Researchers working in the field of clinical trials for addictive disorders have discussed whether the use of responder analyses (analyses which compare the proportion of patients in each treatment arm who achieve the desired response) in these trials represents "setting the bar too high." These discussions involve assumptions about the relative ease or difficulty of establishing a treatment effect using group means versus doing so using responder analyses. In (placeholder for title of McCann paper, Ref. 1), the authors have shown that using a responder analysis identified a treatment effect in methamphetamine dependence, which an initial analysis of group means did not. This demonstrates that responder analysis may be a more appropriate approach, and depending on the study design, may demonstrate differences not appreciated by group means. Other authors have also identified situations in which a responder approach demonstrates an effect where group means did not [2], or where a comparison of means yielded equivocal results of uncertain clinical significance [3]. In addition, Falk et al. [4] recently compared the use of a responder analysis to customarily used group mean comparisons in alcoholism trials and found that their responder definition was as sensitive as customary measures in detecting treatment effects.Addictions are behavioral disorders, characterized by compulsive self-administration of substances despite physical and psychosocial consequences. Although considerable attention is given in addiction trials to biological measures of drug use as endpoints, cocainuria or methamphetaminuria is only a marker and not the disorder under treatment. The aim of treatment is often expressed as an effort to modifying patients' drug use behavior, but the desired effect is improvement in physical and psychosocial consequences. Changing the behavior only minimally, without having impact on the consequences, would be pointless. Drug-taking behavior observed during the brief window of a clinical trial is a surrogate endpoint, as trials intended to show effects on physical or psychosocial consequences of drug use would need to be very long and very large, and may be impractical. When drug-taking behavior is used as a surrogate endpoint, there should be a demonstration of change in behavior that can be reasonably predictive of improvement, such as avoidance of alcohol-related health and social consequences.

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Background Over the past decade, U.S. FDA has approved 10 opioid analgesics in abuse-deterrent formulations (ADFs). ADFs are intended to reduce abuse of a prescription opioid through manipulation of the product to use one or more routes of abuse. Although it is critically needed for evaluation of the abuse deterrent properties of an opioid product, the relationship between systemic exposure and likelihood of abuse of the opioid has not been fully characterized. To fill the current knowledge gap, we have evaluated the association of subjective measures predictive of abuse potential (e.g., scores of “drug liking,” “take drug again”), which are referred to as ‘pharmacodynamic (PD)’ responses for measuring abuse potential, with systemic exposure of the opioid using the data from all the clinical abuse potential trials submitted to FDA in support of the approval of innovator ADFs. Methods Extensive pharmacokinetic (PK) and subjective response data from 11 clinical abuse potential trials in recreational opioid users following oral and nasal administration of intact and manipulated oxycodone, hydrocodone and morphine products from the FDA internal database were utilized for the present analysis. This retrospective study used data collected from January 11 th , 2010 until March 25 th , 2015. The potential relationship between PK metrics, especially those for early exposure measures, and the subjective measures of drug liking and take drug again as PD metrics of abuse potential were explored using linear and logistic regression analyses. Heterogeneity analysis was conducted to assess study-to-study variation and multi-level logistic regression analysis was used to affirm the identified PK-PD relationship based on pooled data. Findings Following oral and nasal administration of intact and manipulated opioids, the maximum visual analogue scale (VAS) for Drug Liking was generally achieved no later than the time to peak plasma drug concentration. Both heterogeneity analysis and multi-level logistic regression indicated insignificant inter study variability for the evaluated PK-PD relationships. Duration of Drug Liking response (i.e., VAS ≥ 65) lasted for 2 to 4 h after drug administration. The early portion of the systemic area under the plasma concentration-time curve (AUC), e.g., partial AUCs in the first 3 h and 4 h were found to be associated with abuse potential measures including maximum Drug Liking VAS and maximum Taking Drug Again VAS. Neither a formulation factor (e.g., immediate-release vs. extended-release, intact vs. manipulated) nor a route of administration was identified as a significant factor together with early partial AUCs to predict the probability of maximum Drug Liking or maximum Take Drug Again responses being greater than or equal to 65. Interpretation Our assessment indicates that the measure of early systemic drug exposure of opioids is the bes...