What's on Steve Nissen's Tape Recorder?

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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.

Changing the Face of FDA...

We couldn't let this news item pass without comment: the first face transplant in the US, performed by surgeons at the Cleveland Clinic.

The patient, naturally is not identified. Perhaps Steve Nissen is taking his campaign for FDA commissioner to the next level? If he looked like Janet Woodcock does he get the job?

The Lesser Of Two Evils?

When Steve Nissen is not qualified to serve on an FDA advisory committee under the agency’s new conflict of interest guidelines, you know things are bad. Really bad.

According to Nissen, and as reported in "The Pink Sheet" DAILY, his position as chair of the cardiology department at the Cleveland Clinic likely bars him from serving another term on an FDA expert panel.

Nissen may not be exactly beloved by the pharmaceutical industry, but no one can argue that the man knows drug development, and is a global expert on cardiovascular drug safety. And when it comes to conflicts, Nissen prides himself in not only disclosing all the companies he has worked for, but also donating all his fees directly to charities so that he can't claim the tax benefit.

Plus, he has served as an advisory committee member before: Nissen was a permanent member of the Cardiovascular & Renal Advisory Committee from 2001 to 2005, that last year as chairman. Since then, he has served as a temporary member as duty calls, like the July meeting on type 2 diabetes clinical trial endpoints. So if he can't serve, then who can?

“The current rules are pretty bizarre,” Nissen told attendees at the recent FDC-Windhover FDA/CMS Summit. “The imputation of conflict of interest guidelines based on institutional contracts eliminates a lot of desirable people.”

In Nissen’s case, the trouble is with a section of the new CoI guidelines that bars the “head of a department” that is conducting or will conduct studies on a product (or its competitors) “that is the focus of a meeting and receives personnel or salary support, designs or advises on any aspect of clinical trials, or reviews data or reports from the trials.”

We emailed Nissen to clarify, and he pointed out that the cardiology department has more than 100 faculty members. So “for most advisory committees, it is highly likely that someone within our department is involved with the company in some fashion.” And given the size of the Cleveland Clinic, Nissen said, “the likelihood that someone...receives funding from the sponsor or its competitors is 100%.”

Of course, Nissen’s inability to serve on an advisory committee is most likely be welcome news for drug sponsors, who see him as, frankly, a pain in the derriere. Granted, this is the man who prevented Bristol/Merck’s Pargluva (muraglitazar) from ever seeing the light of day, and crippled the commercial future for GlaxoSmithKline’s Avandia. So you can understand that angst.

But industry should not be breaking out the champagne quite yet. If it is true that Nissen is no longer eligible to serve on an advisory committee, it underlines a disturbing trend at the agency: FDA’s continued inability to fully staff its expert panels with individuals that qualify under—and are willing to serve despite of—more stringent conflict of interest guidelines.

When we last looked at the staffing problems in the advisory committee system in The RPM Report, there were 83 vacant seats, and three-quarters of the panels did not have permanent chairs. That was despite a major recruitment effort at the agency. Things haven’t improved much since.

And when drug sponsors start to see who is qualified to serve as permanent advisory committee members under FDA’s conflict of interest rules, they may be wishing for Nissen. You tell us. As a sponsor, who would you rather have: Nissen, or Public Citizen’s Sidney Wolfe and Center for Science in the Public Interest’s Merrill Goozner?

The Long Campaign for FDA Commissioner (Part 3)

We’ve given you some of our thoughts on the candidates for FDA commissioner in the new Administration in several recent posts (here and here). Today, though, we tackle a bigger question: Why would anyone possibly want this job?

For a position that may well be the most thankless job in health care, an awful lot of people seem to be lining up to be the next commissioner of FDA.

With all the problems at FDA right now—a deeply underfunded agency with a nearly impossible mandate to protect the nation’s food and drug supply—it’s a wonder anyone would want to lead the agency. Add the prospect of contentious Senate confirmation hearings, a low public opinion of FDA, and a constant threat of whistleblowers, and you don’t exactly have your dream job.

But that hasn’t prevented people from wanting to be the next FDA commissioner. While much of the campaigning is taking place behind closed doors, some candidates are choosing to be a bit more vocal. Those individuals tend to fall into two categories; the Peter Rost Category of Candidates and the Steve Nissen/David Kessler Category of Candidates.

On one extreme end of the campaigning spectrum, there’s former Pharmacia marketing executive Peter Rost. As the Pfizer whistleblower over off-label promotion of the human growth hormone Genotropin, Rost is probably the one commissioner candidate that scares the bejesus out of pharma (or at least Pfizer) more than Nissen. Or he would if he had any chance of actually landing the job.

Not only is Rost openly campaigning, he is, in his words, “running” for FDA commissioner as though it’s an open Senate seat. Rost’s personal blog is now dedicated to his campaign run, and he has successfully solicited letters of endorsement from Sen. Sherrod Brown (D-Ohio) and Rep. JoAnn Emerson (R-Mo.).

On the other end of the spectrum, we’ll cite David Kessler. Kessler isn’t sending out press releases expressing his interest in the commissioner post, but he is indicating he’d be open to the job through public appearances. As we reported in an earlier blog post, when asked for his ideal profile for an FDA commissioner, Kessler essentially described himself.

The same goes for Nissen. While Nissen may be the last thing that anyone in industry wants in an FDA commissioner, he is laying out an agenda that sounds quite reasonable: more money for FDA, an end to the missed user fee deadlines, and restoring integrity to the agency. Indeed, we laid out in an earlier post why we think FDA commissioner Nissen wouldn't be the worst thing that ever happen to industry.

But even Nissen recognizes the challenges facing the next commissioner, and has publicly questioned whether anyone would want the job. Here’s what he said at FDC-Windhover’s FDA/CMS Summit last week:

“The problem is in the current environment, getting anybody confirmed looks like it could be really tough. You know what the last bunch of commissioners have gone through. You have to be a masochist to want to do that, and there aren’t a lot of people who would want to do that.”

Of course, in saying someone would have to be a masochist to want the job, Nissen didn’t mention whether he was a masochist. Knowing what we know about Nissen, we'd have to say yes.

image via run100miles.com. nothing particularly masochistic about that, eh?

The Long Campaign for FDA Commissioner (Part 2)

Yesterday, we told you about Steve Nissen's presentation during the FDA/CMS Summit for Biopharma Executives.

