Addressing Institutional Conflict of Interest to Promote Patient Safety
Studies show that 67% of academic departments have financial relationships with industry (Campbell, 2007b). The Institute of Medicine has warned that academic institutions lack independent review, with resulting tolerance of conflicts due to financial gains, which may pose serious barriers to addressing the issue (IOM, 2009). These financial inducements may result in an emphasis of profits over patient safety (U.S. GAO, 2001).
Such warnings are not theoretical. Institutional forms of conflicts of interest have resulted in institutions and their representatives basing their decisions on financial rewards instead of on an overarching concern for patient safety. The death of teenager Jesse Gelsinger‚Äîa clinical study participant at the University of Pennsylvania‚Äîhighlights these risks.
Addressing institutional conflicts of interest is therefore key to mitigating the risks associated with patient safety. Scrutiny of relationships between industry and academic institutions, as well as establishing internal, independent bodies and policies to improve oversight and intercept conflicts that represent a threat to patient safety must be integrated into systems to avoid tragedies such as the Gelsinger case.
The Jesse Gelsinger Case
Perhaps the most dramatic example of failing to manage institutional conflicts is the death of an 18-year-old study participant, Jesse Gelsinger, in a gene therapy trial at the University of Pennsylvania in 1999 (Rothman 2008). Gelsinger suffered from ornithine transcarbamylase deficiency, which affects the body’s ability to eliminate ammonia (Wolf & Lo, 2000). Although potentially life threatening, Geslinger had managed the condition with a strategy of a low-protein diet and medication, and otherwise enjoyed a normal life (Stolberg, 1999). Gelsinger understood that he would not benefit directly from his participation in the Phase I gene therapy study; his decision to participate was motivated by hope that results from the study would avail him of his restrictive diet routine in the future (Wolf & Lo, 2000).
Gelsinger began the study, but almost immediately clinical problems emerged. The evening of his injection with the gene therapy, he experienced a high fever and abdominal pain, and by the next morning, severe hepatic failure and blood clotting. He then lapsed into a coma. His clinical condition rapidly deteriorated, and over the next several days, Geslinger suffered multi-organ failure and, subsequently, brain death. Only 4 days after receiving the gene therapy treatment, he was removed from life support, and died. Jesse Gelsinger’s death was then reported to government officials (Stolberg, 1999).
Initial investigations by government entities into Gelsinger’s death postulated that the genetic therapy vector that was administered to him caused a systemic inflammatory response syndrome. That led to acute respiratory distress syndrome, and eventually his death due to anoxia (Hollon, 2000). These investigations focused on the safety of the adenovirus gene therapy vector, which was used in the gene therapy, and on potential medical error (Stolberg, 1999).
But beyond these components, systems assessments also reviewed broader issues. In this extended analysis, highly troubling revelations of both individual and institutional conflicts of interests existing between investigators and the university and industry began to emerge, leading to more detailed scrutiny of the motivations and judgment exercised by those involved in the trial (Wolf & Lo, 2000).
Several months later, officials from the FDA announced that Gelsinger should never have been a participant in the study due to his clinical condition. Further, the institution’s investigators violated FDA requirements by failing to immediately report earlier patients who had experienced serious side effects prior to the Gelsinger study. In addition, informed consent documents provided to participants were altered from that approved by the FDA by omitting important information regarding the death of animal subjects that had undergone similar treatment (Stolberg, 1999).
Yet these FDA discoveries were just the beginning. Upon further review, analyses showed Gelsinger’s case was rife with substantive institutional wrongdoing spurred by unmanaged financial conflicts. First, reports submitted by the institution to the FDA, NIH, and IRBs misrepresented the actual clinical findings, and proper disclosures did not occur in the informed consent process (U.S. Department of Justice, 2005). It was also discovered that both the director of the institute leading the research and the University of Pennsylvania itself had significant financial interests in the biotech company that would bring the therapy to market (Rothman, 2008). In fact, both the former dean of the institution’s medical school and the lead investigator of the study stood to benefit financially from the commercialization of the therapy through their patent ownership. As well, the academic medical center also had an equity stake in the biotechnology company collaborator, and would have profited from commercialization that would then inure to all of these individuals and institutions (Fox, 2000).
Further revelations showed even deeper systems problems. The university culture was passive and resulted in nothing being done to address these conflicts. Indeed, although a university committee expressly recognized and noted that there were one or more conflicts of interest between the collaborating biotechnology company and university employees, it nevertheless approved their presence and continued to allow these individuals to plan and conduct the clinical experiments (Fox, 2000).
