CNS CLINICAL TRIALS

SUICIDALITY AND DATA COLLECTION

WORKSHOP SUMMARY

Sarah Hanson, Miriam Davis, and Bruce Altevogt, Rapporteurs

Forum on Neuroscience and Nervous System Disorders

Board on Health Sciences Policy

INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.
www.nap.edu



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Sarah Hanson, Miriam Davis, and Bruce Altevogt, Rapporteurs Forum on Neuroscience and Nervous System Disorders Board on Health Sciences Policy

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THE NATIONAL ACADEMIES PRESS • 500 Fifth Street, N.W. • Washington, DC 20001 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. T his project was supported by contracts between the National Academy of Sciences and the Alzheimer’s Association; AstraZeneca Pharmaceuticals, Inc.; CeNeRx Biopharma; the Department of Health and Human Services’ National Institutes of Health (NIH, Contract No. N01-OD-4-213) through the National Institute on Aging, the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, the National Eye Institute, the NIH Blueprint for Neuroscience Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke; Eli Lilly and Company; GE Healthcare, Inc.; GlaxoSmithKline, Inc.; Johnson & Johnson Pharmaceutical Research and Development, LLC; Merck Research Laboratories; the National Multiple Sclerosis Society; the National Science Foundation (Contract No. OIA- 0753701); the Society for Neuroscience; and Wyeth Research, Inc. The views presented in this publication are those of the editors and attributing authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-14883-2 International Standard Book Number-10: 0-309-14883-9 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624- 6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2010 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: IOM (Institute of Medicine). 2010. CNS clinical trials: Sui- cidality and data collection: Workshop summary. Washington, DC: The Na- tional Academies Press.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal gov- ernment on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of out- standing engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engi- neering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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WORKSHOP ON CNS CLINICAL TRIALS: SUICIDALITY AND DATA COLLECTION PLANNING COMMITTEE* WILLIAM POTTER (Co-chair), Merck Research Laboratories ROBERT GIBBONS (Co-chair), University of Illinois at Chicago CHARLES BEASLEY, JR., Eli Lilly and Company DAVID BRENT, University of Pittsburgh School of Medicine YEATES CONWELL, University of Rochester School of Medicine and Dentistry WALTER KOROSHETZ, National Institute of Neurological Disorders and Stroke THOMAS LAUGHREN, Food and Drug Administration HUSSEINI MANJI, Johnson & Johnson Pharmaceutical Research and Development, LLC DAVID MICHELSON, Merck & Co. ATUL PANDE, GlaxoSmithKline, Inc. PHILIP WANG, National Institutes of Health IOM Staff BRUCE ALTEVOGT, Project Director SARAH HANSON, Associate Program Officer LORA TAYLOR, Senior Project Assistant __________________________ ∗ IOM planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. v

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FORUM ON NEUROSCIENCE AND NERVOUS SYSTEM DISORDERS* ALAN LESHNER (Chair), American Association for the Advancement of Science HUDA AKIL, University of Michigan MARC BARLOW, GE Healthcare, Inc. MARK BEAR, Massachusetts Institute of Technology DANIEL BURCH, CeNeRx Biopharma DENNIS CHOI, Emory University TIMOTHY COETZEE, National Multiple Sclerosis Society DAVID COHEN, Columbia University RICHARD FRANK, GE Healthcare, Inc. JOHN GRIFFIN, Johns Hopkins University School of Medicine RICHARD HODES, National Institute on Aging KATIE HOOD, Michael J. Fox Foundation for Parkinson’s Research STEVEN HYMAN, Harvard University THOMAS INSEL, National Institute of Mental Health STORY LANDIS, National Institute of Neurological Disorders and Stroke HUSSEINI MANJI, Johnson & Johnson Pharmaceutical Research and Development, LLC EVE MARDER, Brandeis University JONATHAN MORENO, University of Pennsylvania School of Medicine MICHAEL OBERDORFER, NIH Neuroscience Blueprint KATHIE OLSEN, National Science Foundation ATUL PANDE, GlaxoSmithKline, Inc. MENELAS PANGALOS, Wyeth Research, Inc. STEVEN PAUL, Eli Lilly and Company WILLIAM POTTER, Merck Research Laboratories PAUL SIEVING, National Eye Institute RAE SILVER, Columbia University WILLIAM THIES, Alzheimer’s Association NORA VOLKOW, National Institute on Drug Abuse KENNETH WARREN, National Institute on Alcohol Abuse and Alcoholism _________________________ * IOM forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. vii

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FRANK YOCCA, AstraZeneca Pharmaceuticals, Inc. STEVIN ZORN, Lundbeck USA CHARLES ZORUMSKI, Washington University School of Medicine IOM Staff BRUCE ALTEVOGT, Forum Director SARAH HANSON, Associate Program Officer LORA TAYLOR, Senior Project Assistant ANDREW POPE, Director, Board on Health Sciences Policy viii

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Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its pub- lished report as sound as possible and to ensure that the report meets in- stitutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confi- dential to protect the integrity of the process. We wish to thank the fol- lowing individuals for their review of this report: Charles Beasley, Jr., Lilly Research Laboratories Eric Caine, University of Rochester Medical Center Joel B. Greenhouse, Carnegie Mellon University Robert Temple, Food and Drug Administration Although the reviewers listed above have provided many construc- tive comments and suggestions, they did not see the final draft of the re- port before its release. The review of this report was overseen by Dr. Charles F. Reynolds. Appointed by the Institute of Medicine, he was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution. ix

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Contents INTRODUCTION 1 Background on the Issues, 2 About the Forum and Workshop, 5 1 PERSPECTIVES FROM THE FDA, ACADEMIA, AND PATIENTS 7 FDA Perspective, 7 Perspective on Methodology Development and Implementation, 11 Perspective of Patients and Families, 14 2 DATA COLLECTION AND OPTIMIZATION 17 New Approaches to Studying the Predictive Power of Suicidal Ideation for Suicidality, 17 Real-Time Electronic Monitoring Systems, 19 The Predictive Validity of Suicide Ideation at Its Worst Point in Time for Suicide Attempts, 20 Neurobiological Contributions to Predicting Suicidality, 22 3 DATA ANALYSIS ....................................................................... 2525 Establishing Causal Relationships in Medicine for Public Health Policy, 25 Benefits and Limitations of Meta-Analyses, 26 Sources of Bias in Antidepressant Clinical Trials, 28 Selection Bias, 28 Regression Toward the Mean, 29 Natural Course of Illness, 30 Confounding by Indication, 30 Other Problems with Meta-Analyses, 31 Observational Studies, 33 xi

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xii CONTENTS 4 PARTNERSHIPS, OPPORTUNITIES, COLLABORATION 35 Core Data to Obtain for Data Sharing, 35 The FDA’s Critical Path Initiative, 37 A Proposal for the FDA’s Critical Path Initiative Under Development for Suicidality, 40 APPENDIXES A References 43 B Workshop Agenda 51 C Workshop Attendees 61 D Biographical Sketches of Invited Speakers 65