Nearing an End to the Longest Review?

Ovation reached a milestone this month in its quest to get its GABA-transaminase inhibitor vigabatrin (Sabril) on the market: It received confirmation from the Food & Drug Administration of a tentative date for an advisory committee meeting.

Given that FDA has held 30 advisory committee meetings so far this year, that doesn’t sound like groundbreaking news. But in the case of Sabril, it’s a major development given the difficulty FDA has had in finding enough qualified advisory committee members under the new conflict of interest guidelines.

We wrote about Sabril as a worst-case example of the approval delays in the new user fee era in last month's issue of The RPM Report. But is also a poster child for what can go wrong under FDA's new conflict of interest guidelines. (We'll have more on that on this blog and in the next issue of The RPM Report.)

But for now, here's the short story: An advisory committee meeting for Sabril was originally scheduled for August, but there was one (tiny) hiccup. It turns out that the only pediatric neurologist on the committee, Dartmouth Medical Centers Greg Holmes, did work on the original NDA when it was owned by Sanofi-Aventis predecessor company Marion Merrell Dow.

That’s a definite no-no under FDA’s new guidelines. Holmes was recused, and it has taken until now for the agency to reschedule the meeting for January 7-8, as reported in this week's issue of "The Pink Sheet." Of course, that’s assuming FDA can find a qualified pediatric neurologist who hasn’t run a clinical trial for vigabatrin (or a competitor), or invested more than $50,000 in Ovation (or a competitor), or is conflicted in some other way.

But perhaps the Greg Holmes snafu is only fitting for a drug like vigabatrin, which has already had an excruciatingly long pathway toward approval.

Vigabatrin was developed in the 1980s by Merrell Dow as an anticonvulsant. Three advisory committee were convened (in 1984, 1985 and 1989) in light of toxicity signals seen in animal models. An NDA finally was submitted in 1994 by Marion Merrell Dow; FDA turned it down twice before it was outlicensed to Ovation in 2004 by Aventis (now Sanofi-Aventis).

Ovation has had much more success with vigabatrin, having moved from the licensing deal to a priority review for a more targeted indication of infantile seizures in three years. (Ovation also is pursuing the original indication for use in complex partial seizures; the company submitted a response to FDA's questions about that application late last year.)

FDA's deadline for a decision on both indications was June 27--more than three months ago. Between the missed user fee deadline and the immense difficulty in finding enough experts to staff an advisory committee, Sabril is the worst-case example of drug regulation today.

Will there be more? Probably. Will it be yours? Stay tuned.

Watson’s Rapaflo Sails Through FDA: The Exception That Proves The Rule?

Analysts don’t expect much from Watson’s Rapaflo, a new entrant in the already crowded alpha-blocker benign prostatic hyperplasia category.

But if the drug is any where as good as relieving obstructed bladders as it was at breaking through the bottleneck at FDA, don’t bet against it.

Let’s recap what we know about today’s FDA. The agency doesn’t have the resources to review applications on time. (See “Talent Squeeze at FDA,” The RPM Report, December 2007.) It also has the strategic good sense to realize that now is not the time to make on-time approvals the top priority. (See “The New User Fee Rules,” The RPM Report, March 2008.)

There’s more. “Standard” review applications will receive at least one “complete response” letter before approval—if they are approved at all. (See “The Data Everyone’s Talking About,” The RPM Report, November 2007.) Inexperienced NDA filers shouldn’t kid themselves into believing they will even get a review by FDA. (See “Rejected Out of Hand,” The RPM Report, February 2008.) And products for crowded primary care indications can only come to market in the US if they have been sold forever overseas (See “When Approvable is Good News,” The RPM Report, December 2007) or if they have clear evidence of comparative advantages over existing therapy. (See “Straight Talk From FDA,” The RPM Report, November 2007.)

So, if you had asked us about Watson’s chances on Rapaflo, filed in December under a licensing agreement with Kissei, we’d have bet all our US Treasury bonds that they’d have at least another year to wait before getting the all clear from FDA.

Good thing you didn’t ask. As “The Pink Sheet” reports, Rapaflo received approval from FDA on Oct. 9—three days before the 10-month standard review deadline.

So here’s a drug entering a huge primary care market (we found one estimate that there are 115 million men worldwide with BPH) approved based on clinical trials in less than 1,000 patients. It has only minimal global market experience (two years in Japan). The sponsor—Watson—is still far better known for its generic drug applications than its new drug savvy, and there are already four brands available in the same class for the same indication.

Can this be the same FDA that just imposed a formal risk evaluation and mitigation strategy on a drug that isn’t even marketed anymore? (It is—FDA is requiring a REMS for Exubera.)

