Expanding Access to Investigational Therapies for HIV Infection and AIDS

March 12–13, 1990 Conference Summary

Eve Nichols

Roundtable for the Development of Drugs and Vaccines Against AIDS

Institute of Medicine

NATIONAL ACADEMY PRESS
Washington, D.C. 1991



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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary Expanding Access to Investigational Therapies for HIV Infection and AIDS March 12–13, 1990 Conference Summary Eve Nichols Roundtable for the Development of Drugs and Vaccines Against AIDS Institute of Medicine NATIONAL ACADEMY PRESS Washington, D.C. 1991

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary National Academy Press 2101 Constitution Avenue, NW Washington, DC 20418 This conference summary was written by Eve Nichols for the Institute of Medicine's Roundtable for the Development of Drugs and Vaccines Against AIDS, chaired by Harold Ginsberg and Sheldon Wolff and directed by Robin Weiss. The document reports major themes of the conference discussions; these themes, however, do not represent policy statements by the Institute of Medicine. The 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 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 advisor to the federal government, and its own initiative in identifying issues of medical care, research, and education. The Roundtable is supported by the American Foundation for AIDS Research, the Merck Company Foundation, the Pharmaceutical Manufacturers Association, the U.S. Army, the U.S. Public Health Service, and the U.S. Department of Veterans Affairs. Library of Congress Catalog Card No. 91-60585 International Standard Book Number 0-309-04490-1 Additional copies of this report are available from: National Academy Press 2101 Constitution Avenue, NW Washington, DC 20418 S345 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.

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary ROUNDTABLE FOR THE DEVELOPMENT OF DRUGS AND VACCINES AGAINST AIDS HAROLD S. GINSBERG (Co-chair), Eugene Higgins Professor of Medicine and Microbiology, Department of Medicine, College of Physicians & Surgeons, Columbia University, New York SHELDON M. WOLFF (Co-chair), Physician-in-Chief, New England Medical Center, and Endicott Professor and Chairman, Department of Medicine, Tufts University School of Medicine, Boston DAVID W. BARRY, Vice President of Research, The Wellcome Research Laboratories, Burroughs Wellcome Co., Research Triangle Park, North Carolina JAMES S. BENSON, Acting Commissioner, Food and Drug Administration, Rockville, Maryland DONALD S. BURKE, Colonel, Medical Corps, U.S. Army, and Director, Division of Retrovirology, Walter Reed Army Institute of Research, Rockville, Maryland BRUCE A. CHABNER, Director, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, Maryland MAX D. COOPER, Investigator, Howard Hughes Medical Institute, and Professor of Medicine, Pediatrics, and Microbiology, University of Alabama, Birmingham MARTIN DELANEY, Co-Executive Director and President, Project Inform, San Francisco DANIEL DEYKIN, Chief, Cooperative Studies Program. Veterans Administration Medical Center, Boston R. GORDON DOUGLAS, Senior Vice President, Medical and Scientific Affairs, Merck Sharp & Dohme International, Rahway, New Jersey ANTHONY S. FAUCI, Associate Director for AIDS Research, National Institutes of Health, and Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland GERALD FRIEDLAND, Professor of Medicine, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, The Bronx, New York L. PATRICK GAGE, Executive Vice President, Genetics Institute, Inc., Cambridge, Massachusetts PETER BARTON HUTT, Partner, Covington & Burling, Washington, D.C. JAY C. LIPNER, Partner, Silverstein Langer Lipner & Newburgh, New York, New York

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary DAVID W. MARTIN, JR., Vice President, Research and Development, The Dupont Merck Pharmaceutical Company, Wilmington, Delaware CATHERINE M. WILFERT, Professor of Pediatrics and Microbiology, Department of Pediatrics, Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina STAFF ROBIN WEISS, Project Director and Director, AIDS Activities SHARON BARATZ, Research Associate RICHARD BERZON, Staff Officer GAIL SPEARS, Administrative Assistant

