1 / 17

Challenges of Abuse Potential Assessment/Future Research Needs

Challenges of Abuse Potential Assessment/Future Research Needs. Science of Abuse Liability Assessment Conference Rockville, Maryland November 10, 2011 Robert Mansbach, Discussant. Disclosure . Consultant to pharmaceutical companies. Challenges and Opportunities.

liseli
Download Presentation

Challenges of Abuse Potential Assessment/Future Research Needs

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Challenges of Abuse Potential Assessment/Future Research Needs Science of Abuse Liability Assessment Conference Rockville, Maryland November 10, 2011 Robert Mansbach, Discussant

  2. Disclosure • Consultant to pharmaceutical companies

  3. Challenges and Opportunities • Integration of assessments into clinical trials • Convergence of measures • Potential benefits of event adjudication • Integration planning • Biopharmaceutical performance

  4. Scientific Advances • Identification of molecular targets • Elucidation of neurocircuitry • Refinement of animal models • Characterization of human subjective effects • Importance of formulation • Post-marketing signal detection and risk mitigation methods

  5. Integration of Measures into Clinical Trials • Instruments for non-abusing population • Planned discontinuation periods • Genotyping Potential for altering spontaneous reporting?

  6. Correspondence Between Parallel Measures

  7. Convergence of Measures Are independent measures mutually supportive? • Correspondence of AE and clinical endpoints with results of psychometric assessments? • Drug withdrawal syndrome and structured instrument • Durability of efficacy and tolerance/dependence • AEs and PD responses in recreational users

  8. Incidence of Euphoric Mood vs. Subjective Response Incidence (% of Subjects) of Euphoric Mood Median Drug Liking VAS Emax Source: KA Schoedel, CPDD Annual Meeting 2011

  9. Blinded Event Adjudication: Benefits • Establish standardized approach to classifying events • Minimize sponsor influence • Facilitate meta-analysis • Focus on events with clearest association Potential for future prospective approach?

  10. Blinded Adjudication of Pediatric Suicide Attempts C-CASA Classification No Yes 299 No Sponsor Classification 78 Yes 343 34 Source: Posner et al., Am J Psychiat 164:1035-43, 2007

  11. Data Integration Planning • Definition of safety analysis sets appropriate for abuse potential • Short-term vs. long-term trials • Different dose ranges or dosing regimens • Inpatient vs. outpatient investigation • Populations with different vulnerabilities • What represents the best approach for estimating incidence rates? • Can incidence rates be used to define threshold criteria?

  12. Biopharmaceutical Performance • Potential alterations in exposure when formulation is intentionally disturbed • Influence of formulation on subjective responses when used as intended Development of medications with increasingly tailored PK profiles

  13. Effect of Formulation on Identification of Pharmacologic Class Source: Mumford et al., Clin Pharmacol Ther 1995;57:356-65

  14. Will Innovator and Generic Products have Equivalent Potential for Abuse? • Standard bioequivalence methods do not capture subtle differences in performance • Regulations do not require identical release mechanisms • Challenges to generic filings • Alza et al. challenge ANDA approval of generic fentanyl patches based on release mechanism—denied by FDA

  15. Sanofi-Aventis Petition: Ambien CR • Sanofi-Aventis alleged that standard BE criteria would not capture aspects of performance directly impacting therapeutic response • Sanofi-Aventis maintained that generic versions should have both IR and ER components • FDA agreed to modify BE criteria but declined to require IR and ER components • AUC0-1.5 • AUC1.5-t • AUC0-∞ • Cmax Bioequivalence Parameters

  16. Implications for Generic Equivalents • Are there circumstances under which generics differ in abuse potential? • Will testing done on innovator product sufficiently characterize generic equivalents? • Will successful challenges to BE or other characteristics represent barriers to entry? • Development of IVIVCs helpful in understanding relationship between in vitro performance/PK/PD

  17. Future Research Needs: Summary • Instruments for use in treatment population • Methods to establish correspondence between measures • Standardized event adjudication--future prospective approach? • Approaches to estimate incidence rates in clinical trials • Impact of generic conversion

More Related