By Greg Hileman, Ph.D, Senior Director of Regulatory Affairs and Principle Regulatory Scientist

On March 5, the FDA approved Spravato (esketamine) nasal spray, for use in conjunction with an oral antidepressant for treatment-resistant depression. Esketamine is the s-enantiomer of ketamine, approved in the 1970’s as an anesthetic, but used off-label since the 1990’s for treating depression. Because of the risk of serious adverse outcomes resulting from sedation and dissociation caused by esketamine administration, and the potential for abuse and misuse of the drug, it is only available through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy (REMS).

Of importance to the development of products in the Division of Psychiatric Products (DPP), the efficacy of esketamine was established in one short-term study (two other, similar short-term trials did not meet the pre-specified statistical tests for demonstrating effectiveness) and one longer-term maintenance-of-effect trial using a randomized withdrawal study design. In this latter study, patients with a stable response while taking esketamine plus an oral antidepressant were re-randomized, with a portion of the group switched to placebo. Patients remaining on esketamine experienced a statistically significantly longer time to relapse of depressive symptoms than patients switched to placebo.

This approval based on an enriched study design was one of the first for the DPP. Industry and FDA have long debated the utility of enriched study design as providing substantial evidence of efficacy. The key issue identified by FDA statisticians is in controlling type 1 error with stepwise randomization schema and subsequently generalizing results from an enriched population to a general population as key. Various enrichment strategies have been proposed to address the large and growing placebo effect in psychiatry clinical trials. FDA guidance on clinical trial designs encourages the exploration of enrichment and other adaptive study designs in Phase 2, but cautions against relying on such trials for generating pivotal evidence of efficacy.

One can speculate that the approval of esketamine for depression may have political roots, since it allows FDA to exercise enforcement authority over the widespread off-label use of ketamine, now that seriously ill patients have a safe and effective approved product in this space. We are optimistic that the approval of esketamine on the basis of this randomized withdrawal maintenance study may herald a new FDA attitude on the topic supported by incoming Acting Division Director Tiffany Farchione, whose first public appearance in that role was at the 12 February Psychiatric Products Advisory Committee Meeting reviewing esketamine. In her opening remarks, Dr. Farchione explicitly stated that the Division considered the randomized withdrawal study to be “adequate and well controlled” for purposes of providing substantial evidence of effectiveness.

The strength of these remarks bodes well for patients suffering a variety of psychiatric disorders where placebo effects have been attributed to the failure of clinical trial not only in depression, but also in anxiety disorders, schizophrenia and most conditions where structured patient interviews serve as the primary endpoints.

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