FDA and REMS: A Symbolic Start

FDA just wrapped up a two day public meeting to review the implementation of its Risk Evaluation & Mitigation Strategy authorities.

The hearing involved almost 70 different presentations from a diverse base of stakeholders offering input into how to make sure that REMS best allow drugs to be marketed safely without disrupting the entire health care system.

It also featured an unusually active and engaged panel of FDA officials; these agency meetings are often fairly magisterial in nature, with FDA listening but saying nothing. Not here: questions and comments aplenty.

So there is tons to digest, and we will have plenty of coverage of the meeting in The Pink Sheet, The Pink Sheet DAILY, and The RPM Report.

But we wanted to take note of how the meeting began, since we think that says volumes about where FDA is going with REMS.

The very first presenter was the American Society of Clinical Oncology’s Karen Hagerty. As we have written, ASCO has some concerns with how FDA has been developing REMS, and especially with how the agency and Amgen put together a new program for use of erythropoiesis stimulating agents in oncology. ASCO wants to make sure that they have more input in the development of REMS in the future.

That, to us, is the key theme of the two day hearing—and it surely says something about FDA’s openness to that theme that it kicked off the two days with a panel of providers, including ASCO, the American Medical Association, specialty pharmacy execs, and Kaiser. Industry (the Pharmaceutical Research & Manufacturers of America, the Biotechnology Industry Organization, Eli Lilly) came second.

The input of outside stakeholders is what prompted FDA to reconsider its REMS implementation—and we’re betting those stakeholders will end up gaining more input into the actually crafting of REMS for products going forward.

It won’t be easy: after all, as FDA officials pointed out, they regulate sponsors and many of the discussions about the potential need for and design of a REMS has to remain confidential. But providers and other stakeholders want in, and they are not likely to give up until they get in.

Take Kaiser. The non-profit health plan submitted a petition at the end of last year that really kicked off the REMS reappraisal at FDA. And Kaiser is clearly committed to seeing the process through: the non-profit had three different representatives speak during the meeting, making a total of six presentations on each of the six topics identified by FDA for the agenda.

For sponsors, the concerns raised by providers may sound like a blessing. After all, anything that stops FDA from slapping restrictive distribution programs and other post-marketing controls on new products willy nilly has to be a good thing, right?

Sure. But one other thing is clear from the two day meeting: REMS are here to stay. Providers don’t want them eliminated altogether, they just want a seat at the table in helping to shape programs before they are launched. We’re not sure how or when they will get their way, but we bet they will eventually. And then sponsors may pine for the days when the REMS was theirs to control.

Asclera: A REMS By Any Other Name…

Quick quiz. There’s a new molecular entity pending at FDA, intended for a cosmetic use. There is a clear signal of a risk of anaphylactic reactions, most likely associated with off-label use at high doses. The review team is in agreement: there needs to be some form of communication plan and special monitoring to assure that physicians don’t casually use higher doses.

Will the product have a Risk Evaluation & Mitigation Strategy as a condition of approval?

We don’t know about you, but our guess would certainly have been yes. After all, FDA seems to be using REMS more and more, right?

Well, not this time.

Here is how Cardio-Renal Drug Products Division Director Norman Stockbridge explained the decision, in the summary review of the March 30 approval of BioForm Medical’s varicose vein treatment Asclera (polidocanol):

“All team members concur on approvability.

An issue to be resolved is how to address the risk of anaphylaxis. There are no such cases in the controlled experience, but there are other allergic reactions—urticaria, hives, sneezing, and what sounds like angioedema. Similar cases to these appear in post-marketing use [overseas]. Post-marketing, there appears to be one reasonably clear anaphylaxis case following low-volume administration to treat a leg varicosity….

Overall, the team has the impression that the risk of anaphylaxis may increase with dose, and that seems plausible. A goal of labeling and any additional post-marketing safety-related activities ought to be discourage off-label use for larger varicosities where the volume of drug necessary will be much higher than it is for the indicated uses.

Dr. Southworth recommends a bolded warning, similar to the one sotradecol has. I concur with this. She recommends a communications plan for healthcare providers for the first few years, and annual review of hypersensitivity reactions. (These can be done outside of a REMS.) I concur with these, too.

She is equivocal on a medication guide, citing the closely monitored setting of administration. I do not favor a medication guide; there is ample opportunity for the patient and physician to discuss treatment options, and practitioners are generally familiar with the risks from use of sotradecol. While I agree with Dr. Southworth that the cosmetic use creates a low threshold for taking conservative measures, I do not think the bar should be quite this low.”

Final decision: approval with no REMS.

So is this a sign that REMS mania has crested? Should sponsors celebrate the return of a standard where REMS are the exception rather than the rule?

Well, not so fast.

First, Stockbridge has already voiced his displeasure with some of the accoutrements of the “Safety First” era, declaring in his memo on Effient that “no one associated with this review should feel good about this.” He meant the endless deliberations about the potential safety issues with Lilly/Daichii’s clot-dissolving drug. Stockbridge was clearly ready to approve the drug long before he wrote those words in April 2009. But Effient itself wasn’t approved for another three months after.

In other words, Stockbridge can’t change anything on his own, and its clear that other FDA review managers have different levels of enthusiasm for the new safety tools. For example, FDA’s Endocrine & Metabolic Drugs Division management, for example, seems to have a very different view of the value of REMS tools. (We’ll have more on that in an upcoming issue of The RPM Report.)

And, while Stockbridge’s rejection of a REMS did avoid a last minute delay for Asclera, it didn’t exactly make this a lightning fast approval. Asclera was first submitted in 1999, and got a “complete response” in 2004. Meanwhile, it continued to be marketed overseas, building the safety database that helped reassure FDA that the risk of anaphylaxis is very rare. That puts Asclera in a venerable class of NMEs that always have an easier time at FDA: those with long marketing histories overseas.

More importantly, while there isn’t technically a REMS on Asclera, there might as well be. FDA and the sponsor agreed to a Dear Doctor letter at launch outlining the risk of anaphylaxis. It isn’t required, so it isn’t a REMS—but it was agreed to prior to approval, and we bet the sponsor doesn’t see much difference there.

And then there is a mandatory post-marketing study—a pretty unusual one at that:
The sponsor will provide “a yearly report (containing both interval-based and comprehensive data) analyzing spontaneous adverse event reports received that describes anaphylaxis or death.” Reports are due annually until 2016.

