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Suggested Citation:"Front Matter." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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

Suggested Citation:"Front Matter." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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.

International Standard Book No. 0-309-05976-3

Additional copies of this report are available from the
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Copyright 1997 by the National Academy of Sciences. All rights reserved.

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The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The image adopted as a logotype by the Institute of Medicine is based on a relief carving from ancient Greece, now held by the Staatlichemuseen in Berlin.

Suggested Citation:"Front Matter." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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.

Suggested Citation:"Front Matter." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
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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.

Suggested Citation:"Front Matter." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
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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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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.

Suggested Citation:"Front Matter." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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

Suggested Citation:"Front Matter." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
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Suggested Citation:"Front Matter." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
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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

Suggested Citation:"Front Matter." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
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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

Suggested Citation:"Front Matter." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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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Suggested Citation:"Front Matter." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
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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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Regulatory agencies within the United States and the United Kingdom, among several other countries, have reviewed extensively the safety and efficacy of Halcion (triazolam)--a once commonly used hypnotic drug. Concerns began to emerge about the safety of Halcion when a Dutch physician reported a possible link between it and a syndrome that included such effects as depression, amnesia, hallucinations, and increased anxiety. In addition, in 1991 its manufacturer, Upjohn, noted that "errors had been identified in a report of one of the clinical studies included in the original" application for approval. Since then, the drug has been removed from the market in several countries, whereas in the United States and Canada, the drug's labeling has been modified to reduce the recommended dose and duration of treatment and to heighten awareness of possible side effects. Yet different data and analyses have resulted in conflicting messages that are difficult to reconcile and interpret. In response to a request from the Food and Drug Administration to resolve these controversial issues related to the safety and efficacy of Halcion, this IOM book assesses the adequacy of the drug's clinical trials; the quality and quantity of data on adverse reactions; overall confidence in the data on effectiveness, adverse events, and side effects at different doses; and whether additional studies are needed.

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