Avandia Decision Today; Steve Nissen Thinks It Will Stay on the Market

Word is that US and European regulators will make separate announcements shortly about the future of Avandia. The status of GlaxoSmithKline's former blockbuster diabetes drug is once again under review, thanks to concerns about a potential increased risk of heart attacks compared to other treatment options.

What will the decision be?

Cleveland Clinic cardiologist Steve Nissen, MD, thinks he knows the answer: FDA will leave rosiglitazone on the market.

That, to put it mildly, isn’t what Nissen thinks FDA should do. But, he tells us, that is what he now believes FDA will do.

One clear sign that FDA is likely to save Avandia, Nissen says, is the agency’s recent red flag for its thiazolidinedione competitor, Eli Lilly & Co.’s pioglitazone (Actos).

FDA announced on September 17 that it had commenced a safety review of Actos after receiving preliminary results from a long-term observational study designed to evaluate the risk of bladder cancer. The agency did note that the review is ongoing and it has not concluded that Actos increases the risk of bladder cancer.

Nissen calls FDA’s analysis “barely statistically significant” for what is essentially a small subgroup of individuals. The Actos review, Nissen says, is a “smokescreen designed and timed to keep rosiglitzone on the market.” (For coverage of the warning, click here).

Indeed, the timing of the Actos safety update is fortuitous for GSK. A key piece of the argument for pulling Avandia is the availability of a “safer” alternative, Actos. However, it would certainly be an odd decision for the agency to pull one product due to a potential increase in cardiovascular risk and recommend use of alternative that may or may not have an increased risk of bladder cancer.

Nissen, of course, has led the calls for Avandia’s withdrawal, and he is convinced that the agency’s actions with the product reflect ongoing challenges with handling post-marketing safety issues. In his view, it basically comes down to how FDA reacts to challenges from outside—and, by implication, the need for change in the drug center management.

[Editor’s Note: Nissen will expand on his views about the decision-making at FDA during The RPM Report’s FDA/CMS Summit for Biopharma Executives in Washington DC Dec. 9-10. For more information or to register, click here.]

Kate Rawson

Avandia and the Revenge of the Brain Dead Kangaroos

We're not ones to call advisory committee members names. We'll let them do that to themselves.

"I was one of the brain-dead kangaroos last time who was on the fence, largely because I did see a signal for harm that was outweighed at that time by the comparison to active comparators, which I think is much more relevant to me than placebo, and I wasn't swayed by the pioglitazone data that was presented at that time because it was pretty preliminary," Morris Schambelan, San Francisco General Hospital, said in explaining why he had voted to recommend removing GlaxoSmithKline's Avandia from the market at the July 13-14 meeting of the Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees, after having voted that it should stay on the market in July 2007. He was in the minority this time, however; the committees voted 20-12 that the drug should stay on the market.

Read more about the revenge of the brain-dead kangaroos in this week's "Pink Sheet" ...

-- Martin Berman-Gorvine

FDA's Sharfstein On Avandia: "An FDA Decision"

FDA Deputy Commissioner Joshua Sharfstein was asked repeatedly during a briefing with media: Who will make the final decision on Avandia?

His answer: "It will be an FDA decision."

In the context of the question being asked, it wasn't a seemingly helpful response. But it gets to the heart of who carries the burden when the dust settles from the two-day advisory committee review on July 13-14.

If FDA chooses to pull the drug, the agency will have to explain to patients and prescribers why the drug, which an advisory committee voted overwhelmingly was linked to increased cardiovascular risks in 2007, has remained on the market for three years and counting. One could make the argument that it's been 12 years.

If FDA chooses to keep Avandia on the market--more restrictions or not--they'll have to explain to patients and prescribers why a drug linked to increase heart attack risks is still available.

Regardless, they have to explain the decision to their overseers in Congress and the public at large.

The gravitas of that decision and subsequent fallout means there is one person at "FDA" who will indeed make the final decision on Avandia: FDA Commissioner Margaret Hamburg.

So whether or not Hamburg literally makes the decision, it's hers.

Avandia: It's All About Question 7

Today, FDA released an army of briefing documents ahead of the advisory committee re-review of GlaxoSmithKline's diabetes drug Avandia (rosiglitazone). To read all of the documents for yourself, click here.

