New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions

1. New Treatments for Addiction:Behavioral, Ethical, Legal, and Social Questions Committee on Immunotherapies and Sustained-Release Formulations for Treating Drug Addiction Henrick J. Harwood and Tracy G. Myers, editors

2. Committee Charge • Advise NIDA about behavioral, ethical, legal, and social issues concerning potential uses of immunotherapies and sustained-release formulations. • Asked for consensus about potential issues. • Decide which issues are the most pressing.

3. HENRICK J. HARWOOD (Chair), The Lewin Group ALEXANDER M. CAPRON, Pacific Center for Health Policy and Ethics, Univ. of Southern California JONATHAN P. CAULKINS, Heinz School of Public Policy and Management, Carnegie Mellon Univ. JAMES W. CORNISH, Philadelphia Department of Veterans Affairs Medical Center and Univ. of Pennsylvania Department of Psychiatry LEWIS E. GALLANT, National Association of State Alcohol and Drug Abuse Directors, Inc., SHIRLEY Y. HILL, Univ. of Pittsburgh School of Medicine MARTIN Y. IGUCHI, Drug Policy Research Center, RAND Corporation THOMAS R. KOSTEN, Yale Univ. Medical School JOSEPH O. MERRILL, Harborview Medical Center and Univ. of Washington S. MICHAEL OWENS, Univ. of Arkansas for Medical Sciences CHARLES R. SCHUSTER, Department of Psychiatry and Behavioral Neurosciences, Wayne State Univ. ZILI SLOBODA, Institute for Health and Social Policy, Univ. of Akron KATHRYN E. STEIN, Macrogenics, Inc., ELLEN M. WEBER, Univ. of Maryland School of Law TRACY G. MYERS, Study Director WENDY KEENAN, Senior Project Assistant Committee on Immunotherapies and Sustained-Release Formulations for Treating Drug Addiction

4. Commissioned Paper Authors and Topics • Paul Pentel, Science Issues • Thomas Kosten and Henry Kranzler, Clinical Trials • George Woody, Lessons Learned • Cindy Parks Thomas and Dennis McCarty, Integration with Current Treatment Systems • M. Susan Ridgeley, Martin Iguchi, and James Chiesa, Legality of Mandated Treatment • Thomas Murray, Ethics and Consent • Mark Kleiman, Costs and Benefits • Robert MacCoun, Behavioral Responses • Frances Miller and Kaley Klanica, Treatment of Minors

5. Major Themes and Issues • Great need for medications and great promise • Risk of over-promising, not a “magic bullet” • Risk from unintended behavioral reactions • Special problems consent/coercion • Risks of off-label use • Some health care systems not ready for these therapies • Need for new standards of treatment success • What NIDA can do . . . and the private sector is unlikely to do: 10 primary recommendations

6. Medical Basis of Medications • Active Immunization • No immediate response (first response delayed for 3-6 weeks) • Requires booster shots every 1-6 months • Timing and duration of effects requires coordination with behavioral and other interventions • Not expensive • Passive Immunization (monoclonal antibodies) • Pre-formed antibodies are administered • Dosing ever 3-6 weeks • Immediate and more predictable effects than active immunization • Currently expensive

7. Medical Basis of Medications (continued) • Depot Formulations • Long-acting (up to 1 month) formulations of current medications to enhance adherence.

8. Medical Basis Conclusions • Potential Uses of Immunotherapies • Overdose treatment (with monoclonal antibodies) • Relapse prevention • Protection against drug use or in vulnerable populations (e.g., fetus) • Depot medications for relapse prevention

9. Medical Basis Recommendation • Recommendation 1 • Support basic immunology studies for increasing the stability and longevity of antibody blood levels for sustained effects. • Develop combination therapies to simultaneously treat a variety of abused drugs.

10. Clinical Trials Considerations • FDA Clinical Trials Process • Phase I-IV considerations • FDA will likely specify the populations and indications. Examples: • Overdose is a different indication that relapse • No medications during pregnancy until proven safe

11. Clinical Trials Recommendations • Recommendation 2 • Since immunotherapy and sustained-release medications will likely be used in off-label situations NIDA should support • Preclinical studies addressing the potential safety and efficacy of these medications in vulnerable populations (e.g., pregnant women, fetus, adolescents, etc.). • Long-term studies with laboratory animals of different ages, as well as their offspring, before undertaking trials with vulnerable human populations.

