1. Fundamentals of Conflict of Interest in Research By Camille A. McWhirter, J.D. Director, Research Compliance USF Health

2. Learning Objectives Generally: Define a conflict of interest (COI) Recognize different types of “self-interest” that can create a conflict of interest Recognize the various ways a conflict of interest can occur in the research context

3. Learning Objectives (cont) Regulatory Context: Understand the difference between the state’s interest in regulating COI and the federal government’s interest in regulating COI Identify the three federal government agencies who have rules regulating COI in research Understand when each agency’s rules apply

4. Learning Objectives (cont) Practical Application: Identify the different types of conflicts of interest in a given scenario Perform a COI review and develop a management plan

5. “Working” Definitions Conflict of Interest A conflict of interest exists when an individual’s professional or ethical obligations might be compromised by self-interest.

6. Conflicts of Interest and Commitment w/ University Employment (Excessive time spent on external endeavors, use of USF resources/name/students in furtherance of private interests, waiver of USF IP rights in private agreements) General Conflicts of Interest (Nepotism, Doing Business w/USF in Private Capacity, Board/Committee Membership, Purchasing Decisions) Conflicts of Interest in Research (Personal financial interests that may bias the design, conduct or reporting of USF Research)

7. “Working” Definitions Conflict of Interest in Research A conflict of interest in research exists when an investigator’s self-interests may compromise, or have the appearance of compromising, an investigator's professional judgment in the design, conduct or reporting of research. Investigator Any person responsible for the design, conduct or reporting of research.

8. COI = Individual + Self-Interest + An Ethical or Professional Duty COI in Research = Investigator + Self-Interest + Objectivity in the Design/Conduct/Reporting of Research HINT: The management goal is to protect the integrity of the research

9. Hypothetical: COI in Research? Dr. Needbucks of Public University invented a drug to prevent Alzheimer’s disease. DevicesRUs, wants to sponsor a study with Dr. N as the PI to develop and test a device that will deliver Dr. N’s drug directly to the brain. Dr. N’s spouse is the president of Lab Solutions, Inc. that manufactures lab supplies and equipment. Dr. N and her staff purchase all of their basic supplies and equipment from Lab Solutions.

10. Ask: Investigator? Yes. The individual is an investigator on a research study. Self-Interest? Yes, financial interest of spouse in a company that sells research products. What is the professional/ethical obligation that is compromised? The duty potentially compromised by this self-interest is the duty of public stewardship--to refrain from using one’s public position to enhance one’s private interests. Conclusion: This is a conflict of interest in a research setting, but not a “COI in Research” as we have defined it because the investigator’s self-dealing, while perhaps a conflict with her public position, does not compromise the integrity of the research results.

11. What if during the course of the study… Dr. Needbucks purchases $30,000 worth of stock in DevicesRUs?

12. Repeat the analysis: Investigator? Yes. The individual is an investigator on a research study. Self-Interest? Yes, Dr. N’s financial investment in the sponsor/manufacturer of the device being tested. What is the professional/ethical obligation that is compromised? The duty potentially compromised by this self-interest is the duty of objectivity in the design, conduct, or reporting of the research study. Conclusion: This is a “COI in Research” as we have defined it. Note that there may be more than one type of conflict of interest at work in the research context—multiple avenues of self-interest and multiple professional or ethical duties.

13. Types of Self-Interest Self-interest can manifest in the form of A financial benefit Enhanced reputation Personal relationships Professional relationships Other interests (personal, political, religious, or intellectual beliefs)

14. What type of self-interest is represented by these examples? Dr. Warren is an investigator for a study testing a new medical device. Dr. Snyder’s brother is one of the owners of the company developing the device. (Personal Relationship) Dr. Mercer sits on the IACUC and reviews a study about cloning. Dr. Mercer thinks cloning is immoral and unethical. (Personal Belief)

15. What type of self-interest is represented by these examples? Dr. O’Connor owns significant stock in a biotech company. The company approaches him about conducting research on the viability of a new genetics test. (Financial Interest) Dr. Tate is the co-founder of a new method of behavioral therapy for which he has received worldwide recognition. He is approached about conducting a study for another form of therapy which, if effective, would render his form of therapy obsolete. (Reputation )

16. What type of self-interest is represented by these examples? Dr. Markham sits on the board of directors of Company X. Company X is developing a new piece of equipment and they ask Dr. Markham to conduct a study on the safety and efficacy of the equipment. (Professional Relationship)

17. State Regulations (Code of Conduct of Public Officers and Employees) The state regulations only address general COI of public officers and employees and are designed to prohibit and/or manage conflicts between a public employee’s duties to the state employer and the employee’s personal interests Example: A public employee acting in a private capacity, may not sell goods to his or her own agency. Example: A public employee may not have an ongoing or regularly recurring conflict with his or her public employment (catch-all provision). What interests are the state COI regulations designed to protect?

18. Federal Regulations (NSF/PHS and Food & Drug Administration) The federal regulations only address financial interests and relationships in research (COI in Research) Example: Universities receiving federal funds to conduct research must have policies to manage bias in the design, conduct or reporting of research funded with federal dollars (PHS/NSF). Example: A sponsor of a new drug/device must certify that COI of investigators in studies supporting the FDA approval of the drug/device either does not exist or is adequately managed What interests are the federal regulations designed to protect?

19. Federal Regulations The federal regulations only address one type of “self-interest”: FINANCIAL INTERESTS (Why?)

20. Federal Regulations Food and Drug Administration Applies in research involving a drug, device or biologic. Requires disclosure at the time of application for approval of a drug device or biologic. Evaluates the impact of the researcher’s financial interests on the reliability of the study.

