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Halcion: An Independent Assessment of Safety and Efficacy Data
Halcion
An Independent Assessment of Safety and Efficacy Data
Committee on Halcion: An Assessment of Data Adequacy and Confidence
Division of Health Sciences Policy
Division of Neuroscience and Behavioral Health
INSTITUTE OF MEDICINE
NATIONAL ACADEMY PRESS
Washington, D.C.
1997
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Halcion: An Independent Assessment of Safety and Efficacy Data
NATIONAL ACADEMY PRESS
2101 Constitution Avenue, N.W. Washington, D.C. 20418
NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance.
This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine.
The Institute of Medicine was chartered in 1970 by the National Academy of Sciences to enlist distinguished members of the appropriate professions in the examination of policy matters pertaining to the health of the public. In this, the Institute acts under both the Academy's 1863 congressional charter responsibility to be an adviser to the federal government and its own initiative in identifying issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine.
Support for this project was provided by funds from the U.S. Food and Drug Administration (Contract No. 223-97-3003). The views presented in this report are those of the Committee on Halcion and are not necessarily those of the funding organization.
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Halcion: An Independent Assessment of Safety and Efficacy Data
COMMITTEE ON HALCION: AN ASSESSMENT OF DATA ADEQUACY AND CONFIDENCE
WILLIAM BUNNEY, JR.* (Chair), Distinguished Professor and Della Martin Chair of Psychiatry,
Department of Psychiatry and Human Behavior, University of California, Irvine
DANIEL AZARNOFF,* President,
D. L. Azarnoff Associates, Burlingame, California
BYRON WM. BROWN, .JR.,* Professor and Head,
Division of Biostatistics, Department of Health Research and Policy, Stanford University, Stanford, California
ROBERT CANCRO, Professor and Chairman,
Department of Psychiatry, New York University Medical Center
ROBERT GIBBONS, Professor of Biostatistics,
Departments of Biometry and Psychiatry, University of Illinois at Chicago
JOHN CHRISTIAN GILLIN, Professor of Psychiatry,
University of California, San Diego, and Veterans Affairs Medical Center.
SANDRAL HULLETT,* Executive Director,
West Alabama Health Services, Eutaw, Alabama
KEITH KILLAM, Professor and Chair Emeritus,
Department of Pharmacology and Toxicology, University of California, Davis
JOHN KRYSTAL, Associate Professor and Director,
Division of Cognitive and Clinical Neuroscience, Department of Psychiatry, Yale University, New Haven, Connecticut
DAVID KUPFER,* Professor and Chairman of Psychiatry,
University of Pittsburgh School of Medicine,
Director of Research,
Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania
PAUL STOLLEY,* Professor and Chair,
Department of Epidemiology and Preventive Medicine, School of Medicine, University of Maryland at Baltimore
IOM Health Sciences Policy Board Member/Committee Liaison
ADA SUE HI SHAW,* Dean,
School of Nursing, University of Michigan, Ann Arbor
Study Staff
ANDREW POPE, Study Director
GEOFFREY FRENCH, Research Assistant
THELMA COX, Project Assistant
Division Staff
VALERIE PETIT SETLOW, Division Director,
Health Sciences Policy
CONSTANCE M. PECHURA, Division Director,
Neurosciences and Behavioral Health
LINDA DEPUGH, Administrative Assistant
JAMAINE TINKER, Financial Associate
*
Member of the Institute of Medicine.
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Halcion: An Independent Assessment of Safety and Efficacy Data
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Halcion: An Independent Assessment of Safety and Efficacy Data
Acknowledgments
The committee would like to acknowledge the input and assistance of the many people who made this report possible. The following colleagues in both the public and private sectors generously shared information, resource material, and their time. From the U.S. Food and Drug Administration: Charles Anello, Jane Axelrad, Patricia DeSantis, Thomas Laughren, Paul Leber, Hillary Lee, Murray Lumpkin, Susan O'Malley, Robert O'Neill, Robert Temple, Yi Tsong, Roger Williams, and Diane Wysowski. From Public Citizen: Larry Sasick and Sidney Wolfe. From Pennsylvania State University College of Medicine, Hershey, Pennsylvania: Edward Bixler and Anthony Kales. From Pharmacia and Upjohn, Inc.: Graham Burton, Robert Paarlberg, Linda Polier, Kenneth Starz, and Mark Todd. Finally, the committee would like to thank Kitty Voith from Health Canada and Patrick Waller of the Medicines Control Agency in the United Kingdom.
