Addressing Institutional Conflict of Interest to Promote Patient Safety

By Bryan A. Liang, MD, PhD, JD; and Tim Mackey, MAS

 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—a clinical study participant at the University of Pennsylvania—highlights 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).

Investigations
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).

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