Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues September 1995 OTA-BP-H-163 GPO stock #052-003-01429-7 Recommended Citation: U.S. Congress, Office of Technology Assessment, Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues, OTA-BP-H-163 (Washington, DC: U.S. Government Printing Office, September 1995). oreword IDS researchers are investigating new vaccines that would prevent infection with HIV and reduce the spread of AIDS. Some have argued that product liabil- ity concerns have discouraged investment in HIV vaccine research and devel- opment. The purpose of this OTA background paper is to describe the current state of development of HIV vaccines, and to discuss what is known about adverse reac- tions that may occur. The background paper provides an overview of ethical issues that arise in the conduct of HIV vaccine trials. The report also discusses alternatives to the current product liability system to encourage the development of HIV vaccines and to fairly compensate those who are harmed as a result of adverse reactions to the vaccine. This background paper was prepared in response to a request from the Subcommittee on Health of the House Ways and Means Committee. It is eleventh in OTA’s series of studies on HIV-related issues. The preceding papers in this series were: Do Insects Transmit AIDS? (9/87), AIDS and Health Insurance: An OTA Survey (2/88), How Effective is AIDS Education? (6/88), The Impact of AIDS on the Kaiser Permanente Medical Care Program (Northern California Region) (7/88), How Has Federal Research on AIDS/HIV Disease Contributed to Other Fields? (4/90), The Effectiveness of Drug Abuse Treatment: Implications for Controlling AIDS/HIV Infection (9/90), HIV in the Health Care Workplace (11/91), The CDC’s Case Definition of AIDS: Implications of the Proposed Revisions (8/92), Difficult-to-reuse Needles for the Prevention of HIV Infection Among Injecting Drug Abusers (10/92), and External Review of the Federal Centers for Disease Control and Prevention’s HIV Prevention Programs (9/94). Other OTA reports addressing AIDS-related issues include: Blood Policy and Technology (1/85), Review of the Public Health Service’s Response to AIDS (technical memorandum, 1/85), The Cost of AIDS and Other HIV Infections: Review of the Estimates (staff paper, 5/87), Medical Testing and Health Insurance (8/88), Adolescent Health (11/91), and The Continuing Challenge of Tuberculosis (9/93). ROGER C. HERDMAN Director iii roject Staff Clyde J. Behney PRINCIPAL PROJECT STAFF PUBLISHING STAFF Assistant Director, OTA Robert S. McDonough Mary Lou Higgs Sean Tunis Study Director Manager Health Program Director Jay Randolph Arna Lane Research Analyst1 Production Editor ADMINISTRATIVE STAFF Thomas McDaniels, Jr. Bonnie Sparks Louise Staley Research Assistant2 Electronic Publishing Specialist Office Administrator Christine Onrubia Carolyn Martin PRINCIPAL CONTRACTORS Senior Graphic Designer Word Processing Specialist David T. Karzon Monica Finch Vanderbilt University Medical Word Processing Specialist Center Charlotte Brown Wendy Mariner Word Processing Specialist Boston University School of Public Health and School of Carolyn Swann Medicine PC Specialist ________________ CONTRACTORS 1Through September 1994 Nancy Kass 2From September 1994 Johns Hopkins University School of Hygiene and Public Health David Schwartz Johns Hopkins University School of Hygiene and Public Health Robert Stein Blicker & Stein iv orkshop Participants ISSUES IN THE DEVELOPMENT AND MARKETING OF AN AIDS VACCINE—April 6, 1994 Lawrence Miike, Chairman Michael Horowitz David Schwartz Health Care Administration Division Senior Fellow Assistant Professor Department of Human Services Manhattan Institute Department of Immunology and State of Hawaii Washington, DC Infectious Diseases Honolulu, HI School of Hygiene and Public Health Peter Barton Hutt Johns Hopkins University Partner Baltimore, MD Don Des Jarlais Covington & Burling Research Director Washington, DC Chemical Dependency Institute and John Siegfried Associate Vice President for Medical Grants Management David T. Karzon Research Support Affairs Professor of Pediatrics, Microbiology Pharmaceutical Research and Beth Israel Medical Center and Immunology New York, NY Manufacturers Association Division of Pediatric Infectious Washington, DC Diseases Christine Grady Vanderbilt University Medical Center Robert Stein Research Associate Nashville, TN Partner National Institute of Nursing Blicker & Stein Research Nancy Kass Washington, DC National Institutes of Health Assistant Professor Bethesda, MD Program in Law, Ethics, and Health Department of Health Policy Tom Vernon Executive Director Derek Hodel and Management School of Hygiene and Public Health