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Review of the Fialuridine (FIAU) Clinical Trials

Committee to Review the Fialuridine (FIAU/FIAC) Clinical Trials

Division of Health Sciences Policy

INSTITUTE OF MEDICINE

Frederick J. Manning and Morton Swartz, Editors

NATIONAL ACADEMY PRESS
Washington, D.C.
1995



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Review of the Fialuridine (FIAU) Clinical Trials Review of the Fialuridine (FIAU) Clinical Trials Committee to Review the Fialuridine (FIAU/FIAC) Clinical Trials Division of Health Sciences Policy INSTITUTE OF MEDICINE Frederick J. Manning and Morton Swartz, Editors NATIONAL ACADEMY PRESS Washington, D.C. 1995

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Review of the Fialuridine (FIAU) Clinical Trials National Academy Press 2101 Constitution Avenue, NW Washington, DC 20418 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for this report were chosen for their special competences and with regard for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The Institute of Medicine was chartered in 1970 by the National Academy of Sciences to enlist distinguished members of the appropriate professions in the examination of policy matters pertaining to the health of the public. In this, the Institute acts under both the Academy's 1863 congressional charter responsibility to be an adviser to the federal government and its own initiative in identifying issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine. Support for this project was provided by the U.S. Department of Health and Human Services (Contract No. 282-94-0022). This support does not constitute an endorsement by the U.S. Department of Health and Human Services of the views expressed in the report. International Standard Book Number 0-309-05279-3 Additional copies of this report are available in limited quantities from National Academy Press Box 285 2101 Constitution Avenue, N.W. Washington, DC 20055 Call 800-624-6242 or 202-334-3313 (in the Washington Metropolitan Area) B543 Copyright 1995 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The image adopted as a logotype by the Institute of Medicine is based on a relief carving from ancient Greece, now held by the Staatlichemuseen in Berlin.

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Review of the Fialuridine (FIAU) Clinical Trials COMMITTEE TO REVIEW THE FIALURIDINE (FIAU/FIAC) CLINICAL TRIALS MORTON SWARTZ, Chair, Professor of Medicine, Harvard Medical School, Chief, James Jackson Firm, and Emeritus Chief of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts ROBERT BRANCH, Director, Center for Clinical Pharmacology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania ROBERT J. LEVINE, Professor of Medicine, Lecturer in Pharmacology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut CURTIS MEINERT, Director, Center for Clinical Trials, Professor of Epidemiology, and Biostatistics, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland GABRIEL L. PLAA, Professor of Pharmacology, Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada MICHAEL SAAG, Associate Professor of Medicine, University of Alabama Birmingham JAMES T. WILLERSON, Chairman, Department of Internal Medicine, Professor of Medicine, School of Medicine, University of Texas, Houston TERESA LYN WRIGHT, Associate Professor of Medicine, University of California, and Chief, Gastroenterology Section 111 B, Department of Veterans Affairs, San Francisco, California Study Staff VALERIE P. SETLOW, Director, Health Sciences Policy Division FREDERICK J. MANNING, Study Director CAROLYN E. PETERS, Research Assistant THELMA L. COX, Project Assistant

