Review of the Fialuridine (FIAU) Clinical Trials -- Copyright -- Preface -- Contents -- Executive Summary -- INTRODUCTION -- CLINICAL TRIALS -- HEPATITIS B AND OTHER VIRAL DISEASES -- EARLY CLINICAL TRIALS OF FIAC AT MEMORIAL SLOAN-KETTERING CANCER CENTER -- OCLASSEN CLINICAL TRIAL R89-001-01 -- OCLASSEN CLINICAL TRIAL R90-001-01 -- OCLASSEN CLINICAL TRIAL R-91-010 -- ELI LILLY CLINICAL TRIAL H3X-MC-PPPA -- ELI LILLY TRIAL H3X-LC-PPPG -- ELI LILLY TRIAL H3X-MC-PPPC (NIH PROTOCOL #93-DK-0031) -- PATIENT INTERVIEWS -- OVERALL ASSESSMENT OF THE TRIALS -- REVIEW OF THE FDA TASK FORCE REPORT -- REVIEW OF THE NIH REPORT -- FDA-PROPOSED CHANGES TO THE CODE OF FEDERAL REGULATIONS -- ANCILLARY ISSUES -- CONCLUSIONS -- RECOMMENDATIONS -- Generic Issues -- Trial Design -- Adverse Event Reporting -- Compliance Audits -- Further Research Into FIAU Toxicity -- 1 Introduction -- GENESIS OF THIS STUDY -- CHARGE TO THE COMMITTEE -- METHODS AND PROCEDURE -- PLAN OF THE REPORT -- 2 Clinical Trials -- IMPORTANCE OF CLINICAL TRIALS -- THE RISK-BENEFIT NATURE OF TRIALS -- THE DRUG DEVELOPMENT PROCESS -- SAFETY REPORTS -- ETHICAL CONSIDERATIONS -- Procedural Requirements -- Substantive Norms -- A Favorable Balance of Harms and Benefits -- Equitable Selection of Subjects -- Compensation for Research-Related Injury -- Informed Consent -- SUMMARY -- 3 Hepatitis B and Other Viral Diseases -- NATURE OF CHRONIC VIRAL DISEASES -- NATURAL HISTORY OF CHRONIC HBV INFECTION -- NEED FOR ORALLY ACTIVE AGENTS -- THE FLARE PHENOMENON -- TOXIC EFFECTS OF OTHER NUCLEOSIDE ANALOGS -- SUMMARY -- 4 Clinical Trials of FIAC at Memorial Sloan-Kettering Cancer Center -- PHASE I EVALUATION OF FIAC IN IMMUNOSUPPRESSED PATIENTS WITH HERPESVIRUS INFECTION -- Comment -- PHASE I STUDY OF AIDS PATIENTS WITH PRESUMPTIVE OR PROVEN HERPESGROUP VIRUS INFECTION -- Comment.

