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Conflict of interest in scientific research covers a wide spectrum of factors that might result in bias, not just financial ones. For example, a desire for publication could lead an investigator to use a skewed research design that favored a positive outcome, in hopes of improving the study’s appeal to a peer-reviewed journal. However, non-financial COIs can be very hard to identify and are likely an inescapable part of the fabric of science. For this reason, we will focus on financial factors influencing research and on different management strategies that have been developed to control the effects of FCOI on research.
In this Topic:
- Translational Research and Conflicts of Interest: Overview
- Federal Rules Regarding Conflict of Interest
- Managing Personal Conflict of Interest in Translational Research
- Institutional Conflict of Interest
- Managing Institutional Conflict of Interest in Translational Research
- Bibliography
Translational Research & Conflicts of Interest: Overview
Translational research refers to the process by which basic scientific knowledge migrates from the laboratory into broad application in the community [1]. In a capitalist society, this migration often involves commercialization of the research and the accompanying expectation that some person or persons will ultimately profit as a new therapy or technology receives widespread use.
'What exactly is translational research? For many, the term refers to the “bench-to-bedside” enterprise of harnessing knowledge from basic sciences to produce new drugs, devices, and treatment options for patients. For this area of research—the interface between basic science and clinical medicine—the end point is the production of a promising new treatment that can be used clinically or commercialized (“brought to market”).' —S.H. Woolf, 2008 [1]
This commercialization of research introduces issues related to financial conflict of interest (FCOI), in which a secondary interest—in this case, money— might affect an investigator’s primary professional obligation to perform unbiased research. However, such bias often cannot be measured. At best, a factor that could reasonably lead to a perception of bias can be identified, but perception is not the same as the actual presence of skewed judgment. Conflict of interest in scientific research covers a wide spectrum of factors that might result in bias, not just financial ones. For example, a desire for publication could lead an investigator to use a skewed research design that favored a positive outcome, in hopes of improving the study’s appeal to a peer-reviewed journal. However, non-financial COIs can be very hard to identify and are likely an inescapable part of the fabric of science. For this reason, we will focus on financial factors influencing research and on different management strategies that have been developed to control the effects of FCOI on research.
Federal Rules Regarding COI
The first set of federal regulations regarding COI in research funded by the U.S. Public Health Service was issued in 1995. These regulations were comprehensively rewritten and reissued in 2011 as 42 CFR Part 50, Subpart F with a parallel set of rules for contractors (42 CFR Part 94). Together, these regulations provide clear rules regarding disclosure of COI and place responsibility on institutions for identifying and managing conflicted situations. However, they offer relatively little guidance on how an institution should actually manage cases of COI. The rules do not at all address the issue of institutional COI, which occurs when the institution where the research is conducted (such as a university or hospital) or the senior officials supervising the research have a financial stake in the outcome. The regulations also exempt the payment of royalties processed through an institution from federal rules governing COI, although the potential for increased royalties may in fact create an enormous incentive for bias.
There are two key definitions in 42 CFR 50 Subpart F that guide how institutions manage COI. The first is the definition of Significant Financial Interest; the second is the definition of a Financial Conflict of Interest.
A few points regarding these regulations should be emphasized:
- The list of what counts as a “significant financial interest” is comprehensive, with the minimal level for “significant” set at $5,000 per year (although some institutions require reporting of any payments at all, regardless of amount).
- Spouses and dependent children are included in the determinations of whether a significant financial interest is present.
- “Institutional responsibilities” on the part of individuals are comprehensive and include research, teaching, clinical work, and administrative tasks. Anyone with outside financial interests that overlap with their institutional responsibilities must be evaluated.
- Section 2 of the regulations requires that most sponsored travel be reported, and includes required reporting of sponsored travel for spouses and dependent children.
- Section 3 defines types of financial interests that are exempt, such as royalties paid through the institution.
42 CFR 50 Subpart F applies to all faculty and staff who receive funding from the Public Health Service, which includes the National Institutes for Health (NIH), the Centers for Disease Control and Prevention (CDC), the Agency for Healthcare Research & Quality (AHRQ), and the Biomedical Advanced Research and Development Authority (BARDA).
