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Review of the Fialuridine (FIAU) Clinical Trials
Subjects were called back for follow-up blood work and questioning about symptoms of possible FIAU toxicity in July and August 1993, after the emergency cessation of the 6-month trial at NIH. No symptoms or indications of toxicity were detected in the 12 subjects that could be located. There has been no further follow-up except for that for a 13th subject (subject 1203), who reappeared in June 1994 inquiring about studies for which he could volunteer. He was also free of any indication of FIAU toxicity.
This study, the only one of which the committee is aware conducted with healthy subjects free of viral disease, is noteworthy in two respects. First, the newly developed RIA for FIAU revealed (when it became available in June, about the time the trial PPPC investigators were beginning to doubt whether their patients could take the drug for a full six months) a half-life for FIAU in blood 10 times as long as previous estimates. Although all drugs reveal longer half-lives when more sensitive analytical methods are developed, since it is then possible to see concentrations reflective of the diffusion of drugs from pools outside the blood, and this longer half-life does not necessarily indicate that a significant accumulation will occur with repeated dosing, it is certainly consistent with potential accumulation and attendant toxicity at a peripheral site.
A second aspect of this trial in need of some commentary was the elevations in the AST and ALT liver enzyme levels in 2 of 17 subjects. Since neither subject was infected with HBV, there is no possibility that these rises were flares associated with the destruction of infected hepatocytes, a fact given great importance by some critics of Lilly (Wolfe and Reid, 1993), who argue that these data should have been sufficient grounds not just for Lilly to stop the trials with these patients but for all ongoing clinical trials with FIAU, including the H3X-MC-PPPC trial at NIH, to be stopped. In retrospect there is no denying that such an action would have prevented a disaster. At the time however, several pieces of information that argued against such an action were available. The total dose received by each subject, 10 mg, was miniscule compared with the doses apparently well tolerated by the presumably less robust patients in previous trials, whose total doses ranged from 100 to more than 1,000 mg. Perhaps more importantly, neither subject with elevated liver enzyme levels had any clinical signs or symptoms. Although the elevations in serum AST and ALT levels occurred after administration of the second dose of FIAU in 2 of the 17 subjects, a drug hypersensitivity reaction caused by intermittent dosing is not likely to be the explanation, since despite receiving three additional intermittent doses, AST and ALT levels in one subject continued to gradually return to baseline levels. Some well-established drugs produce an initial elevation in AST or ALT levels (isoniazid, for example, the most common therapy for tuberculosis, produces a significant rise in about 10 percent of patients, but enzyme levels generally return to normal, despite continued treatment). The committee believes that it would be a mistake to eliminate clinical judgment from clinical trials, and in this case the committee believes that dropping subject 1203 from the trial while continuing to observe him carefully was appropriate and sufficient.