ESA Safety and the New, Transparent FDA

If you are interested in knowing what FDA thinks about important regulatory issues, including specific product reviews, it is time to renew your subscription to the New England Journal of Medicine.
A team of FDA officials, including Office of Drug Evaluation I Deputy Director Ellis Unger and Center for Drug Evaluation & Research Deputy Director for Clinical Science Robert Temple, used NEJM as a vehicle to announce a formal reassessment of the safety profile of erythropoeitin stimulating agents in chronic kidney disease, including an advisory committee review to consider (most likely) whether use should be limited to the minimum amount necessary to avoid the need for a blood transfusion.

The advisory committee isn't surprising; as we reported in The RPM Report last month, FDA was looking carefully at new clinical data suggesting that use of ESAs (Amgen's Aranesp, J&J's Procrit) may increase the risk of strokes in chronic kidney disease patients. And, given all the issues around safety of ESAs in oncology, an advisory committee was probably inevitable.

What is surprising is the forum to announce the plan.

But not too surprising. Unger previously used NEJM to publish a summary of the basis for approving Lilly/Daiichi Sankyo's Effient, after a long and controversial review. Former Merck drug safety head Peter Honig cited Unger's Effient editorial during an Institute of Medicine meeting on drug safety in September as a good way for the agency to explain its thinking about safety issues.

And Commissioner Margaret Hamburg and Deputy Commissioner Joshua Sharfstein announced their agenda at FDA in an editorial published by NEJM on the day Hamburg took office.

We expect a lot more pharma execs will be scanning those headlines in weeks to come.

Plavix Label Change: Good For Effient Now, Bad For Brands in the Long Run?

The Food & Drug Administration's public health alert on Plavix is, as we point out in "The Pink Sheet" DAILY, a nice boost for Eli Lilly and Daiichi Sankyo, who market the competing platelet agent Effient.

But the back story to this regulatory action merits closer attention by all pharmaceutical sponsors. This is no ordinary labeling change, and the implications of how the regulatory response came about only underscore how difficult it will be for all sponsors who hope to sustain (or revive?) the blockbuster model in the years to come.

This labeling change suggests a model for application of pharmacogenomic research that biopharma companies will find very threatening: it sure looks like sponsors hoping to build blockbuster franchises are at a huge disadvantage against payors hoping to limit those opportunities.

And that's why this labeling change may end up being bad news for all brands in the long run--very much including Effient.

First, the news: FDA has revised Plavix labeling to emphasise that the Bristol-Myers Squibb/Sanofi Aventis blockbuster doesn't work too well in patients who are poor metabolizers of the drug. In particular, FDA is concerned about impairment of the CYP2C19 metabolic pathway, whether because of genetic variations or coadministration of other drugs, including the widely used proton pump inhibitor omeprazole (Prilosec).

Okay, none of that is actually news. FDA first issued the warning in January, and quietly modified Plavix labeling in May.

What is news is that FDA has decided that information is now a formal warning, rather than a milder precaution--and, more importantly, the agency chose to amplify that warning (especially regarding PPI use) via a media conference call.

It is easy to see why Lilly and Daiichi would be pleased: anything that complicates the decision to prescribe Plavix will help them make the case that doctors should prescribe Effient (and, as we've already pointed out, they need all the help they can get).

Okay, so this sounds almost reassuringly like a classic story of head-to-head competition in a blockbuster class, and how the regulatory process can play to one side's advantage. Plavix is dinged, Effient benefits.

But this is nowhere near that simple.

Because there are third parties involved: payors and pharmacy benefit managers. The interaction between PPIs and Plavix was first publicized by Aetna and by Medco, both of whom used claims data to suggest an association between PPI use and diminished outcomes for patients treated with Plavix.

Its not just that payors capitalized on a safety issue: they really drove the regulatory response and the application of a newly discovered pharmacogenomic marker. In Medco's case at least, Chief Medical Officer Robert Epstein told us, the whole idea was to find a way to test the emerging theory that CYP2C19 genotyping may predict Plavix response. Since Medco didn't have genotyping data on patients in its database, it looked at concomitant use of omeprazole instead, since the PPI is a known inhibitor of the 2C19 pathway.

FDA's first public health alert followed the Aetna and Medco claims studies; the latest one came after Bristol and Sanofi conducted a drug interaction study confirming the observational results. That's certainly not a regulatory model sponsors are eager to consider--especially since we would be willing to bet that the observational research that triggered the warning cost Medco much less than the clinical trial the sponsors were forced to conduct to confirm it.

Medco, at least, isn't done. As we reported here, the company is now taking the next step, conducting a large scale observational study to test the hypothesis that the superior efficacy demonstrated by Lilly in its head-to-head study of Effient vs. Plavix can be explained by the inclusion of poor metabolizers of Plavix in the comparator group.

And Medco's interest most definitely is NOT in helping either brand in this class.

Medco's interests include advancing the company's positioning as a leader in therapy management, particular as it comes to applying pharmacogenetic knowledge. And Medco certainly wants to work with its payor clients to make sure insured members receive the best possible care.

But what Medco wants above all is to carve out a long term market for generic clopidogrel--and in effect limit Effient's share (as well as the share of all future brands in the class)--to whatever slice can't be held for the generic.

The study design, as Epstein explained to us, is simple: Medco will (at its own cost) run a genetic screen on patients prescribed Plavix to identify those who properly metabolize the drugs. It will then compare 14,000 of those patients to 14,000 Medco members who receive Effient, and see if there is a difference in cardiovascular outcomes.

Medco clearly expects to demonstrate that there is no meaningful difference between the two.

Now this whole thing could backfire on Medco. Its data could end up suggesting superior outcomes even when the comparison arm is enriched for Plavix response. (And Medco has registered the trial on ClinicalTrials.gov, so while we doubt they would trumpet that result, they can't just bury it either.)