He wasn't the only speaker at the conference whose name has been mentioned as possible commissioner material. The opening keynote, for instance, was by Janet Woodcock, the head of the Center for Drug Evaluation & Research and the hands-down first choice of biopharma executives to be the next commissioner.

That is the first reason why she almost certainly won't get the job. As we wrote previously, industry support is definitely not something the Obama team is likely to weigh too highly when it gets around to making the pick. Nor is it likely that the new administration will pass up the opportunity to give the plum post to an outsider it would like to reward, rather than to a career FDAer, even one as abundantly qualified as Woodcock.

Indeed, the day before Woodcock spoke at the Summit, Rep. Bart Stupak (the chair of one of the Congressional committees that oversees FDA) wrote to the President-elect to declare that no agency insiders should be considered for the post even on an interim basis. Stupak, as "The Pink Sheet" reports, wants "a complete change in FDA's leadership."

Stupak, as it happens, chose the losing side in an internal Democratic party fight over leadership of the Energy & Commerce Committee, so his opinion may not carry as much weight as it once would have. But we're betting that the transition team won't be looking to antagonize Stupak unduly by nominating Woodcock for the job.

As for giving her the post on an interim basis, not only would that antagonize Stupak, but it would probably do exactly the opposite of what her supporters want: if Woodcock is the acting commissioner, she would almost certainly leave the agency once a Senate confirmed commissioner comes on board.

So who will the next FDA commissioner be?

We're betting that the closing speaker at the Summit, FDA deputy commissioner Frank Torti, will end up claiming that title--albeit only on an acting or interim basis. That, at least, is what the natural order of things would dictate, a fact that has been clear since Torti joined the agency six months ago.

And after that? Well, that's what campaigns are for.

Stay tuned: On Monday we'll bring you Part 3 of our campaign-for-commish series.

The Long Campaign for FDA Commissioner (Part 1)

Who says Election season is over?

To us, it sounds like the campaign to run the Food & Drug Administration is just heating up. That, at least, is our impression after FDC-Windhover’s FDA/CMS Summit for Biopharma Executives last week.

Exhibit A: The presentation by Cleveland Clinic cardiologist Steve Nissen. As always, Dr. Nissen was energetic, engaging and pretty frank in calling ‘em as he sees ‘em. But we heard some things that sounded a bit different than we have heard before.

As “The Pink Sheet” reports, Nissen—who, with some understatement, observed that he is no fan of the Prescription Drug User Fee Act—nevertheless declared that, having taken the money, FDA needs to follow through by offering an answer in the agreed upon timeline. That isn’t going to make Nissen any new friends at FDA. In fact, Office of New Drugs Director John Jenkins spoke earlier in the day and delivered a passionate defense of the agency’s review performance in 2008, and he sat stoically through Nissen’s presentation.

But some of the industry folks in the audience must have been whispering “amen” under their breaths. Our unscientific read of conference attendees is that they are sympathetic to the challenges facing FDA’s review group, and wary of piling on the agency at the this moment in its history—but they agree with the principle that, given how much they pay in user fees, FDA ought to be able to give them an answer on time.

And we bet one company in particular agrees: Nissen singled out Lilly’s overdue application for prasugrel (Effient) as both a case where the agency owes the sponsor an answer one way or the other. (If you haven’t followed the ins and outs of that application, start here.)

Nissen also declared that FDA’s “core” problem is that it lacks the resources to fulfill its mission—and stressed his view that a strong, credible FDA commissioner will help the agency secure those resources from Congress. (Oh, and he let slip that he had just been up on Capitol Hill himself that morning, chatting with some of his friends in Congress.)

Last but not least, Nissen endorsed the call for a fixed-term for the FDA commissioner (five or six years) to help depoliticize the agency’s leadership. That, to our surprise at least, has become a rallying cry for Big Pharma in the weeks since the election, with CEOs like Schering-Plough’s Fred Hassan and Pfizer’s Jeff Kindler highlighting the idea in appearances before investors.

In other words, Nissen sounded a lot like someone hoping to win some industry support for the FDA job...or at least convince some people not fight too hard to block him.

When asked specifically whether he has his eye on the commissioner post, his answer was “no comment.”

But it was what Nissen said afterward that really caught our attention. “I am going to stay engaged in these issues,” he said. “As an advocate for patient safety, I want to be engaged one way or the other.”

One way or the other? Hmmmm.

Nissen then went on to describe his ideal candidate, and frankly, it sounded an awful lot like him. First, a commissioner should be a physician, “because if you haven’t ever taken care of patients, you don’t really have the necessary perspective.” Check. Nissen is a cardiologist at the Cleveland Clinic.

Next, the commissioner should be a “good scientist,” because the FDA has to be a science-based organization, and “decisions have to be made upon the basis of evidence.” Check. Nissen is deeply involved in pharmaceutical research with a host of drug companies (the money from which, he is quick to point out, is donated to charity without a tax break for him).

The FDA commissioner also “ought to know something about statistics.” Check. As Nissen was quick to point out, he presented a series of statistical slides during an advisory committee meeting in July on the approval standards of diabetes drugs.

Finally, he said, FDA needs a commissioner who is “passionate about the public interests.” Check. Nissen’s critics may question whether he is also passionate about his elevating his public profile, but there is no question that he has patients’ interests at heart in his self-appointed position as a drug safety advocate.

Now, bear in mind that just because Nissen (and others) are campaigning for the job doesn't mean that a pick is anything close to imminent. The new Administration has a lot on its plate, and (as we wrote here) FDA isn't even close to the top of the list. But the Obama team knows a thing or two about long campaigns, so we say: bring it on.

Tomorrow: a word from (and about) some other candidates at the FDA/CMS Summit…

--Michael McCaughan and Kate Rawson

FDA Commissioner: Myths And Reality

Everyone wants to know who the next FDA commissioner will be, and we certainly have done more than our share to stoke speculation about the answer to that question. And we expect to do more of the same in the weeks and months ahead.

But before the frenzy gets entirely out of hand, we would like to offer a few rules of thumb about the commissioner search process.

(1) FDA May Be Your Top Priority, But It’s Not Obama’s

Just because the pharmaceutical industry considers FDA one of the most important positions in a new Administration doesn’t mean the transition team sees it that way.

In this climate, priority goes to economic posts (where the Securities & Exchange Commission is a more critical regulatory agency than FDA) and to Defense/National Security.

Even when the US is not at war or facing a financial crisis, FDA typically is way down the list of posts to fill. The Centers for Medicare & Medicaid Services usually is filled first, for example; with so much money under management by CMS it almost has to be.

