American Journal of Law & Medicine

The death of Jesse Gelsinger: new evidence of the influence of money and prestige in human research. (Follow the Money: The Impact of Economic on the Delivery of Health Care)

I. INTRODUCTION

Ten years ago, Jesse Gelsinger died while participating in a human gene-therapy trial at the University of Pennsylvania ("Penn"). His death came to signify the corrosive influence of financial interests in human subjects research. (1) After Jesse's death, the media reported that one researcher, Dr. James Wilson, held shares in a biotech company, Genovo, which stood to gain from the research's outcome--shares that The Wall Street Journal later valued at $13.5 million, although Wilson maintains he did not make nearly this much. (2) At the time Penn authorized Wilson's deal, internal Penn documents implicitly valued Wilson's stake in Genovo at approximately $28.5 to $33 million. (3)

Jesse's death sparked two separate lawsuits: one by the family, who sued in tort, and one by the federal government, which framed alleged errors in the research trial as a civil False Claims Act violation. Both suits settled, with no public apologies or acknowledgement of wrongdoing in either case. (4) The government refused to make public the documents it collected, despite requests from the family. (5) Thus, in what is arguably the most famous conflict-of-interest case in medicine, we have known for a decade almost nothing about the nature of the financial stakes that Wilson, and Penn, had in the research's outcome, or why Penn authorized a researcher to hold such a substantial stake in that research's outcome. How this web of financial ties came to enmesh Jesse's trial is a subject worthy of exploration because it provides an important lens for evaluating two divergent visions about the role of money in research.

In 2009, the prestigious Institute of Medicine ("IOM") joined a growing chorus of voices that called for significant reforms to the rules governing disclosure of financial conflicts of interest. The IOM and other groups would presumptively bar nearly all equity stakes by researchers like Wilson. Although the IOM's view represents the dominant narrative about financial conflicts of interest, it is not the only one. One influential group urges that financial conflicts can never be removed from medical research and, indeed, should not be. (6)

This Essay evaluates these polar positions by examining Jesse's participation in human research and his death. Drawing on new evidence from the documents collected in the Gelsingers' lawsuit, (7) this Essay asks specifically whether new and better restrictions on financial conflicts of interest would have made a difference in Jesse's case and concludes that more robust restrictions would not have mattered. This Essay argues that rather than attempting to expunge financial interests from research, those interests should trigger significant, ongoing review of the affected clinical trials, much like the post-approval monitoring now used randomly by leading research institutions. Indeed, had Wilson's outsized financial stake triggered mandatory monitoring, people inside Penn likely would have stumbled upon the string of questionable decisions in Jesse's trial, including departures from the research protocol, long before those mistakes cascaded, culminating in Jesse's death.

Part II describes the research trial Jesse participated in and the lawsuits spawned by his death. In particular, Part II recaps the cavalcade of errors that the FDA says plagued the trial long before and up to Jesse's death, errors now largely acknowledged by Wilson. Part III reviews what the researchers told Jesse about the trial's risks, the results of prior animal studies, and the basic protections he would receive as a participant, and contrasts those disclosures with the frank disclosures approved by regulators at the trial's start. The approved disclosures candidly and explicitly revealed the death of animals in prior trials, vital information that was never shared with Jesse. Like the researchers' sterile description of those animal trials, Wilson's and Penn's financial interests in Jesse's trial were disclosed in a single bland sentence. (8)

Part IV then follows the money, showing the nature and extent of Wilson's financial conflict of interest. This Part poignantly demonstrates that a lot of good people inside Penn sounded alarm bells about Wilson's hefty stake, to no avail. Although Penn's administration understood that Wilson's conflict of interest could be bypassed, it chose not to. Part IV also sketches the precautions suggested by Penn faculty to reduce risks to subjects participating in Wilson's research, such as creating a firewall between Wilson and crucial decisions in Jesse's trial. Part V then contrasts those proposed precautions with what actually transpired in Jesse's trial, noting the integral role Wilson played in many key decisions.