And the study could by itself end up promoting the launch of Effient. Certainly, Lilly and Daiichi are only too happy to have Medco's support in spreading the message that their drug is active regardless of that specific genomic marker.

Indeed, as part of the screening effort, Medco is likely to drive some conversions from Plavix to Effient: patients who are genotyped as poor metabolizers will be informed of that status (as will their physician). Medco will not make any recommendations, but it is safe to bet that many identified as poor responders to Plavix will switch therapies. Given that 30% or so of the population has the genotype in question, Medco is likely to notify about 6,000 people that they may not be getting the full benefit of their antiplatelet therapy with Plavix.

But that only underscores the bigger point. Medco is willing to make a relatively big investment--and even to help grow a potential blockbuster franchise in the short term--in order to help limit the size of that market in the long run.

And it will cost Medco far less to do that than it costs for sponsors to bring potential blockbusters to the market in the first place.

Now, Epstein wasn't willing to disclose how much this undertaking will cost, but he did suggest it isn't terribly expensive. Medco collects the outcomes data already, so the only cost will be running the genotyping program. Medco will be doing the tests in house, via its own CLIA-certified lab test, so that expense will be kept as low as possible.

All in all, that is not a trivial expense for a pharmacy benefit management company to take on spec, but we're willing to bet it is less than 1% what it cost for Lilly to "prove" the superiority of Effient in a head to head trial.

Which is why, when it comes to trying to establish blockbusters in an era of high payor influence and ever advancing knowledge of the heterogeneity of drug response, it seems like the odds are stacked in favor of those who want to keep market sizes small.

Look for much more on this topic in an upcoming issue of The RPM Report.

image from flickr user mafleen used under creative commons.

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.

The Effient Launch: Cracking the Door to Primary-Care Marketing

So will personalized medicine be the death of primary care? Maybe not. Maybe just the opposite.

In this edition of the IN VIVO Blog Podcast, Mike McCaughan, our editor-in-chief, gives a decidedly positive (albeit counterintuitive) spin to what some of us in the editorial group thought was a pretty obviously bad piece of news: Effient’s black-boxed approval last July 10.

Yes, Effient (prasugrel) had beaten the competitor, Sanofi/Bristol-Myers’ Plavix, in Lilly’s head-to-head pivotal trial (fewer heart attacks and strokes for Effient’s users, though more bleeding) but still, we wondered, would Lilly – which depends on Effient to get it past the Zyprexa cliff – be able to build much competitive momentum against Plavix while dragging along its black-box warning about bleeding? And even if it manages to gain that momentum, won’t it be stopped dead in its commercial tracks when Plavix goes generic in 2011?

Mike’s notion: that the black-box warning and mandated two-year REMS requirement create the basis for primary-care marketing success – thanks to pharmacogenetics. Not because the data suggests the right population to get Effient – but because it argues that a third of the population getting Plavix get no benefit from it (an argument the FDA evidently agreed with because it added it to Plavix’s label). Lilly reps thus get an FDA-mandated foot-in-the-door to talk to docs about Effient’s risks (and Plavix’s deficiencies)…and, within two years, face a generic with no marketing effort behind it that they will argue doesn’t work in a third of a very high-risk population.

So click below to hear Mike’s full explanation (or you can access the podcast via iTunes).








Image from Flickr user twenty questions and used under a Creative Commons license.

Prasugrel Backlash Doesn't Deter Kaul

Sanjay Kaul doesn’t get discouraged easily.

The very public debacle over Kaul’s potential intellectual conflict of interest with Lilly/Daiichi Sankyo’s anti-clotting agent prasugrel has not deterred the cardiologist from fulfilling his obligation as a member of the Cardiovascular-Renal Drugs Advisory Committee.

According to information posted on FDA website, Kaul will participate in the committee review of Sanofi-Aventis’ antiarrhythmic dronedarone (Multaq). Dronedarone will be his first meeting as a permanent member of the Cardio-Renal advisory committee after being “disinvited” from the February 3 prasugrel panel due to a potential intellectual bias.

At the time, Office of New Drugs director John Jenkins expressed hope that Kaul, a well-known cardiologist at the Cedars-Sinai Heart Institute, would remain a member of the advisory committee, despite that fact that his disinvitation sparked a very public—and at times nasty—post-meeting debate over the integrity of FDA’s advisory committee process. (We’ll have more on that in the next issue of The RPM Report.)

“Dr. Kaul is a new standing member of the Cardio-Renal advisory committee. This would have been his first meeting as a standing member,” Jenkins said in a post-prasugrel interview. “We hope that he will continue to serve and will be a productive member of the committee going forward.”

Jenkins was careful to clarify that Kaul was not to blame for the incident. “He did everything he was supposed to do,” he said. “There’s been some suggestion out there—and maybe it’s even from the FDA press statement—that in some way he did not provide us with the information. That’s not correct.”

“He submitted all the paperwork that was required to be on the committee and to be screened for the committee. And when questions were raised about the abstracts, he responded very promptly.”

Kaul is also expected to participate in the second day of the meeting, which will consider the approvability of Johnson & Johnson’s novel factor Xa rivaroxaban (Xarelto) for use in prophylaxis of deep vein thrombosis. Like prasugrel, rivaroxaban is an antithrombotic, and like prasugrel, it may unseat the standard of care, in this case warfarin/heparinoid therapy.

And if all that isn’t enough reason to tune in this week, here’s one more. Pharmaceutical industry critic and Public Citizen Health Research Group director Sidney Wolfe will be at the conference table, representing the Drug Safety & Risk Management Advisory Committee.

Prasugrel’s Magical Moment

We here at the IN VIVO Blog do love our advisory committee meetings. The anticipation. The preparation. The smell of the reams of briefing documents. And then, there’s the meeting itself, and we find ourselves waiting for that magical moment when the tide turns, and it becomes clear which way the committee is going to fall.