So BioForm doesn’t have to comply with a REMS. But it does have to send a “Dear Doctor” letter warning of a very rare potential adverse event with off-label use, and submit annual analyses of post-marketing reports.

A REMS by any other name still smells as sweet…

Effient and Onglyza Start Slow—And That May Not Be A Bad Thing

When Big Pharma execs start pointing to unusual performance metrics when talking about big product launches, investors get very nervous.

What they want to hear (or, better yet, see for themselves) is simple: clear evidence that new prescription trends are tracking well relative to blockbuster launches of the past. After all, as the prescription data company IMS Health points out, it does seem to be an ironclad rule that rapid initial uptake leads to blockbuster franchises—and slow starts almost never do.

So when Lilly and Bristol-Myers Squibb spent their quarterly earnings calls talking about hospital P&T committee schedules, formulary status, brand awareness levels and “intention to prescribe,” you can see why investors are nervous about the prospects for two of the biggest launches in the industry: Lilly’s antiplatelet drug prasugrel (Effient, partnered with Daiichi Sankyo) and Bristol’s diabetes therapy saxagliptin (Onglyza, partnered with AstraZeneca).

Both products were introduced during the quarter, and both posted similar initial sales (about $20 million in the US) during the period. There’s nothing wrong with those launch sales—but the question is: did any of those pills make it out of the distribution channel and into the hands of patients?

That’s where the underwhelming IMS data have raised concerns. Its early days, of course, but neither product is tracking anywhere near the blockbusters already in the market. Effient hopes to approach the performance of Bristol’s Plavix, now the number two drug in the world, while Onglyza matches up against Merck’s Januvia, which is arguably the one launch of the past five years that bears any resemblance to the blockbuster model of the 1990s.

For Lilly, of course, the starting point is recognizing that the IMS data are more or less irrelevant to the launch, since most prescriptions will be written in the hospital in the context of an acute coronary intervention—and then it’s the refills upon discharge that get picked up in traditional channels.

Still, there’s not much to point to as evidence that Effient is doing well. Here’s what Lilly IR exec Nick Lemen said during Lilly’s Oct. 21 earnings call.

“We are diligently executing our launch plan. Obtaining hospital formulary status is critical to the uptake of a hospital-based product like Effient. As we've said in the past, gaining wide-spread hospital formulary status will take roughly six months. To date we're on track to achieve our hospital formulary goals. As we move forward, in addition to working to gain formulary status, we'll be focused on communicating formulary availability to physicians and seeking initiation of appropriate ACS/PCI patients, particularly those under 75 years of age and those over 132 pounds of body weight who have not had a TIA or stroke. Payer access is also meeting our expectations of interim formulary status of Tier 3 unrestricted. We're especially pleased that as of October 1st Effient has Tier 2 unrestricted access with Express Scripts in both commercial managed care and Medicare Part D.”

That didn’t exactly wow ‘em on the call, especially since—as one analyst pointed out—Lilly had previously talked about achieving “rapid” formulary access in hospitals and the six-month time line sounded new.

As for Onglyza, here is what Bristol President Lamberto Andreotti had to say during that company’s Oct. 22 call:

“I think that's a good opportunity for me to say that we are pleased from what we've seen so far. We are executing against our plan….We are very pleased to see that now we are in the marketplace, awareness is going up from nearly zero at the beginning, to a good percentage now. The number of trials, the number of doctors that are using Onglyza is increasing. I saw some data on intent to prescribe, which is also going in the right direction and access is going the right direction.”

That didn’t exactly set the analysts' hearts a pitter-pattering either.

There’s no denying it: both brands are indeed starting slow. The question is whether the rule of thumb that blockbusters start fast needs revision.

That’s where both Lilly and Bristol have a case to make: the world has changed, and the old blockbuster model has to change with it.

For starters, reimbursement matters now, much more than it did in the blockbuster era. So those stats about formulary access are important—not just something to talk about other than IMS numbers.

And then there is the regulatory change. Effient is covered by a formal Risk Evaluation & Mitigation Strategy, set to be in force for two years. We’ve argued since the REMS were enacted that one implication will be to slow down product launches, with blockbusters more likely to follow something like the Prozac model (a slow uptake followed by an explosive breakout) rather than the billion-dollars-in-year-one-or-bust model.

Onglyza doesn’t have a formal REMS, but it is entering a changed marketplace, redefined by the safety concerns raised in the context of GlaxoSmithKline’s Avandia. Bristol’s challenge is, in effect, to reaffirm the idea that innovation in diabetes care can be safe—a task not made any easier by the fact that the company’s marketing materials still aren’t approved by FDA, even though the drug is.

Indeed, for both Effient and Onglyza, we would argue that a slow start is exactly what regulators want to see—in effect, a final trial period where use expands slowly, rather than take the risk of exposing hundreds of thousands of new patients in the first months after approval.

Rather than focus on the different metrics presented by the two companies, investors would be well served to consider another point Bristol’s Andreotti made. “We launched in a different US than the US of many years ago.”

That is undeniably true. Whether Effient and Onglyza will ultimately achieve blockbuster sales is a different question, of course. But a slow start is no longer enough to rule out a blockbuster finish.

Allergan’s First Amendment Case: REMS vs. Off-Label Promotion – and DTC

Allergan filed suit against the Food & Drug Administration on Oct. 1, challenging the prohibition of off-label promotion of prescription drugs in the context of a new Risk Evaluation & Mitigation Strategy for the botulinum toxin therapy Botox. At the time, we had just gone to press with a story talking about how REMS might redefine pharmaceutical marketing.

Our thesis: that REMS offer at least the opportunity for commercial organizations to redefine practices viewed skeptically—things like speaker’s bureaus, scripted sales calls, “seeding studies,” etc.—as regulatory obligations that promote the public health. And that, done properly, both the commercial organization and the public health might well come out ahead. (You can read the article here.)

We’ve had the opportunity to discuss that article now with marketing professionals in several contexts, including industry meetings and one-on-one conversations. It fair to say there has been a range of opinion on our thesis--ranging from "you are completely crazy" to "you are completely crazy but you just might be right.”

Having had time to explore the implications of the Allergan suit, we now think we weren't crazy enough. It turns out that REMS aren't just offering a path to rehabilitate controversial marketing practices to support approved indications, they may in fact open the door for companies to promote unapproved uses without inviting crushing regulatory and civil penalties. That, at least, is Allergan's argument (which we explained in depth in “The Pink Sheet” here).