Maybe FDA read the analyst reports, which suggest Watson will have at best modest success (say $50 million a year) selling Rapaflo in a generic-first class. But we doubt it. This is definitely a clear sign that the old model FDA is completely dead yet. Product by product, division by division, there are still openings for these kind of approvals.

Though we still wouldn’t build our business on expecting too many more Rapaflo’s in the years to come…

The REMS Pioneers: Amgen’s Nplate Sets Another New Standard

Hymen Phelps & McNamara attorney Frank Sasinowski has a prop he likes to use when he calls on Food & Drug Administration reviewers to talk about a regulatory issue.

It is a new drug application filed by Wyeth 50 years ago. It includes, he says, everything you get in a modern NDA. Evidence of safety and efficacy. A chemistry, manufacturing and controls section. Proposed labeling. Everything.

And you can hold it in one hand, a thin stack of paper, organized by a single binder clip.

It sure is eye-catching. Today’s NDAs are so large and complex it is now silly to imagine them in printed form, except for colorful analogies like Eli Lilly & Co. saying the prasugrel (Effient) NDA would be as tall as the Empire State building if it was reduced to stack of paper.

Sasinowski’s message?

The vast increase in complexity of NDAs is not related to a change in the standard for approvals per se. Rather, it is a result of decisions made by individual FDA reviewers about how much evidence they need to be convinced to allow a drug to be approved.

Well, it looks to us like history is repeating itself in the form of rapidly expanding stacks of paper necessary to comply with the FDA's new Risk Evaluation & Mitigation Strategy authorities. The REMS were created by the FDA Amendments Act of 2007, and we are living through history as FDA and the pharmaceutical industry create a new regulatory framework on the fly.

FDA has now used the REMS authorities about half-a-dozen times for new approvals, and the level of complexity is leaping exponentially—at least as measured by page count.

The first handful of REMS were dealt with in the context of the approval letter FDA sends to sponsors of all new drug applications: less than a page of text invoking the legal authority for a REMS, informing the sponsor of the need for a mandatory medication guide, and setting a bare bones assessment schedule. (You can read The RPM Report's coverage of the “REMS 1.0” group here.)

Then came Entereg. The GSK/Adolor post-operative ileus therapy had the first REMS that included restrictions on access (limiting distribution to hospitals who register with the sponsor) and use (no more than 15 doses in the in-patient setting). In addition to an overview of the REMS in the approval letter, FDA released a 24-page summary of the program, including copies of the packaging and registration materials. (You can read The RPM Report's coverage of the Entereg REMS here.)

Now comes Nplate. Amgen’s new platelet boosting therapy to has a still more restrictive REMS, involving registration of institutions, prescribers and patients. (The first in-depth look at that program appears in “The Pink Sheet.”)

The page count? Ninety-four.

So, in the six months since the REMS authority took effect, we have already seen the approved versions of the program expand about 100-fold.

If that trend continues, maybe the Effient REMS will also be as tall as the Empire State Building?

Entereg Approved at Last

Perspective is an amazing thing.

In June 2004, Adolor Corp. filed a new drug application for alvimopan (Entereg) for treatment of postoperative ileus. The product had "fast track" status, and Adolor and partner GlaxoSmithKline expected to launch the drug by the start of 2005.

What do you think they would have said if you had told them that the drug would not reach the market for four years, and then only with tough restrictions limiting access to the hospital setting and the course of therapy to two weeks or less? We try to keep our blog clean, so we won't speculate on the exact commentary that company executives might have offered.

In any event, here is what Adolor CEO Michael Dougherty did say during a conference call announcing the approval of the drug May 21: "This is such a big day for Adolor...Gaining approval of our lead product is a transforming event for our company. I cannot tell you how excited we are at Adolor."

And so Adolor joins the ranks of company's that are positively giddy at the prospect of becoming pioneers in the new drug safety era.

It joins a handful of other drugs approved by the agency under the new Risk Evaluation & Mitigation Strategy authorities that took effect March 25. (You can read more about the REMS pioneers in The RPM Report.)

Entereg is a precedent-setting new drug approval: the first new molecular entity approved by the agency with a formal, mandatory restriction on the setting of care in which it can be marketed. As part of the program, Adolor and GSK will have to monitor actual use of the drug and take corrective action if it is being used outside of hospitals or for longer than the 15-day therapy maxiumum.

It is surely a measure of how much the world has changed for drug development companies that the approval of Entereg, four years late and weighed down by those tough marketing restrictions, can still be greeted as a good news event. (Adolor shares jumped 10% in after market trading when the approval was announced May 20; profit takers and launch skeptics have brought it back down today.)

