By Susan Levine

The U.S. Food and Drug Administration has found a systemic breakdown in communication and operation of the Johns Hopkins University review boards charged with oversight of clinical trials involving human subjects, according to documents released September 7.

Agency inspectors said there was no evidence that board members' questions about research applications were ever sent to the researchers involved. It also appeared that board members with conflicts of interest in applications being reviewed did not always abstain from voting on those proposals.

"There was a systemic problem in the whole oversight scheme," said David Lepay, the FDA's senior adviser for clinical science. "We had significant concerns."

The FDA documents reflect in narrower scope the malfunction that government regulators have identified throughout the university's medical research program after a healthy young volunteer's death during an asthma study in June.

In late July, that triggered a brief suspension of all of Hopkins's federally supported medical research with human participants -- 2,800 clinical trials involving more than $300 million.

The FDA and the Office for Human Research Protections are conducting inquiries into 24-year-old Ellen Roche's death. Both are part of the federal Department of Health and Human Services.

The FDA's latest findings center on two institutional review boards, including the one that approved the protocol in which Roche enrolled at Hopkins's Bayview Medical Center.

Because the boards' actions were documented so poorly, the extent of the problem might not be clear even in hindsight, Lepay said. Even with meeting minutes and audiotape, inspectors could not reconstruct what happened during those boards' deliberations and resolve discrepancies, he said.

Much of the time, applications were reviewed only by individual members or subcommittees, inspectors found. They were not discussed and considered by the review boards as a whole, and dozens of applications might have been were approved by a one-time vote.

Unlike the Office for Human Research Protections, which clamped harsh restrictions on Hopkins scientists even after lifting its four-day suspension, the FDA has not taken action against the university.

A final report by FDA inspectors will not be sent to agency headquarters for several weeks. Though punitive measures could be imposed, they seem unlikely given Lepay's praise yesterday afternoon for the changes university officials are implementing.

In contrast to Hopkins's early denial of problems, "we do feel that Hopkins is now taking this very seriously," he said.

In a statement yesterday evening, Chi Dang, a vice dean at the university's medical school, said the FDA's findings provide guidance "to further improve our processes for conducting research involving human volunteers." The issues documented are those "that Hopkins has been reviewing and addressing throughout the summer."

Hopkins has already moved to double the number of review boards at its medical centers; strengthened training for board members and faculty in the regulations governing clinical trials; and implement a meeting review process to require full discussion and documentation by review boards.

Roche died of acute respiratory distress less than a month after inhaling hexamethonium. The chemical was central to a clinical trial focused on why the airways of healthy people such as Roche remain open after exposure to allergens and other irritants.

After Roche's death, Hopkins was buffeted by scathing criticism of research at its hospitals and affiliates, as well as work by a faculty member as far afield as India.

In late August, the Maryland Court of Appeals allowed lawsuits to proceed against the Kennedy Krieger Institute over a lead paint study in low-income Baltimore neighborhoods.

The judges said participants in the study, which was overseen by a Hopkins board, were purposely misled about the dangers involved. After the court ruling, the Office for Human Research Protections opened a second Hopkins investigation.

Washington Post September 8, 2001; Page B02