The presence of these forms of institutional conflicts of interest raised important questions regarding the clinical decisions that were made during the course of the study. Specifically, patient safety and ethics concerns were raised regarding whether investigators
- proceeded with the study despite their knowledge of negative data and risks to study participants,
- were inappropriately motivated by financial incentives to develop a marketable product that adversely influenced their clinical decisions,
- set misleading expectations of therapeutic benefit and risks of participation in the study, and
- made inappropriate decisions of eligibility for participation in the study (Wolf & Lo, 2000).
In February 2005, the U.S. Department of Justice issued a release detailing the enforcement actions taken against the University of Pennsylvania and investigators involved in the research. These included over $1 million dollars in punitive fines and placement of restrictive controls on the clinical research activities of the named investigators (U.S. Department of Justice, 2005).
Ultimately, these types of issues are important to recognize for patient safety and systems analyses, both proactively and in root cause analyses. The Gelsinger case epitomizes the inherent risks to patient safety associated with institutional conflicts of interest. It also serves as an important example of identifying systemic deficiencies in monitoring and managing institutional conflicts.
Although the case has been well disseminated, it has yet to lead to comprehensive reform. Unfortunately, this case is not isolated. Indeed, reports have described several additional cases in which investigators in clinical trials disregarded exclusion criteria, used questionable recruitment methods and incentives for participants, and engaged in fraudulent activity for the purpose of maximizing revenue derived from conducting clinical trials. In some of these cases, subjects died as a result of their participation in a study from which they should have been excluded (Whitaker, 1998).
Efforts to Address Institutional Conflict of Interest?
In April 2010, the Council of Medical Specialty Societies (CMSS), a group representing 32 medical societies and boasting a membership of more than 650,000 physicians, adopted a new ethics code addressing interactions with for-profit companies in the healthcare industry (Council of Medical Specialty Societies, 2010). The voluntary code aims to ensure that interactions with industry on the institutional and medical society level are transparent and for the benefit of patients. Included in the guidance is a requirement to develop and make public conflict-of-interest policies, publicly disclose financial relationships, implement programs to ensure that education and research activities are developed independent of industry support, and prohibiting society leaders from having direct financial relationship with the industry.
Motivation for the new CMSS Code comes from repeated investigations, letters, and hearings by Sen. Charles Grassley (R-IA) amid growing public criticism of physician-industry relationships. This includes a number of highly publicized events, such as the Cleveland Clinic’s firing of a cardiologist over conflict of interest allegations, NIH investigation and action against Baylor College of Medicine regarding conflict of interest disclosure in grant funding, and recent changes made to conflict-of-interest policies at academic institutions such as the University of Minnesota and University of Wisconsin (Borrell, 2010; Moore, 2009). Under Grassley’s leadership, disclosure legislation such as the Physician Payment Sunshine Act (Weintraub, 2010) passed in the 2010 healthcare reform bill means industry will have to disclose payments to physicians and teaching hospitals.
CMSS’ creation of its code of ethics is also part of a larger movement to bring more transparency to the extensive, and at times inappropriate, systemic relationship between industry and physicians. Individual conflicts of interest, which have been extensively recognized and discussed (Institutes of Medicine, 2009; PhRMA, 2008), stem from the now familiar marketing and promotion aimed directly at individual providers and include lucrative gifts and entertainment, travel, consulting and speaking arrangements, no-fee continuing medical education, and other direct payments (Wazana, 2000) as well as underwriting research activities. All of these can bias the physician toward using drugs based on marketing, not efficacy grounds (Carey, 2008). These relationships are therefore a threat to patient safety: individual providers may prescribe their patients drugs based on marketing and personal financial benefits. But further, institutional research activities in which these physicians lead and participate may provide biased data and conclusions regarding treatments for which they receive a financial benefit that are disseminated in the medical literature, impacting the broader patient and provider community.
So far 14 council members have signed on to the CMSS Code including the American College of Cardiology, the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, the American College of Preventive Medicine, and the American College of Physicians. Yet although creation of the Code and the Sunshine Act are heartening to show interest in institutional conflict of interest situations, a simple focus on disclosure and education may not go far enough to ensure that patient safety is paramount.
