Conflict of Interest Committee

Financial Conflicts of Interest in Human Subjects Research: Policies and Procedures

Approved by the Conflict of Interest Committee on April 21, 2006 and the Human Research Protection Program Advisory Committee on April 6, 2006.

[For definitions of terms used in this document, see Appendix 1.]

Summary
Background
Policies
Definitions
Procedures
Acknowledgements
References

Summary

The University of Wisconsin Madison (UW-Madison) has legal and ethical responsibilities to review and, where appropriate, to reduce, eliminate, or manage potential financial conflicts of interest in research involving human subjects. To ensure that the safety of research participants is adequately protected, the UW-Madison (1) requires reporting and review of significant financial interests that might present a real or potential conflict of interest with the individual’s research prior to final IRB approval of the research, and (2) limits the participation of individuals who hold significant financial interests related to a research project involving human subjects in that research. Further, the UW-Madison affirms that significant financial interests should not negatively affect data sharing, publishing, and mentoring of students, fellows, trainees, or other research workers.

Background

Generating new knowledge, through research, and translating that knowledge into applications that benefit society is an important mission of many major research universities, including the UW-Madison. The UW-Madison encourages its faculty and staff to engage in research, to share their knowledge, and to promote the application of research results, including in the biomedical fields.

According to the National Institutes of Health, a potential financial conflict of interest exists when an investigator has significant financial interests that could lead an independent observer to reasonably question whether the design, conduct, or reporting of research might be influenced by the possibility of personal gain to the individual or his or her immediate family. Others define conflict of interest situations in terms of obligations. Two activities may interact such that judgment in one activity may be, or may seem to be, influenced by the other activity. Together, these two definitions identify important elements of conflicts of interest. Conflicts of interest:

1. represent a state of affairs, not behavior,

2. frequently involve perceptions, and

3. are judged by others, not by those directly involved.

Significant financial gains are considered to be of ultimate relevance in the current context for understanding conflicts of interest because money is recognized by the general public to be a potent motivator; one that is easily understood, easily quantified, and discretionary. While the focus of conflict of interest considerations is financial gain, other relevant interests inherent in academia, including prestige, promotion, grants, and publications, can also potentially exert influence over research activities.

Financial conflicts of interest can contribute to bias in research reporting, influence judgment, reduce free exchange of research findings, pose a threat to research integrity, and compromise the protection of human subjects. Potential financial conflicts of interest in human subjects research warrant careful scrutiny to ensure that the safety of research participants is adequately protected.

Policies

1. Application
This policy covers all principal investigators (PIs), co-investigators (Co-Is), and other key personnel on human subjects protocols reviewed by UW-Madison IRBs who are (a) UW-Madison employees, (b) UW-Madison students, or (c) other project personnel, regardless of their relationship with UW-Madison, when they or their immediate families have personal financial interests in business entities and whose situations are not reviewed and managed by another institution with respect to potential financial conflicts of interest related to the protocol in question.

2. Reporting
PIs, Co-Is, and key personnel on human subjects protocols reviewed by an IRB have an obligation to report all significant financial interests held by themselves or their immediate families in business entities with financial interests that would reasonably appear to be affected by the conduct or outcome of the human subjects research reviewed by a UW-Madison IRB.

PIs, Co-Is, and key personnel report significant financial interests in Annual Outside Activities Reports and/or in protocol-specific Outside Activities Reports in conjunction with IRB applications, as appropriate.

Additional information can be found in: (1) Appendix 2: Procedures, and (2) the Outside Activities Reports Web pages.

3. Review and Management of Relationships with Business Entities
UW-Madison has an obligation to minimize, eliminate, or manage any financial conflicts of interest as part of ensuring the protection of human subjects. To meet this obligation, the University directs the COI Committee to review all annual Outside Activities Reports and protocol-specific Outside Activities Reports made by human subjects researchers, whether the researchers are employed at the UW-Madison or not, and to recommend appropriate actions to minimize, eliminate, or manage any financial conflicts of interest to UW-Madison IRBs.