But it is also true that the REMS era is beginning about as well as it possibly could for the industry. Each of the first five products covered by the new authority is a drug that was stuck at FDA. The sponsors certainly didn't expect to find themselves bogged down by safety issues at the agency--but they also eagerly embraced the opportunity to become REMS pioneers as a way to get to the market at last.

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.

Cimzia Launch: Nothing Simple About It

When UCB Pharma CEO Roch Doliveux delivered a status report to shareholders 10 days ago on the company's progress in transitioning to life after Zyrtec, one detail caught our eye: he crowed about UCB's ability to launch the TNF inhibitor Cimzia just 48 hours after approval.

In a follow-up press release, the company even identified the first patient to receive the drug!

You can understand UCB's excitment. The Cimzia approval for Crohn's disease was a much needed dose of good news, driving shares up 20% overnight, and surprising a lot of skeptics who wondered whether the drug would make it to the US market anytime soon. (And, yes, we certainly didn't expect it to be approved this soon.)

So a little cheerleading is understandable. But there are at least two reasons why UCB's rapid launch of Cimzia is worth further reflection.

First, it was not so long ago that product launches typically came weeks or even months after FDA approval. Before the beginning of the user fee era 15 years ago, the agency truly was a black box, where sponsors would have no way of knowing when (or if) FDA would be giving an answer. So valuable patent time would tick away while the sponsor digested the approval, scaled up manufacturing and prepared promotional materials for a launch.

Now, full-scale launches within hours of approval are routine. That is the value of the predictability and transparency of reviews in the user fee era. And that is a reminder of what is at stake if FDA fails to maintain that predictability during a period of intense strain. (Read more about how FDA is struggling to preserve predictability even as it plans to miss more user fee deadlines here.)

But there was nothing routine about the Cimzia review, and that is the second reason why Doliveux is right to applaud the work that went into the rapid launch. The Cimzia team faced an unprecedented challenge in getting the drug into the hands of patients: it is the first new molecular entity approved by FDA subject to the new Risk Evaluation & Mitigation Strategy and mandatory post-marketing commitment requirements of the FDA Amendments Act signed into law in September 2007.

The world has changed considerably since Cimzia was first submitted to FDA in early 2006. Its not just that UCB had to create a risk management plan for the drug; that has become a standard approach for many pharma companies for several years.

But it had to take that program and adapt it to the new REMS model, while the application was pending. Indeed, UCB did not know for certain earlier this year whether the REMS provisions would even apply to its product: that section of the law took effect in March, but FDA and industry have an extra six months to convert existing risk management plans into formal REMS. The law said nothing about pending applications; in the event, FDA decided to apply the new legal procedures to Cimzia.

So, not only did UCB have to design a risk management program--which it is calling CIMplicity--that would be robust enough to please FDA, it needed to ramp it up and roll it out on launch. That seems like enough reason to brag about getting the drug out in 48 hours. But doing all that while working through the uncertainy of the regulatory framework for the program is even more impressive. UCB had to stay abreast of FDA's thinking on whether and how the new law would apply to its product, and then make sure to involve everyone in the company who needed to sign off on a formal commitment to comply with the terms of the REMS.

Add to that the now mandatory post-marketing study requirements, another new challenge UCB had to navigate. According to FDA's approval letter for the product, UCB agreed to half-a-dozen post-marketing trials, signing off on them just two weeks before approval.

These are not the "we'll give it our best shot" pledges industry is used to in Phase IV, but legally binding agreements enforceable with fines. So when UCB agreed on April 8 that it would conduct a 10-year, 4,000-patient observational safety study, this was not a simple matter of giving FDA whatever it wants--this is a large undertaking that needs a great deal of organizational support.

So Doliveux is right to shower praise on the Cimizia launch team. The risk management plan may be called CIMplicity, but when it came to getting this product to patients in 48 hours, there is nothing simple about it.

Investigating the Investigators: Another Headache for Drug Sponsors

This would be a good time for biopharma companies to review their ongoing clinical trials to determine whether any investigators involved in the study are vulnerable to potential disqualification proceedings by the Food & Drug Administration.

All signs point to a crackdown coming from the agency, likely to take the form of a spate of proceedings to disqualify individual investigators from participating in clinical trials.

That in turn means a big headache for any drug sponsors that relied on those investigators in pivotal trials of their drugs—any trial those investigators participated in, not just one that prompts a fraud investigation.

