Review of the Fialuridine (FIAU) Clinical Trials (1995) / Chapter Skim
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Executive Summary
Executive Summary
Pages 1-15
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failure, despite only mild jaundice and minimal changes in the aminotransferase measures which generally signal liver damage; severe and rapidly progressing accumulation of lactic acid in the blood (lactic acidosis) ; inflammation of the pancreas to varying degrees (pancreatitis)
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With acute HBV infection patients are frequently fatigued, jaundiced, and complain of abdominal pain. The vast majority of 300,000 persons infected with HBV each year in the U.S.
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HBV infection has also been linked epidemiologically to the development of liver cancer; in males with perinatally acquired infection, life-long risk of development of hepatocellular carcinoma is 40 to 60 percent. An important feature of chronic HBV infection involves the spontaneous loss of viral replication seen in 2.5 to 25% of patients.
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. OCLASSEN CLINICAL TRIAL R89-001-01 This evaluation of the effects of FIAC for treatment of CMV infection in HIV-positive individuals was developed by Oclassen Pharmaceuticals in conjunction with the AIDS Clinical Trials Group (ACTG)
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Like Richman and Corey, Straus had been integrally involved in the development of drugs designed to treat human herpes virus infections, such as vidarabine and acyclovir. Striking reductions in circulating hepatitis B DNA were noted in most patients, with the majority of patients showing decreases in their circulating HBV DNA values to less than the lower limits of the measurement technology.
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The committee concluded that this was a carefully performed study which underwent extensive internal and external review, employed a novel real-time data monitoring system and produced convincing evidence of anti-HBV activity at doses of FIAU producing few adverse effects. Although the deaths of three of the four patients receiving two courses of FTAU treatment caused the committee concern, we concluded that even in retrospect underlying disease and/or more recent medications were more plausible causes of death than FlAU toxicity in each case.
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At the New England Medical Center Site FlAU was administered to a total of only two patients, for periods of 28 and 55 days. One patient noted leg pain and numbness beginning 3-4 months after stopping FIAU therapy.
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Pharmacokinetic measurements performed on blood and urine samples after the RIA was validated in June revealed more rapid absorption of FIAU in syrup than in tablet form, with food generally decreasing the rate of absorption, and a prolonged elimination phase with a terminal half-life of 28-30 hours. Adverse events noted included diarrhea, headache, transient myalgia, and in two cases, transaminase elevations.
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When one of these three developed lactic acidosis, hepatic failure and renal failure on June 25th, prior experience with a single puzzling patient from trial R91 (patient 4D) made the investigators consider FlAU a likely cause.
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Perhaps the most important generalization that can be drawn is that the patients' reports of the informed consent process and their satisfaction with their treatment by the study staff are closely associated with their current health. The 3 subjects interviewed who reported currently suffering from peripheral neuropathy, two of whom were in the R-91 trial and the other in PPPA, all felt that the risk of side effects had been minimized in their discussion of the informed consent documents.
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We agree as well with the conclusions of their review of the preclinical toxicology data that the range and duration of testing was appropriate for the proposed studies and that there was no prior evidence to suggest hepatic or pancreatic toxicity. Like the IOM committee, the NIH subcommittee found no evidence that important data were ignored or overlooked in planning for the PPPC trial, nor did they find any evidence to suggest that pressure for fast-track development was a contributing factor to the untoward events of that trial.
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In regard to the proposed changes requiring a marked increase in safety reporting, we remain skeptical that the benefits from such added efforts will outweigh the increased expense, added time for drug development, delays in access for general use, and so called type II errors—abandoning work on a drug because it is believed to be ineffective or harmful when, in fact, with further testing and development it would have been shown to be both effective and safe. ANCILLARY ISSUES Although the committee's focus throughout this review has been on reducing as far as possible the chance of a tragedy like that of trial PPPC ever occurring again in the course of a clinical drug trial, several ancillary issues came to our attention in the course of the review, clearly very secondary in importance to the principal, unfortunate events that form the basis of this report, but bearing directly on regulatory control of clinical trials.
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Trial Design · — 4. Some form of independent safety monitoring would be a valuable component of any clinical trial in which patients are treated for extended periods, but they are especially important for all double-blind trials and in any trial in which there is reason to anticipate that evidence of adverse reactions could be confused with evidence of disease progression or therapeutic response.
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7. Concerted efforts should be made to include in all clinical trial protocols explicit prospective criteria to help distinguish between adverse events related to drug treatment and changes in the underlying disease, for better or worse, whether or not controls are employed.
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Toxicology studies in at least two different species, using the route of administration intended for use in patients, with dosing for at least as long as intended for clinical trials, and extended followup on at least a subsample of animals should all be key considerations in preclinical testing. Wherever feasible and reasonable, the preclinical assessment should include testing in an animal model of the disease being targeted.
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