The committee also acknowledges the efforts of Michael Hayes as the technical editor, Michael Edington as the managing editor, and Roslyn Matthews for helping with the final preparation of the report. Perhaps most significantly, however, we acknowledge the herculean efforts of Geoffrey French, who, as our research assistant, kept track of extensive quantities of information and was able to provide us with whatever we needed at a moment's notice; the untiring support of Thelma Cox, who, as our project assistant, was delightful and gracious in keeping our administrative details in order; and the steady and thoughtful guidance of Andrew Pope, who, as our study director, skillfully navigated us through the shoals of producing a consensus report.
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Halcion: An Independent Assessment of Safety and Efficacy Data
Preface
The "sleeping pill" Halcion (triazolam) has a long and controversial history in terms of its approval and surveillance and the attention that it has received in the media. The safety and efficacy of Halcion as a drug for promoting sleep have been extensively reviewed by a number of regulatory agencies including those in the United States and United Kingdom. A review of the data, however, suggests that the results of these analyses are inconsistent and, at times, conflicting. In the United Kingdom, for example, Halcion has been removed from the market (following Upjohn's announcement in 1991 that "errors had been identified" in one of the clinical trials). Attempts in the United Kingdom to overturn this decision by committees and panels endorsing the drug have thus far been unsuccessful. In the United States, some scientists were concerned about the drug's safety and efficacy but have not convinced the U.S. Food and Drug Administration (FDA) to withdraw it. Neither proponents nor critics of the drug are completely satisfied with the present status, partly due to the awareness that scientific reviews and determinations may have been subject to political and other external influences.
It is appropriate, then, that these issues concerning Halcion be brought to the Institute of Medicine (IOM). As part of the National Academy of Sciences, IOM occupies a special niche in the science policy arena as an independent adviser to the federal government and others on matters pertaining to public health. IOM provides unique advantages in situations such as this one in which both high-quality science and independent Perspective are important.
In addressing its task, the committee was faced with reviewing, assessing, and evaluating a huge amount of information in a short amount of time. The committee met three times in 3 months to review data and testimony from FDA, Public Citizen, Pharmacia and Upjohn, and Canadian and British government agencies. More than 20 years' worth of clinical trials, postmarketing reports, published literature, statistical analyses, expert opinion, and meeting transcripts were reviewed (see Appendix E). In addition to providing the committee with copies of the New Drag Application for Halcion, FDA was helpful in arranging for committee members to interview and meet with various FDA Staff members who were intimately involved with and highly knowledgeable about the issues. The committee interviewed individuals in the Office of Epidemiology and Biostatistics, the Division of
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Halcion: An Independent Assessment of Safety and Efficacy Data
Neuropharmacological Drug Products, and the Division of Drug Evaluation I, including individuals who worked directly with the evaluation of the safety and efficacy of Halcion and the Spontaneous Reporting System
In addition, the IOM committee heard reports from Public Citizen, a consumer advocacy group that filed a petition requesting FDA to remove Halcion from the U.S. market. Dr. Sidney Wolfe, representing Public Citizen, discussed the issues with the committee at their first meeting. Copies of the petition and all supporting documents were provided to the committee and reviewed. Public Citizen also hosted an additional meeting with Dr. Anthony Kales, a sleep researcher who has been prominent in the Halcion debate, and Dr. Edward Bixler, a professor of psychiatry, both of whom are from Pennsylvania State University College of Medicine, Hershey, Pennsylvania, and have published extensively on the subject of Halcion. Drs. Wolfe, Kales, and Bixler were helpful in providing details about certain aspects of the science, approval process, and safety issues.