Part VI then evaluates the competing narratives about financial conflicts of interest through the lens of Jesse's trial. This Part ultimately concludes that even if Wilson had no financial interest in the trial's outcome, his desire for "recognition by [his] colleagues" and "successful competition for grants and the awarding of academic promotions and tenure" in the "competitive profession" of "academic medicine" likely would have driven him to make the same choices. (9) Hence, deaths like Jesse's are unlikely to be avoided simply by banning financial conflicts. Instead, financial ties like Wilson's should trigger greater oversight of human trials and monitoring for human safety, an idea explored in Part VII.

II. JESSE'S ILL-FATED PARTICIPATION IN HUMAN RESEARCH

Jesse was three months past his 18th birthday when he died 10 years ago on September 17, 1999. (10) This Part explains the impetus behind the human research trial in which Jesse participated, the structure of Jesse's trial, and the principal figures conducting it. It then describes the pair of lawsuits that resulted, the novelty of the claims advanced, and how the settlement of both suits operated to shield from public view mistakes made in Jesse's research trial.

A. JESSE'S RESEARCH TRIAL

Jesse had a rare disease, a liver deficiency called ornithine transcarbamylase deficiency ("OTCD") that made it difficult for his liver to process proteins. If he ingested too much protein, the resulting nitrogen would overwhelm his system, fail to be processed as urea, and turn to ammonia, a poison to the central nervous system and the body. (11)

Jesse managed his OTCD with a special diet developed by the leading OTCD researcher, Dr. Mark Batshaw--a co-Principal Investigator for Jesse's study. Batshaw, in fact, developed a medication that pulled Jesse out of a coma the December before Jesse enrolled in the trial. The coma was brought on when Jesse went off his diet. (12) Aside from these periodic episodes after taking in too much protein, Jesse was a relatively healthy functioning adult-he had just graduated from high school, had a job, and was paying his parents rent. (13) Jesse had just bought a motorcycle. (14)

The idea behind the gene-therapy trial was to use a cousin of the common cold virus, an adenovirus or vector developed by Wilson, as a sort of "taxi" to deliver corrective genes to Jesse's liver in hopes that they would express--relieving Jesse of the hold OTCD had on his life. (15) The third player in Jesse's research trial was the clinician who would oversee the injection of the vector into Jesse's body, Dr. Steve Raper, a surgeon at Penn and Batshaw's co-Principal Investigator. (16) Wilson wore a second hat in the research trial. He was also a sponsor of the trial, meaning that an entity with which Wilson had financial ties, Genovo, had the right to license any technologies developed in Wilson's research. (17)

Jesse participated in a Phase I clinical trial designed to test the safety of an intervention, not its efficacy, which usually gets tested in later phases. (18) Jesse participated in a stair-step dosage trial designed to include 20 subjects in total. Jesse was participant OTC.019. (19)

[FIGURE 1 OMITTED]

As Figure 1 shows, subjects on the lowest stair-step would receive 5,000 fold less of the vector used in prior animal trials in which monkeys and mice died. (20) Those animals received a first generation virus, in contrast to the third generation virus that Jesse and other participants received. (21) Unlike the first generation virus, the third generation virus lacked the portions that cause it to replicate in the body and to make people sick--that is, the parts that cause viral replication and viral pathogenesis. (22)

The protocol for the trial provided that participants on the highest stairstep, as Jesse was, were to get 100 fold less of the vector than the animals received. (23) After Jesse's death, the Institute for Human Gene Therapy ("IHGT"), which Wilson directed at Penn, disclosed in documents filed with the FDA that Jesse received a considerably higher dose--17 fold less of the vector than what the animals that died in a prior trial received. (24)

Jesse's ill-fated participation in the clinical trial began with a June 1999 visit by Jesse and his father, Paul Gelsinger, to Penn to see if Jesse was eligible to participate in the trial. (25) During that visit, Steve Raper went through the Consent Form with Jesse and Paul. (26) Jesse clearly understood that the trial, if successful, would provide no lasting benefit to him, but that it might pave the way to correcting the disease in newborn children. Paul Gelsinger explains that Jesse "signed on to help everybody and, hopefully, himself in the long run." (27) As Part III shows, neither Jesse nor Paul received the unvarnished truth about the results of prior animal studies, nor did they realize the magnitude of Wilson's potential gains from the research trial.

