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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 IVMonday, 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.

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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

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If it were this clear…We wouldn’t be here today

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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: http://www.fda.gov/cder/Offices/CSS/presentations.htm

Audio recording made, working to post on web

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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

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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

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Case Overview

Preclinical Phase I Phase II Phase 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?

DrugDiscrimination

Phys. Dependenceand 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?

QuestionsQuestionsDevelopment ProgramDevelopment Program

• Phase I MDT

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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