The committee requested, received, and reviewed a large amount of detailed information from Pharmacia and Upjohn, including copies of original protocols, case report forms, and final reports from more than 40 studies that the committee considered important. Upjohn additionally provided the committee with integrated summaries of the safety and effectiveness of Halcion and data for subjects withdrawing from Halcion drug trials, and filled numerous requests from the committee for additional data. Upjohn also agreed to disclose all the relevant documents from proprietary files so that the committee could review them as public information (see Appendix F).
Although the database was enormous, the specific task was a narrowly focused one, primarily, to assess the adequacy of study designs and the quantity and quality of the available data related to the safety and efficacy of Halcion taken at different doses and for different durations, including those described in the current labeling. It was not part of our charge to review and evaluate specific concerns of the Public Citizen petition or any other criticisms that have been raised about Halcion. These concerns, however, do relate to the committee's charge, were of great interest to the committee, and have been addressed in our report. Similarly, we were not appointed to second-guess the United Kingdom or any other countries that removed Halcion from the market, but we hope that our report will be of interest to them.
One of the unique aspects of this activity that needs to be highlighted is that the committee performed its own reanalyses of key components of the data. Thus, in addition to examining the clinical trials and other dam to make an independent assessment of their quality, the committee's conclusions are also based on some newly generated data analyses.
Although our task was fairly narrow, the committee was inescapably drawn by the data to an area of broader concern that is addressed in some detail in the report and that became apparent to the committee in the course of assessing the current patterns of Halcion use. As is described in various other reports, including the 1996 FDA task force report, Halcion is often prescribed and used in a manner that far exceeds the recommended labeling with respect to close and duration. This has direct and broad implications for the safety and possible efficacy of Halcion, but is also an issue for other drugs and products on the market. Moreover, only limited data on the actual use of drugs are available, and in the committee's opinion, insufficient effort appears to be directed toward assessing reported adverse events and responding effectively to these issues.
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Halcion: An Independent Assessment of Safety and Efficacy Data
Lastly, this has been a truly interesting and challenging experience. The issues were complex and controversial, and the data were limited in some areas; however, the potential ramifications were large. Because of this, debate among the members was often vigorous. But the purpose was always clear: an objective analysis of the data. It would have been an insurmountable task, however, if not for the support, cooperation, and assistance from all parties involved. Most importantly, it was the vigor, critical insight, and dedication of both the committee and the supporting IOM staff that made this a successful activity.
William E. Bunney
Chair
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Halcion: An Independent Assessment of Safety and Efficacy Data
Contents
EXECUTIVE SUMMARY
1
THE DATA
2
ASSESSMENT OF EFFICACY DATA
2
Conclusions and Recommendations
3
Data Adequacy
3
Clinical Trial Design
4
Tolerance
4
ASSESSMENT OF SAFETY DATA
5
Conclusions and Recommendations
5
Clinical Trials and Surveillance
5
BROADER IMPLICATIONS
6
1
INTRODUCTION
10
HISTORICAL OVERVIEW OF HALCION
11
Overseas Events
12
FDA Activity
13
Spontaneous Reports
13
