Tuesday, August 07, 2007

Death in Gene Therapy Trial

"Death Points to Risks in Research" touts the Washington Post story.

I would like to comment on Rick Weiss’ article, from the perspective of a clinical researcher. The death of Mrs. Mohr, subsequent to her participation in the Targeted Genetics gene therapy trial, is a tragedy, and worse, was perhaps an avoidable tragedy. There does appear to be a need to re-evaluate the safety mechanisms that are employed to protect patients who are candidates for trial participation, and to re-examine the propriety of the exclusion of public participation in the trial review and approval process that was initiated in 2000.

From the description, it appears that there were serious lapses in Mrs. Mohr’s care. However, there are also several errors in this report which do a disservice to the public, who need to be educated about trials and how to assess whether to participate, rather than be needlessly scared away by inaccurate reports.

For example, a “serious adverse event” requires prompt reporting to the FDA, whether or not it is felt to be related to the drug. The definition of a serious adverse event is one that causes death or is life-threatening, is permanently disabling, results in a congenital anomaly/birth defect, or one that results in new or prolonged hospitalization. Most sponsors require reporting from the investigator within 24 hours. The FDA should have been notified within days after Mrs. Mohr’s admission to the hospital (CFR 312.32).

There are two significant factual errors in the claim that “Two fundamental rules of clinical research were violated that day.” First, there is no FDA requirement that a patient take a consent form home and review it. That is also an impossibility on many trials dealing with acutely ill patients, for example. Nor is there any requirement that the investigator not present the consent form to the volunteer. In fact, some times there is no one else capable of explaining the trial in detail and answering the volunteers questions. To avoid this type of question regarding the adequacy of consent, I try to have family members present when I review the consent, so I can address their concerns as well, and also try to include an impartial witness.

It sounds as though the consent form for this trial was inappropriately technical. Consents are generally pitched at an 8th grade level. Obviously, this is harder to do with a sophisticated gene therapy trial, but should be the goal.

It is disturbing and unusual to have an early phase trial include patients who are on multiple medications likely to cause serious side effects. The decision to allow this is now shielded from public review; there must be transparency, public review and accountability of the approval process.

I hope that there will be a thorough, thoughtful and very public review of this and other gene therapy trials, in particular.

However, articles in the popular press, such as the one in the Washington Post, often seem to dwell on the costs of clinical trials, and to ignore the benefits those trials have brought. Before the development of antibiotics, for example, an infection was often a death sentence, most cancers were considered incurable, and there was no way to control the disastrous effects of diabetes, heart arrhythmias, and many other common illnesses. While clinical trials are not perfect, and do sometimes injure those they are supposed to help, we have come a long way in the past 50 years, in terms of our abilities to develop useful interventions while providing reasonable protection to study participants. Every medicine goes through this sort of trial process. We need new medicines for serious diseases, such as infections, urgently.

Protections need to be in place, but they should not incapacitate research nor scare volunteers unnecessarily. Since many of the issues here revolve around potential conflicts of interest, the first step would be greater transparency, public discussion, and debate.

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