NEWS

Why Were NIH Adverse Event Reporting Guidelines Misunderstood?

Robert Finn

The death of a patient in a gene therapy trial last October (see News, Jan. 19, p. 98) highlighted widespread confusion among investigators regarding adverse event reporting. In spite of the National Institutes of Health guidelines, many serious adverse events (SAEs) encountered over the last 7 years apparently were not reported to the Recombinant DNA Advisory Committee (RAC) when they occurred. In the months since the death threw a spotlight on clinical trials of gene therapy, the RAC has received a veritable blizzard of reports on SAEs, many of them years old.

In February, Rep. Henry A. Waxman (D-Calif.) claimed that 94% of 691 gene therapy SAEs had not been reported to the RAC in a timely fashion. Retrospective reports are continuing to mount. From January through mid-April 2000, the committee received 780 gene therapy SAE reports, said Amy P. Patterson, M.D., director of NIH’s Office of Biotechnology Activities, which oversees the RAC.

Although she did not cite the exact proportion of retrospective reports among this year’s SAEs, Patterson said "the number of retrospective reports is declining quite a bit now. I think people have begun to catch up."

Now, NIH and the U.S. Food and Drug Administration are each taking steps to clarify—and perhaps eventually to harmonize and simplify—reporting requirements. But the cause of the apparent confusion among investigators remains unclear.

"I can assure you that 94% of the people doing gene therapy are not complete amoral sociopaths trying to hide everything from view," said Malcolm K. Brenner, M.D., director of the Center for Gene Therapy at Baylor College of Medicine in Houston. "They just simply didn’t understand that the RAC wanted it."



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Dr. Malcolm K. Brenner

 
Patterson reminded institutions conducting human gene-transfer research in a November 1999 memo of Appendix M-VII-C of the "NIH Guidelines" that reads (in part), "Investigators who have received approval from the FDA to initiate a human gene transfer protocol must report any serious adverse event immediately to the local Institutional Review Board, Institutional Biosafety Committee, Office for Protection of Research Risks (if applicable), NIH/ORDA, and FDA, followed by the submission of a written report filed with each group. Reports submitted to NIH/ORDA shall be sent to the Office of Recombinant DNA Activities . . ."

Brenner suggested that some of the blame for the confusion may be owed to differences between FDA and NIH reporting requirements: "For FDA the rules were fairly clear. As far as I’m aware the regulatory requirements are that you only have to report adverse events when a patient is on the study," he said. "As soon as they’re off the study the adverse events don’t, as a regulatory requirement, have to be reported. Now the National Cancer Institute has slightly modified rules for NCI-sponsored studies, which are that any adverse event happening within 30 days of completion of the study should be reported."

Brenner also suggested that researchers may not have realized that the RAC wanted a report of every single serious adverse event. "I know that the stipulations they put up do actually seem quite clear," he said. "But the message that everybody has got, the gestalt that everybody took away, is that the RAC were only interested in adverse events if they were likely to be related to the gene therapy. Otherwise you would just report it to the IRB and the FDA. It turns out that’s not what they wanted, but that’s what everyone took away."

On the other hand, Patterson explained that the RAC’s reporting form clearly calls for investigators to state whether each SAE reported is likely or unlikely to be directly related to the gene-transfer protocol. Most SAEs are in fact judged not to relate to the protocols.

"The vast majority of them were due to the progression of patients’ underlying diseases or other medications such as chemotherapy or antibiotics that were used either separately from or in conjunction with the trial," she said. "Roughly 9% of the events that are reported to the NIH are judged by the investigators to be possibly associated with the gene transfer on initial evaluation. That assessment can and often does change with time."

Staffing Issues

For his part, Brenner knows exactly how he got the wrong idea about reporting requirements: "The reason I had the mistaken impression is that I couldn’t see any conceivable way in which they could analyze adverse events in any sensible way given their staffing levels and the nature of the people making up the RAC. The FDA has a very large group of people who specialize in adverse-event reporting. There’s no point in getting a whole load of adverse events if you don’t know what they mean."

Patterson denied that the RAC staff is unequipped to handle SAEs. "They’ve been doing it historically," she said.

Other researchers may have had the impression that it was enough to report SAEs to their local IRBs and the FDA. But the FDA has quite a different role than the RAC. "The FDA has the authority and the responsibility to look at the conduct of these trials on a day-to-day basis," said Patterson. "The RAC is a scientific and technical committee also charged with looking at the ethics as well as the safety of this line of research, and their goal is to look at trends and identify issues, be they ethical or safety."

Confidentiality is another difference between the agencies. "The FDA is by definition private," said Inder M. Verma, Ph.D., the American Cancer Society Professor of Genetics at the Salk Institute in La Jolla, Calif., and president-elect of the American Society of Gene Therapy. "The reason they’re private is simply because they regulate proprietary things. They can’t just go out and tell people what a company asks of them. They also can’t tell about failures for the same reason, because that’s also a trade secret.



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Dr. Inder M. Verma

 
"The beauty of the RAC is that it publicizes everything. The public has the ability to know what is happening, the ability to participate, and I think that’s an essential component of the RAC—to make their discussions public so that people don’t think anything is happening in the back of them."

At least two working groups—one part of the RAC and one part of the NIH Director’s Office—are investigating whether it may be possible to harmonize FDA and RAC reporting requirements.

Such harmonization is critical, said Brenner, "Otherwise all that’s going to happen is that we’re going to have two sets of bureaucracies which are inevitably going to end up in competition. And it’s just going to make life miserable for the people who are trying to do gene therapy and discourage them from even starting studies, and in the end the people who will suffer will be the patients, particularly the patients with diseases that are not commercially viable and not able to attract drug companies."

Increasing Reporting

Meanwhile, the NIH Office of Biotechnology Activities is taking several steps intended to improve SAE reporting. For one thing, Patterson’s office is in the process of phoning each and every principal investigator involved in a gene therapy trial to discuss reporting requirements.

In addition, not-for-cause site visits are being conducted at a selection of institutions around the country. "They are site visits intended to explore the institutions’ and the investigators’ understanding of the NIH guidelines to discuss what mechanisms and strategies they have in place for assuring compliance and maximizing patient safety," said Patterson.

Another new initiative is a series of Gene Transfer Safety Symposia, sponsored jointly by NIH and FDA. Among the topics to be discussed at these symposia will be data safety monitoring, cardiovascular complications of vector administration, good clinical practice in research, and entry criteria and informed consent for participants in gene therapy trials. The symposia are scheduled to be held four times a year; the first was presented in conjunction with the RAC meeting in March.

Finally, said Patterson, "We have been in very intense dialog with the FDA about safety reports that we’ve been receiving to assure that nothing has fallen through the cracks, that everything has been evaluated appropriately. . . . FDA lets us know every time they get an adverse event report or a reported change to a protocol. We in turn can check our records and see if we received the same report. If we have, that’s good, and we can discuss it with them. If we haven’t, then we can follow up with the investigator."

The intense media coverage surrounding the October death of Jesse Gelsinger in an adenovirus-related gene therapy trial at the University of Pennsylvania has resulted in a controversy that "has clearly brought gene therapy under microscopic study," said Verma. "All the blemishes and all the little warts are now being amplified, which in the long run will actually turn out to be a good thing. Reporting of adverse events is a good thing. If nothing else it builds the database to ask the question of what problem might exist with a given type of vector."

But Verma doubts that the current controversy will cause the NIH, the FDA, the scientific community, or the public to shy away from research in gene therapy. At most, said Verma, "I think it will refocus the question of where adenoviral vectors should be used. Perhaps for that vector it will slow down areas of research in specific diseases."



             
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