And, in this Administration, when attention turns to health care appointments, the focus will be on health care reform teams as much as on agency appointments.

During the last transition, the first political appointment to FDA didn’t come until August, when Dan Troy was named chief counsel. As a Senate-confirmed post, commissioner takes longer—and in 2001 it took until nearly the end of 2002. Everyone hopes that long a delay can be avoided this time, but even with haste, there is unlikely to be a commissioner confirmed and on the job much earlier than 12 months from now.

(2) It’s Not Necessarily Obama’s Pick Anyway

There’s always some give-and-take between the White House staff and the new Health & Human Services secretary when it comes to filling the FDA post, and without knowing for sure who the HHS secretary is—and whether he or she sees FDA as a critical priority—there is no way to handicap that dynamic effectively.

And then there is the Kennedy factor. Historically, Ted Kennedy, the long-time chairman of the Senate Health Committee, has played a pivotal role in the commissioner selection process, holding veto power over any Republican selections and playing an even more direct role in the pick during Democratic Administrations.

However, Kennedy’s health may not allow him to play that role in 2009; if he steps down, his successor (potentially Maryland’s Barbara Mikulski) will certainly want some say in the process. But there may be a stronger voice for House members like Henry Waxman, whose staff has worked closely with the Obama campaign.

So no one can say for sure who will be involved in making the pick—which makes it hard to say who the pick might be.

So let’s face it: at this point, there’s a good chance the nominee will be someone no one has mentioned yet. Remember: Mark McClellan wasn’t even considered for FDA until after he’d already been nominated and confirmed for a different post in the Bush Administration.

(3) It Won’t Be An Insider

The biopharma industry would be thrilled if Center for Drug Evaluation & Research Director Janet Woodcock ends up as commissioner. Heck, the biopharma industry would be thrilled if she were President.

Don’t get your hopes up.

FDA is too plum a post to give to a career civil servant. There are too many people to reward and too few rewards to dole out to allow for that.

Even if the Obama team decided FDA is in such a state of crisis that they have to turn to an insider, the fact that Woodcock is so widely seen as industry’s top choice (like here) probably rules her out. Remember: the Bush Administration couldn’t get an “industry” pick at FDA. Why would an Obama Administration even want to try?

Woodcock could end up with the job nevertheless—but only if the outside choice (and maybe several outside choices) doesn’t make it through the Senate. And, as pleased as industry would be to have Woodcock running FDA, the prolonged uncertainty it would take before she really had a chance to get the job would be tough on the agency—exactly the outcome that industry wants to avoid in backing her for the post in the first place.

(4) It Might Be Nissen

Just as the perception that Woodcock is industry’s top choice isn’t going to help her get the job, the widespread suggestion that the Cleveland Clinic’s Steve Nissen would be the worst for industry doesn’t hurt him.

We have no idea if Nissen will end up at FDA—but as an Obama advisor he has already been vetted in case he is picked for some kind of government post. Maybe there is something in his background that rules him out, or maybe Obama, his HHS secretary, Kennedy, Waxman or someone else will want to go in a different direction.

But this we know: the opposition of industry won’t be the thing that keeps him out of the job.

(5) Nissen Might Not be so Bad After All

There’s no question that Nissen is unpopular with some in industry (like anyone who ever had anything to do with marketing Avandia or Vytorin).

But there are at least three reasons why industry might not be so bad off if he ends up at FDA.
First, as commissioner, Nissen can’t just lob grenades as products the way he has been in recent years. Sure, he might pull Avandia outright, rather than cripple it commercially—but as commissioner he also has to set some constructive public health agenda that doesn’t simply involve taking potshots at individual products.

Second, Nissen is not a drug safety gadfly at heart. Believe it or not, he wants to see industry succeed at developing innovative products. After all, he does drug development himself, and has spoken out in favor of products like Lilly’s prasugrel. As commissioner, you can bet Nissen would work just as hard to encourage the types of products and studies he likes as he would to discourage those he doesn’t.

Last but not least, there is the Kessler Effect: the last time a commissioner was appointed who defined himself by making enemies in industry, he also gave the agency the credibility it needed to establish accelerated approval and the user fee program. Kessler was never popular with industry, and drug companies celebrated his departure. But drug approvals have been in steady decline ever since. Coincidence or not, those were the good old days.

So happy speculating. Say, where is David Kessler anyway?…

The Case for Byetta LAR (Part 1)

Lilly and Amylin say they have one regulatory hurdle to cross before filing for the long-acting formulation of exenatide (Byetta LAR): demonstrating comparability between the clinical formulation of the drug and the proposed commercial supply manufactured by Amylin in Ohio.

Amylin CEO Dan Bradbury told investors during the company’s second quarter conference call July 21 that a recent meeting with the agency gives the company great confidence in its projection of an NDA filing sometime in the next year. The company has said all along that it expects to file by the end of the first half of 2009, Bradbury said; the meeting with FDA suggests that timeline may be conservative, since the agency may end up not requiring a full-fledged clinical crossover study.

At a time when investors are focused on the now clear, unequivocal emphasis on outcomes endpoints for new type 2 diabetes drugs, Amylin’s confidence in a near time filing date for Byetta LAR is big news.

This is a tough time for type 2 diabetes drug development. An FDA advisory committee essentially endorsed the Steve Nissen worldview: that blood sugar reduction is not an end in itself, and new drugs for use by diabetics need to provide sufficient evidence of outcomes benefits—especially cardiovascular outcomes—as a condition for approval.

Our colleagues at “The Pink Sheet” have extensive coverage of the meeting, and—more importantly—FDA’s takeaways from the meeting.

But in case you missed it, after a morning’s worth of warm-up, Steve Nissen—Cleveland Clinic cardiologist and shadow FDA commissioner—went up to the podium and called out the entire profession of endocrinology, telling the committee that they have made glucose reduction a goal in itself and lost sight of the bigger picture. Some committee members fumed visibly—but the panel spent the next day-and-a-half following the agenda laid out by Nissen.

The committee agreed with his premise—that it is no longer acceptable to approve drugs solely based on the ability to reduce HbA1c levels—and with his overall approach to assessing cardiovascular outcomes. They punted on some questions—like exactly how much outcomes research to expect, and under exactly what conditions the studies would be necessary prior to approval instead of as post-marketing commitments.

So what does all this mean, other than demonstrating once again the incredible influence Nissen has on drug development and use in this country at this moment in history?