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary PREFACE The Roundtable for the Development of Drugs and Vaccines Against AIDS was established in 1988 by the Institute of Medicine. Composed of leaders from government, the pharmaceutical industry, academia, and the public, its mission is to identify and help resolve impediments to the speedy availability of safe and effective drugs and vaccines for human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS). The Roundtable accomplishes its mission through regular meetings of its membership, during which urgent issues are identified and discussed, as well as through public conferences and workshops that explore scientific and policy matters central to the development of AIDS therapeutics. This publication is the report of a conference held March 12 and 13, 1990, in Washington, D.C. The call for a "parallel track" for AIDS drug development—a proposal that would allow the early distribution of AIDS drugs to large numbers of patients in parallel with the conventional clinical trials that assess the drugs' safety and efficacy—has sparked controversy within the scientific community. Questions have arisen about the risks to patients of such a plan, about its potential effect on the successful completion of standard controlled trials, and about whether the parallel track will generate useful data. Larger questions have also been raised about whether the parallel track heralds fundamental changes in the philosophy underlying drug regulation in the United States, about the costs and financing of investigational therapies and associated medical costs, and about the role of expanded access mechanisms for drugs in reaching those whose health care generally is inadequate. The Roundtable sought to illuminate these issues by inviting knowledgeable speakers and the public to a two-day conference to examine proposals for expanded access to investigational drugs and possible repercussions of such an action. Two months after the conference was held, in May 1990, the parallel track proposal was published in the Federal Register and comments were

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary sought. A meeting was held in September 1990 by the Public Health Service (PHS) to discuss the comments. As this report goes to press, the PHS is finalizing the document, which, when completed, will constitute a written PHS policy. As the policy takes effect, many of the issues raised in this report will serve as valuable guideposts in evaluating the parallel track experiment. A note on terminology: Although the word effectiveness rather than efficacy was used by Congress in the Drug Amendments of 1962, we have chosen in this report to conform to the definitions of the two terms as they are commonly understood in the field of medical technology assessment. Here, the term efficacy refers to what a method (e.g., a drug) can accomplish in expert hands when correctly applied to a patient; effectiveness refers to its performance in more general routine applications.1 Therefore, most randomized clinical trials assess efficacy; the Food and Drug Administration, in reviewing the results of these trials, is evaluating the efficacy of the drugs under investigation. This report seeks to summarize the conference presentations. It contains no recommendations or conclusions, and the Roundtable has neither altered nor commented on the views and opinions expressed by the speakers, except for purposes of clarity. The Roundtable and staff wish to thank Eve Nichols, whose capable hands crafted the transcript of the meeting into a smooth narrative. We also thank, once again, the conference speakers for their thoughtful presentations, and all participants for the lively and challenging discussions throughout the conference. 1   Institute of Medicine, Assessing Medical Technologies (Washington, D.C.: National Academy Press, 1985).

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary Contents     CONFERENCE PROGRAM   1 1   HISTORICAL PERSPECTIVE   5     Early Development of Expanded Access   6     Drug Amendments of 1962   7     Modern Clinical Trials (Non-AIDS Drugs)   9     The Advent of AIDS   11     Broadening Participation   11     Accelerating the Pace of Drug Development   12     Expanded Access   14 2   RIGHTS AND RESPONSIBILITIES   19     Freedom of Choice   19     Informed Consent   20     Information Resources   20     Access   22     Competing Rights   24     Institutional Review Boards   24     New Attitudes   25 3   EVALUATION OF EXPANDED ACCESS PROGRAMS   27     Treatment Investigational New Drugs   27     Potential Risks   28     Examples from the Past   28     The Target Population   29     Safety Data   30     Impact on Conventional Randomized Trials   31     The Parallel Track Experiment   32

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary 4   CREATIVITY IN CLINICAL TRIALS   35     The Changing Environment   35     Conventional Trials   36     Preference Trials   38     Large, Simple Randomized Trials   39     Physician Participation   40     Quality Control   41     Data from the Parallel Track   41     Efficacy Data   41     Safety Data and Related Information   42     Expectations   43 5   DRUG INNOVATION AND THE PHARMACEUTICAL INDUSTRY   45     Time to Commercialization   46     Direct Costs of Expanded Access   46     Manpower Needs   47     Drug Costs   48     The Small Manufacturer   48     Product Liability   49     Concerns Specific to the Parallel Track   50     Potential Solutions   50 6   THIRD-PARTY PAYERS   53     Blue Cross and Blue Shield   55     Health Insurance Association of America   56     Health Care Financing Administration   58     Medicaid   58     Medicare   60     Resources for Clinical Investigation   60 7   IMPROVING ACCESS TO CARE   63     People of Color   65     Resource Considerations   65     Suspicion   67     Informed Consent   67     Women   68     The Gender Perspective   68     A New Approach   70     The Pediatric Population   71     Scientific Issues   72     Social Issues   72

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Expanding Access to Investigational Therapies for HIV Infection and AIDS: March 12-13, 1990 Conference Summary EXPANDING ACCESS TO INVESTIGATIONAL THERAPIES FOR HIV INFECTION AND AIDS

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