What tea leaves are we reading? How about these comments by the Center for Drug Evaluation & Research’s Office of Compliance director Deborah autor, who told the Food & Drug Law Institute’s annual Enforcement & Litigation Conference yesterday that the Division of Scientific Investigations is “becoming more activist. I think that they are really gaining momentum in what they do from an enforcement context.”

The agency is working on “streamlining” the process involved in disqualifying clinical investigators when FDA uncovers fraudulent or violative practices, Autor said. She acknowledged that the process currently is “Byzantine” and slow-moving—a fact that works to the benefit of investigators facing potential disqualification.

“The agency is working to clean up those procedures,” she told the audience, adding the wry observation that “I’m not so sure this is good from your standpoint.”

Autor’s comments verify the observations of two attorneys sharing the dais with her—Douglas Farquhar of Hymen Phelps & McNamara and Philip Katz of Hogan and Hartson—who sense greater urgency and a tougher stance from the agency in cases involving clients potentially facing disqualification.

A crackdown on investigators accused of fraud would hardly be surprising, given the recent round of hearings and Congressional reports focusing on claims that FDA failed to take action quickly enough to respond to allegations of fraud in clinical trials of the antibiotic Ketek.

We won’t rehash all the allegations here. Suffice it to say that there is bipartisan concern that FDA is not sufficiently vigilant in overseeing the conduct of clinical trials. The debate on the Hill focuses on whether FDA needs new enforcement powers (the subject of the most recent Ketek hearing in the House) or simply needs to use its current enforcement authority more aggressively (as recommended in a report by Republican Representative Joe Barton).

Any move by FDA to step up disqualification proceedings against investigators means headaches for industry.

It's not just the individual accused of fraud or that investigator's clinical center that suffers in a disqualification proceeding, Katz pointed out. “What you then quickly get to is: what do we do with the data that this disqualified clinical investigator has been involved with?”

And it “is not just the data in the study that was the subject that led FDA to the disqualification proceeding,” Katz said, “but also other data with which that investigator was affiliated. That becomes suspect as well.”

In some cases, there may be nothing sponsors can do to avoid the taint—except hope that their clinical trial findings are robust enough to support safety and efficacy even if the investigator’s site is excluded from the analysis of the trial.

But sponsors can also prepare by double checking whether their investigators have been cited by the agency in public inspection documents (known as FDA 483 reports) or, even more critically, in warning letters from the agency. Those are warnings signs that an individual may be vulnerable in an enforcement crackdown.

Autor added that the agency is not relying on enforcement alone, but is working to modernize its overall regulatory approach to clinical trial monitoring.

“The regs, as everybody knows, are outdated and don’t really fit the way trials are done today,” she said. “Hopefully, over time you will see that changing so that clinical trials will really be subject to appropriate regulation for how they are conducted today.” The goal will be “putting the onus on sponsors and monitors to ensure quality in clinical trials.”

That may sound like yet another regulatory burden on drug development (and it is), but if the alternative is a series of enforcement actions that knock out individual trial sites from multiple applications at a time, this may be a case where industry has a lot to gain from moving to a new regulatory model.

FDA’s Search for a Drug Chief Not Going Well: An Internal Candidate Emerges

We know all of you have been passing the time following the Presidential Primaries when the race you’re really interested in is who the next head of FDA’s drug center will be, right? Right.

A number of agency watchers and former officials agree that the longer the search goes on, the more likely FDA will be forced to look inside for a replacement. We talked to one former high-ranking FDA official with some knowledge of the search and here are some of the things we found out.

First, FDA Commissioner Andrew von Eschenbach is “concerned” that the recruitment for a director of the agency’s Center for Drug Evaluation & Research is taking so long and “not looking fruitful.” FDA chief medical officer Janet Woodcock is temporarily overseeing the center’s day-to-day operations until a permanent replacement is named. The absence of a CDER director has been magnified by the vacant director position at the Center for Food Safety and Applied Nutrition.

“He didn’t want the two largest centers without permanent leaders for a long time,” the former official says.

That’s why von Eschenbach made filling the CFSAN vacancy a priority. On January 4, FDA announced Center for Veterinary Medicine director Steven Sundloff would take over the food center.

There’s been some serious difficulty getting a large number of qualified external candidates, the ex-FDAer maintains, since the October 2007 departure of former CDER director Steve Galson due to his appointment as acting US Surgeon General. That’s understandable, according to the individual: “Who’d want a job when you won't know who your boss will be a few months out, where public perception is on the down slope, there’s little likelihood of getting substantial new appropriations, and you won't even be allowed to say you need more resources.”

