By Lisa Seachrist
BETHESDA, Md. - In the aftermath of the death of University of Pennsylvania gene therapy patient Jesse Gelsinger, the National Institutes of Health established the Recombinant DNA Advisory Committee (RAC) Working Group on Adenoviral Safety and Toxicity to assess whether research with these vectors can safely proceed.
At the Friday meeting of the full RAC, the Working Group recommended the research should continue with caution and certain caveats in place. Included in the recommendation was a call for creating scientific standards for proceeding with adenoviral vectors, using traditional drug development methods to evaluate the gene therapy products, and strengthening the informed consent process for research volunteers.
"We as a committee haven't been as obsessed with understanding these gene therapy products as a therapeutic agent, and we need to be thinking of them in that way," said RAC member Theodore Friedmann, professor in the Center for Molecular Genetics at the University of California in San Diego.
The working group proposed developing qualitative, quantitative and scientific standards to improve the comparability and value of the experimental data resulting from clinical trials using adenovirus. Included in those standards should be particle number, vector strength, vector quality and vector toxicity. To that end, the working group also recommended including experiments on null vectors and deletion vectors to determine the safety issues associated with the vector alone.
Because what happened to Gelsinger appeared to be an immune response to the adenoviral vector he received, the group also suggested patients be monitored for immune status, predisposing or underlying conditions and cytokines before and after vector administration. The group said such monitoring would help minimize study variability and potential acute toxicities. It also suggested the RAC review the acquired clinical data on a regular basis in symposia in order to keep researchers abreast of developing trends and potential problems.
Finally, the group advised inform consent documents contain clear statements of risks and benefits, address financial conflicts of interest and address the investigators' conflicts of commitment - the natural tendency to view one's own research in a favorable light. The group also suggested the informed consent process include a disinterested third party or patient advocate.
"They should be called research subject advocates because the people aren't patients," said Ruth Macklin, professor of bioethics at the Albert Einstein College of Medicine in the Bronx, N.Y. "This person would stand up for the subjects' interest. The problem is the people who know the most about the research are the research team."
The RAC considered the possibility of genetic counselors serving as the research subject advocates, but spent the bulk of its time attempting to develop an adequate informed consent process. At which point Philip Noguchi, director of the division of cellular and gene therapies at FDA, noted there were significant scientific issues the committee could address related to adenoviral vector safety.
"There are many nuances coming to light because there hasn't been a way to produce the number of vectors in the past," Noguchi said. "There is an intriguing interplay between the informed consent process and the science needed to understand what happened and how to prevent it in the future."
Committee members Jon Gordon, professor of neurobiology at Mount Sinai School of Medicine in New York, and Xandra Breakefield, a geneticist at Massachusetts General Hospital in Charlestown, Mass., agreed with Noguchi.
"When we look at Jesse Gelsinger's death, did this have something to do with the vector preparation or the number of viral particles delivered, his underlying condition, or something else?" Gordon said. "I'd like to see this committee find ways to get to the bottom of this. If we don't go at this systematically we won't be able to identify the risks associated with it."
"I've read volumes and volumes of data and I still don't know why he died," Breakefield said. "Is the empty virus itself toxic? We don't know, and it would be important to find out, especially when we are looking at gutless vectors."
Noguchi suggested the RAC could serve the field and FDA well by organizing symposia to look at the scientific issues and discovering what played a role in Gelsinger's death. On Thursday, the NIH working group on NIH Oversight of Clinical Gene Transfer Research spent considerable time questioning the RAC on its role in oversight since former NIH Director Harold Varmus stripped it of its approval authority in 1996.
Macklin voiced the feelings of most of the committee when she noted the RAC lacked the ability to get accountability from the researchers whose protocols the RAC has reviewed. She pointed out there had been several occasions in which the RAC was reviewing protocols that were already enrolling and treating participants. In addition, the RAC never knows whether its recommendations are included in the active protocol.
"We've heard that the investigators we've reviewed take this very seriously, but without any feedback we don't know," Macklin said.
The NIH working group is considering whether RAC's approval should be restored in addition to other ways of enhancing the oversight of gene therapy trials.