Human Abuse Liability Studies: Discussions of Various Applications and Limitations During Testing

1. Human Abuse Liability Studies: Discussions of Various Applications and Limitations During Testing Marta Sokolowska, PhD Center of Excellence for Abuse Liability Grünenthal USA Bedminster, NJ marta.sokolowska@grunenthal.com

2. Conflict of interest statement Employee of Grünenthal USA

3. The opinions and information in this presentation are those of the author and do not necessarily reflect the views of Grünenthal

4. Objectives • Regulatory applications (past and future) of the human abuse potential study • To address variabilities among different drug classes that are evaluated by this methodology • To provide advice on the application of a given type of study as one that can be routinely (or appropriately) relied upon by regulatory agencies for describing the abuse potential of new drugs • To discuss new chemical entities (NCE) as well as abuse deterrent formulations (ADF)

5. Introduction • Human abuse liability study paradigm has been developed for over half a century to accommodate evaluation of multifarious NCEs and formulations • Initially developed as an academic paradigm to understand basic science of abuse potential of drugs • Adapted for regulatory purposes to provide basis for scheduling decisions

6. Major challenges for regulatory application of the human abuse potential study • Limited standardization of the study procedures • Lack of data to address some of the methodological concerns • Ongoing efforts to standardize the paradigm • FDA Draft Guidance for Industry: Assessment of Abuse Potential of Drugs (Jan 2010)

7. Study population • Definition of the study population • Historically used study populations Healthy volunteers Recreational drug users Drug abusers Drug dependent / addicts • Draft Guidance recommendation Experienced, recreational drug users who have a recent or current history of using a drug in the pharmaceutical class of the test drug and with drugs with similar psychoactive properties Exclusion criteria should include a current diagnosis of substance dependence, current abuse, and current treatment for a substance-related disorder.

8. Study population • Challenge: • To include only subjects with high sensitivity and ability to recognize the effects of the positive control • Recommendation • Standardized criteria for pharmacological qualification

9. Positive controls • Criteria for selection of positive controls based on the Draft Guidance • Should have measurable abuse potential previously established through experimental studies and epidemiological data. • Should be a drug of abuse in the same pharmacological class and preferably from the same indication as the novel drug

10. Examples of positive controls per drug class

11. Positive control • Challenges: • Application of numerous positive controls with variable dose ranges within a drug class impedes direct comparison between NCEs within the drug class • For NCEs with novel or diverse mechanism selection of positive control based on pharmacology might not be feasible • For some indications there are limited, if any, representatives that are controlled substances • Recommendation • Selection of positive control based on the pharmacology, indication as well as the observed adverse events and pre-clinical behavioral profile • A standard positive control and standard dose ranges should be established for each drug class

12. Outcome measures • To accommodate abuse liability assessment for NCEs with novel and diverse mechanism of action and new formulations multifarious scales have been developed and applied Ratings of liking (“at the moment” and “overall”) and other subject-rated effects Disposition to take the drug again, Drug identification; Subject-rated strength of drug effect Price value assessment Addiction Research Center Inventory (ARCI) Measurement of relevant physiological effects Behavioral and cognitive performance assessment Assessment of mood state changes using Profile of Mood States (POMS)

13. Outcome measures • Validation and selection of measures • Standardization of individual measures • Challenge: methodological differences between individual measures e.g., assessment of Drug Liking “at this moment” Visual Analog Scale (0-100 or 0-29) unipolar (“not at all” – “extremely”) bipolar (0 = “dislike a lot” 50=“neutral’ 100=“like a lot”) Likert scales (e.g., 0-5; -4 to 4) • Challenge: insufficient data to determine the most sensitive methodology

14. Clinically relevant vs. statistically significant findings • Focus on statistical analysis • Statistically significant differences do not necessarily represent a clinically meaningful differences • Evaluation of clinically relevant difference on subjective measures of abuse potential • Assessed only for opioids (Eaton et al., 2011) 10 points on unipolar VAS High 0-100 scale • No definition of clinically meaningful difference for other drug classes • Importance of negative controls (other than placebo) in assessment of clinical relevance

15. Abuse deterrent formulations • Human abuse liability studies are utilized to provide information on the relative abuse potential of a new formulations in comparison to the already approved products (positive controls) using various manipulations and routes of administrations • Challenge: Lack of standardized definitions Selection of the tampering methods for abuse liability studies: naturalistic experiment vs. standardized manipulations Application of the human abuse liability paradigm to assess some abuse deterrent characteristics might not be feasible or safe

16. Example • Impact of gelling properties on intravenous administration of tampered drugs • Many mechanical approaches to abuse deterrence involve gelling to impede IV administration of tampered products • IV administration of the tampered formulation might compromise subjects’ safety • Gelling might hinder syringibility of a drug, it would impact the feasibility to conduct such a study • An alternative paradigm is required to demonstrate effectiveness of gelling on IV abuse

17. Conclusions • Differentiation should be made between the academic and regulatory applications of the human abuse potential paradigm • Multiple factors contribute to the variabilities among different drug classes • Despite recent release of the FDA Draft Guidance on Assessment of Abuse Potential of Drugs, further efforts to standardize the human abuse liability paradigm are necessary • E.g., standardization of the qualification criteria and individual outcome measures • Additional research is required to answers clinical methodology needs • Although human abuse liability studies are essential for comprehensive abuse liability assessment, alternative paradigms should be considered when the human abuse liability studies are not feasible or ethical

18. Thank you