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Review of the Fialuridine (FIAU) Clinical Trials Preface Approximately 200,000 primary hepatitis B (HBV) infections occur annually in the United States. Symptoms of acute infection include fatigue, loss of appetite, nausea, abdominal pain, and jaundice. Most patients recover completely, but about 5 percent of HBV-infected adults develop persistent infection. It is estimated that there are approximately 400,000 to 800,000 individuals with persistent infection in the United States (more than 200 million carriers worldwide), and as many as 25 percent of these may have chronic active hepatitis. Chronic HBV infection results in scarring of the liver (cirrhosis) with complications of ascites, life-threatening gastrointestinal hemorrhages, increased susceptibility to serious bacterial infections and encephalopathy. Annually, as many as 4,000 patients with HBV-related cirrhosis in the United States may die of their disease, and about 800 succumb to complicating liver cancer. Thus, chronic HBV infection is clearly an important disease in terms of its frequency, associated morbidity, and significant mortality. This explains the continuing attempts over the past two decades to develop effective chemotherapy for chronic HBV disease. Although spontaneous recovery from chronic HBV infection is occasionally observed, no effective treatment for this disease was known until alpha-interferon (alfa-2b) was licensed for use in the U.S. a few years ago. Because many of the patients treated with alpha-interferon had not benefited from it or could not tolerate its side effects, fialuridine (FIAU) was greeted enthusiastically as a possible alternative for treatment of this disease when it was shown to inhibit HBV replication effectively and, in early trials, appeared to have minimal side effects. FIAU is one of a family of compounds called nucleoside analogues, which includes AIDS drugs such as zidorudine, dideaxyinosine, and dideoxycytidine. The urgency surrounding the development and testing of these nucleoside analogues is understandable, because they are much needed for the treatment of chronically ill patients with progressive diseases. Such drugs still must endure the rigors of careful preclinical and clinical testing, guidelines for which are in place not only to produce major therapeutic gains but also, most importantly, to protect human subjects. As scientists, practitioners, and occasionally patients, the Institute of Medicine (IOM) committee members charged with reviewing this development process were intent on discovering what went wrong in the clinical trial in which five patients ultimately died of FIAU toxicity and whether and how these guidelines failed. This committee comprised eight individuals with expertise in infectious diseases, clinical research, clinical pharmacology, medical ethics, toxicology, and clinical study design. The committee's purpose was two fold: (1) to perform a thorough analysis of the FIAU clinical trials (and those involving the closely related drug fiacitabine [FIAC] and (2) to focus on recommendations for additional safeguards for the conduct of future clinical trials. In preparing

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Review of the Fialuridine (FIAU) Clinical Trials this report, we performed a thorough analysis of all the FIAU/FIAC clinical trials. The resulting recommendations reflect an intensive review of information provided to us by numerous sources: the FIAU/FIAC clinical study staff, the Food and Drug Administration, the National Institutes of Health, the companies that manufacture the drugs, and several interested parties including patients who formerly received FIAU. This information was culled from volumes of laboratory notes, informed consent documents, study protocols, investigational new drug application (IND) submissions, correspondence, personal interviews, and presentations to the committee. In addition, we were not immune to the pressures of the media and pending lawsuits, and we tried to remain sensitive to the pain of the family members of the deceased patients as we reflected on what recommendations we could make that would prevent such a tragedy from happening again. As we focused on whether any rules or procedures governing the clinical trials process needed to be changed, detailed knowledge regarding the FIAU clinical trials was of paramount importance to the committee. Several individuals from every phase of the IND process were contacted, to ensure that the committee considered a broad set of views in developing its recommendations. The committee is most grateful to those individuals (Appendix C). The committee also wishes to thank Frederick Manning, the IOM study director, for his tireless efforts in weaving our contributions into a cogent and coherent piece of work in such a short span of time with the assistance of his staff, Carolyn Peters and Thelma Cox. We also wish to thank Kenneth I. Shine, president of IOM, Joseph Cassells, acting executive director of IOM, and Valerie Setlow, Director of the Health Sciences Policy Division for their support and perspective. MORTON SWARTS, M.D. CHAIR, COMMITTEE TO REVIEW THE FIAU/FIAC CLINICAL TRIALS

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Review of the Fialuridine (FIAU) Clinical Trials Contents     EXECUTIVE SUMMARY   1 1   INTRODUCTION   16     Genesis of the Study   16     Charge to the Committee   17     Methods and Procedure   18     Plan of the Report   18 2   CLINICAL TRIALS   20     Importance of Clinical Trials   20     The Risk-Benefit Nature of Trials   22     The Drug Development Process   24     Safety Reports   27     Ethical Considerations   28     Summary   32 3   HEPATITIS B AND OTHER VIRAL DISEASES   34     Nature of Chronic Viral Diseases   34     Natural History of Chronic HBV Infection   35     Need for Orally Active Agents   37     The Flare Phenomenon   38     Toxic Effects of Other Nucleoside Analogs   40     Summary   41 4   CLINICAL TRIALS OF FIAC AT MEMORIAL SLOAN-KETTERING CANCER CENTER   42     Phase I Evaluation of FIAC in Immunosupressed Patients with Herpes Virus Infection   44     Phase I Study of AIDS Patients with Presumptive or Proven Herpes Group Virus Infection   46     Phase I Study of FIAC in Bone Marrow Transplant Patients with Herpes Group Virus Infections   47     Phase I Oral Dose Ranging FIAC Study in Immunocompromised Patients with VZV and HSV Infections   48

