Review of the Fialuridine (FIAU) clinical trials

Review of the Fialuridine (FIAU) clinical trials

Detalles Bibliográficos
Otros Autores: Manning, Frederick J. (-), Swartz, Morton N.
Formato: Libro electrónico
Idioma:Inglés
Publicado: Washington, DC : National Academy Press 1995.
Edición:1st ed
Materias:
Hepatitis B > Chemotherapy > Evaluation.
Fialuridine > Testing.
Fiacitabine > Testing.
Clinical trials > Safety measures.
Ver en Biblioteca Universitat Ramon Llull:https://discovery.url.edu/permalink/34CSUC_URL/1im36ta/alma991009820306006719
Tabla de Contenidos:
  • 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 &amp
  • 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.

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