First, it confirms that the bar is indeed higher for type 2 diabetes drugs, that—in effect—they will be governed by a quasi-superiority standard of the type that FDA has begun talking about for NSAIDs (and now antipsychotics).

That in itself should not be news: Remember Pargluva? But it is now clear that new agents for glucose reduction will be expected to demonstrate some compelling reason for approval—better HbA1c control, evidence of reduced toxicity, something—or else face the risk of being asked for definitive proof of outcomes prior to approval.

So there is plenty of reason to wonder whether Lilly and Amylin can in fact move forward with LAR as planned (or even faster than planned).

We think they can…and we’ll explain why tomorrow.

Next Steps for PhRMA and Marketing (Part 3): Let the Sunshine In

Concluding our series of proposals for pharmaceutical marketing to reclaim the high ground. We've already suggested re-defining the mission and combining the Pharmaceutical Research & Manufacturers of America's various codes of conduct.

Today, step three: Let the Sunshine In

“Transparency” is now everybody’s favorite buzzword in Big Pharma. Merck CEO Richard Clark urged his colleagues to embrace the call to "create transparency" during his inaugural address as chairman of PhRMA.

Indeed, the immediate impetus for PhRMA’s effort to update the marketing code came when Congress got serious about pushing “sunshine” legislation. (And the Code is already a success, since that initiative did not make it into law this year.)

The problem with transparency: by definition, you can’t see it. Obstruction you can see. Transparency is invisible.

Since the calls for transparency are motivated fundamentally by mistrust of industry, how will the public (or at least its elected representatives) ever be satisfied that industry is in fact being transparent? Put another way, if industry chooses to hold anything back—for competitive reasons or otherwise—why wouldn’t the assumption continue to be that some ugly truth is being hidden away?

Our suggestion: invite the public in to those conversations. Every pharma company should appoint a transparency committee, a group of independent outsiders--preferably well-known critics. The transparency committee (though we prefer the name "sunshine band") would have carte blanche to review anything and everything related to the company's procedures on information disclosure. They would be empowered to make recommendations that the company would be obliged to respond to. (Not necessarily implement--but at least acknowledge and explain a decision not to implement.)

The transparency committee should report directly to the board—or even better, to a central transparency committee convened by PhRMA. We even have the perfect chairman: Cleveland Clinic Cardiologist Steve Nissen. (He may have bigger plans for his career that rule him out, but still.)

Nissen is a particularly articulate critic of industry on issues like publication bias and clinical trial result reporting. But he is also a clinical investigator and an experienced author of academic research, so he understands the importance of protecting information as well.

That whole idea may sound crazy, but give us a second, we're just getting warmed up.

Industry could go yet one step further than letting its critics shape disclosure policies: it could ask them to review and approve its marketing plans in the first place. Now we know this sounds crazy. Pharma companies went ballistic over a provision in an early draft of the FDA Amendments Act that would have explicitly authorized FDA to review a company’s marketing plan in the context of assessing a proposed Risk Evaluation & Mitigation Strategy.

That provision came out--but the spirit lives on. In fact, we would argue that a suitably motivated FDA can and will demand access to marketing plans for drugs under the REMS authority. And even if FDA doesn't push that way on its own, the fact that Congress thought about it once means it is likely to come up again later.

More to the point: industry says marketing is about delivering valuable scientific information to doctors and patients. It is about education. So why not ask those being educated to review and respond to the curriculum? Who knows, they might even get excited about the new medicine...

Enough opining from us. What do you think?

Diabetes Drug Development and Regulatory Risk: Why the Guidance May Be Good News

The buzz among investors is that a new Food & Drug Administration draft guidance on diabetes drug development makes an already tough regulatory standard even tougher.

An article by Forbes summarizes the reaction, describing the guidance as proposing “tougher standards for how and when diabetes drugs will be tested for risks to the heart” in response to concerns raised by the Avandia controversy. It comes complete with comments from Cleveland Clinic cardiologist and Avandia meta-analyzer Steve Nissen praising the guidance as a step in the right direction—a notion sure to reinforce the view that the standards must be very tough indeed.

It seems to us that this is making a mountain out of a molehill—or perhaps, confusing a molehill (the FDA draft guidance) with the mountain (FDA’s authority to mandate post-marketing authorities).

Here (we think) is the section of the guidance raising concerns:

“Although a recommendation to demonstrate macrovascular risk reduction premarketing may delay availability of many effective antidiabetic drugs for a progressive disease that often requires multiple drug therapy, sponsors should conduct large outcomes trials before submission of marketing applications for drugs in development that show nonclinical or clinical evidence of increasing macrovascular risk. Therapies that have not demonstrated a deleterious effect on cardiovascular outcome during extensive premarketing evaluation may need further post-approval assessment for their effects on long-term macrovascular disease.”

This is news?

FDA would certainly say it would never have approved a glucose-lowering drug with a clear signal of cardiovascular risk without demanding long-term safety trials. The agency’s critics may dispute that, citing Avandia itself as an example.

We'll leave that debate to others. The point is that whatever FDA might have done in 1999, does anyone really think the agency would approve such a drug today? That question may sound rhetorical, but it doesn’t have to be. Look not at Avandia, but at muraglitazar—the Bristol-Myers Squibb diabetes drug that the agency declined to approve in 2005 after Dr. Nissen helpfully pointed out a cardiovascular safety signal in the Phase III trial database. The agency asked Bristol to do a long term study prior to approval, and Bristol opted to discontinue development.

FDA says Nissen’s outside review had no impact on its decision with muraglitazar, and we’ll let others debate that point as well. What the agency did, though, is not debatable—nor is the fact that in doing so it set a standard for requiring more than glucose reduction as an endpoint when a drug carries a significant cardiovascular risk signal.

In any event, if the bar for type 2 diabetes had been raised, it was raised then. Bristol certainly reached that conclusion, opting to partner its Phase III DPP4 inhibitor saxagliptin with AstraZeneca to help share risk in light of the tough climate. (We’ve argued elsewhere that, while Bristol undeniably did very well financially in this deal, it may have been overestimating the regulatory risk based on its experience with muraglitazar.)

We would argue that, in fact, the diabetes guidance is a sign that the regulatory risk in type 2 diabetes is a bit lower than most investors might think.

First, lay to rest any idea that FDA put this guidance out in response to Avandia. Guidance development does not move that quickly at the agency—to say the least. In this case, FDA began drafting a diabetes drug development guideline in 1996, and presented a draft to an FDA advisory committee in 1998.

