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Development of Medications for the Treatment of Opiate and Cocaine Addictions: Issues for the Government and Private Sector Carolyn E. Fulco, Catharyn T. Liverman, and Laurence E. EarIey, Editors Committee to Study Medication Development and Research at the National Institute on Drug Abuse Division of Biobehavioral Sciences and Mental Disorders INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C. 1995

NATIONAL ACADEMY PRESS · 2101 Constitution Avenue, NW · Washington, DC 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 competencies 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 ofthe 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 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 study was provided by the National Institute on Drug Abuse (contract no. No lDA-3-8000~. Library of Congress Catalog Card No. 94-80088 International Standard Book No. 0-309-05244-0 Additional copies of this report are available from: National Academy Press Box 285 2101 Constitution Avenue, N.W. Washington, DC 20055 Call 800-624-6242 or 202-334-3313 (in the Washington Metropolitan Area) B532 Copyright 1995 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 Staalichemusseen in Berlin. Cover: Conrad Marca-Relli, "The Blackboard," from the Eugene Fuller Memorial Collection, with permission from the Seattle Art Museum. Photo by Paul Macapia.

COMMITTEE TO STUDY MEDICATION DEVELOPMENT AND RESEARCH AT THE NATIONAL INSTITUTE ON DRUG ABUSE LAURENCE E. EARLEY, Chair, Senior Associate Dean, Francis C. Wood Professor of Medicine, Office of International Medical Programs, University of Pennsylvania, Philadelphia, Pennsylvania NANCY L. BUC, Buc, Levitt, and Beardsley, Washington, D.C. PETER F. CARPENTER, Visiting Scholar, Center for Biomedical Ethics, Stanford University, Stanford, California J. RICHARD CROUT, Former Vice President, Eloehringer Mannheim Pharmaceuticals Corporation, Rockville, Maryland JOAN A. CULPEPPER-MORGAN, Director of Research Gastroenterology and Nutrition, Norwalk Hospital, Assistant Clinical Professor of Medicine, Yale University, Norwalk, Connecticut DAVID DRANOVE,+ Associate Professor of Management and Strategy and Health Services Management, Northwestern University, Evanston, Illinois KATHLEEN M. FOLEY, Chief, Pain Service, Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York HERBERT D. KLEBER, Executive Vice President and Medical Director, Center on Addiction and Substance Abuse; Professor of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York LEWIS D. LEPENE, Vice President, Business Development, Interneuron Pharmaceuticals Incorporated, Lexington, Massachusetts ERIC J. NESTLER, Jameson Associate Professor, Department of Psychiatry, School of Medicine, Yale University, New Haven, Connecticut CHARLES P. O'BRIEN, Chief of Psychiatry, Philadelphia Veterans Affairs Medical Center, Professor and Vice-Chair of Psychiatry, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania GRANT R. WILKINSON, Professor of Pharmacology, Department of Pharma- cology, Associate Director, Center for Clinical Pharmacology/Toxicology, School of Medicine, Vanderbilt University, Nashville, Tennessee ALBERT P. WILLIAMS, Corporate Research Manager, Social Policy, RAND, Santa Monica, California ALICE M. YOUNG, Professor, Department of Psychology, Wayne State University, Detroit, Michigan Member, Institute of Medicine Resigned from the committee, January 17, 1994 · . .

STAFF CAROLYN E. FULCO, Study Director CATHARYN T. LIVERMAN, Program Officer TERRI BARBA, Project Assistant CONSTANCE M. PECHURA, Director, Division of Biobehavioral Sciences and Mental Disorders ROBERT COOK-DEEGAN, Director, Division of Biobehavioral Sciences and Mental Disorders (to October, 1994) 1V

Acknowledgments The committee appreciates the expert support of the IOM project staff, former division director, Division of Biobehavioral Sciences and Mental Disorders (BSMD), Robert Cook-Deegan and Constance Pechura, current BSMD director, for their practical comments and guidance during the committee's deliberations. We thank study director, Carolyn Fulco for her contributions to the structure and substance of the report and in preliminary editing of this document. We are indebted to Catharyn Liverman for her excellent research skills in collecting, analyzing, and presenting a range of information, in addition to verifying all committee references; project assistant, Terri Barba for providing logistical assistance for the workshop and all committee meetings, and for overseeing report production; and Mary Ann Racin for preparing the camera- ready copy of the report. The committee benefitted from the expertise of Miriam Davis and her input into the committee's deliberations and of Robert Talbot-Stern, consultants to the committee. The committee wishes to express its sincere appreciation to Geoffrey M. Levitt for his excellent research and expert legal advice. The committee appreciates the overall editing by Norman Grossblatt and Kate Kelly; and the assistance of Claudia Carl in guiding the report through review. The IOM staff and the committee appreciate the thoughtful input and contribution of Charles Grudzinskas and his staff at NIDA. We are also indebted to the many representatives of federal agencies, congressional staff, academia, advocacy groups, professional organizations, and the pharmaceutical industry who shared their expertise with the committee. Those individuals are acknowledged in Appendix A. v

