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Introduction

GENESIS OF THIS STUDY

In June 1993 a clinical trial of a promising new medication for hepatitis B virus (HBV) infection was abruptly terminated when one of the 15 outpatients participating in the National Institutes of Health (NIH) study was suddenly hospitalized with liver failure. Although all of the remaining patients were contacted and told to stop taking their medication, six more developed severe toxicity in the next few weeks. Five patients died, and two others were probably saved from death only by liver transplantation. The members of the committee wish to express their sadness at the deaths of these individuals and their understanding of the sudden sense of shock and loss that must have been felt at the time and subsequently by family members and friends.

All of these patients had been taking the experimental drug fialuridine (FIAU) for at least 9 weeks (five patients who had received FIAU for less than 4 weeks showed no clinical or biochemical evidence of toxicity). During the first 8 weeks of therapy, patients had reported only relatively mild side effects—some abdominal pain, fatigue, intermittent nausea, and constipation—and assays for the levels of HBV DNA in their blood showed that they had dropped precipitously. In six of them HBV DNA had in fact become undetectable. Neither the side effects, which were quite mild compared with those typical of the only Food and Drug Administration (FDA)-approved therapy (alpha-interferon), nor the antiviral activity was surprising. These same patients had undergone a 4-week course of FIAU treatment 9-12 months earlier, with mild side effects and strong anti-HBV effects. Once they were off the drug, however, their HBV DNA levels rebounded, which was the stimulus for the 6-month trial. After the 9-week mark, however, the severity of side effects increased; the dosage of FIAU was decreased in four patients, and FIAU was eventually discontinued in three. After 13 weeks one of these patients, who had stopped taking FIAU 17 days earlier, was admitted to his local hospital with a failing liver, shock, and acidosis. At this point all patients still taking FIAU were told to stop taking it, but this did not prevent serious additional toxicity. In retrospect, the committee can identify the distinctive characteristics of this severe toxicity: hepatic (liver) failure, despite only mild jaundice and minimal changes in the aminotransferase measures that 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), and a marked accumulation of fat within the cells of the liver (microvesicular steatoses). All seven patients also developed signs of myopathy and/or peripheral neuropathy (damage to the muscles or nerves in the arms and legs). Although liver biopsies on an additional three patients showed the characteristic fatty deposits (steatosis), their only other sign



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Review of the Fialuridine (FIAU) Clinical Trials 1 Introduction GENESIS OF THIS STUDY In June 1993 a clinical trial of a promising new medication for hepatitis B virus (HBV) infection was abruptly terminated when one of the 15 outpatients participating in the National Institutes of Health (NIH) study was suddenly hospitalized with liver failure. Although all of the remaining patients were contacted and told to stop taking their medication, six more developed severe toxicity in the next few weeks. Five patients died, and two others were probably saved from death only by liver transplantation. The members of the committee wish to express their sadness at the deaths of these individuals and their understanding of the sudden sense of shock and loss that must have been felt at the time and subsequently by family members and friends. All of these patients had been taking the experimental drug fialuridine (FIAU) for at least 9 weeks (five patients who had received FIAU for less than 4 weeks showed no clinical or biochemical evidence of toxicity). During the first 8 weeks of therapy, patients had reported only relatively mild side effects—some abdominal pain, fatigue, intermittent nausea, and constipation—and assays for the levels of HBV DNA in their blood showed that they had dropped precipitously. In six of them HBV DNA had in fact become undetectable. Neither the side effects, which were quite mild compared with those typical of the only Food and Drug Administration (FDA)-approved therapy (alpha-interferon), nor the antiviral activity was surprising. These same patients had undergone a 4-week course of FIAU treatment 9-12 months earlier, with mild side effects and strong anti-HBV effects. Once they were off the drug, however, their HBV DNA levels rebounded, which was the stimulus for the 6-month trial. After the 9-week mark, however, the severity of side effects increased; the dosage of FIAU was decreased in four patients, and FIAU was eventually discontinued in three. After 13 weeks one of these patients, who had stopped taking FIAU 17 days earlier, was admitted to his local hospital with a failing liver, shock, and acidosis. At this point all patients still taking FIAU were told to stop taking it, but this did not prevent serious additional toxicity. In retrospect, the committee can identify the distinctive characteristics of this severe toxicity: hepatic (liver) failure, despite only mild jaundice and minimal changes in the aminotransferase measures that 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), and a marked accumulation of fat within the cells of the liver (microvesicular steatoses). All seven patients also developed signs of myopathy and/or peripheral neuropathy (damage to the muscles or nerves in the arms and legs). Although liver biopsies on an additional three patients showed the characteristic fatty deposits (steatosis), their only other sign