While one could argue that any number of issues will be key in helping FDA determine what regulatory action to take on Avandia, we believe the key to the whole debate is quite simple, actually: question 7.

FDA asked the joint Endocrinologic & Metabolic and Drug Safety & Risk Management Advisory Committees a large number of questions--six of which are formal voting questions with multiple options.

Most of the headline attention will be focused on question 8: "What regulatory action does the panel recommend FDA take on Avandia? A) Allow continued marketing and revise the current label to remove the boxed warning and other warnings regarding risk of ischemic CV events, or B)Allow continued marketing and make no changes to the current label, or C) Allow continued marketing and revise the current label to add warnings, or D) Allow continued marketing, revise the current label and add additional restrictions on use, or E) Withdrawal from the US market."

But none of the questions may be more important to FDA decision makers than the preceding question, number 7:

"Rosiglitazone and other oral anti-diabetic therapies share the same indication of improving glycemic control in patients with Type-2 diabetes. Based on the available data, please discuss the benefit-to-risk profile of rosiglitazone in the context of other available anti-diabetic therapies."

In other words, does Avandia provide a unique benefit over existing therapies on the market? Our bet is that FDA decision makers will be paying particularly close attention to the answers provided by committee members to question 7.

FDA knows what its regulatory options are when it comes to Avandia. But the agency will be looking for arguments--even if they are in the minority--that make the case for a unique Avandia benefit over everything else.

It will be a difficult argument to make.

FDA Takes Control Of Avandia Debate

Score one for FDA.


As "Avandia Week" approaches, FDA made a decision to wrestle control of the debate over the safety and efficacy of Glaxo's diabetes drug rosiglitazone by offering the media an embargoed preview of the agency's briefing documents for the two-day advisory committee meeting on July 13-14.


The decision to let reporters look at the documents early was smart, effective and stands in marked contrast to how the debate on Avandia played out in 2007.


In 2007, the meta-analysis conducted by Cleveland Clinic cardiologist Steve Nissen, which showed a increased risk of cardiovascular events linked to Avandia, was published in the New England Journal of Medicine on May 21, 2007. A few days later, a House Oversight & Government Reform hearing, led by then-Chairman Henry Waxman, was scheduled before FDA ever publicly commented on the findings. On June 6, 2007, the hearing took place.


This time around, FDA has been effective, among other media savy strategies, in granting interviews in response to the Nissen meta-analysis published in the Archives of Internal Medicine and the Medicare beneficiary study comparing Avandia to Takeda's Actos conducted by FDA drug safety official David Graham in the Journal of the Amercian Medical Association.


But allowing access to the briefing documents before they were made public was probably the best stroke yet by the agency. Reporters typically get an email from FDA that the briefing documents are made public, then they have about 10 minutes to "read" 300-400 pages of FDA's in-depth analysis and write a short piece for the wires and mainstream media news sites that capture the essence of FDA's point of view.


Instead, FDA gave journalists a full day and access to FDA deputy commissioner Joshua Sharfstein and drug center director Janet Woodcock, among other officials, to digest the briefing documents and pose questions to the agency officials. Brilliant.


There's no doubt that Nissen and Graham know how to make news. But FDA, as a whole, has been equal to the challenge in both ensuring that outside voices--and voices from within--are heard while simultaneously communicating the facts on Avandia as agency leadership views them.

Drug Safety 2010: Nissen Meets With FDA Leadership as the Avandia Advisory Committee Meeting Looms

The most important single event for FDA’s drug review in 2010 and possibly beyond is coming this summer: the advisory committee re-review of GlaxoSmithKline’s diabetes drug

Since passage of the landmark FDA Amendments Act of 2007, the drug approval climate at FDA has improved steadily. To view The RPM Report’s analysis on the drug approval climate, click here

It appears one potential conclusion that can be drawn is that FDA’s comfort level with the postmarket control and monitoring tools given to them through FDAAA is adding confidence to approval decisions.

But the Avandia re-review could change all that. Whether FDA chooses to pull Avandia from the market, keep the drug on the market, suspend use temporarily or further restrict its use, the agency must ensure that it does one thing: make a credible decision. Any outcome deemed to be unsatisfactory by FDA stakeholders in Congress, and the experts they listen to, puts the improving drug approval momentum in real jeopardy.