After that, the agency’s Endocrine & Metabolism Division veered off into related issues like diabetes claims for weight loss drugs, standards for diabetes prevention claims, and discussion of metabolic syndrome as a potential therapeutic indication. The new draft guidance references a different starting point: a 2004 FDA/National Institutes of Health forum on diabetes. In any event, the guidance is most definitely not, on the whole, a reaction to Avandia or even muraglitazar.

Then there is a misinterpretation of what FDA guidances do: they attempt to lay out the agency’s thinking on drug development—not change that thinking. In other words, the guidance tells you what the agency already thinks. By definition, it doesn’t raise the bar on its own.

That in turn is one reason why issuing the guidance probably lowers regulatory risk: at least sponsors can read for themselves what the agency’s thinking is—and can frame their submissions appropriately to address the issues the agency has identified.

And then there is what the guidance doesn’t do: back away from HbA1c as a fully validated surrogate endpoint. “For purposes of drug approval and labeling, final demonstration of efficacy should be based on reduction in HbA1c (i.e., HbA1c is the primary endpoint of choice, albeit a surrogate), which will support an indication of glycemic control,” the agency says. That is nice and clear.

We suspect that the real issue here has nothing to do with the guidance, and everything to do with the fundamental changes underway in the regulation of drugs prompted by the new safety law enacted in 2007.

One of the key changes in the law: FDA now has the authority to mandate post-marketing studies—and to levy fines for companies that fail to follow through. That means that the wink-wink Phase IV system in place for many years, under which sponsors of products like Avandia agreed to post-marketing commitments as a condition for approval and then failed to complete the trials. Those commitments were typically “negotiated” in the final weeks before an approval deadline, under circumstances that encouraged sponsors to agree to anything FDA requested—and which even FDA recognized seldom led to useful data to resolve legitimate scientific questions.

In other words, if FDA was really worried about a safety question, it would demand more data prior to approval.

Those days are over. Now FDA and sponsors have to agree on realistic, real-world post-marketing studies. For sponsors, that means recognizing that commitments to develop long-term outcomes data in diabetes are indeed commitments.

And for FDA, that means the agency can have the confidence to approve a new anti-diabetic without demanding long-term outcomes data up front.

Botox, Friday Afternoon Press Calls and the Nissen Effect

Blaming the media will never go out of fashion, at least not when it comes to drug safety scares.

Here is Schering-Plough EVP Carrie Cox, summarizing the battle to rebuild Vytorin after the ENHANCE debacle during its earnings call February 12: "Physicians ... understand that the furor around ENHANCE is largely a media driven event."

And GlaxoSmithKline’s recap of the Avandia meltdown of 2007: it resulted from a “distortion of the media” about the risk profile seen with the Type 2 diabetes drug, outgoing CEO JP Garnier said February 7.

There is no question that front-page headlines and national news broadcasts can do immediate and lasting damage to even the most well-established brands, damage that may go far beyond any appropriate medical response to new data.

But that only begs the question: what prompts some safety scares (or, in the case of ENHANCE, a failed efficacy trial) to create a media feeding frenzy, while others seem to pass with barely a ripple?

One answer, to borrow a phrase from religious themed bumper stickers, could be WWSNS: What Will Steve Nissen Say? There certainly does seem to be a strong correlation between the Cleveland Clinic cardiologist’s reaction to new data and the amount of play it gets in the media.

Wall Street seems to believe in the Nissen effect. In a February 11 note, Wachovia’s Larry Biegelsen argued that investors over-reacted to an “early communication” about a potential safety issue involving Allergan’s Botox. The issue, announced by FDA February 8, involved serious adverse events primarily associated with off-label use of Botox in children with cerebral palsy. Investors worried that a safety scare could significantly impact Botox widespread cosmetic use.

Not to worry, says Biegelsen. An “ENHANCE-like impact” on Botox use is “unlikely in our view.” Why? Well, for one thing, “Dr. Steve Nissen has not spoken out against Botox,” the way he did against Vytorin.

Talk about a case where silence is golden.

Biegelsen, of course, knows it isn’t quite as simple as that. Nissen’s silence is one of four factors the Wachovia analyst sees as reassuring differences between the Botox safety issues and the ENHANCE fallout. Only one is under the control of the sponsor: “There does not appear to have been any delay in the reporting of the serious adverse events.”

The other three involve reactions by external parties who have no formal regulatory role: (1) Nissen’s silence; (2) “Congress has not started an investigation into the handling of the Botox data”; and (3) The media coverage of Botox is more benign than the coverage of the ENHANCE data.

How so? “We couldn’t find a story in the print version of the New York Times on Saturday, whereas ENHANCE was front page news the day after the results were released.”

Of course, that last point is not entirely good fortune for Allergan. As we pointed out, FDA issued the “early communication” about Botox on Friday afternoon—part of what is becoming a pattern at the agency. (A safety update on Pfizer’s emerging blockbuster Chantix came out the week before Botox, and FDA’s first response to ENHANCE came the week before that.)

It so happens that Friday afternoon is the time least likely to generate significant news coverage. FDA swears there is no deliberate strategy to bury drug safety events. (At least, they assured Pharmalot of that—you can read more here.)

It certainly is plausible that FDA didn’t get all its ducks in a row to issue the early communications until Friday afternoon. We’ve talked to media savvy FDAers over the years (both in the press office and elsewhere) who routinely lament the review divisions’ habit of issuing approval letters at or after the close of business, often on Fridays, thereby all but assuring that even the most important new drug approvals would not be covered in the national news broadcasts, and sometimes even receive scant notice in newspapers.

The fact is that if FDA is not taking the news cycle into account when making safety announcements, it should be. Overblown safety scares do not serve the public health, so FDA certainly could justify Friday afternoon announcements as a way to better ensure that important new information gets into the public sphere in a more measured fashion.

On the other hand, the news media is the best way to amplify an urgent safety message. If that is the goal, the agency is better served by getting the news out early in the day and early in the week whenever possible.

In fact, that’s what FDA did on Monday February 11, when it announced that Baxter is suspending production of heparin due to severe adverse events--an announcement with urgent public health implications.

As far as we know, Dr. Nissen didn't weigh in on that one...

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.)