Sometimes a meeting can turn on a company presentation, like Biogen-Idec’s case for bringing Tysabri back on the market. Or the power of a single committee member, like the Cleveland Clinic’s Steven Nissen's tirade against attention deficit/hyperactivity disorder drugs. Or the strength of a risk management program, as with Pfizer’s inhaled insulin Exubera (the later commercial failure notwithstanding).

For Lilly and Daiichi Sankyo’s prasugrel, the key moment came from FDA itself.

Prasugrel didn’t come to the Cardiovascular & Renal Drug Products Advisory Committee without a few issues—all of which have been breathlessly reported by your friends here at the IN VIVO Blog. (Hey, when you have a company-saving drug that could replace a $5 billion blockbuster as the standard of care for platelet inhibition, that’s kind of an exciting story.)

Bleeding is a problem with prasugrel. As is the potential that prasugrel may stimulate the growth of existing malignant tumors. Drugs have been taken down for less, and when you put that profile in the context of the current drug safety environment, Lilly had a potential catastrophe on its hands.

We’ve already made the case for why we think FDA will approve prasugrel, but there was certainly still the potential that things could go terribly wrong at the advisory committee—especially given that one of the the drug’s biggest cheerleaders, cardiologist Steve Nissen, wasn’t there to wave his pom-poms and give a big shout-out to P-R-A-S-U-G-R-E-L.

Advisory committees are unpredictable. Anything can happen.

Prasugrel’s magical moment happened when Ellis Unger, the deputy director of FDA’s Cardiovascular and Renal Drugs Products Division, stepped up to the podium. Unger’s take on prasugrel’s risk-benefit profile—as well as his relaxed, often humorous, demeanor—put committee members at ease with the data. (You can read more about that in today’s issue of “The Pink Sheet” DAILY.)

FDA, Unger said, is confident that the bleeding risk is well-characterized and understood, and while there is a possibility that prasugrel stimulates tumor growth, it is not a carcinogen: “Does prasugrel cause cancer? We don’t think so.” Unger lauded Lilly for its presentation, and declared that prasugrel’s superiority over Plavix in preventing non-fatal myocardial infarction was “where the money is.”

But it wasn’t just what Unger said that was magical for prasugrel. It was the fact that he was the only one who said it. The decision to use Unger as the only formal FDA presenter on prasugrel (other senior officials were at the committee table) rather than a parade of statisticians and medical reviewers sent a clear, single message, and avoided the potential for muddying the waters. It was, in effect, the anti-Avandia.

FDA may be criticized for that later by those who believe that dissenting opinions from within the agency—like calls to severely limit prasugrel use—should have been heard. Those opinions were outlined in the briefing documents to the committee. But when it came time for the meeting itself, there was no question where FDA stood on the approvability of the NDA. And that made for a magical moment for prasugrel.

Sunrise photo courtsey of flickr user inanutshell.

Next Steps For Prasugrel: The Anatomy of an Advisory Committee

Eli Lilly and Daiichi Sankyo used the morning of New Years Eve (‘tis the season for hiding news) to announce that the delayed anti-clotting drug prasugrel will be considered by the Cardiovascular-Renal Advisory Committee February 3. (Shameless self-promotion alert: We predicted that February meeting in October.)

Now that a date has been offically set, let the next round of speculation begin.

That news can be viewed in two ways: optimists (like Lilly and Daiichi investors) will argue that the meeting is a signal that the review is wrapping up and a decision is close at hand. Pessimists will argue that the meeting is an indication of the internal strife at FDA over prasugrel’s benefit-risk profile—and that products that go before an advisory committee are less likely to be approved on the first cycle.

Here's our take. First, we should note that the confirmation of the advisory committee meeting is a milestone in prasugrel’s development. It’s the first word to come out of FDA on the drug since June, when the agency extended the review by three months. FDA then let the revised September 26 review deadline pass without an approvability decision.

Another positive indicator for Lilly and Daiichi is that FDA is only convening the Cardio-Renal committee—and is not asking for a joint review with the Drug Safety & Risk Management Advisory Committee. A joint meeting would indicate significant concerns at FDA regarding prasugrel’s safety profile, which we have delved into in this earlier post.

Of course, that certainly doesn’t preclude FDA from drawing from members of the Drug Safety & Risk Management Advisory Committee as needed—including its newest member, Public Citizen’s Sidney Wolfe, who is unlikely to look kindly upon the prasugrel NDA.

Wolfe is just one extra member that could be asked to show up on February 3, given the current vacancies on the Cardio-Renal advisory committee. There are just eight permanent Cardio-Renal members, including a consumer rep (Consumers Union’s Stephen Findlay) and a non-voting industry rep (AstraZeneca’s Jonathan Fox).

That can make for a lot of last-minute additions. At the committee’s last meeting, FDA added 13 temporary members, including two regulars: University of Washington statistician Thomas Fleming and Duke University human cognition expert Ruth Day.

So who might be asked to serve? With a product like prasugrel, one obvious choice for a temporary member is Steven Nissen, the head of cardiology at the Cleveland Clinic—an expert on cardiovascular drug safety and a former chair of the Cardio-Renal advisory committee.

Nissen’s participation on the committee would be a positive development for Lilly and Daiichi, given that he has come out in favor of prasugrel—first giving the drug a thumbs up for approval and then criticizing FDA for not delivering an on-time approvability decision. Nissen isn’t exactly a shrinking violet, so if he still favors a prasugrel approval, he stands a good chance of getting the committee to see things his way.

But those statements may prevent Nissen from serving—especially given FDA’s tougher line on conflicts of interest. Indeed, Nissen himself has questioned whether he is qualified to serve on an advisory committee under the new CoI guidelines. The meeting roster will be out in the next month. Lilly and Daiichi should hope Nissen's name is on it.

Human brain image courtsey of flickr user hduhadaway.

Lilly's Prasugrel Widens the Gap

The gap just got wider.

