Are there “compelling exceptions” – • think of PI COI vs national emergency laws that repeal COI considerations – after the emergency has passed has harm been done to subjects or confidence in integrity of agency Adapted from a 2009 PRIM&R Conflict of Interest Presentation by Suzanne M. Rivera, PhD.

19. Outside Employment RecentCOI Issue for Gov’t Researchers Income from Pharma kept issues quiet = Affected Advice to Pharma vs Pharma’s Advice to PI, = ? Research Results, = ?Treatment Advice, = Self vs Patient’s Interest? e.g. FDA Estimates Vioxx Caused 27,785 Deaths.And, Phase I studies on SSRI drugs did not report Suicides among normal volunteers in Phase I trials because no Federal Dollars were used.

21. New NIH COI Regulations 42CFR50, 45CFR94 mandate that IRB/IO have: • Adequate disclosure mechanisms/transparency • IRB review of COI management plans • Procedures to reduce, eliminate, or manage COI • COI disclosure included in Informed consent • A poll of subjects gave counterintuitive results. COI by PI was seen by subjects as a plus without raising concern about lapsed clinical judgment or conflicted interest • Duty to crosscheck investigator reports against websites that disclose payments

22. How far must we go to assure no harms accrue due to COI? • Before Belmont, personal integrity and other values held by medical researchers directly determined whether or not patients were treated with care and respect or merely exploited for personal gain • As you can see from this presentation, there are many places where personal integrity and character may have influences on the quality of COI information or whether disclosure of any COI is forthcoming • Do we need to become integrity police? • “Conflict of interest represents the potential for biased judgment. But , it is not an indicator of the likelihood or certainty that such judgment or compromises will occur.” Jeff Cohen. 2001 Acad. Med. 76.2 209-214

23. Summary • As long as we are human beings • Have friends and business associates • Are employed or are an employer • Are passionate about our discoveries • Invent industry • Seek profits • There will be opportunities that COI occur • Therefore, it is important to: • become COI self-aware, • have systems in place to prevent COI from affecting judgment or allowing harm to subjects, and • for management of COI if found

24. Arthur O. Anderson MD, (COL MC Ret.) Director, Office of Human Use and Ethics, and Research Integrity Officer US Army Medical Research Institute of Infectious Diseases Fort Detrick, Frederick MD 21702-5011email: art.anderson@us.army.mil Office Phone: 301 619 4723