The Man Pharma Loves to Hate

It’s the headline lay media outlets love to report: “High-Cost Cholesterol Drug Combo Shows No Benefit Over Lower-Cost Generic Statin.” From a health care reporter’s perspective, nothing is more juicy than a study that shows that a cheap generic drug is more effective than a expensive new medicine. Especially when the study is sponsored by a drug company.

And that story is made even better is when Steve Nissen goes on national television to say things like this: “My advice to physicians is to not use these drugs...for first-line indications anymore. These should really be relegated to drugs of last resort until we have some evidence that they produce a health outcomes benefit.”

But that’s exactly what happened to Merck and Schering-Plough’s hot new cholesterol combo, Vytorin. The drug, which combines another relatively new drug, ezetimibe (Zetia) with generic simvastatin, was found to have no effect on the accumulation of plaque in the arteries, and may even increase plaque growth.

Yikes. No wonder Schering and Merck waited two years to release those findings. Wall Street certainly showed its displeasure: Schering’s stock price fell 8% yesterday, and Merck’s shares slipped 1.3%. And Merrill Lynch downgraded its rating on Schering’s stock, from “buy” to “neutral.”

But Merck and Schering aren’t just in hot water with investors. The companies released the data after Bart Stupak (D-Mich.), chairman of the House Energy & Commerce Committee, opened an investigation into the delay. Now Stupak is sure to haul Merck and Schering executives up to Capitol Hill to testify at what surely will be a very public, very messy hearing.

“In light of today’s results, which were released nearly two years after the Enhance trial ended, it is easy to conclude that Merck and Schering-Plough intentionally sought to delay the release of this data,” Stupak said in the statement. Stupak, of course, was the man behind the Ketek hearings last spring, when FDA’s David Graham returned to Capitol Hill to revive his role as a drug safety whistleblower. So he’s not exactly friendly with Big Pharma.

That’s all bad enough for Schering and Merck. But Nissen, head of cardiology at the Cleveland Clinic, twisted the knife in a bit deeper, appearing in virtually all major news outlets to blast the efficacy of Vytorin and Zetia. (In fact, we would challenge anyone to find a major news story that didn’t quote Nissen.)

Nissen became the go-to guy on cardiovascular drug safety following his unauthorized meta-analysis of GlaxoSmithKline’s Avandia data. With Vyotrin, he adds the mantle of Dr. Efficacy. Here’s what he told NBC’s Today show: “It was a shocking result for the medical community, and it suggests that this mechanism of cholesterol lowering produced by Vytorin and Zetia is simply ineffective at providing any benefits to patients.”

It was comments like those that led to the anti-Merck and Schering “hysteria” on Wall Street, according to Sanford Bernstein analyst Tim Anderson. “In isolation,” Anderson says, “the results probably would have led to a share price rise for SGP and MRK, but largely due to negative comments from prominent cardiologist Steve Nissen, share prices declined.” (Well, either that or analysts underestimated, and continue to underestimate, how bad these results really are--particularly for Schering-Plough, and especially as those same analysts estimate that "about 70 percent of Schering’s earnings depend on Zetia and Vytorin," according to this morning's New York Times.)

Either way, the reaction confirms our belief that Steve Nissen has become a pretty powerful force, and why our colleague, Ramsey Baghdadi, labeled him as a “serial drug killer.” (For Ramsey’s profile of Nissen in The RPM Report, you can find it here. Those who aren’t yet subscribers can sign up for a free trial to read the story.)

There is an important distinction in Nissen’s role in Avandia and Vytorin: he isn’t taking down Vytorin with his own analysis, but using the visibility gained from Avandia to publicize what he sees as a drug that provides minimal efficacy. But given the sharp drop-off in Avandia prescriptions after Nissen got involved, you can guess where Vytorin and Zetia scripts may be headed—especially once AstraZeneca (Crestor) and Pfizer (Lipitor) start using the data in sales calls.

And finally, for those of you that thought the DTC advertising nightmare was somewhat over, think again. Here’s Nissen on Katie Couric’s “Eye to Eye” last night: “We see no evidence of benefit from this very heavily advertised, very heavily used medication.” If that's not an open invitation for more attention from Capitol Hill, we don't know what is.

Drug Safety Alarm: "Something Big" Coming?

If you attended our FDA/CMS Summit last week, it was great seeing you. If you missed it, shame on you. The keynote address by Cleveland Clinic cardiologist Steve Nissen on the state of the FDA stirred up a lot of controversy, not surprisingly.

However, one thing we didn't hear in his remarks could be more worrisome to the biopharmaceutical industry than what he actually said. A little birdie told us at the meeting to prepare "for something big" to be released this week.

We have no idea what the "something" could be. Do you? I will say that the last time a little birdie told us at The RPM Report that Steve Nissen was up to "something big," the "something" turned out to be Avandia.

The Nail in the Coffin on Avandia

It doesn't matter what the committee votes now.

The final blow to GlaxoSmithKline's diabetes drug Avandia was not delivered by FDA whistleblower and director for science and medicine in the office of surveillance and epidemiology David Graham, although he gave the most persuasive presentation during the morning session of today's advisory committee meeting on the troubled product. It was his boss, drug safety director Gerald Dal Pan.

Graham gave the last presentation before lunch and predictably came to the conclusion that Avandia should be pulled from the market. He went through a detailed, half-hour talk explaining why he came to his conclusion, using a combination of results from long-term, placebo controlled studies, and meta-analyses to show rosiglitazone's benefits did not outweigh its cardiovascular risks.

"There is no evidence, none whatsoever, to support the benefits of rosiglitazone with these outcomes," Graham said refering to a host of cardiovascular adverse events including heart attack. He paralleled the Avandia situation to Warner-Lambert's Rezulin, saying it had cardiovascular risks other drugs (read Takeda's Actos) in the class did not have. Rezulin was pulled for showing fatal liver toxicities other drugs in the class did not have (read our earlier post).

Everyone expected that from Graham. But it was Dal Pan's endorsement of Graham's findings that effectively killed this drug, even if it does stay on the market with a black box warning. If Glaxo's legal team wasn't already in crisis management mode, they certainly will be now.

Dal Pan was noticeably reserved about the meta-analysis finding of a 43% increased risk of heart attack linked to Avandia during an early July Congressional House hearing. He was not ready at that point to make any determination on Avandia. Now, he has reached his conclusion: it should be pulled. The benefit/risk profile of Avandia "is not favorable" Dal Pan concluded.

Best case scenario for Glaxo, Graham says, is that Avandia was responsible for 40,000 excessive cardiovascular events in 6.5 years since 1999. Graham puts the real number at 80,000 excess cases. A real nightmare, if true.

