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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
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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.
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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
· . .
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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
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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
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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
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. . .
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
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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.
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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
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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
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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
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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
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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
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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
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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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Development of Medications for the
Treatment of Opiate and Cocaine Addictions:
Issues for the Government and Private Sector
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