It is a long shot at best to think that Allergan will pull off a complete victory in the case—long in both the sense that most folks we’ve talked see the odds of victory as slim, and also long in the sense that a complete victory would almost certainly involve litigating all the way up to the Supreme Court.

But regardless of the outcome of the suit, the case is an extremely interesting new wrinkle in the still rapidly evolving field of REMS. (Sorry, there is something about Botox that makes puns irresistible.)

Because the simple truth is that FDA now has the authority to do exactly what Allergan wants—allow, or indeed, require greater communication about off label uses. The suit focuses on the fact that FDA is not allowing as complete communication as Allergan wants—but the fact is that FDA could allow that under the existing law and in some sense “approve” an off-label promotion campaign. We doubt they will for Botox, but we’ll keep our eyes peeled (is that another pun?) for a case where they do.

The Allergan suit highlights another thing marketers should anticipate in the context of a REMS: the re-emergence of commitments by sponsors not to advertise their products to consumers in the context of the new programs.

Early versions of the 2007 law included provisions that would explicitly have allowed FDA to impose a moratorium on DTC in the context of a REMS (and the agency already had done so in at least one “voluntary” risk management program negotiated before the law took effect.) Advertisers worked hard to get that provision stripped from the bill, but they did not get anything written into law that would stop sponsors from negotiating those types of provisions as part of a REMS anyway. (We covered all that here.)

How does that relate to the Allergan lawsuit?

In its court filing, the company lays out the off-label campaign it wants permission to conduct—in essence, the REMS agreement it wishes it could get.

And one of those provisions states: “Allergan does not seek to engage in direct-to-consumer communications about the off-label use of Botox.”

That's another one we'll be watching for: the first REMS that includes some limitations on DTC. And our hunch is it will be an agreement that the sponsor is only too willing to make.

Wyeth Quits On Relistor; Surprise Victory in First REMS Test Market

It is no surprise that Wyeth is willing to pay $10 million to wash its hands of the opioid-induced constipation therapy methylnaltrexone (Relistor), returning all rights to partner Progenics Pharmaceuticals.

The “transition payment” to unload future obligations is clearly a case of a throwing a bit of good money after bad, when the alternative—continuing to support the product as demanded by the partnership agreement despite negligible sales—would entail throwing a lot of good money after bad.

So it is not a surprise that Wyeth gave up on Relistor per se—but it is a surprise that Wyeth gave up on its opioid-induced constipation partnership when GlaxoSmithKline did not.

This time last year, it sure looked like Wyeth and Progenics had a much better chance of making their partnership work, while GSK—big pharma partner for Adolor’s mechanistically similar therapy alvimopan (Entereg)—had no reason to push forward.

Relistor and Entereg have a lot in common. The two drugs were approved at almost the same time in mid-2008 to relieve constipation in high-risk subpopulations. They share a similar mechanism of action, targeting the mu opioid receptor. Both were small molecules developed by small companies (Progenics and Adolor, respectively); both had big pharma partners eager to commercialize them, eyeing a blockbuster market opportunity: routine use to prevent constipation associated with chronic opioid use.

And both ran aground late in development when safety issues emerged.

That’s when things got different.

Neither product had a smooth path through the "Safety First" era Food & Drug Administration, but Entereg came to market with an ultra-restrictive indication (short-term, inpatient use in post-surgical patients only) and even more restrictive post-controls designed to ensure there is absolutely no long-term or outpatient use. It marked one of the first uses by FDA of its new Risk Evaluation & Mitigation Strategies authority granted by the FDA Amendments Act of 2007—and an early example of how the new tools really can dramatically limit the potential patient population for a new drug. (See “Entering the World of REMS,” The RPM Report, July 2008.)

Relistor was also approved with a narrow initial indication (subcutaneous use for terminally ill cancer patients on opioids), but without any special restrictions upon approval, not even mandatory post-marketing safety studies, making it an increasingly rare example of a new molecular entity approved in the FDAAA era without triggering any of the agency’s new post-marketing safety tools. (See “FDAAA Impact Analysis,” The RPM Report, May 2009.)

It’s safe to say that neither GSK nor Wyeth was thrilled with what they eventually found themselves marketing. But if you had to bet which would give up first, it sure looked like a safe bet that GSK would bow out of Entereg. After all, GSK was stuck with a hospital product instead of a primary care blockbuster; Wyeth at least had access to the primary care market, even if it didn’t yet have a blockbuster indication.

Well, it didn’t work out that way.

Not only did Wyeth give up on Relistor first, it paid Progenics an additional $10 million on top of at least $160 million in milestones and product development costs already paid--just to get the brand off its hands.

GSK, on the other hand, backed out of any further development of Entereg, but the company has continued to market the drug for the approved indication—post operative ileus—despite the strict, hospital-only access program. Entereg’s no blockbuster: with sales of just $5 million in the second quarter, it is not even a rounding error in GSK’s results.

But its doing better than Relistor, which posted sales of only $3.2 million during the quarter. More importantly, Entereg’s modest sales could potentially pay off the modest cost of marketing the drug via GSK’s hospital sales organization.

Not so with Relistor, where even a 10x ramp up in sales would make it difficult for Wyeth to justify continued support for the brand—especially in the context of the now complete Pfizer merger.

So, if (as we suggested at the time of the approvals) Entereg vs. Relistor marked an early case study of competition between products saddled by a REMS and products without restrictions, score a victory for marketing under a REMS.

Okay, we’re not overstating the case here. There’s essentially no way that Entereg will pay back GSK’s investment in the product. But there is also no denying that GSK will end up much better off than Wyeth did with Relistor, even though Relistor had the “clean” approval.

Its not like GSK and Adolor wanted a REMS. But having got one, the companies may end up demonstrating that commercial success is possible despite restrictive programs—and may even be enabled by them, since constraints on marketing by definition limit the marketing investment to commercialize REMS products.

Put another way, if you need to create a new commercial model anyway, it may help to be prohibited from using the old one.

VC Financing: Enter Comparative Trials and REMS Post-market Plans

In Washington, the policymakers and legislators are arguing over how to build comparative effectiveness research into the health reform bill.