Federal Regulations Governing COI in Research 42 CFR Part 50, Subpart F (PDF) 42 CFR Part 94
The definition for FCOI used in 42 CFR 50 Subpart F entails two institutional responsibilities. First, the institution should evaluate whether the individual has both a significant financial interest and a role in the research that could affect the design, conduct, or reporting of research. If those two conditions are both fulfilled, the next step is to evaluate whether the financial interest could “directly and significantly” affect the research. Institutions vary substantially as to what they consider direct and significant, and the regulations provide very little guidance beyond the definition.
Managing Personal COI in Translational Research
Management of COI is an imperfect art and is typically inconsistent across institutions. Federal regulations define issues likely to affect research, but are much less likely to suggest means for managing conflicts. The most common COI management strategy requires public disclosure of outside interests, usually in publications, presentations, grant applications, and informed consent documents. Disclosure is, however, a mixed blessing, because many people take industry relationships to be an endorsement as well as a potential source of bias. In addition, COI is often presented in ways—such as simply listing outside interests without disclosing the actual amounts—that trivialize an important and complex issue.
Guidance for Identifying & Managing COI Financial Conflict of Interest (PPT - 12.2 MB) Responsible Conduct Research: Conflicts of Interest AAMC COI Initiatives NIH FCOI tutorial (PDF) FDA Guidance: Clinical Trial Data Monitoring Committees (PDF)
Some institutions restrict the role a conflicted individual can play in the conduct of research. Typical restrictions include limitations on serving as a principal investigator (PI) [2];, restrictions on obtaining informed consent, a requirement for external oversight, or limitations on study authorship and/or participation in data analysis. However, the dollar amount thresholds that trigger different types of management vary across institutions, providing little basis for identifying “standard” amounts.
Institutional Conflict of Interest (ICOI)
Although federal rules only address personal conflict of interest, most institutions also have policies regarding institutional conflict of interest (ICOI). ICOI is usually understood to encompass the financial interests of the institution and those of senior officials— presidents, chancellors, deans, department chairs—able to act for the institution on their own authority. For different reasons related to institutional authority structures, many institutions also include institutional review board (IRB) chairs and faculty who supervise clinical research programs in their ICOI policies.
Institutional Conflicts of Interest ICOI at NIH Grantees (PDF)
The most common way for ICOI to occur happens when institutions license their intellectual property to an outside, for-profit entity. The Bayh-Dole Act of 1980 required that NIH grant recipients pursue patenting and commercialization of intellectual property developed with federal grant dollars, preferably through licensing arrangements with small businesses. A pattern has since emerged in which many of these small businesses are start-ups created by faculty-inventors. The start-up companies then fund early-phase research using federal small-business grants such as those offered through the Small Business Innovation Research (SBIR)/Small Business Technology Transfer (STTR) program, as well as support from angel investors. In SBIR grants, the company is the actual grant recipient, but may subcontract with an academic institution. STTR grants require collaboration between a not-for-profit research institution and the small business. One challenge with both types of small business grants is the mixing of not-for-profit institutions and the small businesses for which their licensing agreements give them a financial stake.
The Jesse Gelsinger Case
ICOI first came to widespread public awareness when a teenaged research participant, Jesse Gelsinger, died after receiving an experimental gene-replacement therapy at the University of Pennsylvania for a rare metabolic disorder [3]. ICOI emerged as a major issue in the case when it became clear that Penn had an enormous financial stake in the intellectual property being tested [4], as well as in Genovo, Inc., the start-up company to which the technology was licensed. Lead investigator James Wilson, who was also the co-founder of Genovo [5], had a substantial personal financial interest in the outcome. Lead plaintiffs’ attorney Alan Milstein argued that neither Penn nor Dr. Wilson had Jesse Gelsinger’s interests foremost in mind and as result made mistakes that included ignoring or obscuring evidence of poor outcomes in animal subjects treated with the experimental therapy [6]—mistakes that reflected biases in favor of gene therapy, exacerbated by strong financial incentives
Discussion of the Gelsinger Case A Death in the Laboratory: The Politics of the Gelsinger Aftermath (PDF) The Death of Jesse Gelsinger: New Evidence of the Influence of Money and Prestige in Human Research (PDF)
In the wake of the settlement of the Gelsinger case, many institutions became very cautious regarding ICOI, to the point that the Association of American Medical Colleges recommended that they operate with a “rebuttable presumption” that the research should be done at institutions with no financial interests [7]. The rebuttable presumption is predicated on a belief that institutions with a financial interest may not provide the level of the oversight they should. In reality, the primary drivers behind ICOI concerns are worries regarding perception and liability. If a bad outcome such as death or disability occurs in a clinical study and the institution has a financial stake, both juries and the public are likely to believe the oversight was lax, even if appropriate institutional checks were in place.
