Titan scores FDA panel victory for opioid addiction implant
This article was originally published in Scrip
A panel of expert advisers to the US FDA on 21 March recommended approval of Titan Pharmaceuticals' Probuphine (buprenorphine hydrochloride/ethylene vinyl acetate) subdermal implant as a maintenance therapy for patients addicted to opioids, like oxycodone, or even street drugs like heroin – voting 10-4, with 1 abstention.
Shares of Titan closed at $1.23, down 3 cents, or about 2.4%, on the OTC market before the final votes were taken.
Probuphine, which is described as a "matchstick-sized implant," is intended to deliver around-the-clock, steady levels of buprenorphine for six months.
Titan said that since Probuphine is an implant that can only be inserted and removed by a trained physician, patients do not have direct access to buprenorphine, therefore reducing the potential for abuse and accidental overdose.
In earlier votes, the FDA's Psychopharmacologic Drugs Advisory Committee (PDAC) voted 10-5 that Titan's trial data provided substantial evidence that Probuphine was effective as a maintenance treatment of opioid dependence, and 12-2, with 1 abstention, the firm had adequately characterized the safety profile of the drug.
But with many questions remaining about Titan's risk evaluation and mitigation strategy (REMS), the PDAC was more torn – voting 5-4, with six abstentions, the plan was adequate to address the possible complications associated with the implantation procedure for the Probuphine implant and the potential for abuse, misuse and accidental overdose with the product.
The PDAC's mixed feelings on the REMS was a result of Titan and its partner, Braeburn Pharmaceuticals, which holds the licensing rights to Probuphine in US, surprising the committee with new information the firms had not yet discussed with FDA about what the companies had worked out with the US Drug Enforcement Administration (DEA) about the model of care and the REMS for Probuphine.
Titan's and Braeburn's proposed REMS submitted to the FDA consists of a restricted distribution component and a training and certification program for health care professionals for implanting the Probuphine product.
Regulators had raised concerns that Titan's distribution system did not conform to the Controlled Substances Act (CSA).
"It is our understanding that a pharmacy must dispense a controlled substance pursuant to a prescription directly to the patient, the ultimate user, and cannot ship to the prescriber's office," said Dr Jason Bunting, a risk management analyst at the FDA.
Dr Bunting also pointed out that one major problem for Titan and Braeburn is the possibility the Department of Health and Human Services, after consultation with the attorney general, may determine that a REMS mandatory training would preclude office-based use of Probuphine under the Drug Addiction Treatment Act of 2000.
But Dr Garry Neil, head of R&D at Braeburn, a wholly owned subsidiary of New York-based Apple Tree Partners, told the committee that his firm had met with the DEA on 18 March – just days before the panel meeting – and worked out a way that would provide appropriate access to the product while minimizing abuse and diversion.
Dr Neil said the model of care now meets the CSA requirements.
"This is a dynamic process, and we realize that the FDA has not had a chance to review our latest revisions," he said.
It's unclear, however, if the FDA will have enough time to review the updated information before the 30 April Prescription Drug User Fee Act action date.
Implanting/removal concerns
Dr Rachel Skeete, a clinical reviewer in the FDA's Division of Anesthesia, Analgesia and Addiction, said the agency had concerns over Titan's small safety database, noting that the experience with inserting and removing the Probuphine implants was limited to the 262 study participants (scripintelligence.com, 19 March 2013).
"There may not have been ample procedures performed to fully characterize the safety with insertion and removal," she said.
Dr Skeete noted that implant rods were frequently broken at the time of removal, potentially complicating the removal process.
But Dr Steve Chavoustie, of the Segal Institute for Clinical Research and the University of Miami, and the principal investigator for the Probuphine studies, pointed out that the process had evolved, with the procedure changing from using a blunt-tip applicator, 5-10mm incision for implant insertions and a standard technique to using a sharp bevel-tipped applicator, smaller 3mm incision for implant and a modified technique for removal, which he said led to fewer removal adverse events in the later studies.
Braeburn's Dr Neil emphasized that Probuphine-treated patients will always be under the care of a physician certified to practice in drug addiction, and while other clinicians, such as nurse practitioners or physician assistants who receive the required training, will be permitted to implant and remove the product, they must be overseen by the physicians.
Under Titan's and Braeburn's revised proposed Probuphine model of care and closed distribution program, after verifying the eligibility of the ordering physician, the specialty distributor will ship the product to the treating physician's office where the shipment will be signed for, logged and stored in a securely locked substantially constructed cabinet, Dr Neil explained.
He said Probuphine may only be ordered for specific patients.
The implanting clinician will insert the Probuphine implants, log the implantation and arrange routine follow up and ongoing treatment, including insertion site care, Dr Neil said.
After six months, the implants will be removed and disposed according to state and federal regulations, and if indicated, new implants will be inserted in the contralateral arm, he said.
If the patient does not return for scheduled follow-up, the physician will make three attempts to contact them. If the patient cannot be contacted in three attempts, they will be considered lost to follow-up, Dr Neil said.
Training
"Clinician training is a key component of the REMS element to assure safe use," Dr Neil said, adding that his company plans to train 2,000 Probuphine implanters over the first 12 months postapproval of the product.
He said the two-part training is intended to be accomplished in a series of regional half-day sessions led by "experienced" clinicians and company representatives, which will include hands-on implantation training.
The Part A "clinical" training program will familiarize clinicians with the existing data for Probuphine, appropriate patient selection, patient counseling and incision care, Dr Neil said.
"The clinicians will also be familiarized with the product label, including warnings, precautions, drug interactions and other safety information. It will also cover the procedures to order and receive Probuphine," he added.
The Part B "procedure" training will be based on the enhanced program developed and used during studies 806 and 811, Dr Neil noted.
"Experts will teach implanting clinicians the relevant anatomy, proper insertion techniques, incision site care, implant localization and removal and adding a fifth implant if necessary," he said, adding that the program also will cover potential complications and their management.
The instructors will assess the competence of each trainee.
Each trained clinician will receive a REMS training kit, which includes DVD, slides and a "model arm" to use for implant insertion and removal practice.
While all treating physicians will only be required to complete Part A, the "implanters" and supervising physicians must complete both parts.
But FDA's Dr Bunting said regulators were worried that under a scenario in which a doctor writes a prescription for Probuphine, but opts to oversee the procedure performed by a nurse practitioner or physician assistant, the physician would not be adequately trained to watch over that procedure.
Dr Bunting also said Titan and Braeburn have "provided insufficient information to validate the proposed training program."
And, he said, the companies have not provided stakeholder input from physicians or other health care providers about the content or format of the proposed training, nor have they provided results from human factor studies about the effectiveness of the programs.