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Review of the Fialuridine (FIAU) Clinical Trials     Phase I/II Trial of FIAC Efficacy in Immunosuppressed Patients with VZV Infection   49     Summary of All the FIAC Clinical Studies at MSKC   50 5   OCLASSEN CLINICAL TRIAL R89-001-01   51     Comment   54 6   OCLASSEN CLINICAL TRIAL R90-001-01 (NIH Protocol 91-AI-0031)   55     Comment   59 7   OCLASSEN CLINICAL TRIAL R91-001-10 (NIH Protocol 91-DK-AI-213)   61     Comment   64 8   ELI LILLY TRIAL H3X-MC-PPPA   66     University of Texas, Galveston Site   66     Tufts New England Medical Center Site   67 9   ELI LILLY TRIAL H3X-MC-PPPG   70     Comment   72 10   ELI LILLY TRIAL H3X-MC-PPPC (NIH Protocol 93-DK-0031)   73     Available Clinical Data Regarding Potential Toxicity   74     Available Safety Data   76     Development of Protocol and FDA Review   76     Patient Selection and Enrollment   77     Conduct of Study   79     Study Outcome   80     Response to the Emergency   87     Long Term Follow-Up   88     Conclusions   89 11   SUMMARY OF PATIENT INTERVIEWS   90 12   OVERALL ASSESSMENT OF THE TRIALS   93     Procedural Requirements   93     Substantive Norms   94     Summary   97 13   RECENT STUDIES OF FIAU TOXICITY   98     Mechanisms   98     Animal Models   99

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Review of the Fialuridine (FIAU) Clinical Trials 14   REVIEW OF THE FDA TASK FORCE REPORT "FILAURIDINE: HEPATICE AND PANCREATICE TOXICITY"   104     Objective of FDA Review   104     Task Force Composition   104     Methodology   105     Results   107     Recommendations   114 15   REVIEW OF "REPORT TO THE ADVISORY COMMITTEE TO THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH   121     Objective of the NIH Review   121     Summary and Recommendations   129 16   FDA-Proposed Changes to the Code of Federal Regulations   133     IOM Committee Comment   135 17   ANCILLARY ISSUES RAISED DURING THE PERIOD FOLLOWING THE H3X-MC-PPPC TRIAL   143 18   CONCLUSIONS AND RECOMMENDATIONS   150     Recommendations   152     APPENDIXES         A CHRONOLOGY OF FIAU/FIAC CLINICAL TRIALS   157     B BIBLIOGRAPHY AND REFERENCES   165     C AGENDAS FROM THE THREE COMMITTEE MEETINGS   178     D INFORMED CONSENT DOCUMENTS   184     R-89 (University of California, San Diego)   185     R-90 (University of Washington)   189     R-90 (University of California, San Diego)   198     R-90 (National Institutes of Health)   203     R-91 (National Institute of Diabetes and Digestive and Kidney Disorders)   210     PPPC   218     PPPA (University of Texas, Galveston)   225     PPPA (New England Medical Center, Boston)   231     PPPG   237     E EXAMPLE OF OCLASSEN FAS DATA SUMMARIES   244     F FIAC AND FIAU PRECLINICAL TOXICITY STUDIES   246     G PATIENT SUMMARIES, LILLY TRIAL H3X-MC-PPPA   251     H STATISTICAL ANALYSIS OF MORTALITY IN THE FIAU/FIAC CLINICAL TRIALS   256     GLOSSARY   266

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