LAST SEPTEMBER, Jesse Gelsinger, an 18-year old volunteer in a gene therapy study at the University of Pennsylvania, died suddenly, apparently as a result of a complication of the experiment. The adenovirus that was designed to deliver a "correct" copy of the altered gene that caused his serious liver disorder caused a massive and irreversible immune system reaction. The experiment was not intended to benefit him directly. It was intended only to obtain lab results that would indicate whether the new genes had been inserted into his cells and had started the production of the enzyme he lacked.
It now appears that Gelsinger and his family were not aware of two primate deaths and complications with other human subjects in the study, and that federal agencies that regulate human experiments were not properly informed of hundreds of "adverse events" in gene therapy research around the country.
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President Clinton has ordered an investigation into the way gene therapy research is regulated. For its part, U. Penn. has denied any serious wrongdoing that led to Gelsinger's death, and his father has switched from supporting the scientists to retaining a lawyer.
Along with cloning and stem cell therapy, gene therapy is on the far end of the cutting edge of modern biological science. It is both among the theoretically most promising approaches to a myriad of diseases that involve "bad genes," and it is also the object of considerable investment.
For the last ten years there have been about 300 studies, but so far no one has been documented to have benefitted from the research. Gelsinger's death has sent a shock wave through the close-knit gene therapy community.
While the federal investigation continues -- the National Bioethics Advisory Commission will hear from senior officials at the end of the month -- the current crisis in gene therapy research should be set against the background of controversy about the adequacy of current protections for human research subjects. That controversy includes how well risks are assessed and how well informed consent works, the way subjects are recruited, whether the research activities are monitored adequately, and potential conflicts of interest on the part of investigators.
For several years, various federal agencies and advisory groups have questioned the current regulatory system. Although there has been no Tuskegee syphilis study scandal in the past 20 years, since the current system went into place, there have been significant changes in the research environment. Some of these changes are basic ingredients in the gene therapy controversy: Local review boards may be over-worked and have inadequate expertise, research now is conducted with many subjects at various sites, and private investment has assumed a more important role in the research and development process than ever before.
Also, somewhat ironically, the success of the current system has lulled many potential study subjects into a false sense of security about research risks. In AIDS and cancer research especially, there is a widespread feeling that to get the best treatment is to get a promising but unproved medication. As one of the most promising, glamorous and highly capitalized fields of medical investigation, gene therapy easily can acquire the same aura.
During the past year, the National Institutes of Health has suspended the clinical trial licenses of nearly a dozen important research centers for failure to follow the general rules governing human protections. These suspensions have been costly and embarrassing, but no one argues that the institutions were not at fault.
Since the death of Jesse Gelsinger, the Food and Drug Administration has suspended a number of gene therapy trials, including all eight at U. Penn., and others have been dropped voluntarily.
One solution now being floated among health policy commentators would correct the current Balkanized system of human research regulation. In the case of gene therapy, at least three federal agencies have some regulatory role, but their jurisdictions and interactions are defined poorly. It may be time to design a single federal agency that regulates and monitors the drug and device development process from lab bench to pharmacy shelf, as is the case in Western Europe.
At the very least, highly novel and potentially valuable fields of study require special handling. Medical scientists and administrators too often have proven apathetic about following the letter of regulatory requirements.
In 1996, NIH Director Dr. Harold Varmus demoted the gene therapy watchdog group within NIH to merely an advisory role -- a move criticized even then by many ethicists. The recent events confirm that critical judgment.
It seems that the archetype of 21st-century medical goals -- replacing bad genes with good ones to cure countless diseases from within -- will present the opportunity to re-evaluate the ethics and economics of modern medical research. All progress comes at a price, including progress in medical science. Our society has determined several times that the rate of progress often must be sacrificed for the sake of more basic values: the well-being of research volunteers and the public's confidence in the integrity of the research system.
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