Medical, Scientific, and Public Health Director of Treatment and Affairs Research Issues Johns Hopkins University Baltimore, MD Merck Vaccine Division AIDS Action Council Bluebell, PA Washington, DC Wendy Mariner Professor of Health Law Roy Widdus Rodney Hoff Health Law Department Consultant Chief, Vaccine Trials Boston University School of Public National Vaccine Program Office Vaccine Trials and Epidemiology Health and School of Medicine Washington, DC Branch Boston, MA Division of AIDS National Institute of Allergy Tom Matthews and Infectious Diseases Associate Professor of Experimental National Institutes of Health Surgery Bethesda, MD Department of Surgery Duke University School of Medicine Durham, NC Note: OTA appreciates and is grateful for the valuable assistance and thoughtful critiques provided by the participants in OTA’s workshop on April 6, 1994. The workshop participants do not, however, necessarily approve, disapprove, or endorse this background paper. OTA assumes full responsibility for the background paper and the accuracy of its contents. v ontents 1 Overview of Findings and Executive Summary 1 Overview of Findings 1 Executive Summary 5 Potential for Adverse Reactions to HIV Vaccines 6 Ethical Issues in HIV Vaccine Trials 13 Liability and Compensation for Adverse Reactions 17 2 Potential for Adverse Reactions from HIV Vaccines 27 Role of Vaccines in the Control of Infectious Disease 28 HIV is a Unique Virus 33 Animal Models 36 Immune Correlates of Protection 37 Development and Clinical Evaluation of HIV Vaccines 38 Adverse Reactions 41 New Generation Vaccines: Implications for Safety 49 Social Harms as Adverse Events 52 Clinical Trials in HIV Infected Individuals 53 Phase III Efficacy Trials 55 Chapter 2 References 58 3 Ethical Issues in the Design and Conduct of HIV Vaccine Trials 65 Basic Ethical Principles 65 Clinical Trials of Vaccines 66 Ethical Issues in the Design of Clinical Trials 67 Selection of Sample 69 Informed Consent 70 Research in Developing Countries 73 Compensation for Adverse Reactions 76 Incorporation into Clinical Practice 76 Conclusion 77 Chapter 3 References 77 vii 4 Liability and Compensation for Adverse Reactions to HIV Vaccines 79 Responsibility for Injury and Compensation 80 Reasons for Compensating Injuries 80 Social Goals of Allocating Responsibility for Injury 83 Potential Deterrents to HIV Vaccine Development 86 Current Vaccine Research and Development 99 Tort Liability for Adverse Reactions to Vaccines 101 Product Defects 102 Potential Liability for Adverse Reactions to HIV Vaccines 112 Alternative Compensation Policy Options 119 Tort Liability Reform 120 Voluntary Contractual Arrangements 125 Government-Funded Insurance Arrangements 126 Public Compensation Systems 128 Elements of A No-Fault Compensation Program 139 Alternative Incentives for HIV Vaccine Development 145 Chapter 4 References 146 APPENDICES A A Technical Review of the Evidence for Adverse Reactions to HIV Vaccines 161 B Acknowledgments 173 C References and Glossary 179 viii Overview of Findings and Executive Summary OVERVIEW OF FINDINGS ❚ Potential and Risks of HIV Vaccines G Although the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS) is the most intensively studied virus of all time, a successful preven- tive vaccine lies at least several years ahead. In addition, we have yet to define the immune response elements necessary for protection from HIV infection. G HIV is endowed with an unusual set of capacities that enables it to evade or manipulate normal immune responses. Because of these unique capacities, a model for an effective HIV vac- cine is much more complicated than the model for other vac- cines. G More than 1,400 volunteers have participated in U.S. trials of HIV vaccines since 1988. Most vaccinees have received enve- lope-based vaccines (proteins present on the surface of the vi- rus). Adverse reactions following immunization with HIV vaccines have been minimal. G Of the more than 1,400 individuals who have participated in “Each of the U.S. trials, 17 have become infected with HIV. There is no evi- HIV vaccine dence that the experimental vaccines increased susceptibility to HIV infection or increased the rate of disease progression in strategies these individuals. may carry G A number of vaccines are being developed that use new strate- gies, and each of these strategies may carry special risks. special risks.” |1 2 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues 1. Vaccines using live vectors, such as the vaccin- G In June 1994, the AIDS Research Advisory ia virus shown to be attenuated in laboratory Committee (ARAC) of the National Institute of animals, may prove to be inadequately atte- Allergy and Infectious Diseases (NIAID) rec- nuated,