Cephalon will have to put its new COVERS risk management system into place on Fentora (buccal fentanyl) and convince FDA that the system is working before the agency will approve a new indication for the product.

The company received a "complete response" letter on the Sept. 13 user fee deadline date for the expanded indication of breakthrough pain. The product is currently indicated for the more limited patient population of breakthrough cancer pain.

The "complete response" letter is not a surprise. Cephalon has been openly stating in recent weeks that it did not expect an approval from FDA and was ready for a "complete response" letter.

The extent of proof that FDA is seeking that the risk management program is working is, however, unpleasant news to the company. The company had hoped to receive word from FDA saying that the agency would be ready to review the new indication once the company had its new patient and prescriber registration system (the COVERS, "controlled voice enrollment registration system") in place for the existing use.

FDA outlines a longer regulatory process

FDA took a firmer line, however, asking Cephalon to "implement and demonstrate" that the new risk management program is working to support the new indication. FDA's request defines a longer regulatory process for Cephalon. That is reflected on one level in the fact that the resubmission for the new indication be a Class 2 filing (allowing six months for FDA action).

FDA also asked Cepahlon to submit the risk management plan separately for review as a new Risk Evaluation & Mitigation Systems (REMS) plan. Unofficially, that sets up a second parallel process for the new indication.

The regulatory route for Cepahlon to extend the Fentora indications appears to encompass several distinct challenges: the company needs to get the risk management program approved as an official REMS program; the REMS program has to put it in place; Cephalon will have to show that it is working to limit use in the existing indication to opioid-tolerant cancer patients, and then the company can seek clearance for the expanded indication.

Cephalon's VP Investor Relations, Chip Merritt, told a Sept. 5 investment meeting sponsored by Thomas Weisel Partners that demonstrating that the COVERS program works before approving the new indication seemed out of the normal order of events to the company. FDA's advisory committee "wanted us to demonstrate the COVERS program and then come back to them," Merritt said. "Well, that is really not how it works; nor is that within their bailiwick to require that."

First time FDA requires REMS demonstration prior to approval

Merritt also maintained that "there has never been an example where the FDA has required a company to demonstrate their risk management program prior to approval." The Fentora situation is difficult for the sponsor because the agency and sponsor agreed that the original risk management program for the drug was not effectively restricting the drug to cancer patients and patients already tolerant to opioid treatment. As much as 80% of Fentora use has been off-label. The company said the extent of off-label use was the reason it undertook clinical trials to show that the drug works in generalized breakthrough pain.

Merritt stated Cephalon's hope for a shorter process to the next indication. "FDA has never required someone to demonstrate a risk management program," he stressed. "So we are hopeful that we can just put it in; it is acceptable; we then get the approval and move forward."

Cephalon says that the new indication is crucial to the product's commercial success. Merritt said: "I don't think this product is ever going to grow unless we are successful getting the broader label. So it's important to get." The product has been used by 20,000 patients (2 million prescriptions) during the first 15 months of marketing, according to information provided by the company to the May 6 joint meeting of the Anesthetic & Life Support Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee (¹ 'The Pink Sheet' May 12, 2008).

Cephalon suggests that the tough regulatory route for Fentora, however, signals that other fentanyl sponsors will face similar hurdles. The company said that it hopes that the COVERS plan will "pave the way for a new industry standard for opioid pain medications." Another oral fentanyl product from BioDelivery Sciences International received a complete response letter from FDA Aug. 28 for Onsolis that also called for more work on a REMS program (² Also see "FDA: BioDelivery Sciences Should Improve “Safe Use” REMS Provisions For Oral Fentanyl Approval" - Pink Sheet, 28 August, 2008.).

-Cole Werble (c.werble@elsevier.com)

Fentora Expansion Awaits REMS Evaluation

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