Eleven miles away in the Maryland suburbs at the Food & Drug Administration’s new White Oak campus, the regulators are figuring out on a case-by-case basis how to apply their new authority to order post-approval education, distribution and testing programs for new drug approvals. under the Risk Evaluation & Mitigation Strategies authority.

But in the private capital markets removed from the political capital, these two issues are already moving from the conceptual, formative stages into real world requirements. Drug and biological entrepreneurs are learning that they better have answers to questions about both requirements when they go into venture capital firms for development funds.

VCs now expect companies seeking funding to bring in plans for comparative research during drug development and to recognize early what level of post-marketing controls FDA will require.

That’s what MPM Capital’s Gary Patou (in the picture above) told a session on successful drug development plans at the recent annual meeting of the Drug Information Association in San Diego. Clear plans for comparative effectiveness testing and post-marketing controls are becoming de rigeur parts of solicitations for funding from VCs, he says. (For a longer examination of the new de facto requirements for drug development plans from venture capital firms, see this story from The RPM Report.)

That means that the funding spigot from private capital will help enforce and establish the new government additions to drug development. Policy is made in DC, but practice is enforced by VCs.

Wacky World of Generics: REMS Edition

Here's a "Catch-22": If the Food & Drug Administration prohibits sale of a drug outside of a tightly controlled restricted distribution program, how on earth is a generic company supposed to obtain supplies of the product to use as a comparator in bioequivalence trials?

If you are Dr. Reddy's, hoping to be first to challenge the patents on the anti-cancer agent Revlimid, you ask nicely. And if you are Celgene, apparently, you answer "no way." That, at least, is how Dr. Reddy's describes the situation in a citizen petition filed with the Food & Drug Administration earlier this month. (We have the full story in "The Pink Sheet" DAILY.)

This petition has all the markings of a test case. The goal is not so much to accelerate a generic challenge to Revlimid (the earliest a generic launch could possibly come is three years from now) but rather to define a process to assure that the new Risk Evaluation & Mitigation Strategies authority given to FDA in 2007 doesn't become a perpetual exclusivity award for sponsors.

The law (known as FDAAA) states unequivocally that restricted distribution programs are not to be used to block or delay generic competition. It's just that, well, it's one thing to say that, another thing to make it so.

Certainly, George Horner--the former CEO of Prestwick Pharmaceuticals--doesn't see any realistic way for generics to compete against products covered by REMS. He told us that in a story on the fascinating development program--and flurry of business development activity--for the Huntington's chorea therapy Xenazine. (You can read all about it in The RPM Report.)

In the petition, Dr. Reddy's is proposing a process that would essentially allow generic manufactures to obtain an authorization from FDA for studies, and then compel manufacturers to provide samples (at market prices) for use in bioequivalence trials. That certainly seems reasonable enough--and we bet (after much regulatory machination) FDA ends up setting a policy along those lines to eliminate the Catch-22 facing Dr. Reddy's.

But that still doesn't address the bigger issue: While it is presumably simple enough to create a bioequivalent version of the active ingredient in Revlimid, is it really possible to create a generic equivalent to the restricted distribution program for the drug? Celgene would argue no. In fact, the company has argued no in the context of the predecessor product--the notorious thalidomide. (Read more about that case here.)

Put another way: does FDA really want to make it simple for dozens of sponsors to launch versions of drugs like thalidomide, when the agency has already determined that the risks of inappropriate use are high enough to merit costly, burdensome post-marketing restrictions? Our hunch: products covered by restricted distribution programs will end up looking more like biotech therapies facing follow-on competition than they will like conventional generic drugs.

And, for now, there isn't even a clear-cut way for generics to begin the process of proving bioequivalence.

Notes from BIO: Getting Comfortable with REMS

No one wanted to use the word ‘albatross’ in the same sentence when describing REMS, or Risk Evaluation and Mitigation Strategy, at a panel session this week at BIO about the FDA Amendments Act of 2007. But the implication was hard to miss from the tone of some of the comments and the body language of some speakers.

A REMS, for those who may not recall, is the newly upgraded program to ensure a company has a strategy in place to manage and communicate a potentially serious risk with its medicine. And the implications are being gauged closely by industry, which is assessing whether REMS will wind up conferring a greater probability of approval or result in commercial dead-ends.

Drug makers, for instance, would like more guidance, according to Jeff Francer, assistant general counsel at PhRMA, who said REMS is the key issue to watch as a result of the FDAAA. “I would say it’s the effects of REMS on the approval process and post-marketing…We should continue to study how REMS and the implementation are affecting patient care. We, in industry, would like more formal guidance…For most of industry, it’s about REMS.”

A few feet away sat Jarilyn Dupont, director of regulatory policy in the Food and Drug Administration’s Office of the Commissioner, who said that “there’s always going to be tension” over the push and pull between industry and regulators over the requirements and implications. But she noted that the REMS program, which gives FDA some enforcement powers, is still new and that guidance will be forthcoming. “It’s really only out since September, so over time, you will see more guidance. But guidance development doesn’t happen over night.”

Another industry rep, Andrew Emmett, director of science and regulatory affairs for BIO, tried a more optimistic line by saying that, as “comfort levels are built and guidance” emerges, the REMS process should become smoother. Still, his comments about forthcoming REMS evaluations suggested an air of anxiety. The FDAAA requires that all REMS must include a timetable for assessments at 18 months, 3 years and 7 years after approval of a REMS. “There are a lot of questions in industry,” he said, “about what those are going to look like.”

FDA's "Secret" Opioid REMS Meeting

Who doesn’t love to find out about secret meetings? Especially secret meetings between FDA and your top competitors?

Well, if you have any interest in FDA’s implementation of Risk Evaluation & Mitigation Strategies—especially if you market opioids—then you’re in luck. Because we’ve got the scoop on what happened at the closed-door meeting FDA held last week about requiring a class REMS for extended-release pain killers.

FDA holds closed-door sessions with industry all the time. But as we reported in “The Pink Sheet,” this meeting was especially significant: the first in a series of discussions to develop a risk management plan that will be, in the words of one FDA official, “orders of magnitide” greater than anything industry has ever seen.

For the opioids under that umbrella—and those that are not—the REMS will change the commerical landscape for prescription painkillers.

To be fair, it wasn't really a “secret” meeting: FDA announced when was taking place (March 3), and disclosed who was invited (16 opioid manufacturers, listed here). But it also wasn't open to the public, and any information about what happened at the meeting had to be gathered after it took place.

