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Suggested Citation:"Front Matter." Institute of Medicine. 1995. Review of the Fialuridine (FIAU) Clinical Trials. Washington, DC: The National Academies Press. doi: 10.17226/4887.
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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

Suggested Citation:"Front Matter." Institute of Medicine. 1995. Review of the Fialuridine (FIAU) Clinical Trials. Washington, DC: The National Academies Press. doi: 10.17226/4887.
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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.

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Copyright 1995 by the National Academy of Sciences. All rights reserved.

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Suggested Citation:"Front Matter." Institute of Medicine. 1995. Review of the Fialuridine (FIAU) Clinical Trials. Washington, DC: The National Academies Press. doi: 10.17226/4887.
×

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

Suggested Citation:"Front Matter." Institute of Medicine. 1995. Review of the Fialuridine (FIAU) Clinical Trials. Washington, DC: The National Academies Press. doi: 10.17226/4887.
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Suggested Citation:"Front Matter." Institute of Medicine. 1995. Review of the Fialuridine (FIAU) Clinical Trials. Washington, DC: The National Academies Press. doi: 10.17226/4887.
×

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

Suggested Citation:"Front Matter." Institute of Medicine. 1995. Review of the Fialuridine (FIAU) Clinical Trials. Washington, DC: The National Academies Press. doi: 10.17226/4887.
×

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

Suggested Citation:"Front Matter." Institute of Medicine. 1995. Review of the Fialuridine (FIAU) Clinical Trials. Washington, DC: The National Academies Press. doi: 10.17226/4887.
×

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

Suggested Citation:"Front Matter." Institute of Medicine. 1995. Review of the Fialuridine (FIAU) Clinical Trials. Washington, DC: The National Academies Press. doi: 10.17226/4887.
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In June 1993 a clinical trial of fialuridine (FIAU), a promising new medication for hepatitis B, was abruptly terminated when one of the 15 out-patients participating in the National Institutes of Health (NIH) study was suddenly hospitalized with liver failure. Although all the remaining patients were contacted and told to stop taking their medication, six more subsequently developed severe toxicity. Five patients died, and two others were probably saved from death only by having liver transplants.

In response to a request from the Secretary of the Department of Health and Human Services, the IOM committee has analyzed the FIAU clinical trials, making recommendations for additional safeguards for the conduct of future clinical trials. This evaluation included the review of documents pertaining to investigational new drug submissions, protocols and consent forms from other clinical trials, as well as information available from other clinical and preclinical experience with compounds related to FIAU and its parent drug, fiacitibine (FIAC), which is metabolized to FIAU. The committee does not seek to affix responsibility for the adverse outcome of this NIH trial, but instead focuses on whether any rules or procedures governing the clinical trials process itself need to be changed, and if so, what burdens or costs such changes might place on future clinical trials.

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