Review of human abuse potential study methodology for abuse-deterrent formulations

Abstract

s / Drug and Alcohol Dependence 140 (2014) e169–e251 e199 ysis and reporting were supported by grants R01 AA0016407, R01 AA018352, P20 AA017831 and NIDA T32DA007292. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.553 Review of human abuse potential study methodology for abuse-deterrent formulations Kerri A. Schoedel1, Beatrice Setnik2, Carl L. Roland2, G.C. Pixton2, M. Shram1, Naama Levy-Cooperman1 1 INC Research, Toronto, ON, Canada 2 Pfizer Inc., Cary, NC, United States Aims: Abuse/misuse of prescription drugs is a significant problem. Various novel approaches to mitigate such use incorporate abuseand tamper-deterrent features into higher risk products, e.g., opioids. Such products should be evaluated in humans prior to marketing to determine their abuse potential. Methodological issues with these products differ from those of new chemical entities and specific design considerations are needed. To provide review of methodology for clinical evaluation of ADFs. Methods: ADF approaches may include chemical or physical barriers, prodrugs or agonist/antagonist combinations.Many products aim to deter intranasal (IN) and/or intravenous (IV) use; some products may also deter oral abuse. Abuse potential studiesmust consider the physicochemical and pharmacological nature of the investigational product (IP), and clinical studies assessing the intended/unintended routes of administration (ROA) should be performed when safe or feasible. Subjects should be experienced recreational drug users, and should also have experiencewith tampering and/or the relevant ROA. Single doses of IP and comparator are generally used, as the effects of the drug substance are usually well-understood. Multiple doses of the IP and comparator may be needed for some products, e.g., those providing “overdose protection”. Studies should typically include placebo. One challenge is the manipulation of products, e.g., crushing for IN/lV use. Manipulations and administration must be carefully standardized. In addition, due to obvious (intended) differences in formulations, blindingmay present a challenge andmust be balanced against the need to evaluate the “real-world” nature of the product. A reduced battery of traditional study endpoints may be used, i.e., those most relevant to abuse and class of interest. Finally, standard statistical analysis is used and may incorporate a “responder” analysis. Conclusions: Traditional human abuse potential study design can be applied to the evaluation of ADFs; however, design modifications may be needed. Financial support: INC Research Toronto Inc and Pfizer Inc. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.554 RCT of drug counseling and abstinence contingent buprenorphine in Malaysia Richard S. Schottenfeld1, Marek C. Chawarski1, M. Mazlan2 1 Psychiatry, Yale University Medical School, New Haven, CT, United States 2 Substance Abuse Center Muar, Muar, Malaysia Aims: To evaluate whether the efficacy of office-based buprenorphinemaintenance treatment (BMT) with brief physician management (PM) and weekly medication dispensing in Malaysia is improved by provision of weekly, individual behavioral drug and HIV risk reduction counseling (BDRC), abstinence-contingent provision of take-home doses of buprenorphine (ACB), or the combination of BDRC and ACB. Methods: Opioid-dependent individuals completing BMT induction (N=234) were randomly assigned to 26weeks of BMT+PM, BMT+PM+BDRC, BMT+PM+ACB, or BMT+PM+BDRC+ACB. PM was provided by 2 primary care physicians working in busy private practice clinics. BDRC was provided by specially trained nurses. Primary outcomes were proportions opioid-negative urine tests and proportions meeting criteria for protective transfer for persistent illicit opioid use. Results: Patients were all male; mean (SD) age 38.7 (10.5) years; 95% ethnic Malay; 93% less than high school education; 44% employed full time; 25% married; 38% current ATS use; 9% HIV positive; 70% Hepatitis C positive. There were no significant baseline differences among treatment conditions. Retention averaged 145 (51) days out of 182 of offered active treatment and did not differ significantly among groups. Proportions of opioidnegative tests across randomization cells were 50% for PM only, 57% for PM+BDRC, 62% for PM+ACB, and 75% for PM+BDRC+ACB (p<0.001); differences related to both treatment componentswere also statistically significant (ACB: p<0.002, BDRC: p<0.05). 25 patientsmet criteria for protective transfer: 14 assigned to PMonly, 4 to PM+BDRC, 5 to PM+ACB, and 2 to PM+BDRC+ACB (p<0.002). Conclusions: The study results support the feasibility and the efficacy of providing behavioral counseling (BDRC), simple contingency management using takehome medications to reinforce abstinence (ACB), and the combination of BDRC+ACBduring officebased BMT in busy primary care practices in Malaysia. Financial support: R01 DA014718; K24 DA00445; CMHC/DMHAS/State of Connecticut. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.555 Impulsivity in substance dependence: A meta-analysis Christian G. Schutz, S. Sahoo, M. Krausz Psychiatry, Institute of Mental Health, Vancouver,