Hunch.
So the FDA asked for clarification on the REMS, Braeburn responded, and the FDA extended the PDUFA date. Sunil has said Braeburn and Titan are working with the FDA to “finalize the REMS and the product labeling.” The biggest REMS issue I noticed was removal of the implant, but now that we are 47 days over the original PDUFA date and I just don’t buy the extension is related to REMS. Going over the FDA briefing material submitted to the PDAC for the Ad Comm, I really think what is being wrestled over is product labeling.
According to the FDA briefing materials, “The labeling proposed by the Applicant [Braeburn] suggests that baseline sublingual buprenorphine dose is the only characteristic required.” In other words, Braeburn wants a label that states: this implant is an effective means of delivery 8mg on buprenorphine over six months. Period, end of story. If a patient needs more buprenorphine, then the physician would be entitled to prescribe him “supplemental” dosages.
Braeburn’s suggested product labeling creates a huge market. Essentially, anyone requiring 8mg or more of buprenorphine a day is included. Although addicts in early stages of recovery might need more, the additional dosage could be supplied sublingually (or as the FDA calls it, through “rescue medication”). Why wouldn’t a doctor prescribe an implant as a “failsafe” measure to ensure compliance for all patients, and just use supplemental sublingual buprenorphine to counteract affects of early stages of withdrawal (and gradually reduce the dosage as the addict weans off opioids)?
This is giving the FDA heartburn. As they wrote in their brief: “…if prescriptions for as-needed sublingual buprenorphine are anticipated to be a routine practice, how these prescriptions will impact the product’s ability to mitigate misuse, abuse, and accidental pediatric
exposure.” And…”if a certain amount of supplemental rescue buprenorphine is to be expected at some phase of treatment, should clinicians be advised to routinely prescribe a supply of “just-in-case” sublingual buprenorphine to patients receiving Probuphine?”
On a purely logical basis, the FDA gets it. Probuphine delivers a non-inferior dosage of 8mg of buprenorphine, and is entitled to be approved on that basis alone. But the FDA may not want to approve labeling that talks about mitigation of diversion, misuse, etc. if the patient class is not limited exclusively to those needing 8mg a day, because they same risk of diversion and misuse will exist for those patients using probuphine in combination with burprenorphine pills.
So, the FDA may wish to have labeling indicate probuphine can only be prescribed “on label” to patients needing 8mg, but again, logic gets in their way. If probuphine is an approved method of delivering 8mg of buprenorphine, then its approved, end of story. They can’t hamstring physicians by denying them the ability to prescribe probuphine in combination with oral therapy. There is no logical basis for it. But they can say to Braeburn "you can't market this as being abuse deterrent if it is going to be used in combination with pills that cause abuse."
So really this is coming down to a battle over marketing claims. And I’m very glad we have a former FDA commissioner on our side.
AI