PHASE I STUDY OF FIAC IN BONE MARROW TRANSPLANT PATIENTS WITH HERPESGROUP VIRUS INFECTIONS -- Comment -- PHASE I ORAL DOSE RANGING FIAC STUDY IN IMMUNOCOMPROMISED PATIENTSWITH VZV AND HSV INFECTIONS -- Comment -- PHASE I/II TRIAL OF FIAC EFFICACY IN IMMUNOSUPPRESSED PATIENTS WITHVZV INFECTION -- Comment -- SUMMARY OF ALL THE FIAC CLINICAL STUDIES AT MSKC -- 5 Oclassen Clinical Trial R89-001-01 -- COMMENT -- 6 Oclassen Clinical Trial R90-001-01 (NIH Protocol 91-AI-0031) -- COMMENT -- 7 Oclassen Clinical Trial R91-001-10 (NIH Protocol 91-DK-AI-213) -- COMMENT -- 8 Eli Lilly Trial H3X-MC-PPPA -- UNIVERSITY OF TEXAS, GALVESTON SITE -- TUFTS NEW ENGLAND MEDICAL CENTER SITE -- 9 Eli Lilly Trial H3X-MC-PPPG -- COMMENT -- 10 Eli Lilly Trial H3X-MC-PPPC (NIH Protocol 93-DK-0031) -- AVAILABLE CLINICAL DATA REGARDING POTENTIAL TOXICITY -- AVAILABLE SAFETY DATA -- DEVELOPMENT OF PROTOCOL AND FDA REVIEW -- PATIENT SELECTION AND ENROLLMENT -- Inclusion Criteria -- Exclusion Criteria -- Re-enrollment -- Possible Adverse Effects -- Informed Consent -- CONDUCT OF STUDY -- STUDY OUTCOME -- Deaths -- Patient 2 -- Patient 1 -- Patient 4 -- Patient 6 -- Patient 7 -- Liver Transplantation -- Patient 3 -- Patient 10 -- Other Nonlethal Adverse Events -- Gastrointestinal side effects/pancreatitis -- Hepatoxicity -- Peripheral Neuropathy/Myopathy -- Fatigue -- No Adverse Events -- RESPONSE TO THE EMERGENCY -- LONG-TERM FOLLOW-UP -- CONCLUSIONS -- 11 Summary of Patient Interviews -- 12 Overall Assessment of the Trials -- PROCEDURAL REQUIREMENTS -- SUBSTANTIVE NORMS -- Favorable Balance of Harms and Benefits -- Equitable Selection of Subjects -- Compensation for Research-Related Injury -- Informed Consent -- SUMMARY -- 13 Recent Studies of FIAU Toxicity -- MECHANISMS -- ANIMAL MODELS -- Lilly Rat Studies -- Comments -- Cornell Woodchuck Studies -- Comments.

14 Review of the FDA Task Force Report "Fialuridine: Hepatic and Pancreatic Toxicity -- OBJECTIVE OF FDA REVIEW -- TASK FORCE COMPOSITION -- METHODOLOGY -- Selected Laboratory Observations -- Clinical Events -- RESULTS -- Animal Pharmacology and Toxicology Studies -- Overview of Laboratory Events in Studies Prior to H3X-MC-PPPC -- Attribution of Toxicity to Adverse Clinical Events -- Review of Adverse Clinical Events in Trial R89-001-01 -- Review of Adverse Clinical Events in Trial R90-001-01 -- Subject 401 -- Subject 406 -- Subject 408 -- Subject 101 -- Subject 409 -- Review of Adverse Clinical Events in Trial R91-010-01 -- Subject 4D -- Subject 6B -- Subject 1C -- Subject 6A -- Subject 3B -- RECOMMENDATIONS -- Clinical Trial Design and Execution -- Consideration of Control Groups -- Prospective Evaluation of End Points -- Assess Expected Incidence of Death or Serious Events in The Study Population in The Absence of The Investigational Drug -- Observed Effects on Identified End Points Should Be Included in The Investigator Brochure and Presumed to Be Drug-Related... -- Extent of Follow-Up -- Adequate Safety Monitoring -- Reporting Requirements -- Summarization of All Existing Safety Data -- FDA Record Keeping -- Further Review of Fiau Toxicity -- 15 Review Of "Report To The Advisory Committee To The Director, National Institutes Of Health" -- OBJECTIVE OF THE NIH REVIEW -- Question 1-Why Were The Fiau Studies Conducted? -- Was The Scientific Rationale For The Studies Sufficiently Strong? -- Were the Patients with Hbv Infections Appropriate Candidates for the Second and Third Nih Trials of Fiau? -- Were the Preclinical Toxicology, Kinetic, and Safety Data Adequate? -- Should the Deaths That Occurred After the First and Second Trials Have Precluded the Use of Fiau in the Third Hepatitis B...

