0 Version: 2/14/08 Challenges for Abuse Liability Testing from Drug Development to FDA Approval Review of FDA/Industry Dialogue Session on Abuse Liability (February 20, 2008) CPDD 2008 – Workshop IV Monday, June 16 Conflict of Interest Statement: All data presented in the case studies for this Dialogue Session were fictitious for the purposes of exchanging opinions on interpretation, and recommendations. No proprietary interests exist, nor was any funding provided that would represent a conflict on the part of any of the speakers.

1 Version: 2/14/08  Overview of FDA/Industry Dialogue Session on Abuse Liability (February 20, 2008)  Mark A. Ammann - Regulatory Affairs, United BioSource Corporation  Presentation of Sample Case A  Beatriz A. Rocha - Regulatory Affairs, Merck Research Laboratories  Silvia N. Calderon – Controlled Substance Staff, Center for Drug Evaluation and Research, FDA  Q & A

2 Version: 2/14/08 If it were this clear… We wouldn’t be here today

3 Version: 2/14/08 FDA/Industry Dialogue Session on Abuse Liability (February 20, 2008)  Organized in partnership with PhRMA  Interactive session between FDA Controlled Substance Staff and Pharmaceutical Industry  Session based around 4 hypothetical case studies  Industry authored and presented case studies (embedded 85 questions)  Collaborative development with CSS (CSS prepared written responses to each question)  Both preclinical and clinical components to each case  Slides presented at the meeting available:  Audio recording made, working to post on web

4 Version: 2/14/08 General Remarks on Case Studies  Companies often have uncertainties regarding scheduling implications  Sponsors often makes “judgment call” as to likelihood and level of scheduling with incomplete information  Hypothetical Cases developed to illustrate some of the situations faced in Development of new agents  Intentionally developed cases with “grey” situations  Used cases to elicit current FDA position  Presented data chronologically, posed questions at discrete milestones  Dialogue allowed FDA’s position to be put “on the table”  Time allowed for very little debate  Identified some areas where current state of science makes interpretation or advice difficult  Maintained a “Parking Lot” of areas where we may need to work to improve methodology

5 Version: 2/14/08 Introduction to Hypothetical Cases  Novel mechanism for a sexual dysfunction indication.  What package is needed to substantiate that this product does not have abuse potential?  Precedented chemical class with some historical evidence of abuse potential  Is there an opportunity to demonstrate that a novel member of this class does not have abuse potential?  Alternatively, if scheduling consistent with the rest of the class is acceptable to the Sponsor, what is the minimum necessary abuse potential testing?  Novel mechanism for CNS indication predominantly treated by scheduled products  What package is necessary to substantiate that the new product is different from the predecessors? Is there a higher burden of evidence in some indications?  Precedented chemical class that is CNS-penetrant, but no historical association with abuse  How much data is sufficient to confirm that another agent in this class does not have abuse potential? Case A Case D Case C Case B

6 Version: 2/14/08 Case Overview PreclinicalPhase IPhase IIPhase III Receptor binding Microdialysis Animal Pharmacology Animal PK CNS Safety Pharmacology 2 week rat toxicology 2 week dog toxicology Phase I FIH Early Preclinical Assessment Are there any early “signals” of concern for Abuse? Any additional data helpful? Drug Discrimination Phys. Dependence and Withdrawal Rat Self- Administration Behavioral Pharmacology Design features of DD and PD&W studies Behavioral Pharmacology Assessment of results of DD and PD&W Design of Self-administration Behavioral Pharmacology Assessment of results of SA Overall conclusion from preclinical assessment Is there a need for a formal clinical assessment of abuse? Phase II POC/Dose-Ranging Study (n=100) Study in drug- abusing patients Phase III Pivotal Efficacy Studies Case A Note: company strategy requires early “de-risking” of target Clinical Assessment Review of AE profile from FIH study How to design Clinical study in drug abusing patients to maximize value? Clinical Assessment Review results of Clinical Abuse study Any further work needed? Questions Development Program Phase I MDT

7 Version: 2/14/08 Parking Lot  Handling/interpretation of [and importance placed on] “outlier” data  When developing new formulations of an existing product, if the comparator selected is the same active ingredient, we need to develop methodology for comparing a drug to “itself.”  Questionnaires for directed evaluation of potential signs of abuse (adverse events) are only validated in drug abusers, not patient populations enrolled in clinical efficacy trials  We need to develop valid methods for assessing “drug hoarding”, misuse and diversion.  Is there value to looking at “pooled” placebo response data across clinical abuse liability studies?  Industry is concerned about bias of looking at data “post-hoc” across many endpoints  A subsequent meeting should be convened to discuss (among other things) post-marketing assessment and risk management – which were not addressed at this meeting