No, we’re not talking about the income inequality gap, or the gender gap, or the generation gap. We’re talking about the approval gap for new drugs and biologics between Europe and the United States.

Some critics of the Food & Drug Administration argue that FDA is more conservative than its counterparts in Europe. (This is what we think of as the “too slow” contingent. FDA is also criticized from other stakeholders—like Sid Wolfe and Chuck Grassley—of being too fast.)

FDA disagrees with both sides. As Office of New Drugs director John Jenkins said at FDC-Windhover’s FDA/CMS Summit for BioPharma Executives, “We review each application on its own merits—not against some goal that we will approve 25 applications this year. Those that meet the standards under the statute get approved; those that don’t, don’t get approved.”

But with last Thursday’s news that prasugrel—Eli Lilly and Daiichi Sankyo’s beleaguered blood thinner candidate that is still sitting at FDA—received a positive recommendation from the European Union’s Committee for Medicinal Products for Human Use, the noise from the “too slow” contingent is likely to get louder.

In an effort to discredit those critics, Jenkins presented data at the FDA/CMS Summit from a preliminary analysis of new molecular entities reviewed by FDA and the European Medicines Agency between January 2006 and October 2008. What Jenkins found was that EMEA approved slightly more novel products than FDA, but that the agencies had a similar approval rate.

Jenkins then looked at new molecular entities that were reviewed by both the Food & Drug Administration. Of those 29 products, FDA approved two that the European Medicines Agency has not, and EMEA approved seven that FDA has not. (Once Lilly and Daiichi receive final approval from the European Commission—which should come in two or three months—prasugrel would make that eight.)

Jenkins argued that the numbers are too small to support any conclusions that FDA is more conservative than its counterparts in Europe—especially given that one of the EMEA-approved drugs (Sanofi-Aventis’ weight loss drug rimonabant) has already been withdrawn from the market.

Pointing to the list, Jenkins said: “Here’s where all the statements about the EMEA being faster are coming from.” But some investors still see the data as a troubling trend. The prasugrel approval in Europe is only likely to feed those beliefs. (You can read all about that debate in the latest issue of The RPM Report.)

So what's up with prasugrel at FDA?

As we’ve reported, FDA is looking at February 2009 for an advisory committee meeting. Assuming that happens, an answer isn’t likely much before March 2009—which would double prasugrel's review time to 12 months. The user fee deadline was initially set for March 2008, but on two occasions was pushed back three months—most recently to September. Since then, it has become just one of a number of missed deadlines at FDA.

Cleveland Clinic cardiologist Steve Nissen, who has accused FDA of being both too fast and too slow, thinks Lilly and Daiichi deserve an answer one way or the other. What do you think? Is FDA more conservative than EMEA? Or is the difference too small to draw any conclusions?

Photo courtesy of flickr user StevenBulman44.

FDA Has a New Guard Dog: He’s a Wolfe

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

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

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

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

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

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

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

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

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

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

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

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

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

How Important Is Prasugrel? Ask The Street

We knew the story on the prasugrel delay was big, but maybe not quite this big.

If you hadn’t already heard, it appears a decision by FDA on Eli Lilly/Daiichi Sankyo’s anti-clotting drug won’t come until March 2009 at the earliest. That projection is based on the convening of an FDA advisory committee tentatively being scheduled for February 2009. To read the rest, click here.

How important is prasugrel? Let’s put it this way: the stock of Sanofi-Aventis, partner with Bristol-Myers Squibb on the blockbuster blood thinner Plavix which prasugrel is expected to essentially replace, was up 9.3% at midday. Bristol’s stock? Up 2.4%. How about Eli Lilly? Down 4%. Remember, it takes a lot to move the needle for all three companies given their overall size.

Lilly and Daiichi put out a joint statement responding to our story. The long and short of what they had to say?

1) The companies are still in discussions with FDA.

2) If FDA chooses to schedule an advisory committee, the companies will be ready for it.

3) The companies believe prasugrel should be approved.

“The FDA can schedule an advisory committee at any time during the review of an application. If one is called, then we will be prepared to participate,” Daiichi’s global head of R&D John Alexander said in a statement.

“Daiichi Sankyo and Lilly are engaged in an ongoing dialogue with the FDA,” Lilly VP-global regulatory affairs Jennifer Stotka said. “We remain confident in the overall benefit-risk profile of prasugrel, and we believe this drug should be approved.”

Wall Street analysts appear to be most concerned with the cancers discovered in the prasugrel arm. Our very basic understanding is that the presence of tumors can be explained by the fact that they were discovered through enrollment and treatment in the TRITON study, not caused by the drug itself. The reasoning? The onset was too rapid to have been caused by prasugrel. That’s only one perspective, though, so do with that what you will. But there is some resentment out there that Lilly did not visibly disclose—if disclose at all—the cancer issue.

Now, the focus shifts to Lilly’s third quarter earnings call slated for Thursday, October 23, where it’s expected the firm will have to address the prasugrel issues in slightly more detail. Or not.

Lilly Prasugrel Delay Could Extend Well Into 2009

It looks like FDA’s decision on Eli Lilly’s anti-clotting drug prasugrel won’t come before March 2009 at the earliest.

Members of FDA’s Cardiovascular and Renal Drugs Advisory Committee have been contacted about their availability for a February panel meeting specifically on prasugrel, sources say. The agency’s Drug Safety and Risk Management Advisory Committee may also be convened.

FDA has scheduled a December 10 meeting of the Cardio-Renal advisory committee. The agenda, however, is already set: Acusphere’s IMAGIFY (perflubutane polymer microspheres) injectable suspension imaging agent. The odds of a change are practically zero.

The potential February advisory committee date means it is almost impossible for FDA to deliver a decision before March. In fact, a March decision is probably the best-case scenario for Lilly and partner Daiichi Sankyo at this point.

