The U.S. Food and Drug Administration (FDA) has issued Titan Pharmaceuticals, Inc. a Complete Response Letter (CRL) to its New Drug Application (NDA) for Probuphine, the company’s investigational subdermal implant for the maintenance treatment of opioid dependence in adult patients.
Marc Rubin, M.D., executive chairman of Titan Pharmaceuticals, commented in a press release: “Titan and our partner, Braeburn Pharmaceuticals, are extremely surprised and disappointed with the FDA’s response. Probuphine is a diversion-resistant formulation that is consistent with the recently-issued FDA guidance supporting diversion- and abuse-resistant products, and the NDA was designated Priority Review by the FDA. We believe Probuphine has demonstrated both safety and efficacy in accordance with primary endpoints that were pre-agreed with the FDA and, moreover, the safety, efficacy and overall approval of Probuphine was strongly supported by the Psychopharmacologic Drugs Advisory Committee. Given the nationally-recognized, growing and devastating opioid dependence epidemic, there is critical need for new safe and effective treatments that reduce the likelihood of abuse, diversion and accidental pediatric exposure, and Titan and Braeburn remain committed to making Probuphine available for patients that need it.”
The CRL states that the FDA cannot approve the application in its present form. Some major concerns with the application in its present form, which were originally detailed on Bio-wire, seem to be:
- Probuphine’s presumably underwhelming dosage remains a big problem.
- Opioid addicted patients may find ways to remove Probuphine from their body and extract the buprenorphine from the “rods.”
- Doctors, particularly psychiatrists, that may want to use this product will have difficulty due to the fact that it has to be surgically installed and removed. With that, many doctors that may use this product don’t have an area in their office suited for any type of surgical procedures.
The FDA has requested additional data supporting the efficacy of Probuphine, including:
- The ability of Probuphine to provide opioid blockade of relevant doses of agonists
- The effect of higher doses of Probuphine, ideally doses more closely approximating the blood plasma levels associated with sublingual doses of buprenorphine of 12 to 16 mg / day
- Human factors testing of the training associated with Probuphine’s insertion and removal
The CRL also included recommendations regarding product labeling and the implementation of the Risk Evaluation and Mitigation Strategy (REMS).
Titan and Braeburn Pharmaceuticals, which has licensed the commercialization rights for Probuphine in the U.S. and Canada, say the companies are committed to addressing the concerns raised by the FDA in the CRL. Titan will discuss with the FDA the scope of the CRL comments to obtain clarification and determine next steps.