Since we published our story, FDA has released a bit more information, posting the agenda and the slide decks from the three agency presentations on its website. Division of Analgesics, Anesthetics, and Rheumatology Products Director Bob Rappaport gave a history of the risk management of the opioid class; Associate Director for Policy Jane Axelrad reviewed FDA’s REMS authorities under the Amendments Act; and deputy division director Sharon Hertz outlined FDA’s initial thoughts on the proposed REMS.

Right now, FDA wants to see a class Medication Guide; elements to assure safe use (certification of health care providers, physician training on proper use, and patient-physician agreements); and an implementation system (database of all enrolled health care providers and a system to monitor and evaluate the REMS). That could all change, of course, but that is FDA's current thinking.

None of those elements are surprising; they have all been used in past REMS. And as scheduled drugs, opioids already carry some restrictions on their use. But given the sheer size of the market involved, the development and implementation of this REMS should be watched closely.

(Image by flicker user Anna C. used with permission through a creative commons license.)

The Good News for Biotech: New Regulation Opens a New Path to Profitability

In the absurdist economic world we now endure – simultaneous credit freeze and market meltdown – we hardly know how to be optimistic about biotech. As we noted here, high-risk investments like biotech attract the extra cash investors have in their funds. And since there’s likely to be precious little extra cash for the foreseeable future and, for mutual funds, some portion of that cash likely to have to stay as cash to cover redemptions, the outlook isn’t rosy.

And yet, long term, there is hope for biotech.

Our view (bits of which we’ve expounded on before, here and here) is this: In starkest terms, the regulatory system, the single biggest stumbling block to pharmaceutical success, is tilting biotech-wards. Within FDA, admittedly, there’s a certain skepticism about small-company development programs (of the “they don’t know enough to do it right” variety). But the fact is that fully a third of the 60 NMEs approved between ’05 and ’07 were from small companies.

And the economics of these approvals are likely to bend even more favorably towards small companies. With the passage of the FDA Amendments Act last year, the FDA now has a tool (Risk Evaluation and Mitigation Strategies, or REMS) that allows it more ways to say “yes” to new drugs – by placing extra restrictions that limit the patient population that can access the product.

Put another way, the path to regulatory approval is easier the more willing a sponsor is to accept limits on how a medicine can actually be sold in the marketplace.

Big Pharma, understandably, hates that idea. Their central business model relies on selling a chronic-care therapy to the broadest possible population of patients. But biotech, without the massive investment in marketing and regulatory infrastructure Big Pharma must support, can – if they’re smart – wholeheartedly embrace the notion.

Take the constipation drug Entereg, which GlaxoSmithKline in-licensed from Adolor hoping to have a blockbuster on its hands. FDA held it up for two years thanks to a cardiovascular safety signal (no more cisaprides!) until it was finally approved, with a REMS that limited it to short-term hospital use and a market of maybe $200 million. An economic non-starter for GSK ... but had Adolor developed the drug on its own, focusing from the get-go on the specialist market and constructing its regulatory and commercial infrastructure accordingly, its investors might have done very well, thank you. (As it is, Adolor is trading at a market cap of about $170 million – back in February ’06 the company was worth nearly $1.3 billion)

GSK took away some lessons from the experience, too. Via its blockbuster put-call-option deal with Theravance (written about in detail here), it had the right to in-license, among many other compounds, the biotech’s promising motility agent, TD-5108. But GSK said no to the compound, having lived through the stomach-churning experiences of Entereg and, before that, Lotronex. (That irritable bowel syndrome drug was pulled from the market for fear of causing intestinal blockages and then delicately relaunched with a kind of early prototype of a REMS approval.)

GSK’s decision casts some fairly deep shadows over Theravance’s original strategy: do the early development of significantly improved versions of Big Pharma’s biggest primary-care drugs and sell the results to Big Pharma.

Certainly, the other Big Pharmas to whom Theravance is now free to sell TD-5108 are going to tread very carefully around the compound, since they’ve also seen what’s happened to Entereg, Lotronex, and Zelnorm -- the Novartis irritable-bowel syndrome drug yanked from the market for yet a different side-effect.

And it’s pretty likely some distressing signal will show up with TD-5108, because the FDA has told Theravance, in effect, that the drug will require huge trials if it wants it approved for a chronic-care population.

But the GSK rejection also opens up what may be an even bigger opportunity for Theravance: going ahead on its own, specialist track. We don’t know if TD-5108 has much of a specialist opportunity. However, if it does, Theravance might be able to recapitulate the Entereg approval, by proposing its own relatively restrictive REMS, but on a profitable, express route.

With about $200 million in cash, Theravance has some runway and—when GSK decided not to buy a majority of its shares, its own investors' stuck with Theravance by not putting their shares to GSK—a kind of permission to build an independent road.

What’s more, any REMS Theravance constructs could be an additional patent-hurdle generics must leap. Even if the REMS itself isn’t patentable, few generics firms will be able to afford the kind of monitoring machinery required to compete.

Indeed, here is another case where smaller market sizes may end up being more profitable: generic companies will go after a billion dollar market regardless of the extra costs of special monitoring. But there will probably be fewer companies willing to sell a generic version of Entereg.

We’re not minimizing the cost of building a REMS-based approval road or the difficulties in financing it. But we are saying that those biotechs who can identify these niche opportunities and raise the money for them have a brand-new opportunity. They can choose a comparatively less risky development path than Big Pharma can afford, and then either sell the results to larger drug companies who want, but are unable to build their own, specialist businesses … or go on to construct self-sustaining commercial organizations right-sized for a REMS-defined world.

That’s the kind of choice investors like to have.


Image courtesy of Holaday98 and used through a creative commons license.

Waiting on Prasugrel: No News is Good News

Another NDA, another missed deadline.

This time around, it’s a product upon which Eli Lilly has hung much of its future, the anti-clotting drug prasugrel (Effient).

Lilly has already been on a rollercoaster ride on Wall Street over prasugrel once the risks associated with the drug surfaced (32% increased chance of bleeding). And time is not on Lilly’s side: the company is racing to establish the drug on the market before 2011, when Plavix generics will complicate the anti-clotting landscape.

Prasugrel has also been closely watched as another sign of how FDA will use its new risk management authorities under the FDA Amendments Act. The billion-dollar questions: would FDA agree that the bleeding risk associated with prasugrel could be appropriately managed by a REMS, or is more needed for approval? And is there any chance for a relatively clean label?

