Mark Ammann, Pharm.D. Chair, CCALC President, Catalyst Regulatory Services, LLC

1. Science of Abuse Liability AssessmentNovember 10, 2011 Perspective of Cross Company Abuse Liability Consortium (CCALC) - Applications and Future Research Needs Mark Ammann, Pharm.D. Chair, CCALC President, Catalyst Regulatory Services, LLC

2. Disclosure Regulatory Affairs consultant to numerous pharmaceutical companies

3. CCALC - Introduction • Founded in June 2006 • “Grass roots” Industry organization • Approximately 80 people representing >25 pharmaceutical companies • Includes regulatory, preclinical, clinical, and risk management/post-marketing workgroups • Objectives: • Collaborate to educate other industry colleagues • Outreach for open scientific exchange with key stakeholders

4. Key activities to date • Dialogue Session I – February 2008 • Purpose: to facilitate open discussion between Industry and FDA on abuse liability assessment for pharmaceuticals • No publicly available guidance • Seeking clarification on CSS positions and policy • Industry posed 85 questions in the context of 4 hypothetical case studies • Written responses provided by CSS • Audio recordings available • http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm180766.htm

5. Key activities to date • Draft Guidance on Assessment of Abuse Potential of Drugs – January 2010 • >250 Comments submitted to Docket ~March 2010 • Dialogue Session II – November 2010 (1.5 Days) • Focused on exchanging opinions on Draft Guidance • Scientific • Procedural (within remit of HHS) • Industry raised issues and made proposals to CSS in response to Draft Guidance • 8 Regulatory, 36 Preclinical, 38 Clinical and 16 Risk Mgmt/Post-Mkt • Point-by-point minutes prepared • Audio available • RAPS Publication: Companies Unite to Advance Regulatory Landscape of Abuse Potential Assessment • http://www.raps.org/publications-amp-resources/regulatory-focus.aspx

6. High Level Objectives • Have preclinical and clinical methodology that… • Is reliable (agreed among stakeholders) • Has clearly interpretable results • Is predictive • So that we can… • Determine whether there is a risk of abuse • Qualify and quantify the risk • Suitable methods need to be available to identify this risk early in development • Some projects are not viable if they have abuse liability

7. Next Steps Issuance of (draft) guidance is important step but clearly only an interim one There remain fundamental scientific questions Continue the scientific exchanges and advances that we have begun

8. Future Research Needs • Application of methodology in new populations • Validation of abuse liability scales for use in healthy drug naïve subjects (i.e. to subjective measures to determine signals in early clinical trials) • Determination of whether there are differences between drug naïve vs. experienced drug users • Validation of methods in treatment populations • Importance of individual data vs. statistical comparisons between groups • Interpretation of outlier data (clinical and preclinical)

9. Future Research Needs • Novel Mechanisms • Selection of appropriate controls • Methodology • Classification of AEs predictive of abuse • Categories appropriate to stimulant, depressant, opiate, cannabinoid, hallucinogen • Standardization of how AEs are gathered (spontaneous, solicitation, etc.) • Threshold of concern for AEs

10. Future Research Needs • Drug accountability • Valid measures of diversion/abuse potential • Need consistent definition of parameters measured and consistent coding • No recognized threshold for concern (i.e. unaccounted for test drug) • Potential differences between the controlled setting of a clinical trial and the marketplace

11. Future Research Needs • Post-marketing evaluation – Epidemiology • Methodology • Weighting of various data sources • Appropriate denominator for risk/rate calculations • Value of internet data as “early warning” signal • Level of evidence required to re-evaluate scheduling and labeling

12. New Drug Development Tools (DDT) • Guideline: Qualification Process for Drug Development Tools – Oct 2010 • For potential use, in multiple drug development programs • Biomarkers • PROs and Rating Scales • Agreement that a DDT can be relied upon to have a specific interpretation and application in drug development and regulatory decision-making • Opportunity for collaboration

13. Pre-Competitive Activities • Pre-competitive initiatives • Companies reluctant to evaluate novel methodology on development compound • Develop new methodology or to refine/validate existing methodology for regulatory decision making • Exchange non-proprietary data from completed experiments • Support experiments to compare methodology in non-proprietary compounds • Critical Path Opportunity List (Mar 2006) • #38 Development of Trial Protocols for Specific TAs • “For example, assessment of drugs for their abuse liability is an important societal and development concern and requires the conduct of specific clinical trials”

14. Continued collaboration(industry, academia, government) • What can CCALC do to facilitate scientific advancement? • Centralized access to large number of Industry experts • Potential access to large amounts of data • i.e. non-proprietary data on control groups, placebo patients • Continued education • Collaboration