Preface Phannacotherapy for the treatment of drug addiction has received far too little attention, despite the clinical success of methadone, which dates back to the 1960s. Over the last 30 years only two additional medications have been approved for the treatment of opiate addiction, naltrexone and levo-alpha- acetylmethadol (LAAM), and it is important to note that both of those medications were developed in the 1960s and early 1970s. There is no approved medication for the treatment of cocaine addiction. During the same 30 year period, serious medical and social problems have evolved as drug addiction has become a route for spreading AIDS through the sharing of contaminated needles and trading sex for drugs, multiple-drug-resistant tuberculosis has become common in immunocompromised HIV-infected drug users, an association between illicit drug use and increasing violent crime has become clear, and the medical consequences for infants of in utero exposure to cocaine has become evident. It was in the climate of a near absence of private sector and government activity in the development of anti-addiction medications and a growing public health crisis that the Congress passed Public Law 100-690 in 1988, which established the Medications Development Division (MDD) in the National Institute on Drug Abuse (NIDA). The division began in 1990 to coordinate and encourage academic, private, and federal regulatory involvement in developing and bringing to market new medications for the treatment of drug addiction. The ADAMHA Reorganization Act of July 1992 (Public Law 102-321) stipulated that the Department of Health and Human Services contract with the National Academy of Sciences to establish a committee of the Institute of Medicine (IOM) to examine the current environment for the development of anti · ~ V11

. . . V111 PREFACE addiction medications. In response to the Congressional mandate, the Committee to Study Medication Development arid Research at the National Institute on Drug Abuse was formed. The 14-member interdisciplinary IOM committee included persons with expertise in behavioral pharmacology, drug abuse treatment, neuroscience, drug development, health-care economics, clinical research, and federal regulatory law. NIDA and IOM decided that a two-phase effort would most beneficially address the complex issues associated with the development of an anti-addiction medication. The committee was charged to Determine the extent to which current scientific knowledge limits the development of pharmacological treatments for drug addiction, Review the background and progress of the NIDA MDD since its inception in 1990, Consider the current role of the Food and Drug Administration (FDA) and other government entities in the process for approving anti-addiction medications, Survey the incentives and disincentives to private development of medications including government regulatory processes and the potential market for anti-addiction medications, and Determine the current role of the private sector in the development of medications for drug addiction. The committee focused its attention exclusively on medications for treating opiate and cocaine addictions, because individuals with those addictions are disproportionately responsible for violent crimes and for the transmission of infectious diseases such as AIDS. The committee recognizes, however, that the two addictive drugs that are most important with respect to morbidity, mortality, and economic costs are alcohol and nicotine. The committee formally met six times during the course of the entire study, in addition to holding a workshop, and meeting in smaller focus groups. From October 1993 through January 1994 the IOM committee met three times to examine the role of the Medications Development Division at NIDA and identify the disincentives to private sector development of anti-addiction medications specifically for the treatment of opiate and cocaine addictions. Additionally, the committee met with senior executives of pharmaceutical companies, representa- tives of federal agencies (the Drug Enforcement Administration, NIDA, the National Institutes of Health, and FDA), and the IOM Forum on Drug Development, as well as conducting a survey of the member companies of the Pharmaceutical Research and Manufacturers of America (formerly the Pharma- ceutical Manufacturers Association), the Biotechnology Industry Organization (BIO), and the Generic Pharmaceutical Industry Association (GPIA). The

