WASHINGTON _ By next year, companies and investigatorsconducting clinical trials may need to comply with a hefty stack ofnew FDA regulations and procedures that will mean more completeand more frequent reporting of adverse events. The proposed rulesare apparently a direct response to the fialuridine (FIAU) clinicaltrial disaster.For the next 90 days, the FDA will receive public comment on itsproposal and a revised proposal and final regulation could bepublished anywhere from 90 days to a year after that. Experts saidthat the entire process could take up to two years.Some observers are already worrying that the FDA proposal willincrease the costs of clinical trials and slow drug development.Meanwhile, lawyers for the families of five patients who died in aPhase II trial of FIAU are pondering whether the rules will beadmissible in court as evidence of the inadequate regulationsgoverning clinical research.The new rules are based in part on the recommendations, made inNovember 1993, by an FDA task force that reviewed the tragedycaused by the experimental hepatitis B drug. The FIAU trial wasconducted by researchers at the National Institutes of Health (NIH),in cooperation with Eli Lilly & Co.FDA task force members concluded that changes were needed inadverse event reporting requirements because investigators in earlierPhase I and I/II trials of FIAU repeatedly failed to attribute patients'adverse experiences to the drug. But when the NIH appointed itsown panel of independent experts to investigate the FIAU affair,they reached a different conclusion.The NIH task force concluded that the trial represented "the best ofcurrent practice in clinical investigations" and that the drug'slethality could not have been detected from preclinical or earlierclinical studies. (See BioWorld Today, June 3, 1994, p. 1.) Onereason for this is that the adverse events that proved deadly in thetrial were liver toxicities, the same type of toxicities that mark thenatural progression of hepatitis B.When a drug's ill effects mimic that of a disease, investigators arehard-pressed to unravel what is going on. NIH investigators solvedthe FIAU mystery too late, after patients began dying."INo set of reporting requirements would have predicted whatoccurred with FIAU," Richard Corlin, a member of the NIH taskforce and vice speaker of the House of Delegates for the AmericanMedical Association (AMA), told BioWorld. Corlin said he had notread the new FDA rules and could not comment on them directly butthat his review of the FIAU case did not suggest that new regulationswere needed."Within a government bureaucracy there's a mindset that everyproblem needs a new set of regulations," he continued. "If there'ssome change in the reporting requirements that would enable us todetect patterns of toxicity not previously evident on a case-by-casebasis, that's fine. But we can run the risk of adding so muchpaperwork that running clinical trials becomes too expensive." "The records on adverse event reporting looked thorough andcomplete to us," agreed David Challoner, co-chairman of the NIHtask force and vice president of health affairs at the University ofFlorida in Gainesville. "I wouldn't have required any more intensereporting than what occurred. In fact, some of the safety testing thatwas done went way beyond the protocol." Challoner and his teaminterviewed all surviving patients from three clinical trials of FIAU,in addition to reviewing their medical charts.A `Knee-Jerk' ResponseCorlin praised the FDA for using the FIAU tragedy as a catalyst toreexamine its systems, "that's always a healthy impulse in medicineand in life," he said. But he expressed hope that the new rules did notrepresent "a knee-jerk response" to a problem that "ends upincreasing costs and discouraging research."A former high-ranking FDA official who asked not to be identifiedoffered a less charitable view of the new rules. "This is a typical[FDA Commisioner] David Kessler response," he told BioWorld."It's pure political correctness, pure grandstanding. These rules willmake the slowest, most conservative regulatory process in the entireworld even more so."The former FDA official told BioWorld that immediately followingthe FIAU disaster in June 1993, Kessler directed all agencyreviewers to automatically assume that all adverse events reported inongoing studies were drug-related. "Right away, he cranked up thestringency and ponderousness unnecessarily," he said. "Now, he'sjust written it in stone."The FIAU story is far from over. Due to the conflicting conclusionsof NIH and FDA panels on the subject, the Department of Health andHuman Services (HHS) has commissioned the Institute of Medicineto prepare a third report on the FIAU Phase II trial. In addition,congressional hearings are slated for next year. Edolphus Towns (D-N.Y.), chairman of the House Government Operations committee'ssubcommittee on Human Resources and IntergovernmentalRelations, called the NIH report a "whitewash of medical negligenceand patient mistreatment" when it was released last June. Towns willlead Capitol Hill's investigation of the FIAU affair.Several multi-million dollar lawsuits have been filed by families ofFIAU victims, representing an unprecedented challenge to thetraditional immunity of clinical trial researchers. The suits rely onlegal constructs of medical malpractice and product liability,applying them to the conduct of an experimental drug trial.Lisa Terry, an attorney from the Washington firm of Feldsman &Tucker, is part of a team representing the family of Carlton Lee, a35-year-old asymptomatic hepatitis B sufferer who died of liverfailure after taking FIAU. "Had these new regulations been in placeand complied with last year, the patients who died might be with ustoday," Terry told BioWorld.Terry said that the question on lawyers' minds is whether the FDA'sissuance of new rules can be used against the government in alawsuit. Lee's family filed a $30 million administrative claim againstHHS earlier this year and has not received a response. "In a sense,the FDA is saying that their prior regulations were inadequate," shesaid. "Clearly, they are trying to correct what happened."Terry said that her clients as well as other potential plaintiffs in theFIAU case have had discussions with Lilly about the terms of asettlement but have not yet reached agreement. A global settlementthat would involve damages paid by Lilly, the U.S. government andpossibly Oclassen Pharmaceuticals Inc. (the firm that licensed thedrug to Lilly) is the goal, she said.Corlin told BioWorld that AMA attorneys are watching the evolutionof the FIAU lawsuits with "great interest" and may jump into thelegal fray. "These suits are trying to equate informed consents inexperimental drug trials with product liability. That's a verydangerous and erroneous equation," he said. n
-- Lisa Piercey Washington Editor
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