Prasugrel, which will be marketed as Effient if approved, has been closely watched by FDA observers, drug sponsors and the investment community alike because of the drug’s blockbuster potential in a primary care market and as a marker of the current state of FDA drug reviews as the agency continues to miss multiple user fee deadlines (See “Running Late: What It Means When FDA Misses a Deadline,” The RPM Report, September 2008).

Developments thus far in the review support those who argue that FDA is exhibiting overly cautious decision-making in an era of drug safety.

Lilly submitted the prasugrel NDA on December 26, 2007; FDA designated a six month priority review for the application in February. At the end of June, FDA extended the review by another three months due to supplemental information submitted to the agency (“The Pink Sheet” DAILY, June 24, 2008). Then, FDA missed the September 26 deadline (“The Pink Sheet” DAILY Sept. 29, 2008).

“This is a very large and complex submission, and it should not be surprising that delays occur,” a Lilly spokesperson says. “We are working diligently with the FDA as they continue their review of the prasugrel NDA.”

But the size of the NDA does not appear to be the cause for the delay with the review now in its 10^th month.

A serious internal disagreement has developed over whether to approve the drug as it stands, sources say.

The decision to grant priority review in the first place suggests that the top review managers—namely, Office of Drug Evaluation I director Bob Temple and director of the division of cardio-renal drug products Norman Stockbridge—are excited about the potential for the drug. However, it appears that another party has made a compelling argument against approval of the application in its current state.

Three issues appear to have impeded an FDA decision: (1) the increase in minor and major bleeding and concerns of related deaths in the prasugrel arm; (2) more cancers discovered in the prasugrel group compared to clopidogrel in TRITON; and (3) a recent formulation issue either related to the active ingredient or excipient substance.

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

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

Time is of the essence when it comes to Lilly’s marketing plans for the anti-platelet therapy, which the company hopes will replace Plavix as the standard of care. (Annualized US revenue of Plavix would be approximately $4.8 billion based on second quarter sales of $1.2 billion). Plavix is scheduled to go generic in 2011 meaning prasugrel will have to compete against generic clopidogrel in clinical practice and on drug coverage formularies. In other words, timing of the approval is of critical commercial importance to Lilly.

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.

Prasugrel: My August Looks Free…and So Does My September

Eli Lilly’s prasugrel team may have some free time on its hands in August and September if FDA’s advisory committee calendar is any indicator.

After FDA extended the priority review deadline of the novel anti-platelet drug by three months on June 23—the deadline was June 26—to September 26, speculation began in earnest around whether the drug would be required to go before the agency’s Cariovascular and Renal Drugs Advisory Committee.

August 19-20 had been tentatively blocked off for a meeting of the Cardio-Renal panel and Wall Street, FDA watchers and industry stakeholders pointed to the dates as a strong possibility for a prasugrel review.

Well, a quick look at FDA’s advisory committee calendar shows the blocks have suddenly disappeared. Moreover, September is completely free of any advisory committee meetings and no new Cardio-Renal meeting has been added to the end of July. We should note that a tentative Peripheral and Central Nervous System Drugs Advisory Committee meeting blocked off for August 6-7 has been postponed.

Do with that what you want. Of course, FDA can add a meeting at any time.

But, if FDA sticks to the extended review deadline and the calendar remains as is, it appears that prasugrel will not go before an advisory committee before a final decision on the application is made. That’s probably a positive sign for Lilly because the committee would have been used to address uncertainties with the application and the postmarket surveillance REMS program.

If, however, FDA adds a meeting in late August or early September, that almost certainly means the prasugrel review will miss another deadline.

A Lilly official says the company still has not been informed by FDA that prasugrel will require an advisory committee review. FDA says there is no Cardio-Renal panel scheduled as of right now. We still think prasugrel will be approved on its first cycle.

We’re not going to rehash our reasoning but you can read it by clicking here and the follow-up is here.

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.

Prasugrel: Signs Point to FDA Approval

[Update: Well, it looks like Lilly will have to wait on the champagne, at least for now. FDA extended the review of prasugrel by three months after receiving "supplemental information" during the review. "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. To read the full release, click here.]

There’s nothing like a ticking clock as a deadline approaches to ratchet up the drama behind an FDA decision. Remember Provenge? On June 26, or possibly before then, Eli Lilly will find out whether its novel blood thinner prasugrel (Effient) will be granted approval, delayed or rejected.

We think Lilly may want to get the champagne ready. Here’s why:

1) The Data: When it comes to FDA approvals, it’s all about the data. No question. In Lilly’s Phase III 13,000-patient TRITON clinical study, 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). By any standard, that’s a compelling result.

There’s been a lot of finger pointing regarding a more cautious FDA when it comes to new drug approvals and we’re not going to dismiss that here. However, sometimes the cases used as evidence to make that argument were for drugs that missed their primary endpoints or made it by the skin of their teeth and had important safety questions.

Those expecting an FDA decision to delay the application point to the statistically significant 32% increase in minor and major bleeding. That’s a strong point against approval in today’s regulatory environment. But when you consider the primary endpoint, those bleeds didn’t lead to deaths, heart attacks or strokes. To read more about our coverage of prasugrel, click here.

2) Priority Review: We think a lot of the hard work on prasugrel was done prior to the priority review designation. Here is what FDA says warrants that designation:

“A priority review designation is given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists....The distinction between priority and standard review times is that additional FDA attention and resources will be directed to drugs that have the potential to provide significant advances in treatment.
Such advances can be demonstrated by, for example:

a) evidence of increased effectiveness in treatment, prevention, or diagnosis of disease;

b) elimination or substantial reduction of a treatment-limiting drug reaction;

c) documented enhancement of patient willingness or ability to take the drug according to the required schedule and dose; or

d) evidence of safety and effectiveness in a new subpopulation, such as children.

Designation of a drug as “priority” does not alter the scientific/medical standard for approval or the quality of evidence necessary.”

