Failure to inform public is undermining confidence in clinical trials

Failure to fully inform the public about the involvement of participants in clinical trials is undermining confidence in the process–and in turn leading to a reduction in the number of studies involving humans.

That was the message from Dr Philip Noguchi, director of the Division of Cellular and Gene Therapies at the Food and Drug Administration, speaking at a recent meeting of the Regulatory Affairs Professional Society in Washington, DC. The credibility of clinical research in this country has been severely damaged,” he said.

The immediate trigger of the concern has been the conduct of gene therapy studies. “Of all the fields that the FDA regulates, gene therapy is the one which is in the public eye,” Dr Noguchi said. But the situation involves all clinical research.

He cited one widely publicised event, the death in 1999 of Jesse Gelsinger, an 18 year old participant in a gene therapy trial at the University of Pennsylvania. Gelsinger had ornithine transcarbamylase deficiency, a condition that prevents the liver from making the enzyme needed to break down ammonia. To reach the target cells in the liver the Philadelphia investigators packaged the gene in an adenovirus vector and injected it into his hepatic artery.

Four days later Gelsinger was dead, probably as the result of an abnormal response to the adenovirus followed by multiple organ failure. Gelsinger was a last minute substitute for another volunteer and probably should never have been enrolled in the trial at all, said Dr Noguchi. The event rocked the clinical research community and gave rise to widespread public concern over gene therapy studies as a whole.

There have been other “hard lessons,” said Dr Noguchi. In 2000 at Jude's Medical Center in Memphis, Tennessee, 20 children with neuroblastoma were given retroviral vectors contaminated by HIV and hepatitis C. Subsequent testing of the vectors by the FDA showed that the vectors were in fact uncontaminated. In the meantime the parents of the children had been alerted, but then to be told it was all a false alarm “is really little comfort to those involved,” Dr Noguchi said.

Also that year the FDA suspended gene therapy trials involving vascular endothelial growth factors at St Elizabeth's Medical Center in Boston, citing a series of violations, including enrolmentof ineligible patients, failure to follow the approved protocol, and failure to protect the welfare of participants.

Before 1999 between 40 and 60 new gene therapy investigations were approved annually by the FDA. Last year there were only 25, although this year the number is rising again, Dr Noguchi said.

He attributes the decline of public confidence in clinical research studies to a failure to fully inform the public about the trials. Assurance that a trial is being ethically conducted rests on disclosing as much information as possible about that trial, he argued. “If they don't know, they assume the worst. For the public to feel reassured, we need to be able to talk more clearly and transparently about what's really going on,” he said.

Yet, as an FDA officer, he is not allowed to discuss ongoing studies on the grounds that doing so involves proprietary information that, if it became public knowledge, could place the sponsor at a commercial disadvantage.

Last year the FDA proposed making public some of the details of ongoing trials. The proposal islimited to gene therapies and xenotransplantation, but it is quite likely to be extended to all clinical investigations. A recent court decision narrowed the definition of proprietary informationto the production process–how a product is made. It excludes ideas or study designs. As a result, when the rule becomes final it has a good chance of surviving any challenges. The proposal was wellreceived, said Dr Noguchi. “We got a lot of excellent comments.”

“The fundamental issue is that clinical trials are a privilege for our society to be able to do,” he added. “But for us to be able to continue trials so as to develop a way of treating currently untreatable diseases, there's a big quantum leap that needs to be taken. We're not at the end point here, we're at the beginning.”