Overcoming the "Valley of Death" in Medications Development for Alcohol Use Disorder - PubMed (original) (raw)

Review

. 2018 Sep;42(9):1612-1622.

doi: 10.1111/acer.13829. Epub 2018 Jul 30.

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Review

Overcoming the "Valley of Death" in Medications Development for Alcohol Use Disorder

Lara A Ray et al. Alcohol Clin Exp Res. 2018 Sep.

Abstract

As the development of novel pharmacotherapies for alcohol use disorder (AUD) has been slow, the discovery and testing of more efficacious pharmacotherapies for AUD represent a high priority research area. In fact, the transition from preclinical to clinical testing of novel compounds has been termed the "valley of death" in medications development. One key obstacle consists of the lack of an articulated set of goals for each stage of medications development. Specifically, the knowledge outputs required to make the transition from safety testing, to early efficacy detection, to confirming clinical efficacy remain unclear, and this is despite a great deal of interest and substantial financial investment in developing novel therapeutics for AUD. This qualitative critical review seeks to draw parallels and lessons from the well-established stage model for behavioral therapies research with alcohol and other substance use disorders and to apply these insights into AUD pharmacotherapy development. We argue that human laboratory models and/or pilot randomized controlled trials should serve as intermediaries in the transition from preclinical studies to large, and costly, randomized controlled efficacy trials. The relative strengths and weaknesses of pilot clinical trials versus human laboratory studies for bridging the "valley of death" are discussed and explored via a Monte Carlo data simulation study. Multiple permutations of suitable research designs informed by the behavioral therapies development model are discussed with the overall goal of promoting consilience and maximizing efficiency across all phases of clinical testing of novel AUD pharmacotherapies.

Keywords: Alcohol Use Disorder; Behavioral Therapies Research; Medications Development; Pharmacotherapy; Treatment.

© 2018 by the Research Society on Alcoholism.

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Conflict of interest statement

Conflicts of Interest: LAR receives study medication from Pfizer and Medicinova. None of the authors have any conflicts of interest to disclose.

Figures

Figure 1:

Figure 1:

Sensitivity results for pilot versus laboratory screening of novel medications. These sensitivity analyses are the result of a Monte Carlo simulation study (n = 10,000 per specification) examining the effect of pilot study sample size, mean medication effect size (Cohen’s d), multiplicative increase in laboratory versus pilot clinical trial (Lab Multiple), and correlation between laboratory and clinic effect sizes. Sensitivity was defined as the expected number of positive screens as a proportion of the total number of true positive medications.

Figure 2:

Figure 2:

Positive predictive value results for pilot versus laboratory screening of novel medications. These positive predictive values are the result of a Monte Carlo simulation study (n = 10,000 per specification) examining the effect of pilot study sample size, mean medication effect size (Cohen’s d), multiplicative increase in laboratory versus pilot clinical trial (Lab Multiple), and correlation between laboratory and clinic effect sizes. Positive predictive value was defined as the proportion of positive screens that represent true positives.

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