Just to recall briefly: In May 2007, a meta-analysis by Cleveland Clinic cardiologist Steve Nissen published in the New England Journal of Medicine found that Avandia (rosiglitazone) was associated with over a 40% increase in heart attack risk. The House Oversight & Government Reform Committee put together a hearing before FDA could respond to the study. In July 2007, FDA convened the Endocrinologic & Metabolic Drugs Advisory Committee and the Drug Safety & Risk Management Advisory Committee to assess Avandia’s future.

The joint committee voted 20-3 that the drug increases cardiac ischemic risk but subsequently voted 22-1 against withdrawal of the TZD. The panel meeting surfaced an “internal disagreement” between the Office of New Drugs and Office of Surveillance & Epidemiology over whether to withdraw rosiglitazone over heart attack risks.

On October 2, 2007, FDA’s Drug Safety Oversight Board voted (8-7) to keep Avandia on the market. The non-public vote was questioned by ranking Senate Finance Committee Republican Charles Grassley (Iowa) due to the lack of transparency. On November 14, 2007, FDA issued a black-box warning for Avandia warning of heart attacks. GSK agreed to conduct a long-term postmarket safety trial of Avandia compared to competitor Takeda’s Actos to confirm a higher CV risk for rosiglitazone; the trial was named TIDE. The TIDE trial is expected to be complete in 2015.

The Senate Finance Committee released a major report on February 22 bringing to light internal emails and memos related to Avandia and heightened CV risks. On February 26, House Agriculture Appropriations Subcommittee Chair Rosa DeLauro (FDA’s chief appropriator) gave a detailed critique of GSK’s RECORD study, which the company maintains supports Avandia’s safety profile.

Now FDA is scheduled to hold another re-review of Avandia, likely July 13-14.

"Congresswoman DeLauro is looking forward to the advisory committee meeting and its findings,” a spokesperson for DeLauro says. “She believes that the TIDE trial is unethical and should be halted immediately, and has urged the FDA before to remove Avandia from the market until a truly independent, science-based advisory panel can evaluate the safety and effectiveness of the drug.”

DeLauro and her staff met with FDA Principal Deputy Commissioner Joshua Sharfstein and Assistant Commissioner for Legislation, and former staffer to Rep. John Dingell, Jeanne Ireland on May 20. The topic? “Drug safety.”

DeLauro isn’t the only one meeting with FDA leadership. Nissen recently met with FDA Commissioner Margaret Hamburg and Sharfstein to make the case that the TIDE trial was unethical and that Avandia needed to be withdrawn.

The major threat to the approval environment and the current FDA review structure is that an outcome on Avandia that is viewed as lacking credibility will energize those who want to split the Center for Drug Evaluation & Research into two separate centers or offices. A split would still be a long-shot, but a possibility nonetheless.

“As far as the FDA’s organization, the Congresswoman believes that serious consideration should be given to creating two independent offices within FDA – one that would be responsible for reviewing drug applications, and another for post-market surveillance,” the DeLauro spokesperson says. “It is something she has been concerned with for awhile, and the Avandia case serves as a reminder of just how important it is to address this situation.”

Here are a few points to consider as the Avandia re-review approaches:

1) How many advisory committee members will be assembled? In July 2007, there were 23 panel members convened for the meeting. That is a large number of committee members, many of whom were given temporary voting status. The makeup of the committee will be equally important in terms of the balance between drug safety specialists and E&M committee panelists (to view the 2007 final roster, click here).

2) Will the full Actos safety data be presented? Our understanding is that FDA asked both GSK and Takeda for every shred of data related to Actos and have had the data for “months.” Whether or not those data are formally presented at the meeting will go to the heart of the credibility question whatever the committee and FDA decide to do with Avandia. The current buzz in Washington is that not all of the Actos data will be presented, but it is still too early to determine whether that will actually be the case in the end.

3) Will Nissen present? At the July 2007 meeting, Nissen did not make a formal presentation of his meta-analysis—the whole reason for the existence of the panel meeting—to the advisory committee. Instead, he sat in a chair along with the rest of the audience. Something similar happened with Sanjay Kaul, a Cardio-Renal Advisory Committee member who was barred from the advisory committee review of Eli Lilly’s anti-clotting drug prasugrel (to read The RPM Report story, click here).