Individuals with certain financial interests in business entities cannot serve as principal investigator (PI), co-investigator (co-I), or key personnel for a human subjects protocol reviewed by a UW-Madison IRB if the entity or entities: a) sponsors the study, or b) owns or licenses a technology tested in the study. Research participation is restricted when individuals have a significant financial interest in the entity or entities that meets or exceeds one of the following thresholds:

1. Compensation of $20,000 or more in a calendar year from a business entity

2. An ownership interest in a publicly traded business entity valued at $20,000 or more or a 5% or greater equity interest

3. An ownership interest in a privately held business entity

4. A leadership position in a business entity (Leadership positions are positions with fiduciary responsibility, including senior managers (e.g. presidents, vice presidents, etc.) and members of boards of directors. Scientific advisory board membership is not a leadership position.)

An investigator may apply to the COI Committee for an exception to this prohibition based on compelling circumstances. If a UW-Madison IRB determines that a study poses no greater than minimal risks to subjects, investigators will normally be granted an exception to this prohibition without COI Committee review, unless a UW-Madison IRB determines that the investigator must apply to the COI Committee for an exception.

Additionally, individuals with the following financial interests must disclose the financial interests to human subjects research participants.

1. Compensation of at least $10,000 but less than $20,000 in a calendar year

2. An ownership interest in a publicly-traded company valued at least $10,000 but less than $20,000 and equal to less than 5% of the equity in the company

UW-Madison IRBs may determine that disclosure of financial interests would be inappropriate and not require it.

For more information on review, management, and exceptions, see Appendix 2: Procedures.

4. Data Analysis and Publication
Under no circumstances may a business entity limit the rights of an investigator to receive, analyze, or interpret any data generated as part of a human subjects research project. The UW-Madison also prohibits restrictions on publication of research results, regardless of research outcomes. An investigator may agree to delay publication for the purpose of pre-publication review for a period consistent with that allowed by other UW-Madison policies (typically less than 30 days).

5. Students, Fellows, Trainees, and Other Research Workers
Significant financial interests may give rise to conflicts with an investigator’s responsibility to foster the academic and professional development of students, fellows, trainees, or other research workers. An investigator’s financial relationship with a business entity may not place restrictions on the activities of students or trainees. In particular, an investigator’s relationship may not prevent or inhibit students or trainees from meeting applicable UW-Madison degree requirements (e.g., completion and public defense of a thesis or dissertation). If the COI Committee determines that it should manage an investigator’s relationship with a business entity, the investigator will be required to disclose the relationship to all students, fellows, trainees, and other research workers at the UW-Madison who he or she supervises in the course of research.

6. Payments from Business Entities
The UW-Madison prohibits payments to individuals from University accounts or directly or indirectly from business entities for particular research results or for research outcomes related to human subject protocols conducted at or through the UW-Madison. Further, PIs, co-Is, key personnel, or their immediate families may not receive any personal incentives from University accounts or directly or indirectly from business entities, such as recruitment incentives, performance incentives, fellowships, or other research support, except through an agreement entered into by the University for a sponsored human subjects study. The UW-Madison only permits payments for subject enrollment, or for the referral of potential subjects to human subjects studies, when all of the following are present:

1. The payment reasonably relates to costs incurred, as specified in research agreements between the sponsor and the UW-Madison.

2. The payment reflects the fair market value of services performed.

3. The payment is commensurate with the efforts of the investigator(s) performing the research.

7. Reconsideration of COI Committee Decisions
An individual may request reconsideration of any COI Committee determination that affects his or her ability to participate in human subjects research. Individuals have ten (10) business days from receipt of notification from the COI Committee or a UW-Madison IRB conveying the determination to request reconsideration. Individuals must make requests in writing and direct them to the Graduate School’s Associate Dean for Research Policy.

8. Noncompliance
Deliberate misrepresentation of information provided to the COI Committee or an IRB or failure to comply with the terms of this policy may result in sanctions including loss of privilege to serve as PI, Co-I, or key personnel on human subjects research protocols.

9. Implementation
The COI Committee will review all Outside Activities Reports submitted for the April 30, 2006 deadline, or later, under the provisions of this policy. To build experience reviewing and managing financial conflicts of interest in human subjects research, this policy will be implemented by UW-Madison IRBs in the following phases:

Researchers	IRB submission	Implementation date
PIs & Co-Is	Initial review	First full IRB meeting on or after approval of this document by the HRPP Advisory Committee and the COI Committee
PIs & Co-Is	Continuing review	In conjunction with online submission of applications for IRB review
Key personnel	Initial and continuing review	In conjunction with online submission of applications for IRB review

Appendices

Appendix 1. Definitions

The following definitions apply solely to the use of the terms in this policy statement.

