NIH Issues New Rules on Oversight and Reporting of Safety Problems in Gene-Therapy
Trials
By JEFFREY BRAINARD
The National Institutes of Health issued new rules on Monday aimed at improving
oversight and public disclosure of safety problems in gene-therapy trials.
The changes follow criticism that inadequacies in safety oversight contributed
to the 1999 death of Jesse Gelsinger, a research volunteer in an experiment
at the University of Pennsylvania.
In a key change, the agency will establish a national committee to review
the safety of gene-therapy experiments. These studies involve inserting DNA
into patients to repair damaged genes, or replace missing ones, that result
in illnesses. The new committee will review reports of serious medical complications
and deaths from gene-therapy experiments around the nation to determine if
they indicate a common pattern of safety problems.
In its announcement in Monday's Federal Register, the agency also requested
further public comment on another proposed change that would relax somewhat
the NIH's existing guidelines requiring researchers to promptly report safety
problems, known as "adverse events." This proposal would make the NIH's reporting
requirements similar to those of the Food and Drug Administration -- a change
sought by researchers who said it would promote simplicity. The agency has
invited public comment until December 19 on that idea.
The new safety board is a response to complaints about the oversight of gene-therapy
trials. The criticism erupted after Mr. Gelsinger died at the University of
Pennsylvania in 1999, the first death ascribed directly to a gene-therapy
treatment itself and not to an underlying disease. The regulations have been
winding their way through the NIH and federal bureaucracy since then.
In the months after Mr. Gelsinger's death, the NIH discovered that gene-therapy
researchers had widely underreported adverse events. Scientists said that
the reporting requirements were vague, and that the agency did not seem to
analyze or use the data systematically. Meanwhile, patient advocates argued
that the public had no easy way to find out about the adverse-event reports
or what they meant.
For the past decade, the NIH's Recombinant DNA Advisory Committee has evaluated
proposed gene-therapy studies -- including the one involving Mr. Gelsinger,
who suffered from a liver ailment caused by a missing gene -- before they
begin. Researchers meanwhile also had to report the same safety information
to the FDA. But the FDA's regulations require it to keep the information secret,
to protect the business interests of the research sponsors. (In December,
the FDA published a proposal to make public such information, but the agency
has not yet followed up.)
The NIH's new safety panel -- to be called the NIH Gene Transfer Safety
Assessment Board -- will be a subcommittee of the Recombinant DNA Advisory
Committee, or RAC. It will analyze safety trends in the approximately 360
gene-therapy studies now under way nationwide, and will provide summaries
of its findings to the full committee for discussion. The RAC has no power
to stop trials, but, unlike the FDA, these meetings will be held in public.
The summaries about safety trends will be posted on an NIH online database
that is scheduled to enter pilot testing next summer. The agency will remove
identifying information about individual patients.
The changes reflect the NIH's belief that "whenever a patient gets enrolled
in a trial, their experience counts," said Amy P. Patterson, director of the
NIH's Office of Biotechnology Activities, which monitors gene-therapy studies.
In Monday's announcement, the NIH clarified existing regulations to say that
the agency expects research sponsors -- which are usually pharmaceutical companies
-- to submit adverse-event reports even if they contain information that a
sponsor considers to be confidential, commercial information. Some companies
had asked the NIH to keep the reports secret, arguing that publicizing them
could allow competitors to replicate their research. Dr. Patterson said the
agency would consider requests for exceptions on a case-by-case basis.
The NIH is holding off on another change that would loosen requirements on
the timing of adverse-event reports. Now, researchers are required to make
the reports "immediately," although there is no specific deadline. Under the
proposal, researchers would have to report within 15 days all unexpected,
serious adverse events -- such as deaths, life-threatening complications,
and other major side effects -- that appear to be related to the experimental
gene-therapy treatment. Scientists would have to report all other adverse
events within one year. In addition, they would have to report any gene-therapy
studies of animals that suggested the therapy posed significant risks for
humans.
The agency had proposed similar wording in December; Monday's announcement
included some fine-tuning, which triggered another round of public comment
on this provision only. Some critics have worried that the proposed change
in reporting requirements might lead the NIH's safety-assessment board to
overlook problems that, viewed individually, did not seem serious, but that
collectively suggested danger.
Dr. Patterson said the change in reporting requirements would allow NIH officials
and the safety panel to focus their attention on the most serious potential
problems. The NIH has received 3,700 adverse-event reports since 1989, most
of them since Mr. Gelsinger's death in 1999, and many scientists have wondered
whether the NIH and the Recombinant DNA Advisory Committee have the ability
to make sense of all of that information.
Under the proposed change, the NIH estimated it would receive only 120 reports
of serious adverse events yearly. "People felt there needed to be a triaging
of effort at the local and federal level," Dr. Patterson said. She added that
the safety-assessment board will also systematically review all adverse-event
reports to look for safety patterns, and for ways to improve the efficacy
of experimental treatments.
Still, Alan Milstein, a Philadelphia lawyer who represented Mr. Gelsinger's
father in a lawsuit against the University of Pennsylvania, said that the
NIH may be relying too much on the willingness of a research team to categorize
and report health problems as adverse events. Researchers face conflicts of
interest, and reporting problems "should be a decision by someone other than
the researcher," he said.