That’s a convincing argument against wanting the job, wouldn’t you agree? When the search began in October 2007, an outsider taking over the drug center appeared to be a slam dunk. But now, as the French would say, c’est pas tout a fait evident. (Note: Washington Redskins fans are a little more cultured than the Eagles fans who occasionally write for this blog. We speak multiple languages, go to art museums, climb mountains…oh and we win Super Bowls.)

It appears that a serious internal candidate has, in fact, emerged.

We don’t know who it is, but we can speculate can’t we? Sure we can.

1) Center for Biologics Evaluation & Research Director Jesse Goodman:

As we noted in our earlier CDER search story, Goodman was the only FDA insider garnering serious consideration for the job at the outset. Goodman, a virologist, was named CBER director at the end of 2002, replacing Kathy Zoon, who moved to the National Cancer Institute.

The CBER head came to FDA in 1998, originally in the Office of the Commissioner directing the US Interagency Task Force on Antimicrobial Resistance. He later moved to CBER, where he worked on bioterrorism preparedness and blood and vaccine safety, eventually becoming deputy director before taking over for Zoon.

Most importantly for Goodman’s chances, he’s shown that he can run a large center within the agency’s organizational structure that operates in a similar fashion to CDER.

Odds: 3 to 1

2) CDER Deputy Director Douglas Throckmorton:

Time and time again, when the CDER search is brought up to FDA observers and former agency officials, I hear: “Why not Throckmorton?” Well, why not? Throckmorton would appear to be the obvious choice considering he has been the center’s number two for the last two and a half years. He served in an acting capacity for a year prior to that.

Before his promotion to deputy director, Throckmorton headed up the cardio-renal drugs division—a very high profile review group within FDA.

He also serves as chair of FDA’s Drug Safety Oversight Board, CDER’s liaison to the agency’s human subjects’ research review board, and chair of the center’s research coordinating committee.

Throckmorton has been involved in some interesting FDA meetings as of late. On January 9, “acting for” Woodcock, Throckmorton made a presentation to students and faculty at Duke University’s Fuqua School of Business along with Office of Medical Policy director Robert Temple. We know, we know, not the strongest evidence that he’s next, but still.

On January 17, the CDER deputy was involved in a senior CDER management meeting with PhRMA board representatives, including soon-to-be-retired Eli Lilly CEO Sidney Taurel, Lilly VP-global regulatory affairs, and PhRMA deputy VP for scientific and regulatory affairs Alan Goldhammer.

Meetings aside, Throckmorton has been viewed as somewhat of a rising star at FDA. He joined the cardio-renal drugs group in 1997 as a medical reviewer. Three years later, he was named deputy director of the division, and director two years after that.

So what’s the problem? One theory is that Throckmorton is too young. That seems a bit dubious considering all of his current responsibilities and fast rise up the career ladder. But if FDA were going to name Throckmorton as Galson’s replacement, they would have done it by now. After all, they passed on giving him the “acting” title altogether in favor of Woodcock, who previously ran the drug center.

Despite initially getting passed over, I still think he’s a very strong candidate and running right behind Goodman.

Odds: 5 to 1

3) Office of New Drugs Director John Jenkins:

Okay, we admit we are a bit in the tank for Jenkins. He recently took the time to speak at length with The RPM Report about the state of new drug approvals (aka the drug approval drought), drug safety, and the new drug reform regulations under the FDA Amendments Act. You can read it here if you haven’t already.

Before the interview, we thought Jenkins was a smart thinker and effective spokesman on regulatory issues. We are more convinced than ever afterwards.

Jenkins’ position alone as FDA’s top drug reviewer is enough for him to warrant consideration. He oversees 17 drug divisions and a number of important office-level groups within CDER. To see them all, click here.

You could argue that Jenkins’ ability to keep drug review times in check—actually reducing priority and standard review times in 2006—while reviewers are spread increasingly thin under a climate of poor morale makes him the most prepared to take over the drug center.

Case in point, FDA/Sponsor meetings have more than doubled over the last five years and Jenkins has calculated in the past that drug reviewers have nine industry meetings every working day of the year. In addition, new drug applications have increased in the 10% range while FDA’s budget has remained flat.

Publicly, Jenkins has been even more impressive. During a June House Oversight & Government Reform Committee hearing looking into the handling of heart risks linked to Avandia, Jenkins performed admirably before a host of Congressional lawmakers looking for blood.

He was equally impressive during a media briefing on January 25 to discuss how FDA planned on handling data from Schering-Plough/Merck’s ENHANCE study on the statin Vytorin. Click here to read our take on FDA’s response to questions about the Zocor/Zetia combination.

