FDA Gives Clarification on Regulatory Decisions on Antipsychotic Trials

Recent public comments around regulatory submissions for antipsychotic compounds have raised questions regarding development of CNS drugs and the role of active comparators in trials submitted for regulatory approval. A half-day symposium on emerging regulatory practice around approvals for antipsychotic compounds was held March 4, 2009, at the Annual Meeting of the International Society for CNS Clinical Trials and Methodology (ISCTM) in Arlington, VA.  The meeting was chaired by Ravi Anand, M.D., Anand Consulting, and Larry Alphs, M.D., Ph.D., Ortho-McNeill Janssen.  Speakers included Jeffrey Lieberman, M.D., Columbia University, Amir Kalali, M.D. Quintiles, Andrew C. Leon, Ph.D. Cornell University, Thomas Laughren, M.D., FDA, Karl Broich, M.D., BfArM.

During this session the background and implications of including or repurposing active controls in clinical trials was presented.  Dr. Laughren indicated that current FDA policy on the role of relative efficacy in risk benefit decisions for psychiatric drugs is that active controls are not required in registration trials, but are recommended because active controls provide a context in which to test assay sensitivity.  Further, negative trials (but not necessarily “failed trials”) count against a drug during review by US Regulators.  He indicated that the choice of the active control is left to the sponsor and that claims for superior efficacy can be considered, but would have to be based on hypothesis testing in a superiority design.  Laughren further indicated that observed inferior efficacy, whether or not resulting from hypothesis testing, may be noted in labeling if it is considered sufficiently robust and clinically relevant.  He acknowledged that drug-drug comparisons are usually unplanned and post-hoc, and indicated that inferiority observed in active controlled trials not specifically designed to test this hypothesis would not likely be the sole basis for failure to approve a new antipsychotic agent.

Dr. Broich indicated that to gain approval of a new antipsychotic product by EMEA, clinical development of new drugs must provide adequate assessment of benefit-risk for the treatment of schizophrenia.  To do this efficacy and safety must be established using randomized, controlled, double-blind clinical trials with the novel compounds.  These trials must include at least two positive short-term studies (6-8 weeks) with both placebo and active controls (for assay sensitivity, distinction of negative and failed studies); and demonstrate statistical significance and clinical relevance (responder rates, e.g. 30 % improvement on PANSS). Demonstration of short-term improvement must be supported by one positive maintenance of effect study (usually 6 months duration with randomized withdrawal as the preferred study design). He indicated that effectiveness studies like CATIE, CUtLASS, EuroSC or SOHO may provide complimentary information for clinical treatment guidance.  However, internal validity of these studies and interpretation of the results might be difficult due to many potentially confounding factors. Therefore, such studies are not required for approval by EMEA.  Broich further indicated that improvements of negative symptoms or cognitive symptoms are considered as possible treatment claims by EMEA.  However, for such studies clinical relevance of improvement must be confirmed by improvement in functional outcome measures studied as co-primary endpoints.

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ISCTM was founded in 2004 to gather representatives of academic and clinical specialties, the pharmaceutical industry, and regulatory bodies to exchange ideas about important clinical and public-health challenges, to examine the design and development of novel treatments for major psychiatric and neuropsychiatric disorders, and to support development of methods of evaluating them that are scientifically sound, ethical, and feasible.