FDA CRL - ACLARIS THERAPEUTICS INC

The FDA issued a Complete Response Letter (CRL) to Clarus Therapeutics, Inc., indicating that its New Drug Application (NDA 206089) for oral testosterone undecanoate (Jatenzo), initially submitted on January 3, 2014, cannot be approved in its present form. Following a review of the application and subsequent amendments, the FDA identified several key deficiencies.A primary concern is Jatenzo's clinically significant increase in blood pressure, observed as a 5.0 mmHg average systolic increase in ambulatory monitoring, with larger increases in hypertensive individuals. This elevation poses an increased risk of serious cardiovascular events, including heart attack and stroke, potentially outweighing the drug's benefits for at-risk men. To address this, Clarus must propose comprehensive risk mitigation strategies within the drug's labeling, such as a Boxed Warning and revised Contraindications, and potentially implement a Risk Evaluation and Mitigation Strategy (REMS).Secondly, the proposed method for monitoring total testosterone concentrations in patients using plasma samples was deemed inadequately validated. The FDA requires Clarus to conduct further studies comparing testosterone measurements across various sample types, temperatures, and time points to definitively assess and prevent ex vivo conversion of the drug to testosterone. Should these studies reveal inaccuracies impacting the Phase 3 trial data, a new efficacy trial may be required.Finally, the nonclinical studies submitted were considered insufficient to support approval via the 505(b)(1) pathway. Specifically, the doses used in fertility and carcinogenicity studies were inadequate to meaningfully evaluate the product's chronic effects. Clarus must provide sufficient and appropriate nonclinical data to resolve these deficiencies.