On September 13, 1999, Jesse was infused with the vector despite the fact that his ammonia levels fell outside the protocol's safety limit. (28) Over the next four days, the vector took over Jesse's entire body, shutting down his vital organs. He died on September 17, 1999.

In the months following Jesse's death, the U.S. Senate and House of Representatives held hearings about his death, as did a host of federal regulators. (29) The Washington Post also uncovered "[t]he first evidence that Wilson's company did in fact have a financial interest in the experiment," (30) raising questions about Wilson's motives. Ultimately, the FDA charged the researchers with protocol violations, misleading disclosures, and other mistakes in the trial. As the next Part explains, despite two separate lawsuits, many of the questions raised by the FDA and others remained unanswered for nearly a decade.

B. A CASE OF FIRSTS

Jesse's death was a case of firsts. Jesse was the first person to die in a human gene-therapy trial. (31) His family's lawsuit was also the first high-profile suit in which a family of a participant sued in tort to recover under a variety of new and creative claims. (32) That suit was also the first to name a bioethicist, the world famous Arthur Cap]an, director of Penn's Center for Bioethics, as a defendant based on the advice he gave the researchers regarding study design--which essentially urged testing the protocol on relatively healthy adults rather than dying infants. (33) The family's lawsuit was also the first to spotlight a financial conflict of interest by a researcher, Wilson. (34)

Jesse's trial was also the first to trigger a lawsuit by the government in which it framed errors in a human subjects research trial as a civil False Claims Act violation, bringing to bear the crushing power of the penalties under that act. (35) And Jesse's trial was the first to bounce researchers from human research for a period of years, albeit by agreement, and then to subject one of them, Wilson, to monitoring for a decade. As part of that settlement, Wilson was required to write an article about Lessons Learned from Jesse's trial as a condition precedent to being readmitted to human subjects research without restriction, another first. (36) In 2009, almost a decade after Jesse's death, Wilson published his long awaited Lessons Learned article. (37)

For a case of firsts, one would think the public would have access to a storehouse of information about the underlying financial conflict of interest and the mistakes made in Jesse's trial, if any. Yet no public record exists of either proceeding because both settled. (38) The family's lawsuit settled for an undisclosed amount less than 7 weeks after filing, before Penn even answered. (39) The government's suit settled before a civil charging document was even filed, burying for nearly a decade crucial details of that case.

Jesse's death is worth re-examining, not only as a gripping piece of medical history, but also because other gene-therapy trial participants have also died. (40) Moreover, because the rules governing conflicts of interest and disclosure of risks have largely remained unchanged since Jesse's death, understanding what went wrong in Jesse's trial can help us to improve the oversight of human subjects research. As the next Part documents, Jesse and Paul were told only partial truths about the risks Jesse would be taking by participating in the trial.

III. "DISCLOSURES" OF RISK AND BENEFIT

The disclosure form that Jesse actually saw and signed left a lot to be desired in terms of securing informed consent. The Consent Form alerts participants repeatedly that the trial is a non-therapeutic safety trial--that is, participants should not expect to gain anything from it. (41) Jesse clearly understood he could not gain anything from participating in the trial. In fact, Paul often says he was a hero for participating precisely because he could not gain anything from it. (42)

The Consent Form also discusses the risks of the trial, and lists three major risks to consider: "that receiving the virus now may prevent you from receiving a therapeutic dose of the virus in the future," and that the virus may cause "an inflammation of your liver [or,] an immune response from your body which could damage the liver." (43) In fact, the latter is what killed Jesse: a massive immune system response. (44) After Jesse's death, Batshaw said it was like Jesse had fallen off of a cliff. (45)

The risk discussion includes one of the three references in the 11 page Consent Form to the possibility of death. As Figure 2 shows, it notes that liver inflammation could be "life-threatening."

Figure 2 (46)

Although we believe the virus is safe, it is possible that it could
cause an inflammation of the liver or hepatitis. It is even possible
that this inflammation could lead to liver toxicity or failure and
be life-threatening.

Elsewhere, as Figure 3 indicates, the Consent Form quantifies the risk of death from a biopsy, which may be needed during the course of the trial:

Figure 3 (47)

There is also a very small risk (1 in 10,000) of serious
unpredicted complications which can include death. … 

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