Business entity means any corporation, partnership, proprietorship, firm, enterprise, franchise, association, trust, or legal entity other than an individual or body politic. This term also includes any entity acting as the agent of a business entity (e.g., a contract research organization).

Human subject means a living individual about whom an investigator (whether professional or student) conducting research obtains data through intervention or interaction with the individual, or identifiable private information. (For definitions of intervention, interaction, and private information, see the Common Rule, 45 CFR 46.102.)

Fiduciary means a person holding the character of a trustee, or a character analogous to that of a trustee, in respect to the trust and confidence involved in it and the scrupulous good faith and candor which it requires. A person having duty, created by his undertaking, to act primarily for another's benefit in matters connected with such undertaking.

Immediate family means: (a) an investigator’s spouse; (b) an investigator’s domestic partner; and (c) any person who receives, directly or indirectly, more than one half of his or her support from the investigator or from whom the investigator receives directly or indirectly, more than one half of his or her support.

Investigator includes any individual (e.g. faculty member, staff member, student, fellow, or trainee, including those with zero percent appointments) who, under the aegis of the UW-Madison or pursuant to the review and approval of any of the UW-Madison’s IRBs, conducts research involving human subjects.

Key personnel means, with respect to a human subjects research protocol, all individuals designing research, directing research or serving as the principal investigator, enrolling research subjects (including obtaining subjects’ informed consent or screening potential subjects) or making decisions related to eligibility to participate in research, analyzing or reporting research data, analyzing or reporting adverse events, or submitting manuscripts concerning the research for publication.

Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

Research means a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge.

Significant financial interests include the following interests of an investigator (and/or his or her immediate family) or a business entity controlled or directed by the investigator or a member of his or her immediate family:

1. Consulting fees, honoraria, gifts or other payments, or “in kind” compensation from individuals or business entities including from a third party, if the original source is a business entity, whether for consulting, lecturing, travel, service on an advisory board, or for any other purpose not directly related to the reasonable costs of conducting the human subjects research (as specified in the research agreement), that in the aggregate have in the prior calendar year exceeded the de minimis criteria established in Public Health Service (PHS) financial reporting regulations (presently $10,000), or are expected to exceed that amount in the next twelve months

2. Equity interests, including stock options, of any amount in a non-publicly-traded business entity.

3. Equity interests, including stock options, in a publicly-traded financially interested business entity that exceed the defined de minimis amount (See exceptions below.)

4. Royalty income or the right to receive future royalties under a patent license or copyright not managed by the Wisconsin Alumni Research Foundation (WARF)

5. Any non-royalty payments connected with research, other than those payments directly related to the reasonable costs of research as specified in a research agreement between the sponsor and the UW-Madison. This includes any bonus or milestone payments to the investigators in excess of reasonable costs incurred.

6. Service in positions with fiduciary responsibility, including senior managers (e.g. presidents, vice presidents, etc.) and members of boards of directors, whether or not the investigator receives compensation for such service

Exceptions. Significant financial interests in human subjects research do not include the following:

1. Interests of any amount in publicly-traded, diversified mutual funds

2. Stock or stock options in a publicly-traded business entity that (when valued in reference to current public prices) meets the de minimis criteria established in Public Health Service (PHS) financial reporting regulations (presently, an interest that does not exceed $10,000 in value and does not represent more than a 5% ownership interest in any single business entity)

3. Royalty income or the right to receive future royalties under a license agreement managed by the Wisconsin Alumni Research Foundation (WARF)

4. Payments managed through the UW-Madison that are directly related to reasonable costs incurred in the conduct of research as specified in the research agreement(s) between the sponsor and the UW-Madison

5. Salary and other payments for services from the UW-Madison

Technology means any diagnostic, therapeutic, medical, or surgical procedure and any process, method, compound, drug, or device.

Appendix 2. Procedures

(a) Reporting

(i) To the COI Committee
All PIs and Co-Is of human subjects protocols who are UW-Madison employees must complete Outside Activities Reports annually. Individuals required to submit annual reports are also responsible for updating their reports anytime there is a relevant change in their outside activities (e.g. new relationships with outside organizations or increased compensation for an on-going activity). Current reports must be on file before an IRB will grant final approval to a protocol application.

