Collaborative Research and Conflicts of Interest

1. Collaborative Research and Conflicts of Interest Delia Y. Wolf, MD, JD, MSCI Associate Dean, Regulatory Affairs & Research Compliance Harvard School of Public Health Email: dywolf@hsph.harvard.edu Website: www.hsph.harvard.edu/ohra February 28, 2014

2. Topics to be Covered • Collaborative Research • Conflicts of interest • What is COI • Regulatory requirements • Institutional policies

3. Collaborative Research Types of collaborative research Points to consider before, during and after collaboration Case studies 3

4. Types of Collaborative Research Within institution With institutions/hospitals Multicenter – within the US Multicenter – transnational Collaborations with industry 4

5. 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 5

6. 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 6

7. 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 of record keeping requirements • Institutional requirements • Sponsor requirements • Government agency requirements 7

8. Case A • 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 • Overseeing of research conduct • Reporting obligations 8

9. Case B • 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? 9

10. Case C • 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. Ben and Carol 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? 10

11. 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.)

12. 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

13. Significant Financial Interest (SFI) • 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

14. 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)

15. 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

16. 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

17. 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

18. 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

19. 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)

20. 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

21. 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

22. University-wide Policy • Harvard University policy on individual financial conflicts of interest policy can be found at: 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

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

24. 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)

25. Managing Financial COI (cont.) • 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

26. COI in International Research • 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)

27. 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.)

28. 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)