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



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page R1
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

OCR for page R1
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. International Standard Book No. 0-309-05976-3 Additional copies of this report are available from the National Academy Press, 2101 Constitution Avenue, N.W., Box 285, Washington, DC 20055. Call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP's on-line bookstore at http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM hope page at http://www2.nas.edu/iom. Copyright 1997 by the National Academy of Sciences. All rights reserved. Printed in the United States of America 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.

OCR for page R1
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.

OCR for page R1
Halcion: An Independent Assessment of Safety and Efficacy Data This page in the original is blank.

OCR for page R1
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.

OCR for page R1
Halcion: An Independent Assessment of Safety and Efficacy Data This page in the original is blank.

OCR for page R1
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

OCR for page R1
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.

OCR for page R1
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

OCR for page R1
Halcion: An Independent Assessment of Safety and Efficacy Data This page in the original is blank.

OCR for page R1
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

OCR for page R1
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

OCR for page R1
Halcion: An Independent Assessment of Safety and Efficacy Data     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

OCR for page R1
Halcion: An Independent Assessment of Safety and Efficacy Data This page in the original is blank.

OCR for page R1
Halcion: An Independent Assessment of Safety and Efficacy Data 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

OCR for page R1
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

OCR for page R1
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

OCR for page R1
Halcion: An Independent Assessment of Safety and Efficacy Data This page in the original is blank.