FDA Office of New Drugs director John Jenkins is one of the most vocal advocates of the value linked to getting a priority review. He often cites the designation as the most telltale sign that a drug will receive a positive, first-cycle decision. It may be a leap, but we doubt such a high-profile drug in a treatment area with an established gold standard would have received a priority review without FDA having a strong idea of what they were going to do with it.

3) The (absence of an) Advisory Committee: This is another positive sign for Lilly, in our opinion. Why? Read this quote from former FDA drug center Steve Galson at a 2006 Stanford Research Group meeting in Washington:

“If it’s clear that the drug is very advantageous and helpful [then an advisory committee may not be necessary]…we’re just wasting everyone’s time because it’s obvious that this drug has to get on the market. On the contrary, if there’s some major drug safety issue that we know there isn’t any real disagreement...then we also don’t want to waste everyone’s time at a whole meeting.”

We think the former is the case with prasugrel when you pair it with the priority review. For example, if you look at Bayer/Onyx’ and Pfizer’s renal cell carcinoma drugs sorafenib (Nexavar) and sutinib (Sutent), respectively, both were priority reviews that resulted in timely approval without advisory committees. Both were viewed as significant advances in renal cell carcinoma therapy, an area that had been bereft of new treatments for years.

4) Sending a Message: Approving prasugrel by the PDUFA deadline would send a strong message to FDA stakeholders that the agency is willing to approve innovative drugs—that carry a pre-determined risk—in a timely fashion if the treatments demonstrate a real benefit to patients. Prasugrel appears to fall in that category. Moreover, a swift approval that meets the user fee deadline would allay many concerns over an FDA memo allowing reviewers to extend deadlines. To read more, click here.

5) Nissen Says Thumbs Up: Controversial Cleveland Clinic cardiologist Steve Nissen has been on record as saying prasugrel is “a good drug that should get approved.” Need we say more?

6) Bad Cordaptive Comparison: Drug company executives, the investment community, and FDA watchers highlight FDA’s decision to delay/kill Merck’s combo cholesterol drug niacin/laropiprant (Cordaptive) with a “non-approvable” letter in late April as a sign that prasugrel could get disappointing news. This is an apple and oranges comparison. Cordaptive was a standard review application in an area, cholesterol therapy, with an extensive number of effective treatments. Moreover, there appeared to be questions over the long-term risks of the anti-flushing agent laropiprant. When FDA reviews combo drugs there must be evidence that each component of the combination product makes a substantial contribution to the safety and/or efficacy of the combination product. In other words, the combination product has to be shown to be more safe and/or effective than either product alone. Clearly, FDA didn’t feel that was the case with Cordaptive.

Two key questions that will impact the decision and whether it will be made by June 26 are: 1) Who made the priority review decision?; and 2) Will prasugrel require an onerous REMS (risk evaluation and mitigation strategies) postmarket surveillance program?

If an office-level director, or Jenkins himself, signed off on the priority review, that bodes better for prasugrel’s chances of approval. It diminishes the chances of an intervention from a higher-ranking official to delay the decision.

We asked FDA who actually decides whether a drug is granted a priority review. Here’s what an FDA spokesperson says: “The decision on priority review designation is made by the OND division director based on a recommendation from the review team and based on the CDER standard as articulated in our guidance.”

The division director in this case is Norman Stockbridge, who reports into Office of Drug Evaluation I director Robert Temple.

As the decision relates to risk management, if a burdensome REMS program is required to monitor the bleeding risk, it could take a few extra months to work out the details.

In the end, based on the tea leaves, that FDA will approve prasugrel with a warning (not black-box) on bleeds and a REMS program that includes a prescribing MedGuide for patients, a physician education program and a postmarket study.

Now it's just a game of wait and see.

A Question of Priorities: Lilly Prasugrel Prospects Looking Up

Lilly shareholders woke up this morning to find their company suddenly worth $1.4 billion more than it was at the close of trading yesterday.

Why? Because the Food & Drug Administration agreed with Lilly and Daiichi Sankyo that the new drug application for the clot-busting drug prasugrel (proposed trade name: Effient) merits a priority review. That means FDA plans to complete its initial review of the application in six months (by June 26) rather than 10 (October 26).

On paper, that sure doesn't seem like it justifies the 2.5% jump in Lilly shares prompted by the news. But Lilly should be used to that by now. Its shares have been on a rollercoaster ride while investors handicap the prospects for a critical new drug for the company.

In this case, the rollercoaster is heading back up, since many on Wall Street view the priority designation as more than just a possible four-month faster review time.

With good reason. A priority review designation implies a much higher probability of a "first-cycle" approval--meaning that not only will FDA provide an answer sooner than it would on a standard application, that answer is much more likely to be "yes" (an approval letter) rather than some form of "maybe" ("approvable" or "not approvable.")

In recent years, first cycle approvals for "standard" applications have become about as rare as white elephants. (We published that data in The RPM Report last year.) But priority applications still have been approved on the first go-around more often than not.

So, statistically speaking at least, the priority designation could mean the difference between a 2008 launch for prasugrel and a 2010 launch. That is a very big deal--especially since Lilly and Daiichi Sankyo desperately want to establish the drug before the market leader Plavix faces renewed generic competition in 2011.

Then there is what the priority designation suggests about the Lilly's plans to position prasugrel as superior to Plavix. Recall that the pivotal study of the drug--TRITON--compared prasugrel head-to-head versus Plavix, and found a significant reduction in cardiovascular events in favor of prasugrel. It also, however, showed an increased risk of major bleeding--though not nearly as big a risk as the magnitude of the efficacy advantage, especially when you exclude some high-risk subpopulations from the analysis.

Still, in a safety-first regulatory climate, the TRITON data spooked Wall Street, prompting concerns that FDA might not approve the drug at all without more data.

The "priority" designation does not guarantee that FDA will approve the drug without more data. It does, however, mean that the agency decided not to use the excess bleeding risk as an excuse to buy more time with a standard review designation.