Jenkins is also an FDA veteran with 16 years under his belt, six as the head of the Office of New Drugs, and considered to be one of Woodcock’s “people.” One thing that could preclude him from getting the job is that the whole Vioxx debacle occurred while he was in charge of OND. But if that’s the case, none of the internal candidates listed here stand a chance of getting the CDER job.

Odds: 7 to 1

4) Office of Medical Policy Deputy Director Rachel Behrman:

Ah, the Dark Horse. There’s always a dark horse candidate. When you flip through the obvious internal candidates, Behrman doesn’t come to mind. However, one former FDA official says Behrman could be the most serious internal candidate.

Behrman was picked by Woodcock to head the Office of Critical Path Initiatives in the Commissioner's Office--an important priority for the agency in general and Woodcock in particular. That is in addition to her role as second-in-command to the dean of drug development Robert Temple in the medical policy office. And in her spare time, Behrman also serves as Director of the Cross-Centers Initiatives Task Force. That’s just the kind of collaborative position FDA Commissioner Andrew von Eschenbach has tried to promote within the agency.

Behrman joined FDA in 1989 and has some experience in the spotlight that the CDER director operates under. For instance, she testified before the Senate Special Committee on Aging regarding in 2005 regarding the impact of direct-to-consumer advertising on seniors. The full testimony is right here. The fact that the Division for Drug Marketing and Communication reports into the Office of Medical Policy probably serves as an advantage as DTC continues to remain a public and political focus.

Behrman’s obvious drawback as a candidate is that she has less direct experience with product reviews than the other candidates. Of course, if FDA's first choice would be an outsider, that drawback could actually be a selling point to the search committee.

Odds: 15 to 1

Place your bets.

"Consensus is not our goal": A Conversation with FDA's Top Drug Reviewer

Drug companies aren't the only ones worried about the sinking rate of new drug approvals. Food & Drug Administration officials are equally concerned over the innovation drought. After all, the number of new drugs making it to market is at its lowest since 1983.

FDA's Office of New Drugs Director John Jenkins, who oversees all new drug applications within the drug center, is especially preoccupied with the lack of results from the drug development process. "We agree that it’s very disheartening that despite the rather massive expenditure of research dollars, we’re not seeing a growth in the number of NMEs submitted to the agency for review," Jenkins says of new molecular entities getting aproved by the agency. "We are seeing a continued growth in the number of new commercial INDs submitted, so there still seems to be a lot of innovation. It’s a question of how to get them out the other end of the pipeline."

Jenkins also addressed other issues ranging from drug safety to how FDA plans to prioritize implementing the new drug reform regulations under the FDA Amendments Act. In particular, he addressed the public disagreement between the drug review and drug safety groups during the Avandia advisory committee meeting last July.

"Consensus is not our goal," Jenkins says. "That strikes some people as odd when they first hear me say that, but I think that if you’re in a regulatory organization and people think that consensus is the goal, that leads to a subtle pressure to conform to the prevailing viewpoint even though you may not agree with the prevailing viewpoint and you may in fact be right."

You can read the whole interview in The RPM Report by clicking here. Free registration for non-subscribers is on the left side; subscribers should just log in.

I would love to hear your comments on Jenkins' views on FDA, drug companies and drug development.

J&J Tests FDA's Pain Threshold with Tapentadol

One line in Johnson & Johnson’s press release yesterday announcing the submission of a New Drug Application for the pain therapy tapentadol caught our eye:

"More than 1,800 patients have been treated with tapentadol IR tablets in clinical trials to date."

Which got us thinking: what makes J&J think they can get a new-ingredient product approved as a pain killer at today's FDA with data on only 1,800 patients? Haven't they noticed how tough it is to get new drugs through FDA, especially in the pain category?

Here are some possible answers:

(1) They are self-absorbed egotists with unfounded views of their own power and infallibility. But that can't be it, can it?

(2) J&J thinks that FDA will relent on pain products in the next year or so. It never hurts to be optimistic, but we haven't seen any signs of that yet.

(3) The product is for limited indications; J&J has a risk management program that will assure that it will stay in that population and they will sell the program to FDA as well as the drug’s safety.

Well, the press release says the product is for "moderate to severe pain" supported by studies in "patients undergoing bunionectomy surgery or for patients with degenerative, end-stage joint disease of the hip or knee," supported by a third study in "outpatients with low back pain or pain from osteoarthritis of the hip or knee." So it sure sounds like J&J is going after a big market based on relatively small studies. Not exactly a recipe for success by cautiously selecting a sub-population.

(4) There is something different about the way this product works which means that it will have no safety or abuse issues.