Dal Pan gives credibility to Graham's findings that did not previously exist. The only reason the Office of Drug Safety did not make a formal withdrawal recommendation is that the whole drug safety team had not had a chance to review the analysis as of yet, according to Graham.

There is clearly a line in the sand between the Office of New Drugs and the Office of Surveillance and Epidemiology (drug safety) within FDA's Center for Drug Evaluation & Research. OND wants to keep it on the market, OSE wants it off. CDER office of drug evaluation II director Robert Meyer argued eloquently against Graham and Dal Pan's conclusions, adding that he himself had not decided on the appropriate "regulatory action."

But that doesn't mean much anymore. Whether or not it stays on the market, GSK's Avandia is dead.

Avandia and Rezulin: Parallels that Should Make GSK Nervous

History doesn’t repeat itself but it does rhyme. That old Mark Twain saying must be making GlaxoSmithKline sweat as Avandia is starting to look more and more like another Rezulin. By our reading of the tea leaves, Avandia is in much more peril than anyone seems to realize.

GSK is hunkering down for continuing assaults on its number two drug, battered initially by Cleveland Clinic’s Steve Nissen whose meta-analysis showed a 43% increase in heart attack risk for Avandia patients compared to control.

During the company's second quarter conference call, CEO JP Garnier clearly was using the "If you sound like a winner, you are a winner" strategy when it came to discussing Avandia with investors, analysts and media.

"We are still encouraged [about Avandia] because we have seen...a lot of evidence recently," Garnier said of the data GSK has submitted to the agency in advance of a Monday advisory committee fact-gathering meeting. "The evidence is supportive of Avandia's risk/benefit ratio, and of its effect on cardiovascular safety."

GSK is hyping a 400,000-patient epidemiology study of patients on Avandia and Takeda's Actos among other treatments that apparently bodes well for the diabetes drugs.

Glaxo has said that they simply have been unsuccesful in boiling down their message on Avandia to a "7-second soundbyte" which is the reason for the more than 45% decline in new Avandia scripts. " In the US, the media has ... had more of an impact on physician and patient impressions than the data itself," GSK's pharma operations chief David Stout said on the call.

Clearly, the message from GSK is: We stand behind Avandia. Unfortunately for the company, there are some discouraging parallels between their diabetes drug and Warner-Lambert's Rezulin.

Warner-Lambert pioneered the glitazone class, but Rezulin caused liver toxicity that ultimately led to its withdrawal. A recap of the regulatory history suggests some uncomfortable parallels with Avandia and the concerns about cardiovascular safety.

Two months after it got to market in 1997, FDA slapped Rezulin with a stricter warning on its packaging (thanks to 35 post-marketing reports of liver injury). At that point, 500,000 patients were already on the drug. Several "Dear Doctor" letters later, FDA's Endocrine and Metabolic Drugs Advisory Committee reviewed the liver tox issues, and recommended keeping Rezulin on the market, but only for patients not well-controlled on other diabetes drugs. One year later, the drug was taken off the market when reports kept coming in.

For Avandia, the toxicity is different--cardiovascular rather than liver--but the slow motion, repeated regulatory reactions are similar.

Avandia labeling was rewritten to strengthen cardiovascular safety warnings in 2001, and the company issued a "Dear Doctor" letter on the topic at that time. The concerns were raised more directly in the context of the review of Avandia for an indication for use with insulin; that use was ultimately approved in 2003. The Nissen paper now has put the regulatory machinery into fast forward, and an advisory committee will discuss Avandia's fate on Monday.

All of that is uncomfortable enough, but there is another parallel to the end of Rezulin emerging at the worst time for GSK: a Senate Committee is raising concerns that FDA reassigned a medical officer who wanted to put stronger warnings on Avandia.

If that sounds familiar, it should. In early March 2000, FDA senior medical officer Robert Misbin wrote a letter to Rep. Henry Waxman (D-Calif.) expressing frustration over FDA's handling of Misbin's attempts during the previous two months to convince the agency's Center for Drug Evaluation & Research that Rezulin had to be withdrawn from the market. Misbin asserted that FDA officials had stopped him from releasing information related to deaths of Rezulin patients.

One other thing: Misbin was the primary reviewer on Avandia and was taken off of the review several years ago. (Apparently, he's not the whistleblower this time around -- for more speculation on who the whistleblower might be, see the next post.)

All in all, Monday's advisory committee meeting doesn’t look good for Avandia. Even if the medical officers keep quiet, FDA will not be presenting a united front to the committee. That's because the agency is once again going to let its most prominent whistleblower, director for science and medicine in OSE David Graham, make a formal presentation. Graham most recently helped ensure that Merck's Arcoxia died a painful public death before an FDA advisory committee. FDA has apparently concluded that they have to let Graham speak at these meetings rather than wait for him to go to Congress to make his presentations. (Here is our coverage of the Arcoxia debacle.)

On Avandia, Graham has already made his position clear in FDA briefing documents. He argues that the current postmarketing studies (in particular the key RECORD study) can't, statistically, demonstrate a heart attack risk related to Avandia: they're underpowered. In other words, the current scientific evidence is all FDA is going to get to make their decision on the future of GSK's drug. Anyone want to venture a guess at where Graham will stand on Avandia?

And its not like FDA won't let the discussion go into whether the drug needs to be pulled. Quite the opposite. Here is one question posed to the committee: "Does the overall risk-benefit profile of Avandia support its continued marketing in the US (VOTE requested)? If yes, please comment on what FDA should do to maximize the risk-benefit considerations (e.g., limit to certain patients, incorporate a boxed warning….)"

That question means FDA is thinking awfully hard about whether this drug should stay on the market. You could argue that they added the question for political cover in order to leave it on the market, but I'm not buying it. I think they really want to know the experts' opinion.
And what will that opinion be? Nissen himself has said Avandia should remain on pharmacy shelves. NIH's Malozowski told us that he didn’t think FDA would pull it. “They will probably add a warning for a subpopulation of patients and a contraindication for its use with insulin."

I also asked Tom Garvey, a former FDA reviewer who runs his own drug development consulting business, what he thought. He concurs with Malozowski. Sort of.

Rezulin could be pulled off the market with less risk, he argued, because there were two other marketed drugs without Rezulin’s liabilities. Moreover, "the absolute risk found by Nissen is small (if, indeed, it exists) and the benefit conferred by Avandia is not inconsequential, especially in certain types of type II diabetics.”