(ii) To IRBs
For human subjects research protocol applications, PIs must:

1. Name all research sponsors

2. Name all business entities owning or licensing technologies being tested

3. Name any additional business entities involved in or potentially affected by the research project

4. Name PIs, Co-Is, or other project personnel who:

   1. have significant financial interests in any business entity sponsoring the study

   2. have significant financial interests in any business entity that owns or licenses a technology tested in the study

   3. have any proprietary interests (royalties, patents, trademarks, copyrights, or licensing agreements) involving any technologies being evaluated as part of the study

   4. receive personal incentives for recruiting human subjects or for any other purpose directly related to the study

5. Submit protocol-specific Outside Activities Reports for any individuals identified as part of 4a, 4b, or 4c who are not required to file annual Outside Activities Reports under this policy or other University policies. These reports must be submitted before an IRB will grant final approval to a protocol application.

(b) Review and Management of Relationships with Business Entities
The COI Committee determines whether any disclosed relationships pose the potential for financial conflicts of interest. The COI Committee evaluates the magnitude of any potential conflicts, and it determines what management conditions, if any, need to be put in place to appropriately reduce, eliminate, or manage any financial conflict of interest issues.

IRBs have the ultimate responsibility and authority to evaluate how any particular financial conflict of interest affects a specific human subjects research protocol. When approving any research protocol, IRBs may impose terms, conditions, limitations, or other management elements in the human subjects research protocol to manage a potential or actual financial conflict of interest in addition to those imposed by the COI Committee.

COI Committee Review
The COI Committee reviews all annual and any protocol-specific Outside Activity Reports from individuals, whether or not the individuals are employed by the UW-Madison, when the individuals are covered by this policy for human subjects research reviewed by a UW-Madison IRB and they report significant financial interests. This review must occur before the IRB grants final approval to a protocol application when PIs, Co-Is, or key personnel have reported financial interests with business entities related to the protocol that would restrict participation in the research or require disclosure of the financial interest to the human subjects research participants.

Colleges, schools, or divisions, and departments or other units also review annual Outside Activities Reports and assure that reports are complete and correct to the best of the reviewers’ knowledge.

When reviewing protocol-specific Outside Activities Reports, the COI Committee makes recommendations to the IRB concerning potential or actual financial conflicts of interest. The COI Committee determines whether the restriction on participation in research or the requirement to disclose a financial interest to human subjects research participants would apply in a given situation. The COI Committee provides a copy of this determination to the investigator. Any management recommended by the COI Committee applies only to an individual’s activities related to the protocol. All other procedures for review of protocol-specific Outside Activity Reports are the same as those for annual Outside Activities Reports.

When reviewing annual Outside Activities Reports, the COI Committee communicates the outcome of its reviews to individuals in writing, if the committee determines that management of a relationship with a business entity is appropriate. The COI Committee communicates the outcomes of its reviews to IRBs, deans, and department chairs, when appropriate. Individuals may request information on the status of an annual review of an Outside Activity Report at any time from the COI Committee.

For a description of how the COI Committee assesses and manages potential financial conflicts of interest, see “Guidelines for Evaluating Potential Conflicts of Interest.” The guidelines are available on the COI Committee’s Web site.

Exceptions to Human Subjects Management Plan Provisions
The COI Committee may grant individuals exceptions to restrictions on participation in human subjects research. The COI Committee only grants exceptions for specific protocols.

The exception process depends on the risk level of the proposed research. If a UW-Madison IRB determines that a study poses no greater than minimal risks to subjects, investigators will normally be granted an exception to this prohibition without COI Committee review, unless a UW-Madison IRB determines that the investigator must apply to the COI Committee for an exception. For all other protocols, individuals must apply to the COI Committee for exceptions in writing.

The COI Committee only grants exceptions for protocols that pose greater than minimal risks to subjects in very rare circumstances. For example, the COI Committee might grant an exception if an individual is uniquely qualified by virtue of expertise or experience to participate in the research and the research could not be conducted as safely or effectively without the individual.

If the COI Committee grants an exception for any particular protocol, the PI must provide the following information to human subjects research participants:

1. the role(s) of the managed business entity in the study

2. the nature of the relationship(s) between the managed business entity and all study personnel

Anyone with an exception must also inform all PIs and Co-Is of the protocol that the COI Committee has granted him or her an exception so that he or she may participate in the project. The COI Committee may recommend that the IRB require additional modifications to the protocol to reduce, eliminate, or manage conflict situations (e.g., require a data and safety monitoring board, restrict the roles of particular study personnel).

