By Lisa Seachrist
Washington Editor
WASHINGTON In the wake of the death of an 18-year-old gene therapy patient and revelations of serious protocol violations by the University of Pennsylvania investigators sponsoring the study, the Senate took a hard look Wednesday at the way gene therapy experiments are conducted and regulated.
Calling gene therapy a promising but as yet unrealized procedure for curing patients who suffer from a host of genetic and non-genetic diseases, Sen. Bill Frist (R-Tenn.), chairman of the Health, Education, Labor and Pensions Committees Subcommittee on Public Health, gathered patients, regulators, academia and industry in an attempt to discover just where the system broke down and allowed for the death of Tucson, Ariz., native Jesse Gelsinger.
Earlier this week, acting National Institutes of Health (NIH) Director Ruth Kirchstein announced that following an October reminder about reporting requirements delivered to all NIH-sponsored investigators conducting gene therapy research, the agency received 652 previously unreported adverse events in gene therapy trials.
It does get down to trust and accountability, Frist said. That appears to be where the breakdown is.
Jay Siegel, director of FDAs Office of Therapeutics Research and Review for the Center for Biologics Evaluation and Research, noted the agency has started an investigation of University of Pennsylvania, the Institute for Human Gene Therapy and investigator James Wilson. While noting the findings from the investigation were still preliminary, Siegel cited a number of problems with the gene therapy trials at Penn.
The investigators had a number of issues with the clinical studies, including informed consent, implementing patient exclusion criteria, following stopping rules, initiating protocol changes and submitting reports of animal deaths, Siegel said. Based upon the concerns raised regarding the adequacy of the monitoring program to protect the safety of human subjects, FDA determined it would be prudent to place all other trials sponsored by Dr. James Wilson and the Institute for Human Gene Therapy on clinical hold.
The FDA is still in the process of determining what punitive measures, if any, it will take related to the protocol violations discovered at Penn.
The issue of informed consent came up several times as the lawmakers tried to evaluate whether adequate systems and guidelines are in place to regulate this emerging technology. Gelsingers father, Paul Gelsinger, told the subcommittee he was unlikely to have supported Jesses decision to enter the study had he known what he learned at the Recombinant Advisory Committee (RAC) meeting in December. Jesse suffered from a rare genetic liver disorder called ornithine transcarbamylase deficiency (OTC), which prevented his body from processing the nitrogen found in food proteins and resulting in a buildup of ammonia.
Jesse and I were told in late July 1999 that a prior patient had shown a clinical improvement of 50 percent in her ability to eliminate ammonia from her system following gene therapy, Gelsinger said. At the RAC meeting in December I discovered that no efficacy was achieved at all in this patient. We were also unaware of the severity of liver injury incurred by several patients prior to Jesse. I learned, after Jesses death, that Penn had removed from the information they gave Jesse and me any reference to deaths of monkeys, which had previously appeared in their documents.
Gelsinger noted liver problems such as hepatitis and liver failure were listed on the informed consent documents Jesse signed, but said Penn investigator Steven Raper downplayed the potential for such harms at the time. He also suggested some sort of patient advocate be included in the informed consent process to make sure investigators arent glossing over critical issues. Gelsinger has retained an attorney but wouldnt comment on whether he intends to sue the government or Penn researchers in connection with his sons death.
In addition to the informed consent issue, the subcommittee explored the differing requirements for reporting adverse events to FDA and NIH. The FDA has regulatory authority over all investigational new drugs (INDs) including gene therapy whether they are sponsored by the private or public sector. As such, it requires that all serious and unexpected adverse events be reported to the agency in 15 days. If the adverse event is also life-threatening, the time clock shortens to seven days. Those serious adverse events that are expected as a result of treatment with a particular drug or biologic are reported annually to the agency.
The NIH, on the other hand, requires all investigators receiving any type of federal research funding to report immediately to NIH any serious adverse event that occurs during the course of a gene therapy trial. However, Amy Patterson, director of the Office of Biotechnology Activities at NIH, admitted researchers havent been following the NIH guidelines.
RAC Approval Authority Being Discussed
Investigators have violated the guidelines, Patterson said. It is possible that with the removal of the RACs approval function [in 1996], researchers believed they were no longer required to report to NIH. We are looking at the possibility of returning to the RAC some approval authority.
The differing reporting requirements cause consternation for academic and corporate researchers alike. All academic researchers conducting gene therapy clinical trials are required to report serious adverse events to NIH immediately, even if the sponsor is a biotech or pharmaceutical company. FDA requires that sponsors not individual investigators report only unexpected serious adverse events in a timely fashion, leaving the rest to the annual reports. H. Stewart Parker, CEO of Targeted Genetics Corp. in Seattle, told the subcommittee that the biotechnology industry would prefer harmonized reporting requirements for both agencies, and the companies would voluntarily submit the information to both FDA and NIH at the same time.
Its very important to harmonize the reporting requirements so that the serious adverse events can be reported to NIH and FDA at the same time, said Parker, speaking for the Biotechnology Industry Organization (BIO). We want to put everything on the table.
Parker said BIO would even agree to the NIHs reporting schedule in order to make sure NIH and FDA get the reports at the same time.
Frist noted the recent events in gene therapy have soured the public view of this research, and as a result, Congress must make sure these experiments are regulated rigorously to protect human subjects. Gelsinger concurred, noting hed lost all confidence in the research. He went on to describe a conversation hed had with Penn investigator James Wilson.
He was worried about how Jesses death might mean losing the institute, Gelsinger said. I told him it could be a lot worse; you could lose one of your children.