Opioid Approval Delay? Class REMS Poses Legal Questions For Pending Drugs

FDA approvability decisions on pending extended-release opioids will be contingent on the resolution of legal questions related to the agency's Risk Evaluation and Mitigation Strategy authorities under the FDA Amendments Act, Office of New Drug Director John Jenkins said.

The agency has announced it will impose a classwide REMS for 24 marketed potent pain products - extended-release and transdermal versions of fentanyl, methadone and oxycodone. Immediate-release and transmucosal products would not be affected.

Given the expected timeline of FDA's closed-door meetings with stakeholders - and a public meeting slated for the spring or early summer - the agency will not begin to finalize the REMS until mid-year, at the earliest. That has led some sponsors to question the fate of pending potent opioids: will they be delayed until the REMS is made final?

Jenkins said the question is still an open one. "We are still evaluating how to handle the products that would be similar to these that we've designated would need a REMS," he said in an interview. "That's still under discussion and review."

FDA's Options For Pending Opioids

One scenario, Jenkins speculated, would be to approve any pending opioids "with programs similar to the risk management programs that are already in place, with later conversion to the REMS." Another obvious scenario - which he did not specifically mention - would be to delay approval until the class REMS was made final.

The issue is one that requires input by FDA's Office of Chief Counsel. "There are some complex legal issues based on the way FDAAA is written, based on the path forward there," Jenkins said.

It is unclear whether the transition to the Obama administration will delay that decision. The office is being overseen by Deputy Chief Counsel Jeffrey Senger; David Dorsey, a staffer to Sen. Edward Kennedy, D-Mass., is anticipated to be the Obama's administration's choice for the post (¹ 'The Pink Sheet' Jan. 26, 2009, In Brief).

Opioid Winners And Losers

Two pending opioids that would appear to qualify for the class REMS are King Pharmaceuticals' Embeda (abuse-resistant morphine) and Pain Therapeutics' Remoxy (abuse-resistant oxycodone), for which King is a partner. FDA issued a "complete response" letter for Remoxy, and missed the user fee deadline for Embeda (² (Also see "FTC Lets King Buy Alpharma Now That Antitrust Problem Is Resolved – But New Embeda Delay Adds Risk To Acquisition" - Pink Sheet, 4 Jan, 2009.)).

According to King, FDA has not informed the company of how a class REMS for approved opioid products will affect Embeda's review timeline.

But the company believes its REMS is adequate to support approval: "The Embeda NDA contains a proposed REMS that we believe is detailed and comprehensive." The REMS includes a communication plan, a prescriber training program, a Medication Guide, patient monitoring and prescription tracking.

FDA Plans March 3 Meeting With Opioid Firms

King is in a good position to make a case for Embeda: as the manufacturer for Avinza (extended-release morphine), King will be involved in the discussions between FDA and companies with marketed opioids. The company said it has been invited to a March 3 meeting on the issue.

Other pending products, like BioDelivery Sciences International's form of buccal fentanyl Onsolis (a soluble film) would not fall under the class REMS, since it is a transmucosal product. Risk management did delay Onsolis, according to BDSI, but the company now expects an approval in the first half of 2009 (³ (Also see "FDA: BioDelivery Sciences Should Improve “Safe Use” REMS Provisions For Oral Fentanyl Approval" - Pink Sheet, 28 Aug, 2008.)).

Cephalon's supplemental indication for Fentora (buccal fentanyl tablets) in breakthrough chronic pain would also fall outside the class REMS. That approval, however, awaits Cephalon's implementation of the COVERS program (⁴ (Also see "Fentora Expansion Awaits REMS Evaluation" - Pink Sheet, 15 Sep, 2008.)

- Kate Rawson ([email protected])