4) Hamburg and Sharfstein have gone to great lengths to brand the Obama Administration’s FDA as a public health agency. The Avandia re-review represents the first major prescription drug safety, public health issue. How will they react? Hamburg has already gone to IoM for ethical and scientific guidance on postmarket studies (to read our analysis in The RPM Report, click here). Probably the best outcome for the drug industry at large would be a risk evaluation and mitigation strategies (REMS) program that controlled the use of Avandia, monitored patients on the drug, and provided FDA with valuable data on its cardiovascular risk profile. That result would validate the use of FDA’s drug safety authorities under FDAAA, hold together FDA’s current regulatory structure and keep the approval momentum going. But is that enough of a public health message for Hamburg and Sharfstein?

5) There are a number of important FDA officials who will be directly affected by the final decision on Avandia--maybe none more than the ones who will make that decision. Hamburg and Sharfstein will bear the brunt of public scrutiny around the decision. Perhaps no one will be under the microscope more than CDER Director Janet Woodcock, who concluded that Avandia should remain on the market in 2007 with stronger warnings. This is a major issue for FDA. Woodcock is held in high regard as a strong leader, effective manager, and there are few individuals at FDA who understand its operations—and runs them as efficiently—as Woodcock. While the FDA drug safety players are the same—Gerald Dal Pan and David Graham—the drug review management is different compared to 2007. In 2007, CDER Office of Drug Evaluation II Director Robert Meyer gave a public refutation of the conclusions drawn by Graham and Dal Pan that Avandia had to be withdrawn. Meyer is no longer at FDA and Curtis Rosebraugh is the current ODE II Director. However, Mary Parks was and remains the Division Director for Metabolic and Endocrine Drug Products. Both Rosebraugh and Parks will be important officials on the Avandia re-review. Lastly, CDER Deputy Director for Clinical Science Bob Temple will play a role in the Avandia decision but it is unclear exactly what kind and how big a role. Temple has presented publicly about FDA’s tough decision-making when it comes to taking a drug off the market.

There is still a lot of time before the advisory committee: much could change and there are sure to be surprises just as there were in 2007. But it would be an understatement to say there is a lot riding on Avandia.

What's on Steve Nissen's Tape Recorder?

click for larger.

The IN VIVO Blog Poll Results: Bye Bye Avandia

The people have spoken, and they expect a long year ahead for GlaxoSmithKline. That’s because Avandia was the run-away winner in our poll based on our purely speculative if not insanely irresponsible notion that the US Food & Drug Administration might just pull a drug to demonstrate that it is taking Congressional concerns about drug safety seriously.

It ain’t scientific, but 42% think Avandia is most likely to be pulled. And, for its worth, that’s twice as many people as think we are crazy to think this way. (See full results below.)

Frankly, we were temped to vote “crazy” ourselves, so we consider this result a bit of surprise.

We also got lots of comments—a few of the “you are crazy” variety (keep it clean, people!), but also some suggesting candidates we didn’t include in the poll. Two votes for Avelox, one for Oxycontin, and one for midrodine. Oh, and one pointing out that we should have listed Accutane for a different side effect.

So folks clearly think there is a risk here.

One final note: the polls closed before readers could digest our two most recent posts, based on our conversation with gadfly and advisory committee member Sid Wolfe. In the first, he--quite unprompted by us--predicted that Celebrex will eventually be withdrawn. In the second, he discussed his relationship with incoming deputy commissioner Joshua Sharfstein.

Celebrex only got 6% of the vote in our poll. Wonder if people feel differently today?

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.

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?

FDA's Internal Advisory Committee Meetings

Avandia. Vioxx. Ketek. Elidel. Palladone.

What do those drugs have in common? The obvious answer is that they are all associated with a major safety problem that resulted in a significant FDA regulatory action—either a “black box” warning in product labeling, or, in the case of Palladone and Vioxx, outright removal from the market.

But they have something else in common as well. In the months preceding those major regulatory steps, each product was the subject of a relatively unknown internal meeting at the Food & Drug Administration: a regulatory briefing.

