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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
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
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