PREFACE 1X committee issued its preliminary report, Development of Anti-Addiction Medications: Issues for the Government and Private Sector, in March 1994 which was disseminated to NIDA, ONDCP, various Congressional committees, other interested parties, and was the subject of a Senate Judiciary Committee hearing on April 19, 1994. The committee held its final three meetings, from April 1994 through September 1994. During the second phase of its work, the committee: provided-a more detailed examination of the issues identified in the preliminary report regarding disincentives to private sector development of anti-addiction medications, further assessed the market environment for developing those medica- tions, and recommended policy and legislative solutions for overcoming the obstacles and disincentives for the development of anti-addiction medications. The committee heard from a wide range of experts at their June 13, 1994 Workshop on Policies to Stimulate Private Sector Development of Anti- Addiction Medications; sessions focused on market issues, treatment financing, federal and state regulations regarding substance abuse research and treatment, and education and training (see Appendix F for workshop agenda and participant list). This report combines the two phases of the committee's work; the organization and content of the report are outlined in the Note to the Reader. The committee, recognizing the medical consequences and socioeconomic problems associated with drug abuse and the dire need for development of anti- addiction medications, yet fully aware of the major disincentives to the industry, grappled with the issue of providing extraordinary incentives to the pharmaceuti- cal industry. Several ideas were discussed at length, including those that were presented at the workshop. These included, granting a patent-extension on some other product marketed by a pharmaceutical company that develops an approved anti-addiction medication; removing the potential for price controls; advance special purchase of an anti-addiction medication; and/or creating a prize or bounty to the first few companies that produce an approved anti-addiction medication. Although, the committee could not adequately envision the implementation of those extraordinary incentives and did not reach a consensus to make specific recommendations on those issues, a majority of the committee agreed that certain of the incentives regarded as extraordinary should be deliberated by policymakers. Thus, in the final chapter of the report, two of those issues, which had support from a majority of the committee members, are presented, not as recommendations, but as approaches for further consideration.

x PREFACE As the committee worked throughout the year on the issue of developing anti-addiction medications, it become obvious that such medications could have enormous benefit and positive impact not only on the lives of drug-dependent individuals but on many aspects of American society. The committee is aware of recent studies which note that every dollar spent on drug treatment is worth seven dollars spent on law-enforcement efforts, clearly demonstrating the cost- effectiveness of treatment. Yet, pharmacotherapy, as an effective and viable adjunct to other treatment modalities, has received far too little attention from the research community, the pharmaceutical industry, public health officials, and the federal government. The committee considered obstacles, large and small, that impede the development of anti-addiction medications. It is the hope of this committee that the issues discussed in this report and its recommendations well be carefully considered not only by the National Institute on Drug Abuse, but also by the Congress and the executive branch as policy options for treating drug addiction are examined and priorities are set. Laurence E. Earley Committee Chair

Note to the Reader This report is the result of a two-phase study as explained in the preface. The first phase ofthe work ofthe IOM Committee to Study Medication Development and Research at NIDA resulted in the desk-top published report, Development of Anti-Addiction Medications: Issues for the Government and Private Sector. That preliminary report was published in March 1994 and was available through the IOM Division of Biobehavioral Sciences and Mental Disorders. It was the intent of the Institute of Medicine to publish the report through the National Academy Press after both phases of the study had been completed; this report incorporates both phases of the committee's work. The chapters in this, the final report, have been reorganized from the preliminary report as follows: . A preface to the final edition An executive summary Chapters 1-3, unchanged Chapters 4 - , new text from the second phase of the committee's work Chapter 7, the text from Chapter 4 of the preliminary report (originally entitled "The Interaction of Federal Regulatory Agencies and the Private Sector") Chapter 8, new text from the second phase of the committee's work Chapter 9, incorporates Chapter 5 of the preliminary report with additional text and recommendations Minor changes were made in Chapters 1-3 and 7 to update prevalence statistics, add cross-references, and incorporate the erratum to the preliminary report. X1

Contents EXECUTIVE SUMMARY 1 INTRODUCTION Public-Health Repercussions of Illicit Drug Use, 27 Economic Costs of Illicit Drug Use to Society, 32 Extent of Illicit Drug Use, 36 Role of Pharmacotherapy, 37 2 OVERVIEW OF THE STATE OF SCIENTIFIC KNOWLEDGE CONCERNING DRUG ADDICTION Concepts of Drug Addiction, 43 Biological Correlates and Psychopharmacology of Addiction, 49 MDD and Strategies for the Discovery of a Cocaine Medication: Description and Critical Analysis, 56 Conclusions and Recommendations, 65 ASSESSMENT OF THE MEDICATIONS DEVELOPMENT DIVISION Structure and Functions of the Medications Development Division, 74 Relationships with Other Federal Agencies and the Private Sector, 83 Assessment of the Medications Development Division, 87 Summary, 91 Conclusions and Recommendations, 92 · . . X111 26 43 74

