(Circulation. 2001;103:e9001.)
© 2001 American Heart Association, Inc.
Cardiovascular News
Gene Therapists Promise Renewed Vigor in Monitoring as Field Progresses
The immediate past president of the American Society of Gene Therapy promised to seek "equitable solutions" to issues of reporting and conflict of interest "so that gene therapy is effective, safe, and as common as immunization is today." Savio Woo, PhD, director of the Institute for Gene Therapy at Mount Sinai School of Medicine in New York City noted, "Patients deserve new and better treatments that are effective and safe."
Dr Woo and other prominent figures in the nation’s gene therapy field spoke at the American Heart Association’s Scientific Sessions 2000 from November 12 through 15, 2000, in New Orleans. Nearly a month later, the federal government published proposed rules that would resolve conflicts over which adverse reactions from gene therapy should be published and in what detail, according to the Washington Post (December 13, 2000). Those who advocate for patients want all adverse events reported and made public. Companies are loath to do so because such reports can adversely affect their profits, and researchers feel hampered by regulations that impede their ability to do research.
The federal government sought a compromise among the factions. Since gene therapy began more than a decade ago, the advisory committee to the National Institutes of Health (NIH) has required that all serious adverse events be reported to it immediately. However, that conflicted with the US Food and Drug Administration’s (FDA) requirement that only serious adverse events believed to be associated with the treatment itself be reported immediately.
Under the proposed rule, the federal government would require immediate reporting of only the adverse events believed associated with the experimental treatment—the FDA’s requirement, the Post reported. Those reports, however, would get extra attention by the advisory panel to the director of the NIH. Other adverse events would be reported in an annual summary. Those with concerns about the proposed rule, which is published in the December 12, 2000, issue of the Federal Register, can comment on it through February 10, 2001.
The rules came about because of what Dr Woo called "an extraordinary year for gene therapy." The year 1999 saw the first loss of a patient as a result of the gene therapy—Jesse Gelsinger, 19, who died after undergoing gene therapy at the University of Pennsylvania School of Medicine for a mild form of a genetic disease.
"The investigators reported the incident to the FDA and the RAC (the advisory committee on gene therapy), as required by federal regulations and guidelines," said Dr Woo. "In contrast to the widely presumed cause of death, subsequent pathological analysis showed the cause was multiorgan failure." The organ failure was the body’s response to the viral vector used to take the gene into the body.
In response to this, the RAC has proposed that viral vectors using disarmed adenoviruses should be given only to patients with terminal diseases. "Apparently, there were multiple protocol violations," said Dr Woo. As a result, all such trials at the University of Pennsylvania were put on clinical hold for a period of time.
At the same time, the RAC began to gather information on all adverse events associated with gene therapy studies. To the committee’s surprise, only 6% of adverse events were reported to the RAC. "Massive underreporting has become a massive concern to agencies and the Congress," said Dr Woo. It occurred because researchers believed they no longer had to report such information to the NIH committee after it lost its authority to approve new gene therapy studies. That approval authority went to the FDA alone. Other researchers thought they only had to report events related directly to the therapy itself.
"These were only explanations, not excuses," said Dr Woo. In response, the American Society of Gene Therapy and its 2500 members agreed to a policy that requires members to adhere to the regulations in place for the field. "It is important to maintain public credibility."
"Another area of major concern to everyone is the real and perceived financial conflict of interest among investigators conducting clinical studies," he said. In one instance, an investigator conducted trials sponsored by a company that the investigator himself owned. In response, the American Society of Gene Therapy has adopted a policy that all investigators and team members directly responsible for selecting patients, obtaining informed consent, and caring for the patients during the study must not own equity or have stock options or similar arrangements in the companies supporting the study. "We have asked all our members to go along with it," said Dr Woo.
"During the past decade there has been enormous progress in the basic science of gene transfer and animal studies. These are serious setbacks. We need to reach an equitable solution and then move forward so we can reach our goals," said Dr Woo.
SmithKline Beecham Halts Tests of Lotrafiban, an Oral Glycoprotein IIb/IIIa Inhibitor
In an action that calls into question the fate of oral glycoprotein IIb/IIIa inhibitors, SmithKline Beecham announced December 12, 2000, that it was halting clinical tests of lotrafiban. In a terse press release, the company merely said that its Phase III study designed to test the ability of the drug to prevent recurrent strokes and heart attacks was being halted on the advice of the data and safety monitoring board, "which found a lack of efficacy and raised safety concerns."
However, the Associated Press reported that the group taking the experimental medication had an unexpectedly high mortality rate of 2.7%. The death rate in the control group was 2%. According to the Associated Press, Eric Topol, MD, the Cleveland Clinic researcher who directed the trial, said that the problems "were totally unexpected." The wire service said that 4% of patients who received the drug suffered major bleeding, while only 1% of the control patients suffered such bleeding. The trial involved >9000 participants, and all were told to stop taking the study medication. This was not the first study to report disappointing results from the use of oral glycoprotein IIb/IIIa inhibitors.
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