But then he added, surprisingly: “All of this having been said, I too get the sense that the drug is probably doomed."

In short, as with Rezulin, an FDA advisory committee could recommend keeping Avandia on the market, in a limited way—while, in parallel, the political and historical momentum builds to yank it off. On the scientific front, the data isn’t clear. Nissen's meta-analysis has come under intense fire, but his results were confirmed by FDA's own meta-analysis, and they had access to a much larger data set. Meanwhile, GSK's RECORD study has been inconclusive on the heart attack risk question.

But the political front will evolve in its own way. And if history really is rhyming, if not precisely repeating itself, FDA will have a hard time keeping Avandia on the market.

Dissin' Steve Nissen?

The New York Times ran an interesting profile of the Cleveland Clinic's Steve Nissen on Sunday in light of his "controversial" meta-analysis finding over a 40% increased risk of heart attack for diabetes patients on GlaxoSmithKline's drug Avandia.

I interviewed Dr. Nissen a few months ago. Check out our July issue of The RPM Report called "Inside the Mind of a Serial Drug Killer" to find out what makes him go, what would make him stop and what he thinks is driving some members of Congress to criticize his efforts. Note, the Times may have higher circulation than The RPM Report , but we had the better headline.

But don't take our word for it. Here are a couple of excerpts:

The RPM Report: What would make you stop doing this type of work in the area of drug safety?

Nissen: It is all of our jobs, not just the FDA’s job to do this. Those of us in the physician community owe it to our patients to give equal balance and weight to positive and negative findings about drugs, and so should the FDA. Even if the FDA were doing an outstanding job, it’s still the responsibility of independent scientists to do these sorts of things, so it really isn’t about the FDA.

The RPM Report: So creating two drug centers—one for premarket review and one for postmarket surveillance—would not stop you from doing this kind of research. You feel this is a moral obligation.

Nissen: It is a moral and ethical obligation; it’s just about good science, it’s a scientific obligation. Science is about pursuing the truth and wherever that leads you. If we had very, very good regulatory agencies looking after this, there may be fewer opportunities to turn these things up.

How did we find out about fen-phen? There was an independent group of physicians that began seeing fen-phen patients with valve abnormalities. They said, “Oh my God, this is a potentially serious problem, let’s publish it,” and they did a great thing, they probably saved a lot of lives; they’re heroes.

The RPM Report: Why is there such a visceral reaction to you and the research you are doing? FDA’s meta-analysis of Avandia studies showed similar findings as your meta-analysis.

Nissen: Right. Part of the problem is this is not about me. One of the issues is sometimes when you don’t like the message; it’s easier to attack the messenger. It’s to be expected, but we’ve got to keep everyone focused on the science. I was very restrained in that [Avandia] hearing, I didn’t attack back. I simply said: this is what we did, this why we did it, this is why it’s important, and I’m going to stay on that message because it’s the right thing to do.

The RPM Report: Rep. Darrell Issa (R-Calif.) seemed particularly unnerved by your analysis and the process you took to get it published?

Nissen: He was wrong about the statistics, you cannot calculate an effect size if there are no events [studies with no heart attack events were excluded from Nissen’s meta-analysis]. He had been briefed by people giving him campaign contributions and that happens to be GSK. I looked it up. The three people on the attack at the hearing were very heavy recipients of GSK campaign money.

For the rest of the interview, subscribe to The RPM Report. Also, Nissen will be speaking at our annual FDA/CMS Summit in December in Washington, D.C. in case you want to hear him in person.

Speaking of Avandia, there is a July 30 fact-gathering meeting between FDA and Glaxo (Takeda, which markets Actos, is an invited guest) regarding the cardiovascular profile of the diabetes drug. While something conclusive could come out of that meeting, it's highly doubtful. So we'll just have to wait and see whether Nissen and his meta-analysis are vindicated for finding risks that hadn't been previously uncovered or his findings were rushed, sloppy and wrong. Stay tuned. It could be a while.

Nissen goes meta on GSK; markets take back $13 billion

Cleveland Clinic cardiologist and Big Pharma nemesis Steve Nissen has struck again, this time calling out GSK's Avandia in a New England Journal of Medicine analysis of the drug's cardiovascular side effects across a variety of clinical trials. Nissen's meta analysis concludes that Avandia patients are 43% more likely to have a heart attack than patients given a placebo or another drug.

GSK's share price stumbled more than 8% as the markets digested the news, wiping a whopping $13 billion off the company's market cap. The Big Pharma for its part predictably "strongly disagreed" with Nissen and co-author Kathy Wolski, pointing out the intrinsic shortcomings of the kind of meta-analysis done by Nissen and Wolski and holding up data from its ADOPT and DREAM studies, which suggested Avandia risk was comparable to that of commonly used diabetes meds metformin and sulfonylurea and placebo, respectively.

The authors acknowledged the limitations of meta-analysis but suggested GSK needed to make public more data from its Avandia program for further analysis to more accurately determine the drug's cardivascular risks.

"The manufacturer's public disclosure of summary results for rosiglitazone clinical trials is not sufficient to enable a robust assessment of cardiovascular risks," they contend. "Until better precision of the estimates of the risks of this treatment on cardiovascular events can be delineated in patients with diabetes, patients and providers should give careful consideration to the risks and benefits of their overall treatment plans."

The WSJ's Health Blog put together a nice list of Nissen's previous pharma takedowns, which includes Merck's Vioxx and Bristol/Merck's Pargluva. Nissen's prominence as a critic of industry and FDA is something our RPM Report colleagues have examined in depth several times (see their May piece for an FDA reaction to his criticism and this June 2006 look at the emergence of academics like Nissen as a shadow-FDA force to be reckoned with).

FDA's medical policy head Bob Temple told the RPM Report that meta-analyses could become standard practice for drugs on the market (and Avandia isn't the first drug knocked around this year with a retrospective analysis: witness Novartis' Zelnorm). For now the FDA is likely to convene an advisory panel ASAP and won't rule out any regulatory action. That said, the agency wasn't able to react as quickly as Rep. Henry Waxman--who announced earlier today that his Oversight committee will conduct a hearing on the matter June 6th.

Whether or not you think Nissen's brand of activism is necessary, harmful, overdue or half-baked, it's here to stay. Today it was GSK that suffered the smackdown (and diabetes competitors like Merck & Co. who will likely get a boost in the aftermath); tomorrow it'll be someone else.