All that makes prasugrel the closest-watched drug approval this year. Indeed, between the September 26 prasugrel user fee deadline and the Wall Street bailout agreement, there were more than a few investors who were constantly refreshing their computer screens as Friday wore on.

While a bailout deal may be at hand, we’ll have to wait a little longer to find out about the fate of prasugrel. For now, Lilly’s not talking, except to say—in a press release that crossed the wires at 5 pm on Friday—that FDA would miss the deadline, that the review is “very far along,” and that Lilly “remains optimistic” that an approval is imminent.

Wall Street’s immediate reaction was not positive—the announcement drove Lilly shares down 3.9% to $45.01 in after-hours trading, and shares opened lower this morning. Les Funtleyder at Miller Tabak expressed his frustration in a research note: “This has become a bit of an unsettling trend at the FDA. The decision tree used to be pass or fail, now there is a third column, the ‘I don't know.’” (Hat tip to CNBC).

We think that pessimism is misplaced.

We told you three months ago why we think FDA will approve prasugrel, and that reasoning hasn’t changed. Indeed, the fact that the agency missed the user fee deadline bodes even better for the drug’s prospects, because it indicates—barring any last-minute surprises—that an approval is close at hand.

Here’s why: Since FDA’s drug review divisions were given the green light to start missing deadlines, most of the applications delayed by workload issues were eventually approved within weeks, based on a recent analysis in The RPM Report. (If you don’t already subscribe, you can sign up for a 30-day trial to access the story.)

For one recent example, look no further than Amgen’s Nplate, which cleared FDA a little over two months after the user fee deadline. GlaxoSmithKline’s Entereg was approved 10 days late. UCB Pharma’s Cimzia was three weeks late. And there are other examples of how small allowances for heavier workloads at FDA have led to product approvals.

There are many reasons for a missed deadline, and some (like finding enough members to staff an advisory committee) have led to months-long delays for new products. But that’s doesn’t appear to be the case with prasugrel: “This is a very large, complex submission, and it should not be surprising that delays occur,” Lilly said.

Given the much-ballyhooed size of that NDA package, perhaps it’s not surprising that it would take FDA extra (and then some more) time to read through it. The absence of an advisory committee meeting for prasugrel is also a positive sign, given that drugs without one have a greater chance for a first cycle reviews.

Sanford Bernstein analyst Tim Anderson agrees that no news is good news: “Our best guess at this point is that while the Effient review is not yet complete, a final decision by FDA is not likely to require that LLY/Daiichi-Sankyo generate new clinical data; the issue may be a smaller one like finessing the label, the risk management plan, etc.”

We couldn’t agree more.

Wacky World of Generics: Thalidomide Edition

Even the title has to cause shivers or a good shake of the head. Thalidomide? Generics? The two words don’t belong together: it can’t be possible.

How can thalidomide (the infamous teratogen and source of the crisis that led to the 1962 FDA efficacy amendments) be the source of a debate about generic use? This is not wacky. This should be inconceivable.

But it’s not.

Celgene’s highly successful Thalomid brand of thalidomide, with sales last year just short of $450 million, has passed its tenth year on the market. And it faces a generic challenge from Barr Labs, which has an ANDA pending for the drug’s initial orphan indication, treatment of the cutaneous lesions of erythema nodosum leprosum.

Now, a struggle is developing on the ability of generic companies to replicate the tight risk management program that Celgene developed to make thalidomide a commercial product.

To get Thalomid to the market, Celgene developed a strictly controlled distribution and patient contact /education program called STEPS. The company devotes more than 175 employees to maintain its risk management programs. The program is so important to the commercial use of the product that Celgene has a patent on the program itself.

STEPS may represent a steep barrier to generic copies; at least that is what Celgene hopes. The company has laid out its arguments against FDA approving generics in a petition filed with the agency a year ago: Sept. 20, 2007. (For an anlysis of the Celgene petition, see our coverage in “The Pink Sheet.")

FDA’s eventual decision as to whether the thalidomide risk management program can be copied or mimicked will be of major significance to the entire industry.

As FDA begins to require more risk management programs (now called REMS – Risk Evaluation & Mitigation Systems) as integral parts of NDA approvals, these post-market controls have the potential to significantly lengthen the life of brands.

Or as Celgene pointedly argues to FDA: "In many ways, the survival of the company depends on the successful implementation of its novel restricted distribution plans." Give away its risk management program to another marketer and FDA will give away the core of Celgene’s ability to market thalidomide safely. The company notes that it has successfully prevented patients from experiencing the horrors of the teratogen. If another company is distributing the ingredient less carefully, it would hurt the public, the drug industry and Celgene’s brand.

But FDA was specifically instructed in the FDA Amendments Act (passed a year ago in September 2007) to prevent companies from using REMS as barriers to generic competition. Something is going to have to give.

The decision on STEPS will be one of the important early precedents arising from FDAAA. It is significant that Celgene used ex-FDA general counsel Dan Troy to craft its arguments to protect STEPS and Thalomid.

Not only is Troy a prominent figure on the issue of FDA’s ability to control industry marketing practices, he has also recently become the general counsel of GlaxoSmithKline – assuring that the issue of the value of REMS as a way to block generics will get the attention of at least one other major pharma player. Indeed, GSK has been--by accident if not design--one of the most active early players in shaping how the REMS authority will be used, having already agreed to three programs for its new products, and with a fourth pending for Promacta.

In the wacky future world of generics, companies will have to learn how to replicate post-marketing control programs as well as how to replicate the chemical structures. The safety programs may turn out to be harder to copy.

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?

FDA's Brain Drain Continues

Sometimes it just doesn’t pay to work at FDA.

Even as FDA bulks up its drug review ranks with new money from Congress, attrition continues to affect the agency—including high-level defections to industry. Indeed, drug sponsors are more than willing to bring former agency officials into their ranks and pay them much more than the average government salary.

Florence Houn is the latest to jump ship; as reported in “The Pink Sheet” this week, the FDA official has been hired by Celgene as VP-regulatory policy and strategy.

Most recently,Houn was involved in vaccines regulation: she was deputy director of the Center for Biologics Evaluation and Research’s Office of Vaccines Research and Review. But she also knows a thing or two about drug reviews, having served in leadership positions of two different Offices of Drug Evaluation during her 15-year tenure at FDA.

