WASHINGTON _ The Institute of Medicine (IOM) has concludedthat although precautions to protect patients from harm duringexperimental drug trials are "exemplary and effective," they willnever render the process risk-free.

IOM, a private, non-profit organization that provides health policyadvice under a congressional charter, was commissioned by Healthand Human Services Secretary Donna Shalala last year to analyze thefialuridine (FIAU) clinical trial disaster that killed five people in1993. FIAU, an experimental drug that had shown promise in treatinghepatitis B in early clinical trials, ended up causing liver failure inseven patients who received it during a Phase II trial. Five of thosepatients died.

"An elaborate system is in place to protect patients during clinicaltrials and serious harm is rare," said IOM committee chairmanMorton Swartz, a professor of medicine at Harvard University inBoston and emeritus chief of infectious diseases at MassachusettsGeneral Hospital. "In this case, researchers were blind-sided byFIAU's toxic effects on the liver. The researchers did everything theycould to protect the lives of these patients, but even so, that's coldcomfort to the families of those who died."

The FIAU deaths prompted investigations by both the FDA, whichhad oversight responsibilities for the trial under an investigationalnew drug application filed by Eli Lilly & Co., and by the NationalInstitutes of Health (NIH), the government agency which employedthe principal investigators running the trial. FIAU was licensed byIndianapolis-based Lilly in 1992 from the privately heldbiotechnology company, Oclassen Pharmaceuticals Inc., based in SanRafael, Calif.

The IOM's conclusions appeared to fall closer to the NIH's study ofthe FIAU trial, which found it to be an example of high qualityclinical research, than to the FDA's assessment, which found thatLilly, Oclassen and several researchers had violated agency rules.

As a direct result of the FIAU tragedy, the FDA issued extensive newadverse event reporting rules for experimental drug trials. (SeeBioWorld Today, Special News Bulletin, Oct. 28, 1994 and Oct. 31,p. 1.) Among those new rules was the adoption of a "worst-caseassumption" for all adverse events observed in early trials. Such anapproach would assume all adverse reactions to be drug-related,unless proven otherwise.

"The committee concurred with the judgments of NIH, and agreed inprinciple with nearly all of FDA's recommendations," stated thereport. "The committee strongly disagreed, however, with FDA's callfor treating all adverse health events in trial patients as related toexperimental drugs. This provision could sharply increase the numberof drugs abandoned early in the development process that, in fact,with further testing and development, could be shown to be botheffective and safe."

Fine-Tune Early-Stage Clinical Trials

Although the IOM report authors, seven independent medicalexperts, said they found no evidence of negligence or carelessness onthe part of FIAU's developers or investigators, they nonethelessissued recommendations for "fine-tuning" the conduct of early-stageclinical trials.

"Although the IOM committee's recommendations are focused onconduct of Phase I and Phase II trials, they do not stem fromperceived deficiencies in the conduct of the investigators or sponsorsin the FIAU studies," stated the report. "As already noted, nodeficiencies were identified."

Following that lukewarm endorsement, however, was a list of 15recommendations. Among the changes proposed were:

* establishment of a system of no-fault compensation for researchinjury by government, sponsors, or some combination of both(several families of the deceased FIAU trial participants have filedsuit against Lilly, Oclassen and the NIH seeking damages for"wrongful death");

* explicit training of all clinical researchers not only on the conductand design of clinical trials and ethical obligations to patients but alsoon legal and regulatory obligations to both the sponsor and the FDA;

* independent safety monitoring of all trials that treat patients forextended periods (the ill-fated FIAU trial involved a six-monthcourse of therapy), especially for all double-blind trials and in anytrial in which there is reason to anticipate that adverse drug reactionscould be confused with disease progression or therapeutic response;

* use of placebo, standard therapy or historical controls wheneverpossible for Phase II studies, particularly in trials involving extendedtreatment (the FIAU trial was uncontrolled);

* explicit prospective criteria to help distinguish between adverseevents related to drug treatment and changes in the underlyingdisease;

* a section in protocols that explicitly addresses determination of thefollow-up period of studies, and, for drugs suspected of modifyingnucleic acids or associated macromolecules, a requirement for sixmonths of follow-up;

* continuing real-time evaluation of all adverse event data rather thanonly after completion of all case report forms for all patients;

* cumulative adverse event reporting accompanied by the sponsor'sexplanation of each event, but not based on a "worst caseassumption" as proposed by the FDA;

* establishment of an appeal process, independent of the FDA,whereby researchers and sponsors who feel they have been unfairlycensured by the agency may argue their case;

* preclinical testing in a least two different species of animals, usingthe same route of administration intended for use in patients and aduration of treatment at least as long as that intended for clinicaltrials.

In its conclusions, the IOM report warned against knee-jerkregulatory responses to rare incidents. "The failure of the public toappreciate the risks of research in the field of drug developmentcompounded with a strong tendency to affix blame on those whocarry out the trials when something goes wrong creates a risk for thefuture of clinical research," stated the report. n

-- Lisa Piercey Washington Editor

(c) 1997 American Health Consultants. All rights reserved.