1. Conflicts of Interest in Research Delia Y. Wolf, MD, JD, MSCI Assiociate Dean, Regulatory Affairs & Research Compliance Email: dywolf@hsph.harvard.edudywolf@hsph.harvard.edu October 24, 2014

2. What is a Conflict of Interest  Many definitions, only some consensus  One possible working definition: an individual or institution has a primary interest or duty (e.g., scientific integrity and objectivity, protection of subjects) that may be affected or undermined by a competing interest (e.g., financial reward, professional advancement, etc.) 2

3. Types of Potential Conflicts  Individual financial interest, examples Equity interests: ownership of stock and stock options in a company sponsoring research Royalty: when an investigator is conducting a research project for a company that is developing the technology, of which the investigator is also the inventor Consulting fees, over-scale honoraria and gifts, or other monetary compensation from companies whose products are affected by investigators’ research results Recruitment bonus or milestone payments from sponsoring company to investigators in order to “accelerate” research process Finder’s fees 3

4.  Significant Financial Interest according to PHS include: An equity interest which when aggregated for the investigator and his/her spouse and dependent children (a) exceed $5,000 in value and/or (b) represents more than five percent (5%) ownership in any single entity Salary, royalties or other payments for service that when aggregated, investigator and his/her spouse and dependent children, over twelve months period, is reasonably expected to exceed $5,000 4 Significant Financial Interest (SFI)

5. Financial Interests Disclosure  Financial interests meet De minimis threshold of $5000 (SFI)  ALL SFI related to the investigator's institutional responsibilities (note: the 1995 regulations required “only those SFI the investigator deems related to the PHS- funded research”)  Travel reimbursements and sponsored travel (De minimis threshold does not apply) 5

6. Excluded from Disclosure  Income from lectures, seminars, or teaching engagements sponsored by public or nonprofit entities; a federal, state, or local government agency, an Institution of higher education, an academic teaching hospital, a medical center, or a research institute that is affiliated with an Institution of higher education.  Income from investment vehicles, such as mutual funds and retirement accounts, as long as the investigator does not directly control the investment decisions 6

7. Conflicts of Commitment  Competing demands on researchers’ time Working on one or more funded projects Teaching and advising students Attending professional meetings and giving lectures Serving as a peer reviewer  Allocation of time Time and effort reporting – seek advice if unsure whether a particular commitment of time is allowed under an institution's or funding agency’s policy  Use of resource Equipment purchased with public funds cannot be used for private research 7

8. Examples of potential COI  An academic researcher in a NIH study section reviews a grant application from a competitor in the same field  A clinical investigator receives $3,000 for each patient she recruits into a clinical trial  A university’s IRB reviews a research proposal sponsored by a company that has recently given $10 million to the university 8

9. Examples of potential COI (cont.)  A university holds stock in a chemical plant but also hires employees to monitor its emissions.  A university president owns stock in a company that sponsors research on campus and has made large gifts to the campus 9

10. Impact of Financial Interests  Existing evidence suggests an impact on science doe to financial relationships: Industry-sponsored studies that are published are more likely to reach pro-industry conclusions (Bekelman et al., 2003) Gifts change physicians’ prescribing behaviors (to the benefit of the gift-giver) In one survey, 15.5% of 3,247 scientists surveyed reported that they had changed the design, methodology or results of a study in response to pressure from a funding source (Martinson et al., 2005) 10

11. How COI is identified/judged  Conflicts usually judged in retrospect  Hard to “prove” causative effect (conflict  bias)  Often only an issue in the wake of an adverse event and compounds the problem for investigators and/or institutions  Public perception/media focus 11

12. Regulatory Requirements  FDA Regulations ( 21 CFR Parts 54; 312.53; 812.43 ) Investigators must disclose certain financial interests to sponsors; sponsors then disclose to FDA FDA may take action if it determines that the financial interests of an investigator raise a serious question about data integrity  PHS Regulations 42 CFR Parts 50 and 94 (1995) Revised final rule public August 2011 12

13. University-wide Policy  Harvard University policy on individual financial conflicts of interest policy can be found at: http://vpr.harvard.edu/content/conflicts -interest http://vpr.harvard.edu/content/conflicts -interest  Approved by the President and Fellows of Harvard College on May 26, 2010  Applies to holders of faculty and teaching appointments at the Schools 13

14. Responses to COI Concerns 14  Common themes in existing responses: DISCLOSURE  Information gathering IDENTIFICATION  Defining what constitutes a COI MANAGEMENT  Disclosure component (transparency)  Reducing impact of conflicted investigator

15. Managing Financial COI  Disclosure to the IRB Protocol-specific $1 threshold at Harvard Catalyst institutions  Following management plan such as: Disclosure to potential research participants Refrain from recruitment activities Refrain from interpretation of data Appoint another investigator to be the principal investigator (PI) 15

16. 16  Limitations of disclosure to subjects: Can subjects make meaningful use of that information? Evidence that some patients view their doctors’ financial interests positively:  Demonstrates knowledge and that they are on cutting edge  If physicians are more vested they will work harder Managing Financial COI (cont.)

