Wednesday, May 14, 2008

The Fentora Rejection (Part II): Primacy of Postmarket Plans

Cephalon’s tough advisory committee review on May 6 for the expanded indication to non-cancer breakthrough pain for Fentora (fentanyl buccal tablets) illustrates the new realities of FDA's postmarket controls and the need for drug sponsors to present a clear picture of the future use for their medications–or face the reality that there won’t be future use.

Cephalon's drive for the Fentora added indication was rejected by the advisory committee; the company hopes to have another shot by working with FDA to effect an acceptable risk management program.

Cephalon went to the advisory committee well armed to defend the product 's use in a new patient population. The company had data on four Phase III studies in non-cancer breakthrough pain encompassing 941 patients with that type of pain.

The company pointed out, in fact, that a noticeable gap exists in approved treatments for this category of breakthrough pain; and, that prior to their development work, there was a paucity of studies specifically aimed at the indication. “To date,” the company told FDA, “no medication has been systematically evaluated in clinical studies or approved by the FDA for the management of breakthrough pain in patients with chronic persistent non-cancer-related pain.”

Yet, the combined FDA advisory committees (Anesthetic & Life Support Drugs and Drug Safety and Risk Management) did not want to hear about the clinical trials. They wanted to focus exclusively on the postmarketing controls for the product: current and proposed.

And when the committees looked closely at Cephalon’s postmarketing controls, they found Cephalon’s current controls wanting (permitting about 80% of current use to occur off-label). The committees further found recent and proposed improvements to postmarketing controls not convincing.

The focus on postmarketing controls (aka risk management/minimization plans) provides a clear picture of the extent of interest that FDA is likely to show about postmarketing plans for products coming to the agency for initial approval, for significant label extensions (like Fentora) and, in the near future, for approved products forced back to the agency after approval for postmarketing re-reviews.

According to FDA’s new authority from the FDA Amendments Act (FDAAA), the agency is scheduling specific dates for checking back on the success of post-marketing controls on approved products.

That’s part of the “evaluation” process in the new Risk Evaluation and Mitigation Strategies process called for by the new act--the next generation name for risk management programs. This form of re-review is essentially what happened in the case of Cephalon’s non-cancer pain indication, making Cephalon's experience a good advance lesson in what these look-backs will be like.

FDA has begun setting look-back deadlines for a number of recent approvals: GlaxoSmithKline’s Treximet, UCB’s Cimzia; Biovail’s Aplenzin, and a new indication for GSK’s Advair. (See “The REMS Era Begins: FDA Applies Soft Touch with New Drug Safety Tools”.)

These scheduled reviews of real-world experience with approved products generally will begin to occur about a year-and-a-half after approval. Mark your calendars: a lively season for these FDA look-back reviews on drugs is set to begin about the end of 2009, just when the next administration's FDA will be comfortable and settling in to full stride.

One of the scary points from Cephalon’s May 6 experience is that the company is not a novice in the risk management field. If any company should have been ready for an advisory committee focused on risk management. Cephalon should have been it.

The company has had experience with formal risk management plans for almost ten years since the approval of Actiq (fentanyl lozenge) in 1999. Cephalon even avows the mantra of risk management: that it is an ongoing and always changing process. Good risk management plans, according to that view and Cephalon's espousal of the language, entail controls and evaluation and then further controls and further evaluation. Good risk management is a repetitious process of refining and improving product control programs.

FDA described the analysis of Cephalon's risk management plans for Fentora as the clear focus of the May 6 meeting. The agency advised the Fentora committees that the key decision it was seeking was assurance that Cephalon had workable plans to “prevent, monitor and intervene” in cases of misuse or abuse.

Because the company already has first-generation risk management programs in place for Fentora, the discussion naturally turned to how those plans are working as well as how likely they will be to succeed with a larger pateint population.

Cephalon CEO Frank Baldino attempted to put the post-market focus of the May 6 advisory committee meeting in the best light possible. He maintained that the meeting focus on post-marketing controls indicated that the efficacy of Fentora is not an issue.

“I was very pleased,” Baldino said after the meeting, “that there was no discussion with the agency or even the panel for that matter regarding the registration studies that were submitted for approval. Clearly the designs of the studies were sufficient from a registration perspective.”

