Review of the Fialuridine (FIAU) Clinical Trials (1995)

This study, conducted at the Lilly Laboratory for Clinical Research in Indianapolis, Indiana, in March and April 1993, was the only one of those reviewed by this committee which utilized healthy subjects rather than patients infected with HIV or HBV. The primary objectives, as stated in the protocol, were to determine the relative bioequivalence of a syrup formulation and two tablet formulations of FIAU, and to determine the pharmacokinetic profile of each (i.e. how much of the dose is absorbed, how fast it is absorbed, how quickly is it eliminated, and in what form is it eliminated). A secondary objective was to determine the influence of food on these processes.

The principal investigator for the study was David L. Hyslop, and Benito J. Cerimele and Karl A. DeSante, were listed as scientific collaborators. All three are Lilly employees; the first is a clinical research physician assigned to the Lilly Laboratory for Clinical Research, the second is a mathematician assigned to the Statistical and Mathematical Sciences Division at Lilly Corporate Center, and the third is head of the Bioavailability and Pharmacokinetics Department and the Clinical Analytical Group at the Lilly Laboratory for Clinical Research. Hyslop, a 1978 graduate of Indiana University School of Medicine, is board certified in internal medicine (1981) and infectious disease (1986), and was Assistant Professor at the University of Missouri-Columbia before joining Lilly in 1987. Although none of his professional publications have dealt with hepatitis, he appears to have been qualified to run this study on healthy volunteers. His more senior collaborators are both established scientists who have published extensively in their fields.

Sixteen subjects each received five doses of FIAU, separated by 3-to 7-day intervals. On three of these occasions the subject received the drug after an overnight fast and continued to fast for 4 hours after taking the drug. The FIAU was provided once as a single 5-mg tablet (between 0.06 and 0.08 mg/kg), once as five 1-mg tablets, and once as 5 ml of 1 mg per ml of syrup. On a fourth occasion subjects were given a 5-mg tablet immediately before a standard meal. Subjects were randomly assigned to one of four groups, balancing the order in which the various formulations were received. The last dose for every subject, however, was a 5-mg tablet, given 30 minutes or an hour before or after the meal. The study ultimately utilized a newly developed radioimmunoassay (RIA) highly specific for FIAU and 250 times more sensitive than the high-performance liquid chromatography (HPLC) assay that had previously been used to estimate a half-life of 1 to 4 hours for FIAU. The RIA technique was not perfected until mid-June, however; so blood and urine samples from this trial were simply frozen for later analysis.

Unlike any of the other FIAU studies reviewed in this report, the volunteers remained at the laboratory for the duration of the study. The laboratory is adjacent to the Wishard Memorial Hospital of the Indiana University Medical Center, where acute medical care is provided to any Lilly subjects who require it. The protocol was reviewed and approved by the Indiana University Medical Center IRB. According to Lilly, this inpatient arrangement not only facilitates control of diet and close monitoring of protocol compliance but also ensures complete data collection and follow-up on frequently unemployed and transient subjects.

Risks to subjects were described in the informed consent document (Appendix D) as including stomach pain, diarrhea, nausea, vomiting, headache, and muscle aches or fatigue. There was no mention of peripheral neuropathy, nor was there any description of symptoms like numbness or tingling in the arms and legs that might imply peripheral neuropathy. The form did note that changes in laboratory test values that measure liver, kidney, and muscle functions, and anemia (low blood count) had also occurred in prior studies. Decreases in sperm production and heart muscle damage "in animals given 3,500 to 14,000 times the dose planned for this study" were also reported, and subjects were warned that FIAU or the procedures used in the study might have other unknown effects. An extensive battery of hematology, blood and urine chemistry, and microscopic clinical laboratory tests was conducted 24 hours after the administration of each dose, but no explicit provision for grading toxicity or discontinuing subjects in the study was included in the protocol.

Pharmacokinetic measurements performed on blood and urine samples after the RIA were validated in June revealed more rapid absorption of FIAU in syrup than in tablet form, with food generally decreasing the rate of absorption, rapid distribution with all forms, and a very prolonged elimination phase with a terminal half-life of 28-30 hours (10 times the half-life previously estimated with the less sensitive HPLC method).

The adverse events that were noted included diarrhea, headache, transient myalgia, and in two cases, elevations in transaminase levels. Although both subjects with these elevations were asymptomatic, dosing was discontinued for one (subject 1203) after his serum ALT level rose to 92 units/liter (from 19 units/liter) and his AST level rose to 56 units/liter (from 17 units/liter) after dose 2. This subject was encouraged to stay at the laboratory despite being dropped from his dosage group, while the investigators worked him up for hepatitis and other possible causes of his ALT and AST elevations, which continued to rise to peaks of 137 and 60 units/liter, respectively, 1 week after receiving his last dose of FIAU. Lilly was later criticized for not promptly reporting this "hospitalization" to the FDA within the 10-day limit for serious adverse events. Lilly's records indicate that he was neither admitted (since he was already staying at the laboratory) nor given any acute medical treatment (since he remained asymptomatic). His transaminase levels returned to the baseline 5 weeks after receiving his second and last dose of FIAU.

The second subject (subject 508), who was also asymptomatic, also showed three- to five-fold increases in ALT and AST levels after receiving dose 2, but the levels of both enzymes decreased on each of the following 3 days and the subject was continued in the study. AST and ALT levels gradually returned to the baseline levels, despite the administration of three additional 5-mg doses of FIAU.

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.