Transcript Slide 1

CPDD 2008 – Workshop IV
Monday, June 16
Challenges for Abuse Liability Testing
from Drug Development to FDA Approval
Review of FDA/Industry Dialogue
Session on Abuse Liability
(February 20, 2008)
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
Case A
Case B
 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?
Case C
 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?
Case D
 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?
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Case Overview
Preclinical
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Case A
Phase I
• Phase I
FIH
Receptor binding
Microdialysis
Animal Pharmacology
Animal PK
CNS Safety
Pharmacology
• Phase I
MDT
Drug
Discrimination
Phase II
Early Preclinical Assessment
• Are there any early “signals” of
concern for Abuse?
• Any additional data helpful?
Behavioral Pharmacology
• Design features of DD and
PD&W studies
Study in drugabusing patients
Note: company strategy
requires early “de-risking”
of target
Development Program
Questions
Rat SelfAdministration
Behavioral Pharmacology
• Assessment of results of SA
• Overall conclusion from
preclinical assessment
• Is there a need for a formal
clinical assessment of abuse?
Behavioral Pharmacology
• Assessment of results of DD
and PD&W
• Design of Self-administration
• Phase III Pivotal Efficacy Studies
• Phase II POC/Dose-Ranging
Study (n=100)
Phys. Dependence
and Withdrawal
• 2 week rat toxicology
• 2 week dog toxicology
Phase III
Clinical Assessment
• Review results of Clinical
Abuse study
• Any further work needed?
Clinical Assessment
• Review of AE profile from FIH
study
• How to design Clinical study in
drug abusing patients to
maximize value?
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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
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