FDA Reassessment
14
FDA Task Force
14
CHARGE TO THE IOM COMMITTEE
15
ORGANIZATION OF THE REPORT
15
2
ASSESSMENT OF EFFICACY DATA
20
PURPOSE AND EVALUATION OF HYPNOTIC DRUGS
21
Evaluating Efficacy
21
FDA Efficacy Requirements
22
Available Efficacy Data on Halcion
22
QUALITY OF PROTOCOLS AND STUDY DESIGN
23
Study Design
29
Endpoints
29
Polysomnographic Studies
32
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Halcion: An Independent Assessment of Safety and Efficacy Data
REVIEW OF STATISTICAL METHODS USED BY UPJOHN AND FDA TO EVALUATE EFFICACY DATA
34
Statistical Reanalysis and Evaluation of Clinical Trial Efficacy Data
35
Random-Effect Regression Models
37
Results of Reanalysis
37
Dose Response
38
LITERATURE REVIEW
39
Polysomnographic Studies of Halcion in the Published Literature
42
CONCLUSIONS AND RECOMMENDATIONS
46
Data Adequacy
46
Clinical Trial Design
47
Tolerance
47
3
ASSESSMENT OF SAFETY DATA
49
WELL-CONTROLLED PREMARKETING CLINICAL TRIALS
49
Adverse Events
50
Integrated Summary of Safety
50
IOM Analysis of Upjohn's Integrated Summary of Safety
59
Analysis of Dropouts
62
FDA Analysis
62
IOM Analysis
67
Summary
71
DATA SETS FOR POSTMARKETING STUDIES
72
Randomized Study: Protocol M/2100/0235
72
Randomized Polysomnographic Studies
73
A Nonrandomized Controlled Study: EMIC
74
VAMP: A COHORT STUDY
75
SPONTANEOUS REPORTING OF ADVERSE EVENTS: THE FDA SYSTEM
79
Statistical Evaluation of the SRS Data
80
LITERATURE REVIEW
82
Pharmacokinetic and Pharmacodynamic Issues Regarding the Comparability of Triazolam to Other Benzodiazepines
82
Pharmacokinetic Issues
82
Pharmacodynamic Interactions
84
Unique Effects of Triazolobenzodiazepines on Locus Coeruleus Neurons
85
Summary
85
Consideration of Amnestic Effects of Halcion
86
Performance of Memory Tasks After Single and Multiple Doses
86
Spontaneous Reports of Memory Impairment
87
Halcion and State-Dependent Learning
87
Summary
87
Review of Data Regarding Possible Anxiogenic or Insomniac Effects Associated with Halcion Administration or Withdrawal
88
Halcion Effects on Daytime Anxiety
88
Withdrawal-Related Anxiety or Insomnia Following Short- and Long-Term Halcion Use
88
Summary
89
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Ataxia, Disinhibition, and Psychotogenic, Confusional, or Dissociative Effects of Halcion
89
Consideration of Other Potential Adverse Effects
90
Early Termination of Use
90
Adverse Effects Defined Generally
90
Other Adverse Effects
90
Summaries and Meta-Analyses
91
Closing Comments
91
CONCLUSIONS AND RECOMMENDATIONS
91
Clinical Trials and Surveillance
92
4
ADDITIONAL COMMENTS ON BROADER IMPLICATIONS
94
REFERENCES
97
APPENDIXES
A
Fda Safety Tables
107
B
Summary Tables Of Literature Reviewed For Safety Of Halcion
123
C
Glossary
143
D
Acronyms
145
E
Resources Reviewed by the Committee,
146
F
Upjohn Consent to Disclosure,
150
G
Committee and Staff Biographies,
153
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List of Tables, Figures, and Boxes
TABLES
1
Committee Tasks and Summary of Relevant Conclusions and Recommendations
9
1-1
Common Benzodiazepines and Their Trade Names
11
2-1
Low-Dose Premarketing Studies Reviewed by IOM Committee for Efficacy of Halcion (less than 0.5 mg)
24
2-2
Results of IOM Committee Review of Low-Dose Protocols, Pivotal Protocols, and Postmarketing Protocols
30
2-3
Polysomnographic Data Results for Tolerance for 0.25-mg Dose in Controlled Clinical Trials
33
2-4
Pivotal Premarketing Studies Reviewed by IOM Committee for Efficacy of Halcion
36
2-5
Observed Proportions of Four Primary Endpoints for Subjects Who Received 0.25 mg of Halcion Versus Those for Subjects Who Received Placebo
38
2-6
Observed Proportions of Four Primary Endpoints for Geriatric Subjects Who Received 0.125 mg of Halcion Versus Those for Subjects Who Received placebo
39
2-7
Selected Polysomnographic Sleep Studies Evaluating Triazolam (Halcion) for Insomnia
44
3-1
