WASHINGTON Reports in January about questionablefederally funded radiation experiments in humans have led tothe creation of presidential commissions and congressionalhearings, putting a spotlight once again on the imperfect yetcritical science of clinical research.However, at a meeting of the Congressional BiomedicalResearch Caucus here on Monday, an ethicist, a physicianresearcher and a top National Institutes of Health (NIH)official told legislators that despite some high-profilemistakes, the conduct of experimental studies in humans hasimproved vastly in the past 20 years.Some researchers are worried that lawmakers, in an attempt toaddress wrongs perpetrated by a handful of unethicalinvestigators in the past, will impose more layers of regulatoryreview on the conduct of clinical trials."Don't legislate clinical research out of business," warnedJules Hirsch, a physician-researcher from RockefellerUniversity Hospital in New York. "We need clinical scholarsin our war against disease and we must test new therapies inhumans."Hirsch said that biomedical research was at high tide due tothe near-complete mapping of the human genome. He saidthat the role of innovator once played by universities is nowbeing played by biotechnology companies that initiate andfund clinical trials of new biologicals at a breakneck pace.Despite scientific advances in curing disease, "a cloud ofsuspicion has been cast over biomedical researchers," AlbertJonsen, chairman of the Department of Medical History andEthics at the University of Washington School of Medicine inSeattle, told legislators. Jonsen said that infamous examples ofabuse such as experiments Nazi physicians performed onconcentration camp prisoners in World War II, the 40-yearTuskegee Study (1932-72) of untreated syphilis in black menin Macon County, Ala., and the recent radiation experimentshave led to strict regulations that protect the rights of researchsubjects and limit the rights of investigators.The establishment in 1974 of the National Commission for theProtection of Human Subjects for Biomedical and BehavioralResearch revolutionized clinical research, according toJonsen. Before commission-sponsored regulations werepassed, the conduct of trials was dependent upon the privateconscience of investigators.Now issues such as the informed consent of research subjects,lie in the hands of institutional review boards (IRBs) at eachindividual site where human research takes place. "Theestablishment of IRBs involved thousands of people in theprocess of clinical research," said Jonsen. "Investigators nolonger live in their own private world."Gary Ellis, director of the NIH¿s Office for Protection fromResearch Risks (OPRR), agreed that IRBs are the "cornerstoneof the American system of protection of human subjects."IRBs are, by federal regulation, composed of a minimum offive people, including at least one scientist, one non-scientistand one person not affiliated with the research institution.According to Ellis, IRBs provide the best quality control onclinical research because they are composed of individualswho know the resources of the local research institution, thecapabilities and reputations of its investigators and staff, andthe prevailing values and ethics of the community and likelysubject population.Ellis said that federal regulations have created a system inwhich research subjects are protected by a "chain ofjudgments" that begins with that of the volunteer researchsubject, and is then reviewed by the principal investigator, theIRB, officials from the research institution, a scientific reviewgroup, and executive officials from the entity that funds thetrial."What is the possibility of a catastrophic failure in humanjudgment running through six or more layers?" asked Ellis. "Iwould characterize that possibility as remote." If such a failuredoes occur, OPRR and Congress have powers of oversight.Ellis said that the federal government is currently fundingroughly 15,000 studies in human subjects at 1,000 separateresearch institutions. Of those 15,000 studies, 57 are beingactively investigated for compliance with federal regulationsby the NIH's OPRR.Ellis declined to comment on the recent Phase II trial of theexperimental hepatitis B drug, fialuridine (FIAU), whichunexpectedly killed five patients last year. He did say that thetrial was not currently one of the 57 under investigation byOPRR, but that it could be in the future.An FDA report on the FIAU study concluded that clinicalinvestigators were too quick to attribute adverse events inpatients enrolled in the trial to causes other than the studydrug. The report said that the researchers may have beenmisled by their optimism about the drug and thus failed torecognize patterns of toxicity that surfaced in pilot studies ofthe nucleoside analog.A follow-up FDA review of the actions of the principal FIAUinvestigators and their compliance with federal regulations isexpected in the next few weeks. Although an internal NIHinvestigation concluded that the researchers followedregulations, NIH Director Harold Varmus has ordered anadvisory committee to review the conduct of the trial.Ellis said that once the NIH director's study and the FDAstudy are complete, OPRR will review all of the data anddecide whether a formal review is warranted.

-- Lisa Piercey Washington Editor

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