17. COI in International Research 17  Globalization of research/clinical trials Increased outsourcing of research by industry  This has resulted in the outsourcing of COIs as well (Gatter, R.)  Drug company payments to health professionals in resource-poor countries can double or triple their annual incomes (Washington Post, Dec. 2000)

18. COI in International Research (cont.)  Reliance on industry funding Many countries want to be viewed positively to industry as a good place to site trials Trials bring funding for research as well as access to investigational therapies and, for resource-poor countries, often additional capacity-building for the institution and/or nation that goes beyond the research study (e.g., access to standard of care therapy for all patients, funds to improve facilities, etc.) 18

19. COI in International Research (cont.)  Government involvement In many countries, regional and/or national approval of research is required Governments may have incentives either to ensure research happens (reflects positively on country, financing is dependent on it) or block it (if anticipated results may damage country’s reputation) 19

20. CASE STUDY 20 A U.S.-based pharmaceutical company is conducting a drug trial in a resource-poor country; the protocol involves studying the safety and effectiveness of a new drug for hypertension. In addition to the research budget, the local investigators are being paid through consulting agreements to advise the company on research and political strategy and to liaison with local officials (the amounts, while modest by US standards, are 3 times what the investigators make in annual salary at their institutions). The consulting agreements give the company the rights to control access to data and approval any publications. The local institution’s Ethics Committee is comprised primarily of hospital management and prominent community members. In addition to the institutional EC, the protocol must be reviewed by a regional Ethics Committee, the Chair of which holds a prominent position in the local government.

21. CASE STUDY 21 Local government officials have repeatedly expressed a desire to improve their reputation as a “research-friendly” locale. The local health system, including the site, desperately needs investment in infrastructure. The standard of care for hypertension in the US is currently prohibitively expensive for the site’s patient population. The company has offered to invest a significant amount of resources in improving the site, building local health clinics, as well as providing infrastructure and resources for the EC. The company has also offered to ensure that all patients at the site (whether on protocol or not) receive the standard of care for hypertension during the course of the trial and for 3 years following; additionally, if benefits are shown, the company has offered to make the new drug available to all patients at the site for the same time- frame.

22. CASE STUDY: Q & A 22  What conflicts do you see with this arrangement?  Whose responsibility is it to question the validity of the regional EC approval?  How should the reviewing ECs balance just reward to the site for participating against the potential to create conflicts?  What management techniques might work in this context?

23. 23 Collaborative Research  Types of collaborative research  Points to consider before, during and after collaboration  Case studies

24. Types of Collaborative Research  Within institution  With institutions/hospitals  Multicenter – within the US  Multicenter – transnational  Collaborations with industry 24

25. Points to Consider  Before any work is undertaken Clear understanding of the nature of the collaboration  Roles and responsibilities Sufficient resources  Time, space Written agreement (between/among collaborators)  Who does what  Who owns what  Criteria to identify and rank contributing authors Necessary review and approval from institution  Grants/contracts  Technology transfer  IRB/IACUC 25

26. Points to Consider (cont.)  During the course of collaboration Following research plan/study protocol Communication  Report Progress  Share findings  Discuss problems Documentation  If it is not documented, it is not done! Training and supervision Verification Good record keeping  Time and effort 26

27. Points to Consider (cont.)  After the completion of a collaborative research project Submit final report/closure to relevant offices at researcher’s institution  IRB office Be aware if record keeping requirements  Institutional requirements  Sponsor requirements  Government agency requirements 27

28. Case A  Amber, Ben and Carol have just received funding from a small pharmaceutical company to test one of its imaging agent.  Amber is a neuro-radiologist at BIDMC, who will be the PI, as well as the IND holder, Ben is a psychiatrist at MGH, and Carol is a biostatistician at HSPH. All three will serve as co- investigators.  Study is going to be conducted at BIDMC. Both Amber and Ben will be interact with research participants; Carol will not have direct contact with participants, but will have access to participants’ identifiable information. Which office(s) will they have to deal with Do all three need to get IRB approval from each of his/her institution Do they need an agreement among themselves? If so, what should be included in the agreement? 28

29. Case B  Dr. D is a biostatistician from HSPH. He is the PI for a data coordinating center that oversees and analyzes all data collected from a multi- canter clinical trial involving 12 sites in the US and 10 sites outside of the US. What are Dr. D’s responsibilities in terms of meeting regulatory requirement?  Obtaining IRB approval  Oversight of research conduct  Reporting obligations 29

30. Case C  Dr. M is the overall PI for a multi-center Vitamin A supplementation clinical trial that is sponsored by NIH. She is a faculty member at HSPH, but no study activities will be conducted in the US. There are a total of three sites in India, Tanzania and Botswana. Does Dr. M need to get HSPH IRB approval to work on the study? Which country’s rules should be followed for regulatory oversight? Since she only visits each site once a year, how can she fulfill her responsibility as a PI? 30