Tuesday, May 13, 2008

Cephalon's Fentora Rejection: The Challenging Environment

Cephalon CEO Frank Baldino’s characterization of the May 6 FDA advisory committee review of Fentora (fentanyl buccal tablets) as “challenging” is a masterpiece of understatement.

Here is the crux of Baldino’s post-mortem on the failed attempt to get a major label expansion for the pain control product from the current limitation for breakthrough cancer patients to more generalized breakthrough pain patients: Cephalon was not surprised by the 17-3 vote against an expanded indication in the current cautious approval environment at FDA, according to Baldino.

Although we're disappointed,” the CEO declared, “we're not surprised in the results.” Cephalon recognize[s] that it faced a panel “at this challenging time with the FDA” with an application for a “challenging subject.”

How “challenging?"Well, the fundamental dichotomy between the company’s interpretation of current use patterns for the drug and FDA’s is about as far apart as any sponsor can expect to face.

Cephalon felt that extensive off-label use of the product in the marketplace (up to 80% of the drug use going beyond approved patient populations) would convince FDA of the real-world demand for different labeling. Cephalon’s application embodied the logic of those advocates who believe that the medical community and a lightly controlled medical market will get the best medicines to the appropriate patients.

Showing how far the regulatory system is moving away from those arguments, FDA said that the existing prescription patterns for Fentora do not indicate demand; instead they demonstrate that the company cannot control appropriate use of the product—a drug which relies on an active ingredient with a very tricky, narrow therapeutic range.

The agency’s internal reviewers had harsh words for the company about its existing attempts to control use of the product. A new risk management system based on spoken acknowledgments of risks and appropriate use to permit prescribing (by physicians) and receiving prescriptions (by patients) was submitted too close to the date of the advisory committee for FDA or its advisors to give it full consideration.

How’s this for FDA’s introduction to a request for expanded use? The agency told its advisory committees (two were combined for the Fentora review) that fentanyl can quickly be lethal in kids and the elderly, so it will demand an effective risk mitigation program.

And, the agency is changing the environment in some other important ways. Its advisory committees are getting tougher.

To judge the Cephalon request for an expanded indication, the agency assembled a group of advisers who were anything but sympathetic to the drug sponsor and wider use of the product.

When the Cephalon team got up to support the expanded indications, they faced a committee that included Public Citizen’s Sidney Wolfe, MD (right), as a “temporary voting member” of the Drug Safety & Risk Management Committee, which met with the Anesthetic & Life Support Drugs Advisory Committee on Fentora on May 6.

For Cephalon and the rest of the industry, the recruitment of Wolfe creates, as Baldino so gently puts it, a “challenging” time.

Wolfe is legendary in the drug industry and has embodied persistent and effective attacks on the industry for over 30 years in Washington as the indefatigable voice of the Nader movement in health care from the 1970’s. Now the agency has brought him into the fold to act as an official advisor. Wolfe was a “temporary” member at the May 5-6 meetings.

The word among FDA observers is that industry will be seeing Wolfe more frequently on the agency side of the table at advisory committees.

Wolfe has been a frequent public speaker at advisory committees as an outside commenter over the years. Politically, he would be an astute selection as a permanent member. He would bring immediate credence and credibility to the first wave of the agency’s risk management decisions following the new FDA Amendments Act. As part of FDA’s advisory committee team, Wolfe can push the agency to use its new tools aggressively. If his opinions are built into the standard risk management reviews, then his concurrence should shield the agency (and drug sponsors) from further criticism.

And Wolfe performed right to form at the Fentora meeting. He engaged a top FDA official in an unofficial colloquy at the advisory committee meeting on how the agency can and should use its new post-marketing powers to correct prescribing practices: for current drugs and future uses. (For further coverage see "The Pink Sheet").

The agency clearly intends to take the development of more effective post-market control programs more seriously. They are not going to be shy about demanding tighter control of products in the post-market. And they are going to get advisory committee members who agree with them on that authority.

Baldino calls the situation “challenging.” It may be more accurate to call it a sobering look at the future for drug sponsors.

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