Review of the Fialuridine (FIAU) clinical trials / Frederick J. Manning and Morton Swartz, editors.

Format:

Book

Contributor:

Manning, Frederick J.

Swartz, Morton N.

Language:

English

Subjects (All):

Hepatitis B--Chemotherapy--Evaluation.

Hepatitis B.

Fialuridine--Testing.

Fialuridine.

Fiacitabine--Testing.

Fiacitabine.

Clinical trials--Safety measures.

Clinical trials.

Physical Description:

1 online resource (279 p.)

Edition:

1st ed.

Place of Publication:

Washington, DC : National Academy Press, 1995.

Language Note:

English

Summary:

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.

Contents:

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

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

PHASE I ORAL DOSE RANGING FIAC STUDY IN IMMUNOCOMPROMISED PATIENTSWITH VZV AND HSV INFECTIONS

PHASE I/II TRIAL OF FIAC EFFICACY IN IMMUNOSUPPRESSED PATIENTS WITHVZV INFECTION

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)

7 Oclassen Clinical Trial R91-001-10 (NIH Protocol 91-DK-AI-213)

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

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

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

11 Summary of Patient Interviews

12 Overall Assessment of the Trials

PROCEDURAL REQUIREMENTS

SUBSTANTIVE NORMS

Favorable Balance of Harms and Benefits

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

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

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

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

R-90 (UNIVERSITY OF CALIFORNIA, SAN DIEGO)

UNIVERSITY OF CALIFORNIA, SAN DIEGO MEDICAL CENTER CONSENT TOACT AS A RESEARCH SUBJECT

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.

Notes:

"Committee to Review the Fialuridine (FIAU/FIAC) Clinical Trials, Division of Health Sciences Policy, Institute of Medicine".

Includes bibliographical references (p. 165-177).

ISBN:

9786610192922

9780309176613

0309176611

9781280192920

1280192925

9780309573443

0309573440

9780585142388

0585142386

OCLC:

228064162