?Patient safety concerns are also deeply imbedded in the medical culture through institutional passivity of questionable relationships that have resulted in systemic harms. Examples include ghostwriting — paying researchers who did not do the work to put their names on academic publications written by corporate sponsors — and funding of potentially biased medical education as well as research such as in the Gelsinger case. Industry involvement in these categories is also systemic, with greater than 90% of physicians having a relationship with the pharmaceutical industry (Campbell et al., 2007a). Indeed, beyond illicit authorship and research support, detailed assessments have found that these types of conflict also include equity holdings or royalty arrangements, intellectual property transfer agreements, institutional participation on a company’s board of directors, and institution officials who have financial conflicts of interest (Liang & Mackey, 2010). It bears emphasizing that these relationships can result in misleading or inaccurate information about pharmaceutical products being relied upon by the broader medical community as well as risks to study participants, which translates to adverse consequences for patients and patient safety. Despite liability resulting from some of these activities, (U.S. Department of Health and Human Services, 2009) they continue.
Consequently, when the institution or an individual acting on the institution’s behalf has an external relationship or financial interest with the industry, these institutional conflicts of interest represent broad patient safety risks. These forms of conflicts are difficult to detect, undermine legitimacy and trust in clinical investigations, and lead to potentially suspect commercialization of research and dependence on industry. At present, there are no laws or regulations to deal systemically with institutional conflicts of interest, and the voluntary CMSS Code does not address these key patient safety concerns.
Yet despite these extensive safety holes, which represent an even broader and deeper risk to patient safety due to the extensive implications in the treatment and clinical trial settings, these institutional conflicts have not garnered significant attention. There have been calls for recognition and cultural change by groups including the Association of American Universities, Association of American Medical Colleges, and the U.S. Dept. of Human and Health Services. However, fewer than 38% of academic medical centers had adopted any policies addressing these institutional conflicts (Ehringhaus, 2008). This may be a cultural norm reflecting the close economic partnerships between medical institutions and industry encouraged by the Bayh-Dole Act, which allows institutional commercialization of publicly funded research (University and Small Business Patent Procedures Act, 2000).
Addressing Institutional Conflict of Interest
?Recent assessments have focused on external approaches to address institutional conflicts of interest. However, a report by the Office of Inspector General has concluded that NIH oversight of financial conflicts of interest of grantees is not adequate (U.S. Department of Health and Human Services Office of Inspector General, 2009). In addition, institutional conflicts in key government agencies have also been discovered. This has led to reform efforts, including new draft guidance by the FDA on transparency of advisory committees and an NIH proposed rule that includes institutional responsibilities (U.S. Food and Drug Administration, 2010; Bureau of National Affairs, 2010). Yet the NIH as well as CMSS efforts focus on disclosure rather than on integrating patient safety oversight and monitoring of conflicts into institutional culture.
Due to the lack of patient safety focus in addressing institutional conflict of interest, a more comprehensive and uniform strategy may be necessary that integrates the current fragmented framework of inadequate and incomplete self-regulation into one harmonized and standard approach subject to federal audit. One proposed solution would be to establish an independent “centralized system” within a healthcare institution to manage conflicts of interest (Liang & Mackey, 2010).
This centralized system would be an internal independent entity. Its goal would be to detect, manage, and implement institutional conflict-of-interest policies free of internal or external influence to ensure patient safety. It would proactively review, manage, approve, and conduct continuing assessments to identify conflicts, provide cooperative guidance on effectively managing such conflicts particularly as they relate to patient safety, and would have independent power to evaluate any violations and enforce policies, if necessary, using sanctions. The centralized system would also manage any industry funds and pharmaceutical samples received by the entity. Creation of such as system could be a condition of participation for public healthcare program reimbursement (Medicare and Medicaid) and federal grant funding, with periodic audits by federal regulators or third-party accreditors such as the Association for the Accreditation of Human Research Protection Programs (Liang & Mackey, 2010).
Beyond creating this internal, independent body, the institutional conflict-of-interest policy itself should be standardized. A model policy has been proposed, and would provide for disclosure requirements, separate management of commercial enterprise units from academic units, voluntary remediation of conflicts, and recurrent education on institutional conflicts of interest. Importantly, to reinforce and renew a culture of independence in medical education, academic detailing, which provides information using neutral academic sources and representatives, should replace current industry-reliant, marketing-focused “education” (Liang & Mackey, 2010).
Using such a system, patient safety can be promoted on multiple levels. Academic work published in the medical literature and used in continuing medical education for community providers can be relied upon as more robustly reflecting medical evidence rather than being overwhelmed by industry marketing (Carey, 2008). In addition, redundancy of review and proactive analysis of clinical research on individual and institutional levels can ensure oversight, patient protection, and patient safety. It can also provide for important insights and considerations for root cause analyses of adverse events and near misses to more deeply understand systems factors contributing to identified weaknesses in care and research. Finally, such an approach can wean institutions and individual providers therein from industry reliance while promoting a culture of independence, accountability, and patient safety.
