After reviewing data from a clinical trial that killed five people,an FDA task force has proposed sweeping changes in thedesign, analysis and reporting of clinical studies conductedunder investigational new drug applications.
In a report issued this week, the task force concluded thatresearchersU optimism about fialuridine's (FIAU) efficacy ledthem to evaluate adverse events in positive terms instead ofconducting Rworst-caseS analyses that might have allowed themto discover a pattern of toxicity. As a result, the task forcerecommended increased requirements for reporting adverseeffects and new, more stringent rules that would requireclinical trial investigators to assume that toxicities reported bypatients in drug trials are drug-related.
The task force was assigned to review data from clinical trialsof FIAU, an experimental drug believed to have potential forthe treatment of chronic hepatitis B. Eli Lilly & Co. ofIndianapolis licensed the compound from OclassenPharmaceuticals Inc. of San Rafael, Calif., in August 1992.
Five patients in a 15-patient Phase II trial died from liverfailure as a result of taking FIAU, a tragedy that has promptedthree separate investigations of the drugUs clinical history. TheFDA task force's 90-page report is the first of the three to bemade public. Still to come will be an internal review currentlyunder way by the National Institutes of Health (where thePhase II trial was conducted by lead NIH investigators JayHoofnagle and Stephen Straus). In addition, a congressionalsubcommittee is researching the conduct of the trial todetermine whether public hearings are warranted.
FDA Commissioner David Kessler told the Washington Post thatthe agency has already begun the process of adopting the taskforceUs recommendations.
According to FDA spokeswoman June Wyman, the agencyintends to write letters follow-up letters to investigatorsinvolved in the Phase II trial of FIAU, as well as to thoseinvolved in earlier Phase I and pilot studies of the drug. Shesaid the letters, which will be made public, will Raddresswhether or not individual researchers followed current FDArules in reporting serious adverse events.S
The report concluded that researchers failed to note FIAUUstoxicity in part because the drugUs ill effects on the livermimicked those of hepatitis B. As a result, the task force maderecommendations to tighten adverse-event tracking andclinical trial design so as to better detect such elusive toxicities.
The task force recommended that drug sponsors should:
-- Prospectively identify drug toxicity endpoints that target thesame organs/body systems as the underlying disease beingtreated in the study.
-- Presume that any events related to identified endpointsrepresent drug toxicity and report them as such in investigatorbrochures and informed consent documents unless aRcompelling counter-argumentS is accepted by the FDA.
-- Report all expected and unexpected deaths, serious adverseexperiences and discontinuations that occur in a given trialwithin six months of the last dose of the study drug (instead ofonce a year as current rules stipulate).
-- Perform a Rworst-caseS analysis of all adverse event datathat assumes the investigational drug is responsible, and thenrefute that assumption with appropriate data and evaluationssubmitted to FDA.
-- Lisa Piercey Business Editor
(c) 1997 American Health Consultants. All rights reserved.