Did the Investigators Adequately Consider All Data Available to Them in the Design and Conduct of the Protocols, or Were... -- Was The Third Study Prematurely Implemented or Put on A "Fast-Track"? -- Was The Third Study Accelerated By Pressure From Eli Lilly & Company? -- Question 2-How Well Were The Fiau Studies Conducted? -- Compliance With Nih Multiple Project Assurance And The Quality and Thoroughness of Irb Review of Protocols -- The Design of Clinical Studies with Particular Reference To The Third Protocol (Lilly Pppc/Nih 93-Dk-0031 Trial) -- Quality and Content of The Consent Process -- Reporting to The IND Sponsor and FDA -- Clinical Care of Patients -- Question 3-How Well Were The Adverse Events in The Fiau Studies Handled? -- Question 4-Could The Adverse Events Have Been Avoided, Particularly in The Last Study? -- Could The New, Highly Sensitive Ria Method Have Alerted The Attending Physicians to The Possibility of Hepatic and Pancre... -- Could Damage to Mitochondria Be Responsible for The Delayed Toxicity Seen in The Extended Fiau Trial? -- Would New Knowledge Concerning The Delayed Clearance of Fiau Have Changed The Daily Regimen Used in The Third Trial? -- What Effect Might An HBV Infection Have on The Hepatic Toxicity of FIAU? -- Would A Different Accrual Pattern of Recruitment in The Final Protocol Have Affected The Outcome? -- SUMMARY AND RECOMMENDATIONS -- Recommendations from The Nih Subcommittee -- Mechanisms of Toxicity -- Preclinical Tests in Animals -- Patient Enrollment -- Patient Follow-Up -- 16 FDA-Proposed Changes To The Code Of Federal Regulations -- STUDY DESIGN AND PROTOCOL -- REPORTS -- Safety Reports -- Semiannual Reports -- Special Safety Summary -- Final Clinical Study Report -- CLINICAL HOLDS -- TERMINATION -- REVIEW OF ONGOING INVESTIGATIONS -- IOM COMMITTEE COMMENT -- Formal Real Time Monitoring -- Controls.

Follow-Up -- Stopping Rules -- A Statistical Analysis of Mortality in The Fiau/Fiac Trials -- Reporting -- 17 Ancillary Issues Raised During The Period Following The H3x-Mc-Pppc Trial -- 18 Conclusions and Recommendations -- RECOMMENDATIONS -- Generic Issues -- Trial Design -- Adverse Event Reporting -- Compliance Audits -- Further Research Into Fiau Toxicity -- Appendixes -- A Chronology of FIAU/FIAC Clinical Trails -- B Bibliography and References -- C Institute of Medicine Committee to Review the Fialuridine (FIAU/FIAC) Clinical Trials -- AGENDA -- INSTITUTE OF MEDICINE COMMITTEE TO REVIEW THE FIALURIDINE (FIAU/FIAC)CLINICAL TRIALS -- AGENDA -- INSTITUTE OF MEDICINE COMMITTEE TO REVIEW THE FIALURIDINE (FIAU/FIAC)CLINICAL TRIALS -- AGENDA -- D Informed Consent Documents -- R-89 (UNIVERSITY OF CALIFORNIA, SAN DIEGO) -- UNIVERSITY OF CALIFORNIA, SAN DIEGO MEDICAL CENTER CONSENT TO ACTAS A RESEARCH SUBJECT -- UNIVERSITY OF CALIFORNIA, SAN DIEGO -- EXPERIMENTAL SUBJECT'S BILL OF RIGHTS -- R-90 (UNIVERSITY OF WASHINGTON) -- UNIVERSITY OF WASHINGTON HARBORVIEW MEDICAL CENTER CONSENT FORM -- INVESTIGATOR'S STATEMENT -- Purpose and Benefits -- Procedures -- Risk and Discomforts -- Alternatives -- Other Information -- SUBJECT'S STATEMENT -- UNIVERSITY OF WASHINGTON HARBORVIEW MEDICAL CENTER CONSENT FORM -- INVESTIGATOR'S STATEMENT -- Purpose and Benefits -- Procedures -- Risk and Discomforts -- Alternatives -- Other Information -- SUBJECT'S STATEMENT -- R-90 (UNIVERSITY OF CALIFORNIA, SAN DIEGO) -- UNIVERSITY OF CALIFORNIA, SAN DIEGO MEDICAL CENTER CONSENT TOACT AS A RESEARCH SUBJECT -- UNIVERSITY OF CALIFORNIA, SAN DIEGO -- EXPERIMENTAL SUBJECT'S BILL OF RIGHTS -- R-90 (NATIONAL INSTITUTES OF HEALTH) -- R-91 (NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISORDERS) -- PPPC -- PPPA (UNIVERSITY OF TEXAS, GALVESTON) -- SUBJECT CONSENT.

PURPOSE OF STUDY.