BETHESDA, MD. _ An independent panel of scientists convened bythe National Institutes of Health (NIH) to review last year's fialuridine(FIAU) clinical trial disaster has concluded that the trial represented"the best of current practice in clinical investigations" and that thedrug's lethality could not have been predicted from preclinical studies.FIAU, a nucleoside analog to treat chronic hepatitis B, killed fivepatients out of 15 who enrolled in a Phase II clinical trial run by NIHphysicians between March and June of 1993. The drug was originallydeveloped as an AIDS therapy by Oclassen Pharmaceuticals Inc. of SanRafael, Calif., but was licensed to Eli Lilly & Co. of Indianapolis inAugust of 1992 as a treatment for hepatitis B.In a 41-page report released on Thursday at the biannual meeting of theNIH Director's Advisory Committee, a panel of seven NIH-appointedexperts concluded that there was a justifiable scientific rationale for theNIH FIAU studies, that the conduct of the trials "exceeded regulatoryrequirements where such applied," that the NIH's response to theunfolding medical crisis was appropriate and that FIAU caused a"novel type of toxic reaction not previously encountered" and thereforenot predictable.The panel reached its conclusions after six months of scrutinizing trialdocuments and interviewing physician investigators, protocol nursesand all 10 surviving FIAU patients from the Phase II trial. The group'sreport differs markedly in tone from a spate of warning letters sent bythe FDA to FIAU investigators and industry sponsors on May 11. Inthose letters, the FDA cited "significant violations" of federalregulations in the conduct of the FIAU trials and gave the recipients 15days to respond. Due to extensions, responses are now due to FDA byJune 29.In a report published in November 1993, the FDA concluded that acombination of loose adverse event reporting requirements andoptimism about FIAU had led investigators to miss spotting patterns oftoxicity seen in earlier FIAU trials. As a result, the agency plans totighten its adverse event reporting regulations.In addition to FDA warnings, questions about the FIAU trial havesparked congressional inquiries _ hearings on the subject are slatedfor later this summer _ and the Secretary of Health and HumanServices is negotiating a contract with the Institute of Medicine (IOM)to study the trial. Two families of patients who died have filed multi-million dollar lawsuits against the government and Eli Lilly claimingwrongful death.David Challoner, vice president for health affairs at the University ofFlorida in Gainesville and David Kipnis, professor at the WashingtonUniversity School of Medicine in St. Louis, co-chaired the NIH panelthat studied the FIAU trial. Both argued on Thursday that the "apparentdiscrepancies" between their review and the FDA's would likely beresolved once the matter was studied more closely.Richard Corlin, a San Diego physician and official of the AmericanMedical Association who served on the NIH panel, said that the FDAlooked primarily at whether statutory and regulatory deadlines for thefiling of paperwork were adhered to in the conduct of the FIAU trial. Inits letters to investigators, the FDA listed adverse events reported in thetrial in a way that implied a direct causal link to FIAU and thatsuggested the symptoms were new, he said.Patients Had Previously ReportedSymptomsIn fact, according to Corlin, matters were much less clear toinvestigators making judgment calls as the trial progressed. He saidmany of the symptoms cited in the FDA letters were symptoms thatpatients had complained about prior to receiving FIAU and thusphysicians would have had no way of distinguishing their relevance orlinking them to FIAU."With one exception, none of the (surviving FIAU) patients weinterviewed felt there was any lack of attentiveness to or any efforts tominimize symptoms on the part of the investigators in this trial," saidCorlin. Kipnis added that "classic audit techniques" used by the FDAare weak tools for evaluating complex "clinical judgments" such asthose made in the FIAU trial."The institutes and investigators have not yet had a chance to respondto the FDA letters and until you see their responses, you can't draw anyconclusions about whether the FDA is right," cautioned Challoner."There is a discussion to be had about the accuracy of the FDA's auditof this trial."Rep. Edolphus Towns (D-N.Y.), chairman of the House GovernmentOperations Committee's Subcommittee on Human Resources andIntergovernmental Relations, called the NIH report, "A whitewash of amedical negligence and patient mistreatment. The blatant contradictionin findings between the NIH and FDA confirms my prediction lastOctober that the NIH is simply not sufficiently removed fromculpability to evaluate impartially the tragic events that occurred."NIH director Harold Varmus told BioWorld that he stands by theconclusions of the NIH expert panel. "I asked our people to be veryindependent but I'm also aware that their independence may bechallenged," said Varmus. "Inevitably, in a world of increasingpolitical suspicion, an NIH-commissioned study of NIH activities maybe questioned. We'll just have to see what an additional level ofindependent reviewers at IOM concludes."Meanwhile, FDA spokesman Jim O'Hara, who had not yet seen a copyof the NIH report, said that the FDA also stands by its FIAU analyses."Reporting requirements and timetables are there to insure thatappropriate data is collected and to protect patients, and we expectinvestigators and sponsors to abide by those regulations," O'Hara toldBioWorld. "We found a failure to follow regulations and we stand byboth our November report and the letters sent on May 11."Whatever new insights congressional hearings and IOM review bring,Kipnis predicted that the FIAU trial will have profound consequencesfor the conduct of clinical research and the public perception ofexperimental drug trials. n

-- Lisa Piercey Washington Editor

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