Remoxy's Woes Stoke Criticism Of FDA's Review Of Abuse-Deterrent Opioids

FDA's complete response letter includes extensive list of new studies needed to support abuse-deterrence claims not featured in two prior CRLs, Pain Therapeutics says, wondering why the agency is only now raising issues that could have been discussed previously.

Pain Therapeutics Inc.'s Remoxy (oxycodone controlled-release) is no stranger to FDA complete response letters (CRLs), but the company was perplexed by the new direction taken by the agency in the third CRL issued for the abuse-deterrent opioid.

The latest letter, announced Sept. 26, details new studies and data needed to support specific abuse deterrence claims for Remoxy. The letter raises "a whole new set of discussions and issues" than the prior CRLs, received in 2008 and 2011, Pain Therapeutics CEO Remi Barbier told a conference call. The earlier letters focused instead on manufacturing facility, stability and bioequivalence issues.

The CRL is "a speed bump, not a death blow," Barbier stated, adding that one "could call it a low blow." He wondered why the letter raised issues that had not been discussed previously and why FDA cancelled a tentatively scheduled advisory committee where the issues could have been aired. (Also see "Pain's Remoxy Skips Over Panel On Rocky Road To Market" - Scrip, 1 Jul, 2016.)

Despite the high public profile of concerns about opioid abuse, FDA and industry have struggled over interpretation of the agency's 2013 guidance on abuse-deterrent formulations (ADFs). Shortly before the third Remoxy CRL was announced, KemPharm Inc. reported that it would appeal a CRL for its abuse-deterrent immediate-release opioid Apadaz (benzhydrocodone and acetaminophen) through FDA's formal dispute resolution process.

Kempharm's appeal is focused solely on issues "related to the abuse-deterrence properties of Apadaz and what constitutes abuse-deterrence in the context of a label claim," the company said. (Also see "KemPharm Seeks FDA Dispute Resolution Over Apadaz's Abuse Deterrence" - Pink Sheet, 16 Sep, 2016.)

Four Abuse Deterrence Claims May Be Unrealistic

The Remoxy NDA sought abuse deterrent claims for the four routes of abuse – injection, inhalation, snorting, and chewing – recognized under the agency's guidance on abuse-deterrent opioids. Pain Therapeutics now sees that seeking four ADF claims may be "unrealistic," Barbier said, noting that approved long-acting oxycodone products like Oxycontin claim to deter abuse by at most two routes.

The CRL outlines the steps needed for Remoxy to obtain labeling for deterring abuse by injection, inhalation, and snorting, Pain Therapeutics reported, but rules out a claim for oral abuse by chewing. The company said that the oral human abuse liability study in the NDA met its co-primary endpoints and "also met several, but not all, secondary endpoints," but "the CRL asks us to submit a revised proposed label to indicate results of this study do not support a label claim against abuse by chewing."

The new studies FDA has requested for injection and inhalation abuse "are not long, complicated studies," Barbier said, wondering why FDA had not communicated its updated data needs earlier. For the injection ADF claim in particular, he said, "the goals have now changed" from the company's understanding of FDA's position in previous discussions and agreements.

The company must "repeat an injectability/synringeability study using thin films of drug, smaller volumes of solvents, additional mixed solvents and alternative extraction methods and syringe filter," Pain Therapeutics reported. For the inhalation ADF claim, FDA wants the firm to repeat a volatilization study. The studies will likely compare Remoxy ER against a commercially available oxycodone ER product.

Recommended Intranasal Abuse Study Poses Practical Challenges

The study requested by FDA to support a label claim against abuse by snorting is a bigger challenge, Barbier indicated. The NDA includes a large animal intranasal abuse potential study, which he characterized as common practice. The CRL, however, calls for an intranasal abuse potential study in human volunteers "with drug applied directly inside the human nasal cavity."

"Somehow we'll find a way to do" the human intranasal abuse study, Barbier declared, but the circumstances are difficult. Remoxy is a capsule that incorporates Durect Corp.'s Oradur technology to form a gel that is like "Vaseline combined with Super Glue," he said. The company must find a way to safely apply and remove the gel from volunteers' noses in a way that meets institutional review board (IRB) standards to protect human subjects.

At Least Another Year Before Resubmission

Pain Therapeutics thinks it can conduct the additional studies requested by FDA within a year at a cost of about $5m. Nonetheless, Barbier said, "we can't just keep doing studies ad infinitum."

Changing standards, he suggested, have unnecessarily prolonged the already-lengthy development of Remoxy. "We did have written guidance, written reviews and written comments" on the inhalation and injection abuse claims in particular, Barbier noted, but the CRL calls for different studies.

"If we knew what FDA wants," he said, "we could have done it."

FDA is also keeping a close watch on Pain Therapeutics' public communications. The agency issued an untitled enforcement letter for preapproval promotion on Sept. 8. (Also see "FDA's Drug Promotion Advisory Reviews Taking Longer" - Pink Sheet, 28 Sep, 2016.)