FDA certainly could have gone that route: Bristol and Sanofi Aventis, for example, will argue that the apparent superiority of prasugrel in TRITON is simply an artifact of the loading dose of Plavix used in the study. A higher dose of Plavix, they say, would have shown the same reduction in cardiovascular events (and the same increase in major bleeds).

By granting a priority review, FDA is accepting the sponsors' claim that the drug would be an advance over Plavix based on the TRITON data. And the agency is also saying that it won't avail itself of an extra four months to dig into the data before making a decision.

Last but not least, the stock market's reaction reflects the element of surprise. Just yesterday, Daiichi Sankyo hosted an analysts briefing in Japan which included a slide suggesting an action deadline of October 26 for prasugrel.

The company said that it still hadn't heard from the agency regarding the formal designation of the application, but they sure seemed to be joining in the general belief that when it comes to priority designations, no news is bad news.

FDA's procedures call for notification to the sponsor of priority or standard status 60 days after filing. However, since 60 days is already one-third of the way through a priority review schedule, the agency often alerts sponsors that they have priority status well before that deadline.

So Wall Street, at least, seemed resigned to a standard review timeline. Now they have to reassess their perceptions of the drug.

The next milestone for prasugrel will be the scheduling of an advisory committee. Daiichi Sankyo says it fully expects one for prasugrel, noting that the new FDA Amendments Act directs FDA to convene committees for all new molecular entities or else provide written justification for skipping one. Separately, the agency also has to answer to Congressional overseers who want to see open discussion of any dissenting views on applications--making it even more perilous for the agency to skip a committee if there is anything but total consensus on approvability.

For now, FDA's next tentatively scheduled meeting of the Cardio-Renal Drugs Advisory Committee is June 24-25. If prasugrel is added to that committee, it clearly won't be approved by the end of June. But there is nothing (apart from logistics) to prevent FDA from scheduling a meeting before those dates. FDA typically announces a meeting agenda at least a month in advance, so that would imply a notice in the March/April timeframe.

One thing you can bet on: this rollercoaster ride isn't over yet.

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.)

Prasugrel: Lilly Tries to Stop the Bleeding (Part 2)

The speculation about the prospects for Lilly’s clot prevention drug prasugrel continues.

The latest turn has been a rebound for Lilly, prompted at least in part by a November 28 note by Credit Suisse analyst Catherine Arnold. The note reports some interesting survey data on projected use of prasugrel by cardiologists. What Arnold heard in the responses is further support for her view that the drug will indeed be a significant new product for Lilly, with peak sales in the range of $2.5 billion.

Lilly shares have been on a rollercoaster ride for six weeks now surrounding release of the pivotal trial data for prasugrel. Unfortunately for Lilly, most of the ride has been downhill. (We wrote about Lilly CEO Sidney Taurel’s response to the media and investor frenzy surrounding prasugrel last week.)

For now, many analysts remain concerned about an increased risk of major bleeding associated with the drug. In today’s world, they fret that even a demonstration of superior efficacy vesus the market leader, Bristol-Myers Squibb/Sanofi Aventis’ clopidogrel (Plavix), isn’t enough to overcome any hint of a safety risk.

The pivotal trial data undeniably limit the market for prasugrel (approximately 20% of the patients enrolled in the trial were in one of three subgroups Lilly says shouldn’t get the drug). Some analysts expect that the impact will be greater than that, with doctors choosing the more conservative approach of using Plavix first as much as possible. And the biggest fear of all is that FDA simply won’t approve the drug.

Arnold, clearly, is in the more bullish camp. In her view, investors have over-reacted to the safety issue. Even with limitations on the patient population, prasugrel only needs to capture about a 25% share of the current market for Plavix to generate $2.5 billion in peak revenues.

That type of market share is very achievable, Arnold says. The survey suggests that cardiologists will use prasugrel in more than a third of their PCI patients.

“Surprisingly, the respondents were also very likely to use prasugrel in patients with coronary artery disease who are being medically managed (patients with unstable angina or a recent MI who do not undergo PCI) and patients with established peripheral arterial disease,” Arnold reports. “These are large segments of the antiplatelet market where there is no data to support the use of prasugrel currently but, based on these results and other research we have conducted, we think prasugrel will generate modest off-label use.”

That sure sounds like good news for Lilly. But is it?

The willingness of cardiologists to shrug off the safety questions about prasugrel may be perfectly justified medically, and it would certainly be a great boost for the drug commercially. But it is also exactly the reason why FDA has been so tough on NDAs—and why Congress has given the agency new drug safety tools to control the use of new drugs after approval.

To us, the path for approval of prasugrel seems clear. First, Lilly needs to convince FDA that the subpopulations it has identified where the drug should and should not be used are indeed supported by the data. Lilly says the risk/benefit profile is not supported for the drug in patients over 75 years of age, patients who weigh less than 60 kg, and patients with a prior history of stroke or transient ischemic attack. If those patients are excluded from treatment, the relatively benefits of prasugrel look even better compared to Plavix.

Second, and most important, Lilly will need to convince FDA that the drug will in fact only be used by the subpopulations for which it is appropriate. In that case, the perception that cardiologists are eager to use the drug more broadly actually hurts—rather than considering the risk benefit profile if only the right patients use it, FDA has to consider the risk benefit profile if the wrong patients use it.

FDA’s decision on prasugrel will almost certainly come down to Lilly’s ability to present a credible risk management plan that will give FDA the confidence to say yes to the drug. In that context, the survey data showing a readiness for cardiologists to use prasugrel off-label is an obstacle, not an opportunity.

Prasugrel: Lilly Tries to Stop the Bleeding (Part 1)

We were a bit taken aback by Lilly CEO Sidney Taurel’s editorial in the Wall Street Journal earlier this week recounting the damage done by the frenzy of speculation about the prospects for the platelet aggregation inhibitor prasugrel.

