How the Food and Drug Administration Drug Approval Process Relates to the Potential Approval of Intravenous Racemic Ketamine for Treatment-resistant Major Depression.

This column focuses on the status of intravenous racemic ketamine for the treatment of patients suffering from a form of major depressive disorder that does not respond to trials of currently available biogenic amine antidepressants. To provide context, the column reviews the 3 pivotal elements of the usual Food and Drug Administration (FDA) drug approval process: (1) the unmet medical need (ie, the indication) for which the drug is being developed, (2) the efficacy of the drug for that condition, and (3) the safety/tolerability of the drug. This column is based on the author's 45-year history of drug development work and is not a statement of the FDA. There are typically 3 phases in the drug development process: (1) studies done in normal volunteers, (2) typically small-scale proof of concept studies, and (3) large-scale registration trials. This third phase is critical in determining the efficacy, safety, and tolerability of the drug in a manner that most closely follows the clinical use of the drug. This column focuses specifically on whether generally small-scale studies done in academic centers are sufficient for drug approval, and it briefly reviews lithium and clozapine as examples of psychiatric medications that had such academic research in the literature, as well as clinical use in other countries. Those data supported the unique value of these medications in patients with bipolar disorder and treatment-resistant schizophrenia (ie, the unmet medical need), respectively, and the findings led American psychiatrists to advocate for FDA approval of these medications. Their efforts led to the needed registration trials for FDA approval of these medications. This column reviews the key features of registration trials and the reason that they are critical for FDA approval, and it discusses 2 special considerations related to the intravenous administration of racemic ketamine. First, racemic ketamine is not esketamine but, instead, it contains R-ketamine in addition to S-ketamine (ie, esketamine). The second consideration is that differences between intravenous and intranasal administration may affect the safety of the drug. While safety concerns were specifically addressed in the registration trials for esketamine, comparable research remains to be done for intravenous racemic ketamine. Understanding how the FDA's drug approval process works is important for prescribers, their patients, and the public.