FDA Guidance for Industry: Assessment of Abuse Potential of Drugs: Overview, Issues and Framework for a Decision Tree

1. FDA Guidance for Industry: Assessment of Abuse Potential of Drugs: Overview, Issues and Framework for a Decision Tree Michael Klein, Ph.D. FDA/CDER/CSS The Legacy Hotel & Meeting Centre, Rockville, MD November 10, 2011

2. The opinions and information in this presentation are those of the author and do not necessarily reflect the views and policies of the FDA

3. Abuse potential assessment is not about a single decision tree, but a progressive row of decision trees that will take you to a destination of appropriate abuse assessment of a drug.

4. Background • FDA Draft Guidance for Industry– Assessment of Abuse Potential of Drugs Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM198650.pdf (Published January 27, 2010) • To assist in assessing abuse potential of NMEs • Early signal in drug development • Stepwise approach • Provides details on application of scientific methodology that is highly predictive of abuse potential • Recommends few additional special studies beyond those carried out for drugs without abuse potential

5. Guidance – Key Points • Data from abuse potential studies contribute to develop product labeling & drug scheduling recommendation • If animal and human abuse potential studies and the AEs profile do not show rewarding effects or other abuse-related behaviors or pharmacology similar to other controlled substances, a scheduling recommendation is unlikely • Sponsors are encouraged to proactively interact with FDA in planning to conduct abuse potential studies

6. Abuse Potential • Characterizes the ability of a drug to produce positive psychoactive effects, which is viewed as correlated with, or predictive of its intentional use in non-medical situation, repeatedly or even once • Positive psychoactive effects may include euphoria, hallucinations, perceptual and other cognitive distortions, and mood changes

7. Why is abuse potential assessment important? • Healthcare providers, patients, and the public need to know whether the new drug is likely to be abused after approval and marketing • For protection of the public health • Because a scientific assessment of the properties of a drug are most predictive of its abuse • To consider as part of the safety evaluation of drugs • To provide the basis for regulatory actions related to drug control

8. Future Research • Experiences from the past, and lessons learned, show us there is need for future research to help guide future regulatory actions in this area • We continue to develop a body of scientific methods to help us in assessing the public health risks related to abuse of new drugs • Regulation of new drug candidates should rely on the best scientific data that can be acquired • Pharmaceutical Industry representatives and others offered numerous questions and comments related to our guidance on the science of abuse liability

9. Today’s Program • Preclinical challenges - New sites of action • Human abuse potential study • Subjects, Design, Outcome Measures, Statistics • Adverse events as a signal for abuse potential • Relevant AEs, Drug class effects, Validation • Decision tree to assess abuse potential in drug development

10. 6 7 8 9 10 6 Scheduling Timeline CSA 7 8 9 10 ? ? ? ? ? OCC CSS scientific scheduling determination “8 Factor Analysis” is drafted CDER FDA FDA FOIA clearance Process For Review After NDA Submission Months NDA Timeline FD&C and PDUFA Conduct Review* and Issue Discipline Review Letters AC meeting window Complete primary reviews* Complete secondary reviews CSS NDA review Complete CDTL review NDA Action Date Publish in FR ASH DEA Advisors and Consultants Clearance Management Reviews NIDA Consult

11. Abuse Potential in Relation to the Drug Development Timeframe Nonclinical Testing R&D Clinical Research & Development Phase I • Chemistry • Receptor Binding • Functional Assays • Animal Pharmacology • Animal PK • Active Metabolites • CNS Safety Pharmacology • Toxicology Studies • Drug Discrimination • Self-Administration • Clinical Studies-AEs • Acute Performance N D A I N D Phase II • Clinical Studies-AEs • Drug Discrimination* • Self-Administration* • Dependence & WD • ___________ • * Examine therapeutic dose range Phase III • Clinical-Studies-AEs • Abuse Potential Studies

12. NDA – Basis for Scheduling • Proposal for scheduling & labeling (Module 1) • Summary of abuse data: Public health risk, comparison to pharmacologically similar substances (Module 2) • Chemistry (Module 3) • Structure, Synthesis, Extractability, Solubility • Pharmacology (Module 4) • Binding, Functionality, Animal behavioral studies, Toxicity, Overdose, PK-PD • Clinical Trial Data (Modules 4 & 5) • Analysis of adverse events, Performance impairment • Tolerance, Physical dependence & withdrawal • Subjective effects - drug liking, euphoria, good drug effects

13. Objectives of Decision Tree • To establish a simplified decision model for improved regulatory efficiency, consistency, and transparency in drug abuse potential assessment • To establish a progressive decision model that aligns with real-world, clinical development models for all Sponsors • As a draft document, to provide an opportunity for stakeholder feedback on regulatory model expectations and abuse potential development

14. 20 QUESTIONS - Abuse Potential Assessment Decision Tree (ROADMAP) 1 2 3 PK in animals? Chemistry? 4 Binding? 5 Receptor Function? CNS-active? AEs in animals? 6 7 Effects in animals? 8 Abuse AEs in patients? 9 10 Reward effects in animals? 11 Physical dependence in animals? 12 Study plans? Abuse AEs in healthy humans? 13 Physical dependence in humans? 14 20 15 Human abuse potential study? 16 Label appropriate? Reward effects in humans? 17 Abuse AEs in larger patient population? 18 19 Submission complete? NDA info shows abuse? Reports of actual abuse outside U.S.?

15. Are the NME or its active metabolite(s) CNS active? (Nonclinical) No STOP Conceptual Framework For Decision Making Yes Do NME or active metabolite(s) have opioid, cannabinoid, stimulant, depressant or hallucinogenic properties (Nonclinical)? No STOP Yes No For relative ABUSE POTENTIAL Reinforcing or rewarding properties in animals or humans (Phase I)? STOP Yes HUMAN ABUSE POTENTIAL STUDY (EOP2 or 3): If safe; if necessary for scheduling relative to positive control; if placement in one of two CSA schedules are possible Demonstrate in humans similar reinforcing or rewarding properties & dependence liability as other Controlled substances For DEPENDENCE LIABILITY • 1. NONCLINICAL • 2. CLINICAL • Assess signs, symptoms, severity & • similarity to other drug classes; • Manage symptoms of withdrawal Assessment of: 1. ADVERSE EVENTS (Phase 1,2,3) 2. ABERRANT Behaviors (Phase 2,3) 3. Animal & Human PHARMACOLOGY Are the abuse and dependence properties of the NME similar to other drugs that are scheduled? Yes No RECOMMEND SCHEDULING NO SCHEDULING

16. In conclusion • Today’s program will cover preclinical and clinical approaches and challenges • Visit the poster room where we have selected poster presentations that are related to the oral presentations • We hope to have adequate time for discussion of all issues at the end of the day • Any questions?

17. Acknowledgments • Silvia Calderon, Ph.D. • Corinne Moody • Sandra Saltz • Stephen Sun, M.D. • Katherine Bonson, Ph.D. • Ling Chen, Ph.D.