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NIH Not Told Of Deaths in Gene Studies
Researchers, Companies Kept Agency in the Dark

By Deborah Nelson and Rick Weiss
Washington Post Staff Writers
Wednesday, November 3, 1999; Page A01

Scientists and drug companies have failed to notify the National Institutes of Health about six deaths that occurred in gene therapy experiments in the past 19 months, keeping details of the deaths from becoming public, according to interviews with researchers and federal officials.

The deaths are the first in gene therapy to come to light that were purposely withheld from the NIH, one of two federal agencies charged with overseeing the safety of the controversial field of medical research, which seeks to cure diseases by giving patients new genes.

The lack of disclosure provides new evidence of a shift toward secrecy in gene therapy, traditionally one of the more open fields of medical research, and reflects escalating efforts by gene therapy companies to weaken federal reporting regulations.

Confirmation of the six deaths follows revelations last week of a death and two serious illnesses in gene therapy patients that were reported to the NIH with the unprecedented insistence that they be kept confidential, in defiance of a long-standing agency policy of public disclosure.

The six deaths occurred in heart studies headed by two leading gene researchers--Ronald Crystal of the New York Hospital-Cornell Medical Center in Manhattan and Jeffrey Isner of Tufts University in Boston. The two are racing to be the first to grow new blood vessels around blocked ones as an alternative to bypass surgery.

Crystal and Isner said that, unlike the widely reported death of a teenage patient at the University of Pennsylvania in September, they believe that the fatalities in their studies were not directly caused by the gene therapy but by complications stemming from the patients' underlying illnesses.

Because they decided the deaths weren't caused by gene therapy, they argued, federal regulations don't require them to notify the NIH--a new interpretation of those regulations that stands in sharp contrast to the one held by NIH officials and a decade of practice.

The researchers said they reported the deaths to the Food and Drug Administration, which keeps such information secret.

But NIH officials in the federal office that oversees gene therapy are adamant that even deaths not initially believed to have been caused by the therapy must be reported to the NIH and made public, because often it is not clear until later whether the therapy actually caused the deaths.

"It may take five, six, seven patients ill, or 20 patients, before you find out, 'Hey, this is also happening in other people's trials,' " said Amy Patterson, who heads the NIH Office of Recombinant DNA Activities (ORDA), which oversees gene therapy studies. "And if you don't know what's going on in other people's trials, then you can't put two and two together."

The FDA can suspend a study if it determines that the therapy being tested is dangerous, but the agency only makes such information public if the therapy eventually is approved or with the permission of the study's sponsor.

Most of the new deaths are coming to light only because federal officials put out a plea for gene researchers across the country to report any undisclosed deaths or illnesses, after the death of the teenager at the University of Pennsylvania. His death is thought to be the first directly caused by gene therapy, and NIH officials are looking for indications of similar problems in other studies that may not have been attributed to the treatments themselves.

Carol Goodrich, a spokeswoman for Parke-Davis, which is sponsoring Crystal's study, said the company had forwarded details of the deaths to ORDA on Oct. 20. She said the deaths had previously been reported to the FDA, but she refused to say whether that agency had agreed with the company's determination that the deaths were not caused by the therapy. The FDA has not decided whether to fulfill a Washington Post request to release information about deaths and illnesses in gene therapy trials.

Federal regulations have long held genetic treatments to a higher level of public scrutiny than conventional new therapies because of public discomfort with the idea of manipulating people's genetic makeup.

For example, federal regulations require researchers to report the deaths and serious illnesses of patients enrolled in gene therapy experiments not only to the FDA, but also to the NIH for public review by a special advisory board.

But as the field has become increasingly dominated by private industry, drug companies and scientists with a financial stake in their research are challenging the historically broad interpretation of that rule. They are filing reports with demands for confidentiality or maintaining that they don't have to file them with the NIH at all.

Isner and Crystal helped found competing gene therapy companies--Vascular Genetics of Durham, N.C., and GenVec of Rockville, respectively.

Asked why he hadn't reported his deaths to the NIH, Isner said yesterday that it was an oversight and, in any case, it was not clear that he had to.

Crystal said Parke-Davis has assumed responsibility for reporting deaths to the appropriate agencies. However, he added that while he supported the reporting of deaths and illnesses to the NIH, he did not consider it a legal requirement. He also said he believed that the NIH should keep some reports confidential, particularly to protect patient privacy.

Both researchers said they have discussed some of the deaths at scientific meetings and in professional journals.

Crystal was the first to request confidentiality from the NIH for a patient death report, in May 1998, just two weeks after GenVec announced its initial public offering of stock. NIH staff said yesterday that, at the time, Crystal cited concerns about the impact on his business if the death were made public. In the past week, Crystal has said the public offering had no bearing on his confidentiality request and has offered varying reasons for that request--including a need to study the death further and concerns about patient confidentiality.

The issue of confidentiality requests surfaced at the September meeting of the Recombinant DNA Advisory Committee (RAC), the NIH group that reviews gene therapy experiments and collects reports of serious side-effects and deaths.

In addition to Crystal, RAC members learned, Schering-Plough had demanded confidentiality for three recently filed reports of serious patient illness during gene therapy trials. The lead scientists in two of those studies determined that the complications "probably" were caused by the gene therapy; Schering-Plough officials had downgraded those assessments, saying they were "possibly related" to the therapy.

In the third case, the researchers and the company agreed that the complications "possibly" were related to the therapy.

This week, Schering-Plough, of Madison, N.J., issued a statement defending its recent requests that the NIH keep the illnesses of three patients confidential. Company officials and others are expected to make their case for more confidentiality at a December RAC meeting, where the NIH will seek to clarify its reporting guidelines.

© Copyright 1999 The Washington Post Company

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