XIV 4 TREATMENT SETTING AND EFFECTIVENESS Treatment Setting, 95 Demographic and Financial Profile, 100 Treatment Effectiveness and Cost-effectiveness, 106 Conclusions and Recommendation, 1 15 TREATMENT FINANCING AND TRENDS IN HEALTH INSURANCE Financing of Treatment, 121 Financing of LAAM for the Treatment of Opiate Addiction, 126 Impact of Health Insurance Trends on Medications Development, 129 6 TRAINING AND EDUCATION Expanding the Core of Researchers and Clinicians, 135 Increasing Knowledge and Skills Among Primary Care Physicians, 143 Comprehensive Drug Abuse Centers, 147 Summary, 151 FEDERAL LAWS AND REGULATIONS Creation of a Drug by the Pharmaceutical Industry, 154 Food and Drug Administration, 159 Drug Enforcement Administration, 165 Conclusions, 171 8 STATE LAWS AND REGULATIONS State Regulatory Landscape, 174 LAAM: A Case Study, 180 Conclusions, 183 Recommendations, 183 9 MARKET OBSTACLES AND CREATING INCENTIVES Market Obstacles to Private Sector Investment, 190 Need for Federal Leadership, 196 Conclusions, 197 Options for Further Consideration, 198 CONTENTS 95 120 134 154 173 187

CONTENTS XV APPENDIXES A Acknowledgments B Organization and Mission Statements of NIDA's Medications Development Division and Its Branches C Diagnostic Criteria for Psychoactive Substance Dependence D Survey of Pharmaceutical Companies E Model Federal Programs in Pharmaceutical R&D F Workshop Agenda and Participants G Health Care Reform Legislation H Acronyms 201 207 211 215 227 238 242 248

Tables, Figures, and Boxes TABLES 1.1 AIDS Cases Related to Injection of Illicit Drugs, 30 1.2 Estimated Economic Costs of Drug Abuse, 1990, 33 1.3 Percentage of Drug Users Based on Surveys of Various Populations, 38 3.1 NIDA FY95 Budget Appropriation, 79 4.1 Treatments for Cocaine and Opiate Addiction, 99 4.2 Demographics of Methadone and Cocaine-Dependent Patients in Treatment, 102 5.1 Trends in Financing of State-Supported Alcohol and Other Drug Abuse Services by Largest Funding Sources, 125 6.1 NIDA Research Training Funding as a Percentage of Total Extramural Research Funding, 140 C.1 Diagnostic Criteria for Psychoactive Substance Dependence (DSM-III-R), 211 C.2 Diagnostic Criteria for Psychoactive Substance Dependence (ICD-10 Draft), 213 E.1 Model Federal Pharmaceutical Research and Development Programs, 229 FIGURES 1.1 Summary of the Economic Cost of Illicit Drug Use, 1990, 34 1.2 Federal Drug Control Budget Trends (1981-1993), 35 2.1 World Health Organization Schematic Model of Drug Use and Dependence, 45 2.2 Schematic Model of Drug Use and Dependence, 46 2.3 Schematic Model of Drug Use and Dependence, 47 2.4 Cocaine Treatment Screening Flowchart, 59 4.1 Percentage of Patients in Treatment by Setting, 98 4.2 Effectiveness of Methadone with Counseling and Rehabilitative Services, 107 4.3 Average Cost per Admission for Methadone and Cocaine Treatment, 109 4.4 Treatment Is Less Expensive than Alternatives, 111 xv rl

CONTENTS · . XV11 4.5 Additional Cost of Reducing Cocaine Consumption by One Percent with Alternative Cocaine-Control Programs, 1 14 5.1 Narcotics for the Treatment of Narcotic Addiction are a Legally-Defined Subset of Narcotics and Controlled Substances, 121 5.2 Payments for Methadone Treatment, All Types of Drug Abuse Treatment, and All Types of Health Care, 124 7.1 Pipeline Concept of Drug Development, 158 9.1 Current Problems in Anti-Addiction Medication Development, 188 B. 1 Organizational Structure of MDD, 210 D.1 Survey Results, 221 BOXES 6.1 Some Organizations Involved in Training and Education, 138 6.2 NCI Cancer Centers Programs, 148

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Pharmacotherapy, as a means of treating drug addiction in combination with other treatment modalities, has received too little attention from the research community, the pharmaceutical industry, public health officials, and the federal government. Medications to combat drug addiction could have an enormous impact on the medical consequences and socioeconomic problems associated with drug abuse, both for drug-dependent individuals and for American society as a whole. This book examines the current environment for and obstacles to the development of anti-addiction medications, specifically those for treating opiate and cocaine addictions, and proposes incentives for the pharmaceutical industry that would help overcome those obstacles and accelerate the development of anti-addiction medications.

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