It surely doesn’t sound that way in the press release. J&J says it has "a unique profile with two mechanisms of action, combining mu-opioid receptor agonism and norepinephrine reuptake inhibition in a single molecule." That may be a great profile, but from a safety perspective it suggests a higher burden on J&J to show that the drug is free of two different potential risk profiles.

As for efficacy? According to J&J "data from these clinical trials suggest that tapentadol has efficacy comparable to strong opioids."

Is this a winning profile at today's FDA? We'll all find out later this year.

The Big Winner in the Vytorin Debacle? It Might be Lilly

Steve Nissen's latest star turn, advising doctors everywhere to stop using Vytorin until there is better evidence it improves health outcomes, is surely going to be a boon for Pfizer and AstraZeneca.

Those companies' good old fashioned statins (Lipitor and Crestor, respectively) will surely pick up a bit of ground in the cholesterol market.

But that is sure to come at a price: If (when?) Congress holds hearings on the Great Cholesterol Coverup (we’re guessing at the hearing topic here), you can bet everyone in the cholesterol class will take some lumps for their aggressive marketing. It won’t help that the Energy & Commerce Committee which is investigating Vytorin is also investigating Pfizer’s Lipitor DTC campaign.

Here's another company that stands to gain: Eli Lilly & Co.

Why? Because the emergence of Steve Nissen as perhaps the most visible critic of pharmaceutical industry practices and products means that people are sure to pay even more attention when he says a drug company did things right.

Here is what Nissen had to say about Lilly's anticlotting drug prasugrel during our FDA/CMS Summit for Biopharma Executives. "The company did a courageous trial against an active comparator and they informed the medical community: What were the benefits, what were the risks, and a reasonable and sensible person can look at that and say I get it.”

"The results with prasugrel were a very good result," Nissen said. "The drug prevented more myocardial infarctions than the bleeding episodes it caused. I think the drug is an advance."

Nissen said more or less the same thing to the New York Times when the pivotal trial results on prasugrel were published, and he has since given more interviews underscoring his belief that the drug should be approved by FDA as quickly as possible.

That, to put it mildly, would be wonderful news for Lilly. The company lost about 15% of its value during the fourth quarter as Wall Street fretted about the mixed data. (The RPM Report has just published more on this topic on our website. You have to be a subscriber to The RPM Report to read our complete analysis, or sign up for a 30-day free trial to get a taste of what you are missing.)

Another Dismal Year for New Drug Approvals

When does a drought stop being a drought, and just become a desert?

That question has to be raised when contemplating yet another disappointing year for innovative pharmaceutical launches in the US.

FDA approved just 17 new molecular entities in 2007—the lowest single year total since 1983, when there were 14 NME approvals.

FDA’s official tally will probably be 19, including two therapeutic biologics approved by the Center for Drug Evaluation & Research. FDA began including biologics in its total in 2004, so that makes historical comparisons difficult. But even if you count all 19, this was still the worst year since 1983.

That’s 25 years ago, folks. Gandhi won best picture. Toto won album of the year. A Philadelphia sports team actually won a championship.

If you want to understand the decline in productivity industry wide, consider this: total R&D spending by brand-name companies in 1983 was $3.2 billion, compared to $43 billion in 2007. In other words, the industry spent $228 million per NME approved in 1983, compared to $2.5billion each in 2007. Or, if you prefer, the extra $40 billion in R&D spending brought with it a total of five additional therapies.

Big Pharma didn’t have anywhere near as many mouths to feed in 1983 either. The entire domestic brand business was just under $17 billion, according to data reported by the Pharmaceutical Research & Manufacturers of America trade association. Domestic sales of brand companies today are ten times higher. (If you haven’t read Roger Longman’s post yesterday about the importance of adjusting industry infrastructures, please do so now.)

Of course, looking at any single year doesn’t tell you anything about the overall health of the new product flow in the industry. Pharmaceuticals do have a relatively long commercial life, so as long as there is a health bolus of new products every few years, things should be fine.

Unfortunately, looking across multiple years doesn’t make the picture any brighter. Last year was the worst for new product launches since 1983. The second worst? 2005. Third worst? 2006. Fourth? 2002. In fact, FDA has approved more than 30 novel molecules only once this decade, when it cleared 36 in 2004. FDA approved more than 30 every year in the second half of the 1990s.

Or consider this: over the past three years, FDA has approved a total of 61 new molecular entities and novel biologics. The agency approved 60 in 1996 alone.

We like to track our own statistic, Innovative Commercial Therapies. That represents our attempt to measure the number of truly novel molecules (no enantiomers, metabolites or pro-drugs, where the basic question—is it safe and effective in humans?—has already been answered; no diagnostics; and no non-commercial products like biodefense agents developed by the Department of Defense.)