For Celgene, Houn couldn’t come at a better time: the company is working to comply with the Risk Evaluation and Mitigation Strategies provision of the FDA Amendments Act. Celgene is responsible for two of the most restrictive REMS: thalidomide (Thalomid) and lenalidomide (Revlimid), a thalidomide analogue.

In deciding to leave FDA for industry, Houn is taking a page from her husband, former Office of Antimicrobial Drug Products director Mark Goldberger, who left in early 2007 for Abbott Labs. Other recent high-level departures from within the agency include former ODE II director Robert Meyer, who joined Merck in late 2007.

The Office of Drug Safety has probably had the hardest time holding onto talent. Predecessors to current director Gerald Dal Pan left for industry within a year or two of assuming the top drug safety post: Peter Honig to Merck as VP-risk management and Victor Raczkowski to Cephalon as VP-regulatory affairs.

Dal Pan is showing no signs of leaving anytime soon (and given the Office of Drug Safety's new powers and authority, why would he?). But given the monumental changes in drug regulation under the Amendments Act, FDA expertise is surely fetching quite a premium these days. For the agency's sake (and all of industry's), let's hope few other agency officials take advantage of it.

The REMS Pioneers: GlaxoSmithKline Edition

By our count, the Food & Drug Administration has used its newest regulatory tool--Risk Evaluation & Mitigation Strategies--seven times since the authority took effect at the end of March.

The REMS is the centerpiece of the new drug safety legislation enacted in 2007, giving FDA much greater authority to regulate drugs on the market using tools like consumer medication guides, enhanced communication programs, and restricted distribution. (If you haven't been keeping up, you should be: start here.)

Remarkably, one sponsor--GlaxoSmithKline--has been involved in four of the first seven. GSK (or its partner) has negotiated a REMS as part of the approval process for the migraine combo Treximet (developed by Pozen), a broader indication for Advair, the new drug Entereg (developed by Adolor), and a pharmacogenomic safety screen on Ziagen. (And GSK isn't done: another REMS is in the works for the pending Promacta application.)

The other REMS all involve different sponsors: UCB's new biologic Cimzia, Biovail's new salt formulation of bupropion Aplenzin, and a revised label for Schering-Plough's Intron A.

So GSK's regulatory affairs group sure has been busy lately, since the new REMS authorities involve unchartered territory for both FDA and the sponsors.

But don't feel too bad for GSK. The company has had more than its share of the early work on navigating the REMS process--but it also has benefited in at least two ways.

First, as we wrote here, the intial wave of REMS pioneers have all involved applications stuck at FDA. So GSK has shouldered a greater burden in figuring out how the REMS will work in the regulatory process, but it has been rewarded with the opportunity to sell two new products--Treximet and Entereg--that might not otherwise have been marketed at all. The broader labeling for Advair also helps the company tell a good news story about the drug at a time of ongoing safety concerns for the long-acting bronchodilator class.

The Ziagen REMS may be the most interesting of all--a real world case-study in personalized medicine--but its hard to say it is paying off for the sponsor. (You can read more about that REMS in "The Pink Sheet.")

Here's the second payoff for GSK: the company now knows the most about how the new drug safety regulatory system works. FDA officials have put it better than we can: this is the most important change in the drug approval process in generations, and essentially every new approval sets a precedent. FDA plans to draft guidance to explain the new system to sponsors, but not until it has more experience. So the only way to learn is by doing.

GSK finds itself as the early leader in that learning.

Now, does that pay off in a competitive advantage for the company as it tries to get more drugs to market? We'll see....

REMS to the Rescue? Why FDA's Drug Safety Tools May Mean More Approvals This Year

The statistics aren't encouraging: fewer new drugs approved by FDA so far this year than last--and last year was arguably the worst year all time for the innovative industry.

But we are boldly predicting a big finish to the year, in part for an unlikely reason: FDA's new mandatory post-marketing safety tools that allow it to compel labeling changes, Phase IV studies, and--most significantly--Risk Evaluation & Mitigation Strategies.

The REMS authorities kicked in in March, and we’re learning a bit more about how FDA is using its new tools. And while there was much nervous anticipation as industry braced for FDA to start wielding its new (now mandatory!) risk management tools, the reality has been pretty positive.

There have been a lot of required post-marketing studies, and relatively few full-fledged REMS programs for new molecular entities. In fact, it looks like REMS is turning out to be a way to revive applications that once looked dead (or at least terminally “approvable”).

FDA has applied the new drug safety tools to three new molecular entities so far this year--CV Therapeutics/Astellas’ Lexiscan, UCB’s Cimzia, and GSK/Adolor's Entereg. And in every case the sponsor has been thrilled to have a product to market at all. (Read about some of the early experiences with REMS here.)

That's just the tip of the iceberg.

A REMS is definitely in the works for GSK’s platelet growth stimulator Promacta (eltrombopag), and Lilly has hinted that its antiplatelet agent Effient (prasugrel), partnered with Daiichi Sankyo, could have some form of a REMS – although Lilly is suggesting it would be on the less intensive end of the spectrum. Both NDAs received three-month review extensions, an emerging pattern for reviewing REMS proposals.

The premature press release snafu for Amgen’s Nplate also revealed that a REMS program called NEXUS is slated to accompany the approval of romiplostim, a fusion protein that, like Promacta, treats idiopathic thrombocytopenic purpura.

FDA’s new authority opens a new parlor game of guessing which applications could be REMS-worthy. According to Pharmaceutical Approvals Monthly, there are at least 30 NMEs pending with user fee deadlines coming up during the second half of the year. Which ones could have a REMS?

Pfizer/Ligand’s Fablyn (lasofoxifene) for treatment of post-menopausal osteoporosis: The post-Evista SERM class has had trouble clearing the final approval hurdle at FDA, in part because of safety issues. Prior to the Fablyn submission Jan. 15, lasofoxifene (then Oporia) was found not approvable for prevention of PMO in 2005, and then not approvable again, for treatment of vaginal atrophy, in 2006. Wyeth’s SERM Viviant (bazedoxifene) has been approvable twice for osteoporosis prevention and once for treatment. Further data was requested on stroke and venous thrombotic events.

