By Lisa Seachrist

Washington Editor

BETHESDA, Md. - Gene therapy researchers would be required to report all serious adverse events in patients undergoing gene therapy should a proposal being considered by the Recombinant Advisory Committee (RAC) go into effect.

The regulation was proposed in response to some gene therapy researchers labeling adverse events as confidential, proprietary information. Because the RAC is a public forum, those situations couldn't be openly examined.

However, in light of the death of a gene therapy patient and the discovery that the researchers conducting that experiment failed to fulfill some reporting requirements, the RAC is considering instituting a policy whereby all serious adverse events must be reported to the committee within 15 days of their occurrence.

"We are seeking two things with these new regulations," said Ruth Macklin, professor of bioethics at Albert Einstein College of Medicine in the Bronx. "One is to clarify the existing guidelines. The second is to expand the reporting of serious adverse events. Whatever is done, there should be a close collaboration between the RAC, NIH and the FDA."

In the end, a closer collaboration between the interested parties appeared to be the only proposal the RAC, academia, industry and FDA could agree upon.

As human experiments, all gene therapy trials come under scrutiny by FDA. At a minimum, the agency requires the sponsor of the investigational new drug to submit expedited reporting of all serious and unexpected adverse events within 15 days of discovering the adverse event. In cases where the adverse event is fatal or life-threatening, the sponsor must call or fax in the report within seven days and complete the written report within 15 days. Other serious adverse events are reported in annual reports.

Some members of the RAC found unsatisfactory the distinction between an expected adverse event and an unexpected adverse event triggering a written report.

"I still don't understand the relationship with expected and unexpected adverse events," said RAC member R. Scott McIvor, director of the gene therapy program at the Institute for Human Genetics at the University of Minnesota in Minneapolis. "When an adverse event occurs, we should be told about it."

Philip Noguchi, director of FDA's division of cellular and gene therapies in the Center for Biologics Evaluation and Research, pointed out the agency often requires additional notification for certain adverse events that are more likely to occur or more worrisome, on a case-by-case basis. In addition, when an adverse event is expected, the researchers can conduct additional tests to catch the situation at an early and perhaps manageable stage.

Nevertheless, the RAC working group proposed a system that would result in more adverse event reporting than currently required by FDA. In addition to unexpected adverse events, RAC would require the reporting of expected adverse events and reporting of the events even if the event isn't related to the gene therapy. The group is still in the process of trying to figure how to manage the massive amounts of information should the regulations go into effect.

"I like the notion that we don't leave up to the judgement of the investigator whether an adverse event is the result of gene therapy," said RAC member Jon Gordon, professor of neurobiology at Mount Sinai School of Medicine in New York. "On the other hand, I don't want us to simply generate a blizzard of paperwork for the investigators."

H. Stewart Parker, CEO of Seattle-based Targeted Genetics Corp., speaking on behalf of the Biotechnology Industry Organization (BIO), told the committee its proposal is at odds with current reporting requirements for both FDA and international regulatory bodies. Instead, Parker proposed a data-sharing arrangement.

"As an alternative to the NIH proposal, BIO companies propose the following structure for the future oversight of gene therapy," Parker said. "Sponsors agree to voluntarily provide serious, related and unexpected adverse event reports that are currently sent on an expedited basis to FDA, to NIH/OBA. Sponsors would also send to RAC the safety data summarized in the IND annual progress report currently provided to FDA. In this way, OBA and the RAC would have access to adverse event reports at the same time as the FDA."

Parker went on to suggest if after a preliminary review of the adverse event report, RAC has safety concerns, FDA and RAC could jointly evaluate the data and the results of the joint deliberations could form the basis of public discussion at a RAC meeting.

Former RAC chair Leroy Walters, an ethicist at Georgetown University in Washington, suggested a more expansive reporting system. Walters first noted the requirements for reporting adverse events to RAC have been in place since 1985 despite the fact that many researchers don't comply with those requirements. Walters maintained that as a novel therapy, gene therapy should be the subject of enhanced oversight in the form of adverse event reporting.

"It's good ethics - it helps protect the human subjects," Walters said. "Its good medicine - it helps the physician to avoid causing undo harm. It's good science because scientific research needs to be based on the best science available. Is it also good business? I'm not qualified to answer that. It will level the playing field, so all I can say is that it's fair."

RAC will continue to develop its guidelines and those will be published in the Federal Register. However, not all members of the committee are sold on the current proposal. Louise Market, associate professor of pediatrics at Duke University in Durham, N.C., expressed caution about jumping into an area where RAC lacks expertise.

"I don't want to see the events that are expected," Market said. "I don't want to have to look it over. I think FDA has years of experience in this and I would like to follow their lead in reporting serious events."