Trials and Tribulations

Abstract

By all accounts, Jolee Mohr was an active woman in relatively good health. Though she had rheumatoid arthritis, it did not keep her from holding down an office job and spending her leisure time boating with her husband and their young daughter. But the thirty-six-year-old Illinois woman's life came to an unexpected end last July, three weeks after an experimental gene therapy was injected into her right knee during a phase I/II clinical trial aimed only at assessing the agent's toxicity. Mohr's rheumatologist had recruited her for the study and had given her the injection in his office. Her death was caused by organ failure from histoplasmosis, a common fungal infection that normally produces only mild illness. The tragedy immediately sparked comparisons with the story of Jesse Gelsinger, a vital eighteen-year-old who died in 1999 during a gene therapy trial at the University of Pennsylvania. Gelsinger's death was the first to be definitively linked to a gene therapy trial. Would Mohr's be another? The trial was halted pending an investigation by the National Institutes of Health's Recombinant Advisory Committee. The RAC's report, released last December, delivered a mixed message. It concluded that the experimental treatment was unlikely to have contributed to Mohr's death, but it also said that the possibility cannot definitively be ruled out. Howard Federman, the committee chairman, told Science, we are still missing key pieces of information needed to answer the ultimate question posed by Mohr's husband: Would she be alive today if she had not enrolled in the trial? In any case, the Food and Drug Administration allowed the trial to resume. The investigation, though, brought to the surface disturbing aspects of clinical research left inadequately addressed since Gelsinger's death: the pressure to enroll record numbers of human subjects in record numbers of trials, financial conflicts of interest, shortcomings in oversight by the federal government and ethical review boards, and the implication of all of these trends for the safety of human subjects. These problems have been aired in medical and bioethics journals, op-ed pieces, and some memorable investigative journalism. But the Mohr case gave them new urgency. By infusing the all-too-familiar issues with flesh-and-blood drama, it revived concerns that clinical trials generally--not just research on gene therapy--may be headed for crisis. So far, there are more questions than answers. Should someone who is not seriously ill be enrolled in a phase I safety study, or is the risk too high? What can be done to prevent subjects from developing the misconception that they will benefit from an experimental therapy? Is this misconception exacerbated when the researcher recruiting the subject is his or her physician? Did Mohr have this misconception, even though the consent form stated, We do not expect you to receive any direct medical benefit from participation in this The financial relationships between drug company sponsors and researchers and between the drug companies and ethics review boards constitute a conversation all their own. What regulatory changes are needed to prevent financial interests from turning scientific research into a marketing tool and the ethical review process into a rubber stamp? Researchers are obliged to disclose any financial relationships with the research sponsor to the FDA, but not to potential research subjects. Would Mohr have consented had she known that her physician was being paid by the trial sponsor, Targeted Genetics, to recruit her for the study? Did the money lead her doctor, consciously or not, to talk up the benefits of volunteering for the trial and downplay the risks? Government regulations are supposed to protect human research subjects from unethical treatment and unsafe conditions. But this task has gone from merely challenging to excruciatingly difficult in recent years. …