The recent tragic and widely publicised death of Jesse Gelsinger in a gene therapy trial has many important lessons for those engaged in the ethical review of research. One of the most important lessons is that ethics committees can give too much weight to ensuring informed consent and not enough attention to minimising the harm associated with participation in research. The first responsibility of ethics committees should be to ensure that the expected harm associated with participation is reasonable.

Jesse was an 18-year-old man with a mild form of ornithine transcarbamylase (OTC) deficiency, a disorder of nitrogen metabolism. His form of the disease could be controlled by diet and drug treatment. On September 13 1999 a team of researchers lead by James Wilson at the University of Pennsylvania's Institute for Human Gene Therapy (IHGT) injected 3.8 X 10¹³ adenovirus vector particles containing a gene to correct the genetic defect. He was the eighteenth and final patient in the trial. The virus particles were injected directly into the liver. He received the largest number of virus particles in a gene therapy trial.¹ Four days later he was dead from what was probably an immune reaction to the virus vector. This was the first death directly attributed to gene therapy. It resulted in worldwide publicity, an independent investigation, the Federal Drug Administration (FDA) suspending all trials at the IHGT, an FDA, and a senate subcommittee investigation.

At a special public meeting at the National Institutes of Health (NIH) in December 1999, James Wilson, also the director of the IHGT, said they still did not understand fully what had gone wrong.² Even though a massive dose had been used, only 1% of transferred genes reached the target cells. (None of the patients in the trial showed significant gene expression. Art Caplan, the University of Pennsylvania's outspoken bioethicist, is reported to have said: “if you cured anyone from a Phase 1 trial, it would be a miracle” and “there was never a chance that anyone would benefit from these experiments”.³) Wilson claimed the death was the result of an anomalous response. Jesse's bone marrow had very low levels of red blood cell precursors, which probably predated the experiment. This may have reflected another genetic defect or a parvovirus infection. While most gene therapists at the meeting agreed that Jesse's response was unusual, some claimed it was foreseeable, given the ability of adenovirus to elicit an immune response and the high dose employed.²

The death also resulted in a wrongful death lawsuit which alleged³:

• that members of the IHGT team and others were careless, negligent and reckless in failing to adequately evaluate Jesse's condition and eligibility. Jesse had an ammonia level 30%-60% higher than the eligibility criterion stated in the protocol approved by the FDA;

• that the adenovirus vector was unreasonably dangerous;

• that storage of the vector for 25 months led researchers to underestimate its potency;

• that a conflict of interest existed. Researchers and members of the University of Pennsylvania held patents covering several aspects of the technology employed. Wilson and colleagues also hold equity holdings in Genovo, the private sector biotechnology collaborator in the project. These conflicts of interest were alleged to have not been disclosed to the participant;

• that researchers failed to notify the FDA of adverse events in prior patients and animals.

The lawsuit also named Art Caplan, director of the University of Pennsylvania's Bioethics Center. It was also suggested but not explicitly alleged that Caplan had a conflict of interest because his centre was funded by Wilson's department. The complaint also drew attention to Caplan's intervention to persuade Wilson and others to use older participants who could consent (but who had a mild form of the disease) rather than newborns who could not consent (but had an otherwise lethal form of the disease).³

Other concerns related to this trial have included⁴:

• Researchers continued to increase the dose despite signs of toxicity in other patients;

• Volunteers were recruited by direct appeal on a patient advocacy website which described “very low doses” and “promising results”. Such appeals had been rejected by federal officials as being coercive.

• The original consent reviewed publicly by the NIH mentioned that monkeys had died from the treatment but the final version did not mention that.

• The NIH's Recombinant DNA Advisory Committee (RAC) discussed the potential for lethal liver inflammation related to this experiment in December 1995, after reviewing toxicity results in rhesus monkeys and the death of one monkey from an extremely high dose of a first-generation vector. They recommended administration through a peripheral vein rather than directly into the liver. Food and Drug Administration regulators were concerned about infection of reproductive cells (germ line modification) and made researchers go back to direct liver injection.¹

In February 2000, at a senate hearing, Paul Gelsinger, Jesse's father, asserted:

1. that his son had not been told important preclinical evidence of toxicity (including the deaths of monkeys);

2. that his son was led to believe that his participation would be clinically beneficial, despite this being a Phase 1 trial where no benefit was envisaged.⁵

James Wilson while acting as director of the IHGT, was also involved in several clinical trials and basic research. Judith Rodin, the University of Pennsylvania's president and William Danceforth, the lead author of an independent report into Jesse's death, said that Wilson was “overloaded”.⁶ The IHGT has been downsized and no longer conducts clinical trials. The Department of Health and Human Services has said it intends to introduce laws which will fine researchers up to $250,000 and institutions up to one million dollars for failing to meet new stricter standards.⁶