Number (percent) of Subjects Reporting CNS-Related Adverse Events in Adequate and Well-Controlled Phase II/III Studies ( = 0.5%) with a Duration of Treatment of 1 to 92 days
51
3-2
CNS-Related Medical Events for Adult Insomniac Subjects, 1 to 2 Weeks of Treatment
52
3-3
CNS-Related Medical Events for Adult Insomniac Subjects, 4 to 6 and 12 to 13 Weeks of Treatment
54
3-4
CNS-Related Medical Events for Geriatric Subjects, 1 Week of Treatment
56
3-5
CNS-Related Medical Events for Geriatric Subjects, 1 to 2 and 4 Weeks of Treatment
57
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Halcion: An Independent Assessment of Safety and Efficacy Data
3-6
Comparisons of Observed and Expected Incidence of Four Adverse Events in Subjects in Controlled Clinical Trials Receiving Low Doses of Halcion and Flurazepam
61
3-7
FDA Analysis of Dropouts for ''All Psychiatric" in the 25 Studies for 1992 Advisory Committee Meeting
64
3-8
FDA Analysis of Dropouts in the 25 Studies for 1992 Advisory Committee Meeting
65
3-9
IOM Summary of FDA Analysis of Dropout Rates by Category of Events
66
3-10
Adverse Event Frequencies for Halcion-Treated Groups in 25 Parallel-Group Studies
68
3-11
Adverse Event Frequencies for the Flurazepam-Treated Groups in the 15 of the 25 Parallel-Group Studies That Used Flurazepam as a Comparator Drug
69
3-12
Adverse Event Frequencies for Placebo-Control Groups in the 12 of the 25 Parallel-Group Studies That Included a Placebo Control
70
3-13
People Reporting Neurological, Medical, Psychological, and Emotional Medical Events in EMIC
76
3-14
Aggregate Number of Domestic Spontaneous Reports, Reporting Rates, and Reporting Rate Ratios for Certain Adverse Behavioral Reactions to Halcion and Temazepam for First 7 Years of Marketing of Each Drug, as Reported in SRS
81
FDA Safety Tables
A-1
Non-Geriatric Studies: Anxiety
108
A-2
Non-Geriatric Studies: Confusion
109
A-3
Non-Geriatric Studies: Depression
110
A-4
Non-Geriatric Studies: Irritability
111
A-5
Non-Geriatric Studies: Memory Impairment
112
A-6
Non-Geriatric Studies: All Psychiatric
113
A-7
Non-Geriatric Studies: Sedative/Hypnotic
114
A-8
Geriatric Studies: Anxiety
115
A-9
Geriatric Studies: Confusion
116
A-10
Geriatric Studies: Depression
117
A-11
Geriatric Studies: Irritability
118
A-12
Geriatric Studies: Memory Impairment
119
A-13
Geriatric Studies: All Psychiatric
120
A-14
Non-Geriatric Studies
121
A-15
Geriatric Studies
122
Summary Tables of Literature Reviewed for Safety of Halcion
B-1
Evaluation of Comparability, Pharmacokinetics, and Pharmacodynamic Interactions of Halcion
124
B-2
Results of In Vitro Binding Studies: Displacement of Flunitrazepam in the Human Cortex
127
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Halcion: An Independent Assessment of Safety and Efficacy Data
B-3
Displacement of [3H]Flumazenil in Rats as Determined by In Vivo Autoradiography
128
B-4
Relative Lipophilicity of Benzodiazepines
129
B-5
IOM Summary of Studies Investigating Possible Unique Amnestic Effects of Halcion
130
B-6
IOM Summary of Studies Investigating Possible Unique Anxiogenic Effects During Administration of Halcion, and Anxiogenic or Insomnia-Promoting Effects with Withdrawal
133
B-7
IOM Summary of Studies Investigating Possible Unique Ataxic or Dyscoordination Effects of Halcion
137
B-8
IOM Summary of Studies Investigating Possible Unique Disinhibiting Effects of Halcion
138
B-9
IOM Summary of Studies Investigating Possible Unique Psychotigenic, Confusion, or Dissociation-Generating Effects of Halcion
139
B-10
IOM Summary of Studies Investigating Other Possible Adverse Events Related to Halcion
140
Figure
2-1
Observed dose-response relations for efficacy measures: placebo and Halcion at 0.25 and 0.5 mg in non-geriatric subjects
40
Boxes
1
Resources Reviewed by the Committee
2
1-1
Pharmacology of Triazolam
12
1-2
Timeline of Significant Events in Halcion's History
16
2-1
Four Primary Endpoints and Their Respective Rating Categories Used in the Questionnaires
35
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