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Review of the Fialuridine (FIAU) Clinical Trials of toxicity was mild and reversible gastrointestinal discomfort. Many of these toxic effects have been reported to some degree with other antiviral drugs, most notably the anti-human immunodeficiency virus (anti-HIV) agents zidovudine (AZT) dideoxycytidine (ddC), and dideoxyinosine (ddI). CHARGE TO THE COMMITTEE In the weeks following the revelation of the FIAU deaths, outcries arose in the popular media, the medical establishment, and the Congress demanding to know what went wrong; how such a disaster could have taken place, especially at NIH, widely regarded as the flagship of U.S. medical research; and why federal regulation and supervision of drug development had failed to prevent a tragedy of this proportion. The FDA quickly began an investigation of whether any FDA regulations were violated and appointed a task force to examine the question of whether some difference in process or behavior on the part of the trial's sponsors, the scientists conducting it, or the FDA itself might have prevented the damage. The director of NIH assembled a committee of medical scientists from around the country and asked them to conduct a fact-finding review of the FIAU studies that took place at NIH. Most relevant to the present document, the secretary of the U.S. Department of Health and Human Services (DHHS), Dr. Donna Shalala, told Congress she would commission an objective and independent study by the National Research Council's Institute of Medicine (IOM). In June of 1994 a contract for such a study was signed. In it IOM was tasked to assemble a committee of experts in a variety of fields (clinical research, pharmacology, toxicology, and medical ethics as well as hepatology) to perform a thorough analysis of all the FIAU clinical trials, as well as those of fiacitabine (FIAC; a related compound that is rapidly converted to FIAU in the human body). The committee was to focus on whether any rules or procedures governing the clinical trials process needed to be changed and what burdens or costs such changes might place on future clinical trials. More specifically, the committee was asked to review the reports of FDA and NIH and any background documents on the FIAU and FIAC clinical studies, investigational new drug applications (IND) and protocols necessary to determine: Whether investigators, sponsors, FDA, and NIH acted appropriately in all phases of the clinical trials of FIAU and FIAC, particularly the H3X-MC-PPPC trial (see glossary) that ended with five deaths. This is to include the development and review of the IND submission; the development and review of the protocols and consent forms, including mechanisms to ensure the ethical design and conduct of the trials regarding risks to research subjects; and the conduct and monitoring of the H3X-MC-PPPC trial (in which the five deaths occurred) and other trials of FIAU or FIAC. The review was to pay particular attention to information available from other clinical and preclinical experience with compounds related to FIAU or FIAC, from clinical trials of FIAU and FIAC prior to the H3X-MC-PPPC trial, and from the H3X-MC-PPPC trial itself.

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Review of the Fialuridine (FIAU) Clinical Trials Whether the rules or procedures governing the clinical trial process need to be changed to address the problems, if any, identified in the FDA and NIH reports, or problems identified independently by the committee. METHODS AND PROCEDURE Although this report touches on a few studies of FIAC done in the early 1980s at Memorial Sloan-Kettering Cancer Center, it focuses on the six clinical trials sponsored by Oclassen Pharmaceuticals or Eli Lilly & Co. listed in Table 1-1. Column 1 of the table shows the trial "names" (e.g. R89-001-01). These designations are those of the drug company sponsors. We have also provided the NIH protocol number for those trials conducted at NIH, since some of the references and documents in the appendices use that terminology. For ease of reading, however, we have attempted to use the following abbreviated "names" in the text: R89, R90, R91, PPPA, PPPG, PPPC. Appendix A is an integrated chronology of the major events involving those trials and the patients who participated in them. The IOM contract with DHHS provided for access to all documents held by FDA, subject to the same restrictions on disclosure that govern FDA itself. Additional documents were provided by NIH, the drug companies and scientists involved in the trials, and scientific and popular publications. A full list is provided in Appendix B. The committee also questioned representatives of the drug companies, the principal investigators, and various officials from NIH and FDA at two 2-day meetings (Appendix C). Telephone interviews were conducted with all of the surviving patients from the 28-day and 6-month trials at NIH who indicated to the NIH Clinical Center patient representative that they were willing to be interviewed (14 of 22), and all 5 of the patients who participated in the New England/Texas study (H3X-MC-PPPA). PLAN OF THE REPORT After an introduction to clinical trials and their role in the drug development process and to hepatitis and chronic viral diseases, the report describes each of the FIAC/FIAU clinical trials, in chronological order covering as objectively as possible the rationale for that trial, the qualifications of the investigator and the facility involved, the conduct of the study from informed consent through reporting to the study's sponsor and FDA, analysis of the results, and long-term follow-up, including continuing investigations into the mechanisms action of FIAU. The subsequent section of the report provides the committee's analysis of the whole series of trials with respect to such issues as informed consent, oversight, reporting of adverse events, and response to the emergency. Next the report reviews and comments on the patient interviews and the previous professional reviews: the FDA Task Force Report, the NIH Review, the FDA warning letters, and the changes to the Code of Federal Regulations recently proposed by FDA. The report concludes with a section dealing with recommendations for the future regulation and conduct of clinical trials.

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Review of the Fialuridine (FIAU) Clinical Trials TABLE 1-1 Clinical Trials Reviewed in Detail by IOM Trial No. Sponsor Principal Investigator Location Patients Planned Duration Start Stop R89-001-01a Oclassen Corey Univ. of Washington 2 HIV+/CMV+ 35 days 3/90 5/90     Richman   10 HIV+/CMV+ 35 days 11/89 3/90       Univ. of California, San Diego         R90-001 Oclassen Corey Univ. of Washington 25 HIV+/HBV+ 14 days 10/90 6/92     Richman   4 HIV+/HBV+ 14 days 5/91 5/92       Univ. of California, San             Straus Diego 14 HIV+/HBV+ 14 daysb 4/91 6/92       NIH         R91-010 (NIH protocol 91-DK-AI 213) Oclassen Hoofnagle NIH 24 HBV+ 28 days 4/92 9/92 H3X-MC-PPPA Lilly Paar U. of Texas, Galveston 3 HBV+ 3 months 5/93 6/93     Kaplan New England Medical Center 2 HBV+ 3 months 5/93 6/93 H3X-MC-PPPG Lilly Hyslop Lilly Lab. for Clinical Res. 17 healthy males 27 daysc 3/93 4/93 H3X-MC-PPPC (NIH protocol 93-DK-0031) Lilly Hoofnagle NIH 15 HBV+d 6 months 3/93 6/93 NOTE: HIV+, human-immunodeficiency-virus positive; CMV+, cytomegalovirus positive; and HBV+, hepatitis B positive. a FIAC trial; all others FIAU. b Four patients were retreated 45-100 days after the first 2-week treatment. c Five doses at 3- to 7-day intervals. d Ten of these had also participated in the R91-010 trial.