It has been more than 10 years since the death of Jesse Gelsinger as well as the Institute of Medicine report, To Err Is Human. Yet, with marketing and promotion activities essential to the industry’s bottom line, and increasingly tight budgets for providing care and performing research, institutional conflicts of interest and their relationship to patient safety have garnered little attention. In order to ensure patient safety, as well as public trust in physicians and healthcare institutions, proactive approaches that identify, manage, and address conflicts of interest are necessary. The CMSS code and other efforts are a good start. Yet the presence of conflict on the institutional level must be taken as seriously as a threat to patient safety. Medical leaders and patient safety advocates cannot ignore these conflicts and must systemically address them if they are to ensure that patient safety is the paramount concern in healthcare delivery systems.
Tim Mackey is senior research associate, Institute of Health Law Studies, California Western School of Law, and doctoral student, University of California, San Diego-San Diego State University Joint Program on Global Health. ???
Campbell, E., et al. (2007a). A national survey of physician-industry relationships. New England Journal of Medicine, 356, 1742-1750.
Council of Medical Specialty Societies. (2010, April 21). Council of Medical Specialty Societies releases voluntary code for interactions with for-profit-health sector. Available at http://www.cmss.org/DefaultTwoColumn.aspx?id=110.
Ehringhaus, S., et al. (2008). Responses of medical schools to institutional conflicts of interest. Journal of American Medical Association, 299, 665-671.
Institutes of Medicine. (2009). Conflict of interest in medical research, education, and practice. The National Academies Press, 1-414.
Lemmens T., & Miller, P. (2006). Regulating the market in human research participants. PLOS Med., 3, 1237.
Liang, B. A., & Mackey, T. (2010). Confronting conflict: Addressing institutional conflicts of interest in academic medical centers. American Journal of Law & Medicine, 36, 136-187.
Moore, J. (2009, December 4). U medical ethics group has industry ties. Star Tribune. Available at http://www.startribune.com/business/78569782.html?elr=KArksUUUoDEy3LGDiO7aiU.
PhRMA. (2008). The facts about pharmaceutical marketing & promotion. Available at http://www.phrma.org/files/attachments/Marketing%20and%20Promotion%20Facts_071108_FINAL.pdf.
Rothman, D. J. (2008). Academic medical centers and financial conflicts of interest. Journal of the American Medical Association, 299, 695-697.
Stolberg, S. (1999, November 28). The biotech death of Jesse Gelsinger. New York Times. Available at http://www.nytimes.com/1999/11/28/magazine/the-biotech-death-of-jesse-gelsinger.html?scp=2&sq=gelsinger&st=cse&pagewanted=1.
U.S. Department of Health & Human Services. (2009, September 2). Justice Department announces largest health care fraud settlement in its history. Available at http://www.hhs.gov/news/press/2009pres/09/20090902a.html.
U.S. Department of Health and Human Services Office of Inspector General. (2009). How grantees manage financial conflicts of interest in research funded by the National Institutes of Health. Available at http://oig.hhs.gov/oei/reports/oei-03-07-00700.pdf.
U.S. Department of Justice. (2005, February 9). U.S. settles case of gene therapy study that ended with teen’s death. Available at: http://www.durrelllaw.com/UofPSettlementReleaseFinal.pdf?ei=1&en=af6a5b2bd7ce8a6f&ex=1086747872&pagewanted=print&position.
U.S. Food and Drug Administration. (2010, April 21). FDA announces draft revised guidance on transparency and advisory committees. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm209119.htm.
U.S. General Accounting Office. (2001). Biomedical research: HHS direction needed to address financial conflicts of interest. Available at http://www.gao.gov/new.items/d0289.pdf.
University and Small Business Patent Procedures Act, 35 U.S.C. § 200 (2000); 37 C.F.R. §
Wazana, A. (2000). Physicians and the pharmaceutical industry: Is a gift ever just a gift? Journal of American Medical Association, 283, 373-380.
Weintraub, A. (2010, April 26). New health law will require industry to disclose payments to physicians. Kaiser Health News. Available at http://www.kaiserhealthnews.org/stories/2010/april/26/physician-payment-disclosures.aspx.
Whitaker, R. (1998, November 17). Doing harm: Research on the mentally ill. Boston Globe, A1.
Wolf, L. & Lo, B. (2000). Association of Professors of Medicine. Ethical issues in clinical research: An issue for all internists. American Journal of Medicine, 109, 82-85.