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.

Table of Contents


Front Matter
Executive Summary
Introduction
Clinical Trials
Hepatitis B and Other Viral Diseases
Clinical Trials of FIAC at Memorial Sloan-Kettering Cancer Center
Oclassen Clinical Trial R89-001-01
Oclassen Clinical Trial R90-001-01 (NIH Protocol 91-AI-0031)
Oclassen Clinical Trial R91-001-10 (NIH Protocol 91-DK-AI-213)
Eli Lilly Trial H3X-MC-PPPA
Eli Lilly Trial H3X-MC-PPPG
Eli Lilly Trial H3X-MC-PPPC (NIH Protocol 93-DK-0031)
Summary of Patient Interviews
Overall Assessment of the Trials
Recent Studies of FIAU Toxicity
Review of the FDA Task Force Report 'Fialuridine: Hepatic and Pancreatic Toxicity'
Review of 'Report to the Advisory Committee to the Director, National Institutes of Health'
FDA-Proposed Changes to the Code of Federal Regulations
Ancillary Issues Raised During the Period Following The H3X-MC-PPPC Trial
Conclusions and Recommendations
Appendix A: Chronology of FIAU/FIAC Clinical Trials
Appendix B: Bibliography and References
Appendix C: Agendas from the Three Committee Meetings
Appendix D: Informed Consent Documents
Appendix E: Example of Oclassen Fax Data Summaries
Appendix F: FIAC and FIAU Preclinical Toxicity Studies
Appendix G: Patient Summaries, Lilly Trial H3X-MC-PPPA
Appendix H: Statistical Analysis of Mortality in the FIAU/FIAC Clinical Trials
Glossary