12. Clinical Trial Recommendations (Continued) • Recommendation 3 • NIDA should support studies of the likely extent and nature of off-label medication use • Including factors and incentives that would promote or retard such use. • Point out policy options for policy makers to intervene if the patterns of off-label use depart from what is in the best interest of the society.

13. Treatment and Financing Issues • Opportunity to substantially expand treatment. • Potential to change social views of addiction. • Challenges for current system. • Organization • Philosophy • Costs • Privacy • Discrimination

14. Lessons Learned from Previous Pharmacotherapies • There are lessons to be learned from patient populations being treated for • Opioids: stigma, NIMBY, patient acceptance, cost • Alcohol: ideology, system capability, cost, effectiveness . . . • Nicotine: good patient/clinician acceptance, more effective w psychosocial services, marketing • These lessons are both positive and negative.

15. Treatment and Financing Recommendations • Recommendation 4 • NIDA should support studies of potential for patient discrimination due to • Long-lasting markers in the blood or urine. • If these markers deters people with drug dependence from accepting immunotherapies. • False-positive and/or false-negative drug testing.

16. Cost Issues • Cost: how much do different formulations and modes of delivery cost? • Sensitivity to effectiveness: partial effectiveness may result in different client responses (decreases or even increases in use) • Cost-effectiveness: need to compare these therapies to general health using CEA or CBA

17. Treatment and Financing Recommendations (continued) • Recommendation 5 • NIDA should support clinical effectiveness studies and financing models that integrate the new pharmacotherapies with psychosocial services in specialty and primary medical care settings.

18. Behavioral Responses Possible unintended consequences • Users attempt to overwhelm a partially effective treatment (like low dose methadone) • Drug substitution: e.g., cocaine to METH • Risk calculations: risk reduction may increase the behavior • Drug seller behavior: if use of drugs declines sellers might “compete” for market share by price or force

19. Behavioral Response Recommendations • Recommendation 6 • NIDA should support studies of behavioral consequences such as • Potential for accidental overdose. • Changes in drug use patterns include switching drugs, increasing drug dosage or overall consumption. • Changing the route of administration (e.g. nasal to intravenous for greater bioavailability)

20. Behavioral Response Recommendations (continued) • Recommendation 7 • NIDA should support studies that • Examine the extent to which the availability of immunotherapy medications might reduce the perceived risk of drug use. • The effects of such perceptions on drug use behavior in various populations.

21. Behavioral Response Recommendations (Continued) • Recommendation 8 • NIDA should support studies of the potential effect of immunotherapy medications on illicit drug markets and market-related behaviors.

22. Consent and Coerced Treatment • Vulnerable populations at risk • Frequently excluded from clinical trials • Responses to medications unknown • Can be pressured to take medications based on inherently coercive setting or circumstances

23. Consent and Coerced Treatment, Continued • Right to determine care • Legal issues • Ethical considerations • Parents may ask to give medication to minor children • Legal mandates for treatment for competent adults

24. Consent Recommendations • Recommendation 9 • NIDA should support studies to clarify procedures and standards to be applied when immunotherapy medications are considered for use in the criminal justice and child welfare systems. • This includes due process protections when there is a government-imposed treatment requirement.

25. Consent Recommendations (Continued) • Recommendation 10 • NIDA should support studies to carefully articulate the behavioral, ethical, and social risks associated with treatment of pregnant women and their fetuses and protective therapy in minors. • Develop clinical practice guidelines for such use or discouragement of such use.

26. Major Themes and Issues • Great need for medications and great promise • Risk of over-promising, not a “magic bullet” • Risk from unintended behavioral reactions • Special problems consent/coercion • Risks of off-label use • Some health care systems not ready for these therapies • Need for new standards of treatment success • What NIDA can do . . . 10 primary recommendations