The COI Committee communicates the determination that it has granted an exception to the individual, the IRB, the Institutional Official with responsibility for oversight of human subjects research, the individual’s dean, and the individual’s department chair, when appropriate. The written exception must be in place before the IRB can grant final approval for a protocol involving an individual who would otherwise be prohibited from participating in the research study.

Appendix 3. Acknowledgements

We are grateful for the guidance provided in the Association of American Medical Colleges Task Force report on financial conflicts of interest in human subjects research and for their willingness to grant us permission to incorporate segments of their report in this policy statement.

A COI Committee-IRB Task Force developed the principles, policies, and procedures detailed in the UW-Madison’s first “Policies and Procedures for Conflicts of Interest in Clinical Research,” which became effective on May 1, 2003. Task Force membership: R. Timothy Mulcahy (chair), Howard Bailey, Lois Brako, Paul DeLuca, Norm Fost, Brian Fox, Steve Harsy, Kathleen Irwin, Helen Madsen, Alice Page, and George Wilding. The COI Committee and the All Campus IRB reviewed and approved the statement. In the spring of 2006, the COI Committee and the Human Research Protection Program (HRPP) Advisory Committee revised this statement.

Appendix 4. References

Association of American Medical Colleges and Association of American Universities. A Report of the AAMC-AAU Advisory Committee on Financial Conflicts of Interest in Human Subjects Research. “Protecting Patients, Preserving Integrity, Advancing Health: Accelerating the Implementation of COI Policies in Human Subjects Research.” February 2008. http://www.aau.edu/research/Rpt_AAU-AAMC_COI_208.pdf (accessed May 27, 2008)
https://services.aamc.org/Publications/showfile.cfm?file=version107.pdf &prd_id=220&prv_id=268&pdf_id=107 (accessed May 27, 2008)

Association of American Medical Colleges. Task Force on Financial Conflicts of Interest in Clinical Research. “Protecting Subjects, Preserving Trust, Promoting Progress – Policy and Guidelines for the Oversight of Individual Financial Interests in Human Subjects Research.” December 2001.
http://www.aamc.org/research/coi/firstreport.pdf (Accessed on May 27, 2008)

Association of American Universities. Task Force on Research Accountability. “Report on Individual and Institutional Financial Conflict of Interest.” By Steven B. Sample and L. Dennis Smith, Co-chairmen. Washington D.C.: AAU, October 2001.
http://www.aau.edu/research/COI.01.pdf (Accessed on May 27, 2008)

Bekelman, Justin E, Yan Li and Cary P. Gross. “Scope and Impact of Financial Conflicts of Interest in Biomedical Research.” Journal of the American Medical Association 289, no. 4 (January 2003): 454 – 465.
http://jama.ama-assn.org/cgi/reprint/289/4/454.pdf (Accessed on May 27, 2008)

Davidoff, Frank et al. “Sponsorship, Authorship, and Accountability.” Journal of the American Medical Association 486, no. 10 (September 2001): 1232 – 1234.
http://jama.ama-assn.org/cgi/reprint/286/10/1232.pdf (Accessed on May 27, 2008)

Morin, Karine et al. “Managing Conflicts of Interest in the Conduct of Clinical Trials.” Journal of the American Medical Association 287, no. 1 (2002): 78 – 84. This article is based on a Report of the Council on Ethical and Judicial Affairs that was adopted by the American Medical Association in December 2000.
http://jama.ama-assn.org/cgi/reprint/287/1/78.pdf (Accessed on May 27, 2008)

Thompson, Dennis F. “Understanding Financial Conflicts of Interest.” The New England Journal of Medicine 329 (1993): 573 – 576.
http://content.nejm.org/cgi/content/full/329/8/573/ (Accessed on May 27, 2008)

U.S. Department of Health and Human Services. Office for Human Research Protections. “Financial Relationships and Interests in Research Involving Human Subjects: Guidance for Human Subject Protection.” Washington, D.C., 2004.
http://www.hhs.gov/ohrp/humansubjects/finreltn/fguid.pdf (Accessed on May 27, 2008)

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