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Review of 'Report to the Advisory Committee to the Director, National Institutes of Health'
Pages 121-132

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From page 121...
... . OBJECTIVE OF THE NIH REVIEW In October 1993, the then Acting Director of NIH asked a subset of his standing advisory committee of outside experts to conduct an independent, fact-finding review of the FIAU studies conducted at NIH.
From page 122...
... Were the Patients with HBV Infections Appropriate Candidates for the Second and Third NIH Trials of FIR U? The TOM committee agrees with the subcommittee's conclusion that the justification for developing Phase AT studies directly with patients with HBV infection was appropriate.
From page 123...
... An extensive review concluded that the range and duration of testing were appropriate for the proposed studies and that there was no prior evidence to suggest targeted hepatic or pancreatic toxicity. in a subsequent study reported by Eli Lilly on January 14, 1994, a threetimes-daily, oral Savage dosing study with 100 times the human dose in Fischer rats provided the first evidence of hepatotoxicity associated with lactic acidosis in a nonhuman test subject, but no elevations in AST or ALT levels were noted.
From page 124...
... No stones were found, and the patient developed intractable ascites and lactic acidosis. On evaluation by NIH investigators in December 1992, his liver enzyme levels were normal, but he was in liver failure.
From page 125...
... The IOM committee concurs with the NTH subcommittee that the sequence of development of FlAU was within existing guidelines and there is no evidence to suggest that fast-track development was a contributing factor to the untoward events induced by FlAU. Was the Third Study Accelerated by Pressure from Eli Lilly & Company?
From page 126...
... This included review of patient records and direct interviews with all 10 surviving patients, the investigators, the research nurses, the chairs of the two involved IRBs, the institute directors, and the acting director of the Clinical Center. The subcommittee was satisfied that the patients were provided full, informed consent and were impressed by the teamwork between investigators and staff.
From page 127...
... Question 4- Could the Adverse Events Have Been Avoided, Particularly in the IJast Study? The subcommittee considered it unlikely that changes in the research protocol or additional testing in animals or humans would have provided signals that would have delayed or prevented use of FlAU in patients with chronic HBV infection.
From page 128...
... Following licensure to Eli Lilly, a 1 00-fold more sensitive assay, the RIA, was developed in June 1993 and was used to estimate a half-life of 29 hours rather than the 1-4 hours estimated previously. The IOM committee concurs with the NIH subcommittee that even if information from the RIA had been available before implementation of the final protocol, it would not have changed the study design or focused attention on hepatic or pancreatic toxicity.
From page 129...
... Conversely, if the studies had proceeded along less rigorously controlled conditions, it is probable that a major disaster involving large numbers of subjects would have occurred in the Phase IT} studies that were about to be implemented. "Delayed, fatal human toxicity due to FlAU represents a novel type of toxic reaction not previously encountered." , ~ , ~ ]
From page 130...
... The lOM committee strongly endorses the need for further research to more clearly understand the mechanisms involved in FIAU toxicity. This is clearly vital not only for antiviral drug development but also for gene transfer studies.
From page 131...
... Patient Enrollment As noted previously, the subcommittee recommended that when patients were entered into Phase ~ or Phase IT clinical trials of drugs with the potential for entering or modifying nuclear or mitochondrial DNA, there should be a delay between recruitment of each cohort to minimize the chance that many patients would be at risk of delayed toxicity if it should occur. The TOM committee suggests extending this recommendation of staggered entry to any study that involves prolonged therapy (i.e., 6 months or more)
From page 132...
... There is a need to maintain flexibility in study design and tailor protocols for specific drugs to specific clinical situations.


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