We think that gives a more accurate indication of the real output of big pharma and biotech pipelines. That only makes the picture that much grimmer: there were just 14 ICTs in 2007. Below are the statistics over the past decade.

If you divide that chart in half, you can see that FDA approved a total of 199 ICTs in the six years from 1996 through 2001. That compares to just 122 in the six years from 2002 through 2007, a decline of 39%.

Okay, enough gloom and doom. Looking on the bright side, at least there were fewer first time generic launches in 2007 than there were new molecular entity approvals. As we reported last year, for the first time in memory the industry suffered a net loss of patented medicines in 2006.

Of course, it was a close race. By our count, there were 14 first time generic launches in 2007, balanced against the 16 NMEs. And boy is it hard to imagine the crop of new drugs launched in 2007 matching the commercial peaks of the brands that lost exclusivity—products Norvasc, Ambien, Lamisil, Coreg, and Protonix.

And, since the industry suffered a net loss of two patented molecules in 2006, that means that the entire pharmaceutical industry has only stayed even in the number of patented medicines on the market for the past two years. That, to put it mildly, is not a recipe for sustained growth in the industry in the years ahead.

Bear in mind that, not only is the absolute number of new product approvals declining, so is the likely peak market size for new products. In other words, at a time when the industry desperately needs the pipeline to pump out more new products than ever, it is getting only a trickle.

Something needs to change.

Please Note: This post has been updated.

Our initial count of drug approvals in the IN VIVO Blog was off by one. It turns out there were 17 new molecular entity approvals, not 16—Fresenius Kabi’s hypovolemia agent Voluven (hydroxyethyl starch) was approved December 27.

Voluven was approved under the 505(b)(2) mechanism as equivalent to other blood volume enhancers, so it definitely does not add to our benchmark statistics (innovative commercial therapies, or ICTs). The extra NME also doesn’t change anything else in our analysis: 17 NMEs is still the lowest total since 1983, as is 19 novel molecules (NMEs plus novel biologics). Voluven is nevertheless an interesting approval: it is the latest example of the emerging follow-on biologics pathway at FDA.

What’s that? You think there is no such pathway? Not so. Congress has yet to enact a legislative pathway for follow-on versions of biologics regulated under the Public Health Service Act. But for biologics that happen to be regulated under the FD&C Act (like human growth hormone, insulin, insulin-like growth factor, etc. etc.) follow-on approvals keep trickling out of the agency. Look for more on that topic as well, coming soon in The RPM Report.

So Cimzia Will be Late, After All

It's official: UCB's Cimzia will be late. (Or rather, even later.) No one really doubted that UCB's anti-TNF antibody fragment would fail to meet its planned 2Q 2007 launch for Crohn's disease, ever since the FDA Complete Response Letter in December 2006. (UCB shares have tumbled 20% since then.)

The only surprising part was CEO Roch Doliveux's apparent refusal to contemplate any slippage. "We're preparing everything for the launch," he declared at UCB's preliminary results meeting barely a month ago.

The preparations will be long (let's hope they haven't hired any reps yet). Turns out that FDA wasn't happy with the design of one of Cimzia's trials, so UCB announced today it needs to do another one, to "confirm the induction of clinical response" in Crohn's patients. That's worrying; so is the fact that it'll take until late next year to do the study.

Cimzia matters to UCB. Not just financially, although the drug is--or was--expected to contribute significantly to UCB's EBIT, but also strategically, in terms of defining and confirming UCB's transition from a chemicals conglomerate into a biopharmaceuticals firm. Doliveux has made much of this transformation, triggered by the $2.7 billion acquisition of Celltech Group in 2004. Thus setbacks to Cimzia casts doubt not just on one legacy project from Celltech (already delayed for a variety of reasons), but on UCB's skills in integrating large-molecule science with its chemistry heritage.

It doesn't do management's credibility much good, either. By and large, Doliveux and his team have done a bloody good job--don't forget he also bought Schwarz Pharma last fall, a move which looks more perceptive as Cimzia's troubles deepen. But management's apparent confusion as to the nature of the FDA response and subsequent meetings--whether reflecting real uncertainty or just caginess--concerns some analysts.

When and if Cimzia does get to market, it will face plenty of competition, not least from Abbott's Humira, which filed for approval in the US and EU last September and is easier to administer. UCB's plan was to get to market in Crohn's before Humira (which is already on the market for RA). Now it's not a question of whether it will be behind, but how far behind. The additional trial won't be done until late 2008, and although UCB says it's unclear whether will be a pre- or post-approval requirement, I know where my money is.