21. Federal Regulations Public Health Service (PHS) & National Science Foundation (NSF) Applies to institutions receiving grants from these agencies Requires development of a COI policy that meets certain minimum requirements Deliberately vague to permit flexibility in the administration of policy PHS and NSF regulations were developed cooperatively to make the regulations consistent.

22. FDA Regulations “Anyone who submits a marketing application of any drug, biological product or device must submit certain information concerning compensation to, and financial interests of, any clinical investigator conducting studies covered by this rule.” 21 CFR Part 54

23. What is the “certain information”? Applicant must EITHER certify that: No financial arrangements have been made with an INV where study outcome could affect compensation. INV has no proprietary interest in the tested product. INV does not have significant equity in sponsor and has not received other payment

24. OR Disclose the specified financial arrangement and any steps taken to minimize the potential for bias. Then, FDA will determine whether conflicting interest could jeopardize the integrity of the study. Such a determination can result in severe delays and significant financial losses. So….institutions are doing it for themselves.

25. Potential FDA Actions If the FDA is concerned about the conflict, the FDA can: Audit the data derived from the INV in question Request further data analysis to evaluate the effect of the INV data on overall results Request additional independent studies Refuse to use the data to support an FDA action

26. PHS/NSF COI Regulations Investigator Responsibilities: Must report any significant financial interests (including those of spouse and dependent children) to a designated institutional official.

27. Significant Financial Interests Anything of monetary value, including salary, consulting fees or honoraria, equity interests (stock, ownership interests) and intellectual property rights.

28. EXCEPTIONS: Salary from your own institution Ownership interest in an institution applying for an SBIR grant Income from speaking engagements sponsored by government or non-profit Income from advisory boards of G or NP Equity interest < $10,000 or 5% Annual payments < $10,000

29. PHS/NSF COI Regulations Institutional Responsibilities: Written enforced policies on COI Designated institutional official Ensure that each investigator submits a disclosure form for PHS and NSF research annually Provide guidelines for review of COI and manage COI Maintain records for 3 years Establish enforcement mechanisms and sanctions Report failures to comply to awarding agency

30. Problem for Institutions COI can be subtle and complex, often involving ethical issues beyond the scope of regulation. Also, the regulations that do exist are purposefully flexible in order to allow the institutions to apply them in the way that best suits the institution. So the regulations can often seem vague and open to interpretation.

31. Solution: Guidance Documents Consequently, a number of federal government agencies and national professional associations have published guidance documents to help individuals and institutions cope with COI in research issues regulated by the federal government. Among these organizations are the American Medical Association (AMA), the Association of American Universities (AAU), and the Association of American Medical Colleges (AAMC).

32. Conflict of Interest Committee Many of the guidance documents recommend that institutions create a Conflict of Interest Committee (COIC) to evaluate, manage COI resulting from external financial interests in research, and to ensure that the institution’s COI policies and procedures and applicable COI regulations are met.

33. General Principles in Dealing with COI in Research COI is virtually unavoidable. COI does not preclude participation of an investigator in a project. Must have a culture of honest and full disclosure so that steps can be taken to manage conflicts effectively Not all COI can be managed.

34. COI Committee Review MOTIVATION How much incentive does the INV have to bias the design, conduct or reporting of the research? OPPORTUNITY Is the INV in a position to bias the design, conduct or reporting of the research?

35. Possible Steps to Manage COI Elimination of the conflicting interest (e.g., divestiture of financial interest or removal from project) Substitution of non-interested personnel on the project Public disclosure of the financial interests (journals, research subjects, collaborators, etc.) Monitoring of research by independent reviewers Look for inherent management controls (e.g., the research has objective endpoints that are not subject to manipulation by the investigator)

36. COI Committee: Hypothetical Investigator Scully has regular and ongoing consulting agreements with various sponsors of clinical trials on which he conducts studies. The aggregate of income for any one sponsor can be anywhere from $8,000 - $30,000 per year.

37. COI Committee: Hypothetical Investigator Scully is approached to conduct a study for Company X and files a financial disclosure stating that he anticipates receiving $9,999 in income from Company X over the next 12 months. Scully also served on the advisory board of Company X to assist with the study design and analysis on the study that he has been asked to conduct for Company X. Scully might receive more $$$ from Company X if he is asked to give lectures on the study during the year.

38. COI Committee: Hypothetical Additional facts: The study in question is a multi-center trial that will obtain data from 10 different sites aggregate. Scully is the PI for one of the sites. Data analysis is externally conducted—i.e., Scully is not involved in the analysis of study data The COI is disclosed in manuscripts submitted for publication per journal requirements.

39. COI Committee: Hypothetical The research subjects’ informed consent will outline Scully’s interests related to Company X. There are other investigators on the study who do not have an interest in Company X.

40. Some Issues to Consider What information do you need from INV Scully? How would you handle the “uncertain” amount of income that may be received annually? Is there sufficient motivation to be concerned about bias in the design, conduct or reporting of the study?

41. Some Issues to Consider Is there sufficient opportunity? Is this conflict manageable? How does the involvement of human subjects influence your decision? Would your opinion change if the amount of annual consulting compensation was $100,000?

42. For further consideration… A colleague reports that Scully is diverting the best grad students to work on the Company X project to the detriment of other unfunded research projects in the Department. Should this issue be addressed in your review?

43. Other types of conflicts of interest that occur in the research context: Nepotism (hiring relatives to work on your grant) Use of university resources to benefit a private entity Excessive time spent on external endeavors Waiver of University patent rights in a private consulting agreement