Johnson & Johnson’s paliperidone palmitate: Can the once-monthly version of J&J’s antipsychotic Invega do better than the “not approvable” letter issued to Lilly’s fellow atypical antipsychotic Zyprexa for its once-monthly depot, Zyprexa LAI? The long-acting injection formulations may have a new risk of excessive sedation. Given J&J’s flagging public enthusiasm for the project, and its renewed interest in Alkermes’ claim that its technology can now support a once-monthly version of Risperdal Consta, does J&J really care?

Schering-Plough’s Bridion (sugammadex): The prospect of the first selective relaxant binding agent, which was just approved in the EU, has stirred up the anesthesia market. But signals from FDA could indicate caution. The agency extended the user fee goal by three months to review a hypersensitivity study. And in an unusual set of events, a March advisory committee supported approval, but could not make a formal recommendation because data had been submitted shortly before the panel met.

Moving beyond the bounds of pending NMEs opens a plethora of potential REMS. One likely candidate is Cephalon’s fentanyl product Fentora. The advisory committee review of a breakthrough cancer pain indication for the approved drug focused on the inadequacies of the existing RiskMAP. Other extended-release pain products, like Labopharm’s tramadol formulation, are also potential REMS contenders.

Review the list yourself and play along at home. What else looks REMS worthy to you?

--Bridget Silverman

Jumping the Gun on Nplate

Whoops.

It seems like that’s all that can be said about the premature announcement of FDA's still-pending approval of Amgen’s platelet drug romiplostim (Nplate).

Business Wire erroneously sent out a press release yesterday morning announcing that the biologic had been approved for the treatment of thrombocytopenia. Amgen quickly retracted the release, saying that the Nplate application was still under FDA review, and Business Wire acknowledged its error.

It's pretty obvious that FDA and Amgen are wrapping up final details on Nplate and that approval is imminent. But that shouldn’t come as much of a surprise, given that FDA was handed a unanimous recommendation for approval by the Oncologic Drugs Advisory Committee in March.

FDA still has more than a week to approve Nplate by its July 23 user fee deadline; the review was extended by three months to allow time for the agency to consider Amgen’s Risk Evaluation & Mitigation Strategies (REMS) plan, which was submitted as a major amendment to the BLA in March.

So what, if anything, can be gleaned from the retracted release? Well, as reported in “The Pink Sheet” DAILY this morning, Amgen’s REMS program for Nplate will include the Network of Experts Understanding and Supporting Nplate and Patients, or NEXUS, program. We’ve written extensively about the lessons learned from the first REMS in The RPM Report; you can access those stories here and here.

But perhaps the best news out of the Nplate slip-up is for branding firms: NEXUS pretty much guarantees that REMS programs (like major clinical trials) will continue to be referred to as acronyms-that-are-not-quite-acronyms. (Some of our favorites include TOUCH, IDEAL and CIMplicity.)

While some might liken that craft to seeing religious figures in pancake batter, we suppose someone has to come up with those clever (silly?) names.

Photo courtesy of Flickr user dejajib under a creative commons license.

Prasugrel Delay Shifts Focus to August Advisory Committee Date

Attention will now turn to a tentative August 19-20 FDA Cardiovascular and Renal Drugs Advisory Committee meeting date as the next major prasugrel milestone after FDA extended the review of the novel anti-platelet drug by three months on June 23.

The original user fee deadline for the priority six-month review application had been scheduled for June 26; the new deadline is September 26.

The agency has yet to make public the agenda—or whether they’ll even hold a meeting—for the tentative August date. The drug's manufacturer, Eli Lilly, says it has not been notified by FDA that prasugrel (Effient) will be the subject for review at the meeting, if FDA chooses to hold one.

Whether or not prasugrel gets slated for an advisory committee review is at the center of speculation regarding the future of the potential blockbuster. A panel meeting would provide some level of clarity to FDA’s position on the application in the form of questions to the committee and public briefing documents related to the agency’s medical review of prasugrel data. However, it also adds the variable of a group of scientific experts from different disciplines questioning the merits and scrutinizing the safety concerns of the drug in a public setting.

A late August advisory committee meeting would also put FDA under a time crunch to deliver a decision by the new September deadline given the additional guidance it will have to process from the panel.

Senior FDA officials have said in the past that if the benefits of a drug are so obvious to agency reviewers and clearly outweigh the risks, an advisory committee meeting is sometimes unnecessary. However, a major drug safety issue that fosters consensus among FDA reviewers could also render convening a panel of outside experts to review the drug a needless exercise, officials have cautioned.

In renal cell carcinoma market, for example, Bayer/Onyx’ sorafenib (Nexavar) and Pfizer’s sutinib (Sutent) both were priority reviews that resulted in timely approvals without advisory committees. Both were viewed as significant advances in renal cell carcinoma therapy, an area that had not seen major advances in years.

The extension is a minor setback for Lilly and is certainly a better outcome for the company than a number of different decisions the agency could have made.

A three-month extension is relatively common for new therapies that may carry extensive postmarket requirements, such as risk management plans. The extension is triggered if the sponsor submits significant supplemental information to FDA during an ongoing review and the agency simply needs more time to comb through the additional data.

The extension keeps the application in a first-cycle review timeline. An “approvable” or “non-approvable” decision at this point would have been significantly less favorable for Lilly and require the company to re-submit the application and restart the review clock.

“We will continue to work closely with the FDA throughout the review process and continue discussions to determine if any requirements under the new FDA Amendments Act (FDAAA) will apply,” Lilly VP-global regulatory affairs Jennifer Stotka said in a statement.

Lilly’s public reference to FDAAA indicates the company may be working on a REMS (risk evaluation and mitigation strategies) program for the drug, which would further explain the extension. REMS were created under the new drug reform law to improve postmarket surveillance of drugs entering the market.

Biogen Idec/Elan’s natalizumab (Tysabri) for Crohn’s disease and Celgene’s cancer drug lenalidomide (Revlimid) are two recent examples of drugs that received three-month deadline extensions to review risk management programs but were approved promptly thereafter.

Lilly’s Phase III 13,000-patient TRITON clinical study of prasugrel produced a 19% reduction in the composite primary endpoint of cardiovascular death, non-fatal heart attacks or non-fatal strokes when compared with clopidogrel (Plavix).

However, the study also demonstrated a statistically significant 32% increase in minor and major bleeding. But when you consider the primary endpoint, those bleeds didn’t lead to deaths, heart attacks or strokes.

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.