Conflict of Interest in Human Subjects Research

Conflict of Interest in Human Subjects Research Ross McKinney, Jr, MD Duke University Medical Center

Declarations • NIH Funding (CTSA, IMPAACT, PPRU) • DSMBs for Gilead Sciences, Applied Genetic Technologies Corporation • Unpaid consulting with GSK anticipated

Definition • A conflict of interest exists when a primary interest or responsibility is (unduly) affected by a secondary interest or responsibility • For example, a physician’s primary obligation is to the individual patient, and a friendly relationship with a sales rep could unduly influence a decision to use a specific drug

COI Conceptual Problems • It is impossible to easily measure the effect of secondary influences on an individual decision • Collectively it’s easy to demonstrate COI problems (just look at variability in health care costs…) • Denial is the norm

Overview • Conflicts of Interest are complex • Multiple levels may affect investigator judgment • Financial (esp. with sponsor) • Psychological (care about outcome) • Personal (promotion, reputation) • Research itself may be a COI with the fundamental physician-patient relationship

Goal • Establish systems that allow investigators to work with industry without the reality or perception that the results of subsequent research are biased by the potential for personal gain • In science, reproducibility is the key test • In clinical research, often too expensive to reproduce • Bias may introduce risk for HSR participants

COI Regulations • Mostly institutional • NIH regulations define SFI – significant financial interest (>$10,000; private equity >5%) • NIH defines “investigator” • NIH defines need for institutions to manage, reduce, or eliminate COIs • AAMC and AAU released guidance documents in 2001, 2002, and 2008 • ANPRM posted this Spring (closed 7/7)

FDA COI Regulations • Certification that: • No financial arrangements with an investigator have been made where study outcome could affect compensation; • The investigator has no proprietary interest in the tested product; • The investigator does not have a significant equity interest in the sponsor of the covered study; • The investigator has not received significant payments of other sorts; and/or • Disclosure of specified financial arrangements and any steps taken to minimize the potential for bias • Thresholds: Equity $50,000; Payments $25,000

Typical Institution • Annual reporting to the COI program • Event based reporting with IRB submissions (also grant & IACUC applications) • Regular communication between the IRB and COI Offices • Thresholds for disclosure and restrictions in HSR • Better defined rules for personal than institutional COI

Problems • No consistency between institutions • No clear guidelines about what or how to manage conflicted investigators

Is COI a Real Problem? • 2007 Study of COI at 2001 & 2002 American Academy of Orthopedic Surgeons Meetings • Looked at all presented abstracts (n=519) • 40.8% had some COI • Comparisons – were results positive? • Author has consulting COI: 97.8% • Author had no COI: 89.0% (p=0.01) • Author with Options: 100% vs. 84.7% (p=0.04 – less common)

JAMA – 2003 – Als-Nielsen, et al • 370 randomized trials • Considered: 1) Outcome of trial; 2) Sponsor • Non-profit Sponsor - 16% recommended experimental drug as treatment of choice • Funding not reported: 30% • Mixed funding: 35% • For-profit organization: 51% • Difference significant (p<0.001)OR: 5.3; 95% CI 2.0-14.4)

NY Times: Spine Study • Synthes study of Prodisc artificial disk for low back pain • Study found disk better than fusion • Lead author (Jack E. Zigler, MD) and physicians at half the research centers had COI, not disclosed • Physicians invested in start-up company “Spine Solutions” (for example, one physician investigator invested >$250,000)

Spine study - 2 • Patient data appears to have been screened out if results were not good (according to the NYT)

More on Synthes • In addition, on July 20, 2009, two Synthes executives (inc. the former President) pled guilty to running a non-FDA regulated trial of Norian XR bone cement • Asked physicians to use the approved compound for unapproved uses and stated the company would support publication • Three patients died in the studies (200 involved) [NY Times 6/17 and 7/21/2009]

Kuklo Case (NY Times/WSJ) • Timothy Kuklo, MD – orthopedist employed at Walter Reed AMC then Washington U • Falsified positive result about Medtronic’s Infuse bone growth product: published in British J Bone & Joint Surgery • Received $800,000 in personal compensation from Medtronic 2006-2009 • Did not report COI to Washington U officials

“Innovation” Also an Issue • Off-label use of “Infuse” for Neck surgery • FDA in July reported 38 reports of serious adverse events, including airway compromise • WSJ later reported number of FDA reported events actually >280 • Innovation is not normally a bad thing, but many of the practitioners were receiving direct payments for consulting from Medtronic

Empirical Research • COINS Study: NIH funded – Sugarman, Weinfurt, Hall, et al • Several projects • Most informative was study of an ICF for a mock trial that enrolled 470 “participants”. All were cardiology patients with Coronary Artery Disease (Duke, JHU, Wake Forest) • Study of “Corvascflo” – new drug • Am Heart J 2008;156:691

COINS - 2 • In some ICFs, investigator had Financial information disclosed • Control group with no Financial Disclosure • Disclosure of per capita payment of MD and staff to cover costs • Disclosure that “the person running this study has an investment in First Rate pharmaceuticals…[whose value] might be affected by the results of this study”

COINS Results • When Financial Info was included in the ICF • Equity Holdings - less willing to participate • 5.3% refusal vs. 1.4% for no COI • More negative comments – 18.9% vs 0% no disclosure • Per Capita Payments (to “cover costs”) • No effect on willingness to enroll – 0.6% refusal vs 1.4% controls • Some negative comments – 6.3%

What are the Objectives? • Protect human participants in research • Biased design • Problems in conduct • Fair reporting • Allow for an appropriately informed consent • Is the potential participant given the information they should have to decide whether to participate?

Recommendations • Develop a “common rule” for COI in clinical research • NIH, FDA, OHRP, DOD, etc. • Define expectations for informed consent • Consistency is key to provide assurance to potential participants • Consistency will facilitate multi-center studies – institution-by-institution rules are not helpful.

Recommendations • Consider whether limitations would be useful • Complete exclusion is NOT ideal – the inventor may be critical to developing a new drug or technology • Disclosure by itself is not adequate • Suggest management approaches: • Oversight Panels • Shared responsibility for projects

Conflict of Interest in Human Subjects Research