By Jeffrey H. Brochin, J.D.
The FDA is addressing drug development and trial design issues relevant to the study of depot buprenorphine products (i.e., modified-release products for injection or implantation) with a draft guidance for use by industry entitled ‘‘Opioid Dependence: Developing Depot Buprenorphine Products for Treatment." The guidance reflects the FDA’s current thinking regarding the drug’s development and trial design issues and focuses on the development of products for which submission of a new drug application (NDA) through the pathway described in section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDC Act) may be appropriate. (Notice, 83 17666, April 23, 2018).
Background. Buprenorphine is an opioid which, at sufficient plasma exposures, can block the effects of exogenous opioids and, at lower plasma exposures, may be sufficient for maintaining patients who have achieved sustained clinical stability on other buprenorphine therapies. Passive-compliance formulations such as sustained-release injectable depots and implants can provide effective treatment of opioid dependence in a treatment paradigm that may be less subject to misuse, abuse, or accidental exposure compared to self-administered formulations such as transmucosal tablets and films.
Depot buprenorphine applications. Generally, an application for a depot buprenorphine product can be submitted through an abbreviated new drug application (ANDA) under section 505(j) or an NDA under section 47 505(b)(2) of the FDC Act. The regulatory pathway and the need for additional studies depend on the characteristics of the proposed depot buprenorphine product (e.g., delivery system, formulation) relative to an approved buprenorphine product. For example, a proposed monthly subcutaneous depot buprenorphine product that does not meet criteria for submission under an ANDA may be submitted under a 505(b)(2) NDA with relative bioavailability pharmacokinetic studies, and may not require additional efficacy and/or safety studies in certain instances. Applications for other depot buprenorphine products with novel features could also be eligible for submission through the 505(b)(2) pathway, but may require efficacy and/or safety trials.
Types of studies and efficacy trials. The draft guidance breaks down the study approval process into two scenarios: (1) depot buprenorphine products that are similar to an approved depot product; and (2) depot buprenorphine products with novel features relative to approved depot products.
When a sponsor needs to conduct efficacy trial(s), it should include the following elements: (1) the trial should be a blinded, controlled trial studying the doses or regimens established as blocking in the blockade study; (2) controls should include placebo or an approved formulation of buprenorphine; (3) The characteristics of patients enrolled in the trial should reflect the intended use of the proposed depot buprenorphine product; (4) an initial titration period using an approved transmucosal buprenorphine formulation may be employed if this is the intended regimen for transitioning to the proposed depot buprenorphine product; and (5) weekly patient assessment.
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