Commentary on Falk.
Authors: R. Meyer
Year: 2011

T HE PAPER BY Falk and colleagues (2010) is a very important contribution to the clinical trials literature in the alcohol field. It highlights the leadership role that has been played by NIAAA in its efforts to establish valid and reliable endpoints for medications development in the treatment of alcoholism, through the reanalysis of important archival data sets. Without agreement on a robust indicator of treatment efficacy, pharmaceutical companies faced a daunting task in selecting a primary outcome criterion from among the dozen or more different outcomes that had been used in the multiple published clinical trials over the past 2 decades. The consensus process that the leadership of NIAAA began in 2001 (Allen, 2003) was affirmed in their definition of high risk drinking in guidelines issued in 2007 (National Institute on Alcohol Abuse and Alcoholism, 2007). Defined as 4 or more drinks per drinking day for women and 5 or more drinks per drinking day for men, the frequency of heavy drinking days is the final common pathway to increased risk of the broad array of medical and psychosocial consequences of alcoholism. To apply the standard of ‘‘heavy drinking’’ in Phase 3 clinical trials of efficacy, it was necessary to develop a dichotomous endpoint. In 2006, the FDA defined the percent of subjects with no heavy drinking days as the primary endpoint for registration trials in the alcohol field. Subsequently, the American College of Neuropsychopharmacology (ACNP) convened a meeting of academic leaders, pharmaceutical industry sponsors, and representatives from NIDA, NIAAA, and the FDA to highlight the needs and opportunities for medications development in the treatment of alcoholism and drug addiction. That meeting highlighted the extraordinary consensus that had emerged among the leadership at NIAAA, the relevant leadership at FDA, and leading researchers regarding efficacy criteria necessary to establish a pathway to new drug approval. At this point, 7 companies have provided support to ACNP to continue the process of collaboration among academia, government, and industry to advance medication development in the alcohol field through improved clinical trials methodology. The process, ably chaired by Raymond Anton and Raymond Bartus, has considered other relevant issues including subject selection, potential moderating variables, handling data from dropouts, and the necessity for a ‘‘grace period’’ before evaluating early signs of efficacy. Falk and colleagues, in their secondary analysis of the databases from COMBINE (Anton et al., 2006) and from the multisite trial of topirimate (Johnson et al., 2007), address these same points in their analysis of grace periods and imputation. In general, the reanalysis supports percent of subjects with no heavy drinking days as the primary outcome. Appropriately, Falk et al. also encourage the search for ‘‘more sensitive and clinically meaningful outcome measures, including alcohol sensitive biomarkers.’’ At this stage, medications development in the alcohol field seems to be at a very good place. In a number of ways, the level of interest and excitement about the prospects for new drug development in the alcohol field is reminiscent of the early days of psychopharmacology (1956 to 1970). In this, there should be both a sense of opportunity as well as a note of caution. The early clinical psychopharmacologists developed rating scales that continue to define the efficacy for new drug development to this day. Perhaps related to this phenomenon, the drugs that have been developed since the late 1980s have demonstrated at best a different safety profile and equivalent efficacy—compared with their predecessors. The animal models that were developed in the early days were focused on differentiating between sedating anxiolytics, antipsychotics, and antidepressants, and these methods have continued to inform decision points in the preclinical phase of drug development. Curiously, the animal models for anxiolytics failed to predict the clinical efficacy of selective serotonin reuptake inhibitor (SSRI) and serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants in a variety of anxiety disorders. There has been no strong base of translational research linking developments in neuroscience to early studies in informative patient samples. The symptom—focused basis of pharmacotherapy inevitably led to a symptom—based diagnostic system (DSM-III) that has gone through several additional iterations driven by a consensus process, and not by scientific developments. A DSM diagnosis defines eligibility for clinical trials in psychopharmacology, but subjects entering antidepressant clinical trials can meet the same diagnosis through different criteria. More particularly, this has resulted in placebo response rates approaching 50%, and drug companies routinely expect to run multiple Phase 3 trials of new antidepressants to obtain 2 successful outcome studies (Gelenberg et al., 2008). In addition, nearly all psychotropic From the Best Practice Project Management Inc., Bethesda, Maryland. Received for publication December 5, 2010; accepted December 7, 2010. Reprint requests: Roger E. Meyer, MD, Best Practice Project Management, Inc., PO Box 30219, Bethesda, MD; Tel.: 301-9519552; Fax: 301-951-0739; E-mail: rmeyer@best-practice.net Dr. Meyer is Professor of Psychiatry at Penn State Hershey Medical Center, Adjunct Professor of Psychiatry at the University of Pennsylvania and Clinical Professor of Psychiatry at Georgetown. The work was not paid for or supported by NIH. Copyright 2011 by the Research Society on Alcoholism.