Taurel takes financial journalists to task for trading in “leaks and rumors where scientific data are concerned” and calling on “would-be pundits” who “have not had firsthand exposure to the scientific results or specialized knowledge under discussion” to “qualify your comments if you must make them at all.”

Its not that we disagree with Taurel. Like most self-respecting journalists, we are only too happy to join in any critique of the sloppy practices of our competitors (since we of course are the exception that proves the rule, right?).

No, what took us aback about the piece was its premise: the almost quaint notion that pharmaceutical companies can somehow put the genie back in the bottle and have the final say in when or how information about their products—even unapproved products like prasugrel—will be disseminated to the public.

Taurel’s argument, in effect, is that journalists, analysts and investors should have waited patiently for the release of the pivotal trial data on prasugrel (the TRITON study) at the American Heart Association meeting November 4, rather than engaging in a frenzy of speculation based on news that Lilly had suspended two other trials of the drug. Lilly decided to report that data there, and in a companion piece published by The New England Journal of Medicine.

Lilly, of course, couldn’t release the data early because it committed to an embargo prior to the AHA presentation. “Such guarantees of exclusivity are not only common, but also appropriate, in focusing expert attention on important research,” Taurel writes. “A definitive source and a ‘zero hour’ of first-hand disclosure for complex scientific data help to limit misinformation.”

Ah, the good old days. Things used to work that way for sure. But in the era of the internet, clinical trial registries, managed care claims databases, FDA drug safety newsletters, and emerging active surveillance systems, it is simply no longer possible for drug sponsors to hope to control the information flow about their products. (Not too mention the unbelievable proliferation of would-be pundits known as bloggers.)

In this case, Taurel laments, “10 days before our ‘zero hour,’ word leaked out, causing us to confirm that the two prasugrel trials had been suspended, although our promises to NEJM and AHA prevented us from explaining why.”

The truth, as Taurel explains, was that prasugrel performed very well in the pivotal trial, but that there were “three small subgroups of patients” in whom a risk of excessive bleeding appeared to outweigh the benefits. “Based on the small chance that patients in the three identified subgroups might be given prasugrel and experience serious bleeding, we advised our researchers to suspend the two trials pending a review,” Taurel writes.

But the damage was done. “The media entered a feeding frenzy, catered by commentators on Wall Street and elsewhere who speculated that prasugrel posed broad risks and had probably failed its major trial. Our stock began its trip south and, more seriously, some doctors and patients were left with false impressions.” Lilly’s shares recovered somewhat after the data were finally reported on November 4.

We might quibble a bit with choosing prasugrel as the case to make this argument—claims of patient harm seem overdone here when we are talking about a drug not yet approved by FDA. Commercial harm, yes. Harm to Lilly’s investors, yes. But it is a bit of stretch to say patients were harmed.

But still, Taurel is right about the potential for media feeding frenzies to cause tremendous harm. Its happened before, for sure. Maybe Avandia is an example, or even Baychol—cases where coverage of an unexpected side effect led many patients to discontinue treatment on their own, leaving at least the possibility that more harm was done by untreated diabetes or high cholesterol than by the adverse events in question.

Even so, Taurel sounds a bit like Lear raging against the storm. We understand his concern, but it is hard to imagine any way he or any other industry CEO can reverse the winds.

We aren’t the only ones who think that. Plenty of smart people in government and industry are talking about the revolutionary changes in information flow about medicine—including a whole bunch of executives at Lilly. In fact, though this is impossible to handicap, we would be willing to bet that Lilly is at the forefront of recognizing and adapting to a world where the pharmaceutical company sponsor is no longer at the center of the information flow about drug products.

We have heard several Lilly executives speak publicly and privately on this very theme. During a panel discussion on clinical trial policy at the University of North Carolina in February, one Lilly executive talked about the move towards active surveillance as potentially engendering a “Wikipharmacy” model in which product use information is no longer generated by FDA and the sponsor in labeling negotiations, but rather by a global community of users exchanging information on real-world experiences with the drug.

And Taurel himself has talked about it. During a policy address at the Cleveland Clinic early this year, Taurel focused on the revolutionary potential of healthcare IT advances. He even talked about the importance—and benefits—of public access to data once jealously guarded by manufacturers.

“For businesses that generate health data and new knowledge, it’s time to learn the benefits of openness," Taurel said in Cleveland. He went on:

"We need to open our minds to the notion that electronic outcomes data – once the privacy of individual patients is protected – represent a legitimate ‘commons,’ a resource to which access should in most cases be widespread and easy.”

“That’s not to ignore the fact that great effort and expense goes into collecting many types of health information. Certainly at Lilly, we spend hundreds of millions of dollars every year on clinical trials. But the key insight in our situation, and I think it applies quite broadly, is that unlike most other assets, health information actually becomes more valuable the more it is used, studied, and applied. It does not depreciate.”

So what gives with the Journal editorial? Did Lilly decide that openness is wrong? Hardly. Taurel even repeats his argument that openness is critical for industry: “Trust hinges on our openness in sharing everything we know about who should use our products—along with when, how and at what dose—and who should not.”

What we are really seeing here is not a vain attempt by a pharma company to turn back the storm, but an example of one way to try to advance against the wind.

The frenzy around prasugrel hurt Lilly, but it also provided an opportunity for the CEO to talk about the product in a prominent forum. The fact is that Lilly (and its partner, Daiichi Sankyo) plan to submit a new drug application based on TRITON to FDA before the end of the year. Anything Lilly can do to shape the climate for that review is critical.

When you look at it that way, maybe the most important line in the editorial is the sentence at the end of the fifth paragraph, citing a quote from the Journal’s earlier reporting on prasugrel: “If you can't get a drug on the market with that kind of data, we should stop developing drugs.” That is a message not just for business and science reporters, but for FDA reviewers as well.

So will Lilly get this drug on the market with this kind of data? Coming Monday, one would-be pundit will share his thoughts on what it will take to make that happen.