Bühlen M1, Broich K1
1Federal Institute of Drugs and Medical Devices (BfArM), D-53175 Bonn, Germany
In September 2010 the European Medicines Agency (EMA) has released a Guideline on the development of medicinal products for the treatment of alcohol dependence (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.
The ultimate treatment goal in AD patients is stable abstinence. However, a clearly significant reduction in alcohol consumption with subsequent harm reduction is recognized as a valid treatment goal on the way to full abstinence.
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. In studies designed to focus on the intermediate goal of “clinically significant moderation in drinking”, efficacy should be expressed by the following endpoints: change from baseline in total consumption of alcohol (as amount of pure alcohol in g/day) as well as by reduction in number of Heavy Drinking Days (HDD, i.e. more than 60 grams of pure alcohol in men and 40 grams in women). Both are considered primary variables, since HDD are associated with specific risks such as acute cardiovascular outcomes or accidents. A clinically relevant difference compared to placebo should be demonstrated. As the key secondary endpoint, efficacy should also be evaluated in terms of responders, reflecting an expected significant improvement in health outcome on an individual patient level. This could be done by evaluating the proportion of subjects with a 50%, 70% and 90% reduction in alcohol consumption, as well as the proportion of patients achieving stable abstinence. Alternatively, evaluation of the proportion of subjects with a categorical shift in WHO risk levels of drinking is proposed.
Being the first issue of a European Regulatory Guideline directed at potential clinical trial sponsors in the field of AD, ongoing clinical development may identify points that require further specification. The presentation will therefore try to address issues that may require future regulation and discuss the guideline in the light of recent scientific developments.
Dr. Michael Bühlen & Dr. Karl Broich
Federal Institute for Drugs and Medical Devices (BfArM), Germany