But as pleased as Baldino professed to be with the status of clinical work, the company faces an uphill climb to the new indication. And the rest of the industry should worry with Cephalon about that challenge, watch closely how Cephalon responds, and learn from it. (See “The New World for New Drug Approvals: Evolution in Strategies for Getting FDA Drug Approvals”).

Cephalon apparently could see problems coming in advance of the May 6 meeting and actually made some drastic last-minute revisions to its plans to demonstrate an increased seriousness and commitment to restricitng the use of Fentora.

In the weeks before the advisory committee meeting, the company cut back on the proposed physician market for the product substantially.

In briefing materials prepared well in advance of the meeting, Cephalon said it would commit to restrict detailing to about 17,000 physicians and limit promotions to 30,000. That would limit commercial efforts to doctors who specialize in serious pain management, the company said.

“These physicians regularly prescribe both long-acting and pure short-acting opioids, and treat a significant number of the subgroup of patients with chronic pain and breakthrough pain for whom Fentora would be indicated.” The company was ready to track the product, collect information and “ensure that growth is managed” for the first 18 months after approval of the expanded indication.

By the time of the meeting, however, the company was ready to tighten those restrictions. The company told the advisory committees that it would restrict detailing for one-year after the approval of the new indication to the 6,000 physicians who have already been prescribing the drug (to approximately 20,000 patients).

The company’s chief medical officer Lesley Russell made the commitment in a presentation on May 6. If, after a year, “no issues are identified, we will, in consultation with FDA, expand the detailing to an additional 6,000 patients and repeat the exercise. We will not expand the detailing of Fentora to beyond the maximum 30,000 physicians,” Russell said.

That’s a significant tightening of control over the product: one that would clearly make it tough for the company to meet previous predictions to the investment community about 15% growth for the product.

During a post-mortem conference call after the May 6 meeting, one analyst asked whether the company still had hopes for the 15% growth based on the advisory committee rejection. The tougher question is whether Cephalon could have produced the growth from the product if their voluntary restrictions are approved. Baldino skipped answering the status of previous growth projections and told the analyst that the company would be discussing the risk management plans and controls with FDA.

But even the eleventh-hour proposal to be more aggressive with its limitations on detailing and promotion was not immediately acceptable as a route to the expanded indication.

The problem: the company has not shown very much success to date controlling use of the product by those same 6,000 prescribing docs. Those are the docs who have been using the product off-label up to 80% of the time.

As part of its efforts to convince FDA to permit the extra indication, Cephalon also submitted a revised program called COVERS (Controlled Voice Enrollment Registration System) about one-week before the advisory committee. It was too late, however, in reaching the agency to get a thorough review by the advisory committee.

FDA took a harsh view of the company’s success with the initial risk minimization program from September 2006. “Based on our review of the post-marketing experience with Fentora,” the agency wrote in advance of the advisory committee meeting, “we do not believe the RiskMAP has been effective in minimizing the risks it was developed and implemented to minimize.”

FDA further does not feel that the company has followed up adequately on its original RiskMAP commitments. The company has “never submitted information that interventions and/or adjustments were proactively considered or instituted to address RiskMAP goal failures.”

Cephalon got a thorough review of its experience with Fentora because the company wanted to parlay off-label use into a new indication. One advisor to the company, University of Utah anesthesiology professor Perry Fine, MD, noted the high off-label use as evidence of the medical need and called the absence of the indication for non-cancer patients “not sustainable.”

The company, however, found out that the high off-label use can be a damaging piece of evidence if a prerequisite for getting FDA approval is actually showing that you can control your product in the postmarket.

That highlights at least one message that other sponsors should take from the initial Fentora rejection: be careful about using current use patterns as evidence for more favorable labeling. Those arguments can just as easily backfire.

There is a second, broader message: be prepared for FDA reviewers and advisory committees that are focused on the specifics of limiting real-world use of a product to proposed patient populations. Not every company will face it to the same extent as Cephalon; but every company should be aware of the new barrier to approval.

1 comment:

Michael Lucas, Pa said...

I think using fentora in an indication other than brakthrough cancer related pain, should be allowed if it used properly. Plus the doctor precribing the medication knows the off label uses of the drug. Also mention that this is a medication that comes with Black Box warning. The patients that the doctor will be precribing too. Will have to be hand picked and meet the terms and safety measures already on the medication. I think it could be used only if in mind that it be done in a professional manner!