Current regulatory perspective on the development of new medications for the treatment of alcohol use disorders (AUD)

In the field of addiction research the ultimate treatment goal in alcohol dependent (AD) patients remains stable abstinence. However, treatment success rates in abstinence-oriented trial settings were modest in the past. Therefore, a clearly significant reduction in alcohol consumption (AC) is suggested as a valid treatment goal in patients not willing or able to immediately engage in treatment approaches aimed at full abstinence. Discussions about the suitability, clinical relevance and regulatory acceptability of study endpoints measuring moderation of drinking are on-going (Anton RF et al. Neuropsychopharmacology (2012) 37, 402 – 411). In September 2010 the European Medicines Agency (EMA) has released a Guideline on the development of medicinal products for the treatment of AD. It is intended to provide the regulatory framework for the conduct of future clinical trials in terms of valid treatment goals, study design, and clinically meaningful study endpoints. Hence, two types of clinical studies may be conducted: 1) relapse prevention trials oriented at full abstinence demonstrated by the continued abstinence rate and 2) harm reduction studies. If the study is designed to focus on the intermediate goal of “clinically significant moderation in drinking”, efficacy should be expressed by the following co-primary endpoints: change from baseline in total AC (grams of pure alcohol per day) as well as by reduction in the number of Heavy Drinking Days (HDD ≥60 grams of pure alcohol in men). Responder analyses, reflecting an expected significant improvement in health outcome on an individual patient level, are proposed as key secondary endpoints. Most recently, nalmefene was the first drug that was approved in Europe based on the Guideline provisions as outlined above. On-going clinical development may identify points that require further regulatory specification. Apart from providing an overview on current guideline stipulations, the presentation will therefore also try to address issues that may require future regulation, like e.g. the need for clearly delineating target populations within the wide range of AUD, handling of missing data in case of high withdrawal rates, or difficulties in demonstrating clinical relevance of treatment effects by combination of AC reduction results with epidemiological data.