Managing Institutional COI in Translational Research
For most institutions, the central COI management strategy relies upon the “rebuttable presumption” described above. Under this rule, unless there is a clear and defensible reason that the institution should do the research, clinical studies should be done elsewhere. Examples of possible exceptions include the need for a particular technical skill (for example, a surgeon who is implanting a device that he or she invented), access to a limited patient population (particularly in rare or “orphan” diseases), or a piece of highly specialized equipment. If a decision is made that the work can be done at the inventor’s institution and the institution has invested, one option for managing ICOI is for the institution to divest itself of its financial interests (although most institutions are reluctant to take such a step). They can also monetize their interests by selling their equity and future royalties to investors, or donate royalties to another charity.
Additional Resources AMC Meeting and Symposia Proceedings The Scientific Basis of of Influence and Reciprocity: A Symposium (PDF) Protecting Patients, Preserving Integrity, Advancing Health:Accelerating the Implementation of COI Policies in Human Subjects Research (PDF) Institute of Medicine Report Conflict of Interest in Medical Research, Education, and Practice
If a decision is made to proceed with the research at the conflicted institution without eliminating the conflict, ICOI management should focus on moving oversight of the study to an external entity in order to limit any perception that the institution is serving its own self-interest. This externalization should include the use of an IRB that is not affiliated with the institution in question, because most IRB members are employees of the institution that has the ICOI. If the study is taking place at multiple research sites, this goal can be achieved by using the IRB from one of the other study sites to oversee the investigation. As a second layer of ICOI management, some institutions use an oversight board made up of external members. Operationally, this approach can combine COI oversight with functions related to data and safety monitoring. The research protocol should be reviewed for evidence of bias in design prior to submission to an IRB. Monitoring reports should be evaluated to be certain there are no biases in endpoint evaluations or study conduct. Finally, publications should be assessed to ensure that they present the study’s results fairly and accurately.
Information regarding any institutional interests in the research should be provided to potential research participants in the informed consent documents, and notice of the conflict should be included in publications, presentations, and grant applications. Some institutions may also create a system of external monitoring for clinical trials, using hired staff from a contract research organization (CRO).
Bibliography
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1. Woolf SH. The meaning of translational research and why it matters. JAMA. 2008;299:2437-9. PMID: 18182604. doi: 10.1001/jama.299.20.2437. ↑
2. Institute of Medicine (US) Committee on Conflict of Interest in Medical Research, Education, and Practice; Lo B, Field MJ, eds. “Conflicts of interest in biomedical research.” In: Conflict of Interest in Medical Research, Education, and Practice. Washington (DC): National Academies Press (US); 2009. Available from: http://www.ncbi.nlm.nih.gov/books/NBK22942/. Accessed June 11, 2013. ↑
3. Stolberg SG. The biotech death of Jesse Gelsinger. The New York Times. Nov 28, 1999. Available at: http://www.nytimes.com/1999/11/28/magazine/the-biotech-death-of-jesse-gelsinger.html?pagewanted=all&src=pm. Accessed June 12, 2013. ↑
4. Wilson RF. The death of Jesse Gelsinger: new evidence of the influence of money and prestige in human research. Am J Law Med. 2010;36(2-3):295-325. Available online at: http://scholarlycommons.law.wlu.edu/cgi/viewcontent.cgi?article=1125&context=wlufac. Accessed June 11, 2013. PMID: 20726398. ↑
5. PRN Newswire. Biogen announces major gene therapy research collaboration with Genovo, Inc. August 15, 1995. ↑
6. Weiss R, Nelson D. Methods faulted in fatal gene therapy: Teen was too sick for experimentation, federal probe finds. The Washington Post. Dec 8, 1999. Page A01. Available at: http://www.washingtonpost.com/wp-srv/WPcap/1999-12/08/089r-120899-idx.html. ↑
7. The American Association of Medical Colleges. Protecting patients, preserving Integrity, advancing health: Accelerating the implementation of COI policies in human subjects research. A report of the AAMC-AAU Advisory Committee on Financial Conflicts of Interest in Human Subjects Research. February 2008. Page 6. Available online at: https://members.aamc.org/eweb/upload/Protecting%20Patients,%20Preserving%20Integrity.pdf. Accessed June 12, 2013. ↑
Topic chapter originally published on January 3, 2014.
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