A Wolfe In Wolf's Clothing

No one expects Sidney Wolfe to sit on his hands at an FDA advisory committee meeting, and at his first outing as a permanent member of the Drug Safety & Risk Management Advisory Committee, he didn’t disappoint.

During a two-day meeting last week to consider the approvability of two abuse-resistant pain medications, Wolfe took a few minutes to grouse about one of his favorite topics, direct-to-consumer advertising, and specifically Purdue’s $600 million fine over misleading advertising and promotion of OxyContin. Here’s what he said:

“The gorilla, or donkey or elephant in the room is advertising and promotion. If OxyContin was that dangerous ... maybe it would be off the market. The number-one culprit—and the number two, three, four, five, six and seven—and the reason for the $650 million penalty was misleading advertising and promotion.”

Wolfe also couldn’t help but take a dig at the two products up for approval decisions: Alpharma’s abuse-resistant form of morphine, Embeda, and Pain Therapeutics’ abuse-resistant form of oxycontin, Remoxy. (Neither drug won kudos from advisory committee members; you can read our coverage on those meetings here and here).

“Any company that wants to develop...a product that is novel and has significant benefits over existing products—something I haven’t seen over the last couple of days—is going to spend a huge amount of money advertising and promoting,” Wolfe said.

It’s true that advisory committee members sometimes go off the reservation on issues like pricing and insurance coverage. And we don’t necessarily disagree with what Wolfe is saying—we’ve also suggested that industry take a hard look at DTC advertising and whether it’s really worth all the potential political and legal headaches.

But for companies with products slated to go before Drug Safety & Risk Management Advisory Committee—and given the ubiquitous nature of REMS, there will be many—those are the type of comments to expect out of Wolfe. In the case of Embeda and Remoxy, his comments only reinforced the direction the committee was headed in anyway. That may not be the case next time.

What’s next for Wolfe? The next meeting of the Drug Safety & Risk Management Advisory Committee is two-day discussion on the safety of long-acting beta agonist inhalers in December. That’s big-name products like GSK’s Advair, AstraZeneca’s Symbicort and Schering-Plough’s Foradil. Stay tuned.

FDA Has a New Guard Dog: He’s a Wolfe

The election is near and Washington is rife with chatter about who will go where in the next administration.

But FDA made a Washington appointment in early August that will have as much (if not more) impact on many drug sponsors for the next four years than many of the more visible and high-profile appointments expected in the health field.

On August 8, FDA made long-time consumer advocate and pharma gadfly Sidney Wolfe (above) a permanent four-year member of the Drug Safety & Risk Management Advisory Committee. His term began August 8 and lasts through May 31, 2012. The information was only recently posted publicly by the agency.

Wolfe has headed Public Citizen's Health Research Group for 36 years. There are only a handful of products during that period with safety issues, where the issues were not brought to the public attention by Wolfe. He earned a MacArthur genius award in 1990 acknowledging his ability to use the political/media/regulatory system to question the safety and use of pharmaceuticals.

How much impact can one person have on an advisory committee ?

Ask Cephalon, which faced Wolfe at a May advisory committee looking into an expanded indication for Fentora. What the sponsor hoped would turn into an important expanded use for the product turned instead into an inquisition about how the company had lost control of a drug of abuse in the marketplace. Far from getting an expanded indication, the sponsor faces the task of showing FDA that it can cut back existing use in the market.

Wolfe played a significant role in setting the tone and timber of the Fentora advisory committee. He urged FDA to use its new post-market control powers to increase control of use of the drug for approved patient populations.

Cephalon did not know that Wolfe would be part of that review until three days before the meeting was scheduled. He was an unpleasant surprise for the sponsor. It might not be much better for companies prepared for sessions with him; and, at least five sponsors have upcoming dates with him in the next two months.

Pain Therapeutics and Alpharma have opioid pain management products (Remoxy RT and Embeda) scheduled for a joint meeting of the Anesthetic & Life Support Advisory Committee and Drug Safety & Risk Management Advisory Committee on Nov. 13-14. That meeting could be a reprise of the Fentora meeting and offers the advisory committee a further opportunity to encourage FDA to move toward tougher post-market controls on abusable pain management products. It could help set the tone for the post-market for the wide range of pain drugs and formulations in development.

In December, the drug safety advisory committee will be meeting with the Pulmonary Drugs Advisory Committee and the Pediatric Drugs Advisory Committee on a class of products that reaches a much wider patient population: asthmatics using beta agonist inhalers. The advisory committees have two days set aside for discussion of the safety of long acting beta-2 agonists (salmeterol and formeterol). The ingredients appear in a number of major products (Serevent, Advair, Symbicort and Foradil) from GSK, AstraZeneca and Novartis.

From his advisory committee post, Wolfe will be able to push for more active post-marketing monitoring and control programs across the broad gamut of drug classes. FDA calls in the drug safety committee for joint meetings across drug classes. Wolfe won't be restricted to any narrow single class of product.

That leads to one final thought about where he may be asked to offer his opinions in the near future. Wolfe's resume shows an early interest in the cellular mechanisms of blood clotting. It will be interesting to see if FDA asks either the drug safety committee or Wolfe as a visiting advisory committee member to bring that knowledge to upcoming reviews as new anti-clotting compounds come up for approval .

Eli Lilly better hope that, if there is an advisory committee for prasugrel next February, FDA does not turn loose its new Wolfe.

FDA Advisory Committees: Who’s Running the Show?

You wouldn’t think of running your company without a CEO, right? Sure, from time to time, your company might find itself with an acting chief executive due to a merger or sudden departure. Maybe it’s a member of the board, or a former company official that comes out of retirement. But since that’s not a great situation for anyone, you try to quickly find a permanent replacement.

So it may make you a bit uncomfortable to know that at your next FDA advisory committee meeting, chances are that not only will the committee be lacking a permanent chair, it’s likely it won’t have had one for quite some time.

In fact, three quarters of advisory committees in the Center for Drug Evaluation & Research do not have a permanent chair. That’s 12 out of 16 committees. Only four—Anethestic & Life Support Drugs, Pharmaceutical Science, Psychopharmacologic Drugs and Reproductive Health Drugs—have permanent leadership.

(For an analysis of the advisory committee system—including a handy chart of vacancies in each committee—read this story in the October issue of The RPM Report.)

Chairs play a big role in the way advisory committee meeting is conducted. They can steer the discussion one way or another, tweak the questions from FDA, and be more or less forgiving in allowing the sponsor to clarify discussion points. Some chairs are better at managing meetings than others, and the absence of a clear leader can make the process less predictable for drug sponsors.

The absence of leadership at the top is really indicative of the systemic problems across FDA’s advisory committee system. Chairs are typically “promoted” from within, so when there aren’t enough committee members to go around, chairs—with the extra responsibilities that come with the job—are even harder to find.

And FDA is having a hard time finding committee members. Between the new conflict of interest rules and the existing downsides to serving on a committee, FDA has a major problem on its hands.

That might not be such a big deal, so long as FDA wasn't holding many advisory committee meetings. But that’s not the case. In fact, the agency will bring more new products before an advisory committee this year than it has since at least 2004. That’s a lot to juggle at a time when FDA is having a hard time filling those seats with permanent members.

Given the amount of time spent on preparing for an advisory committee review—including those mock panels—it would be nice to at least know who you’ll be facing across the conference table. And in case you’re still not convinced that FDA's problem with filling vacancies is also your problem, consider this: how would you like to have Sid Wolfe as a voting member at your next review?

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.