Regulatory briefings can be described as “internal advisory committees” at FDA—a chance for review divisions to ask others in CDER for advice on how to handle a tricky regulatory or scientific decision. (For more on regulatory briefings, check out our coverage in The RPM Report. If you’re not a subscriber, you can sign up for a free trial to view the article.)

If you’ve never heard of a regulatory briefing, you’re not alone. Regulatory briefings have been kicking around FDA’s Center for Drug Evaluation & Research for more than a decade, but because they are closed to industry—and review divisions don’t always inform sponsors when one is held—many companies are unaware that they exist. But now FDA is holding more of them, as many as one per week. And they are quite popular with reviewers.

The good news for drug sponsors is that regulatory briefings are not intended to be decisional meetings; the final approvability decision remains with the review division after the meeting is over. But given the typical attendance list—John Jenkins, Janet Woodcock, Bob Temple, Doug Throckmorton and 50-100 other drug reviewers—it would be hard to ignore any advice.

A drug does not have to rise to the level of an Avandia or a Vioxx to be discussed during a regulatory briefing—given the frequency of such meetings, that could not possibly be the case. But, as the list above indicates, they do tend to skew toward the more problematic end of the continuum. The need for a regulatory briefings should not spell doom and gloom for a sponsor, but it could be an indication that something is wrong. That alone makes them worth watching.

image via FDA

The Avandia Effect

Type 2 diabetes just entered the new era of drug development.

FDA’s Endocrine & Metabolic Drugs Advisory Committee’s recommended (by a 14-2 vote) that cardiovascular safety become a standard requirement for type 2 diabetes drug candidates.

That pretty much guarantees that FDA will increase the approval requirements for type 2 diabetes drugs—making development of new products all the more expensive. (Read more coverage of the advisory committee meeting in today’s issue of “The Pink Sheet DAILY”.)

That in itself isn’t much of a surprise. As we’ve said previously, FDA was headed in that direction already, having released a post-Avandia draft guidance document much to that effect. Plus, as Office of New Drugs director John Jenkins pointed out after the advisory committee meeting, the recommendations are just an “extension” of what FDA already does for drugs with a safety signal.

But the advisory committee went even further, and recommended cardiovascular outcomes data for all investigational type 2 diabetes products—even those for which no evidence of a cardiovascular risk was seen in clinical development.

That kind of standard requirement for a prospective cardiovascular study is unprecedented in drug development—with the exception of non-steroidal anti-inflammatory drugs. That, in effect, makes diabetes drugs the next NSAIDs. Welcome to the new world of drug development.

Committee members did not agree on how best to study the cardiovascular risk, but threw out a number of options—ranging from a prospective “pooling” of all Phase III studies to a standalone long-term cardiovascular safety study. Other options included extending Phase III studies longer term or conducting pre-approval screening studies.

However FDA decides to move forward, it will be a change over current requirements for a diabetes drug approval, and a higher number of patients exposed to the drug prior to approval. Right now, FDA typically asks sponsors to enroll 2,500 patients in Phase II and III, with 1,500 patients studied for at least one year.

Drug developers did avoid a double-whammy on diabetes drug development: the advisory committee agreed that the surrogate endpoint of hemoglobin A1c levels should remain the standard for demonstrating glycemic control.

That efficacy endpoint was called into question when two long-term studies (ACCORD and ADVANCE) found that aggressively controlling blood glucose in type 2 diabetics at high risk for cardiovascular disease doesn’t result in a statistically significant reduction in either CV events like heart disease and stroke or CV-related death. (We wrote on that fun finding in an earlier post.)

Given all the talk about changing that endpoint, industry got lucky on that one. But when it comes to drug safety, it's not business as usual anymore.

Avandia Warning Letter: A Sign of Things to Come

You don't have to have finely honed news instincts to realize that if GlaxoSmithKline failed to disclose everything it knew about Avandia to the Food & Drug Administration, you are sure to have a big story.

So you will probably be reading a lot about the warning letter issued by FDA to GSK after inspecting the firm's post-market adverse event reporting procedures.

Many in industry may be tempted to dismiss the letter as just the latest in a series of woes for GSK and its once-blockbuster type 2 diabetes therapy, just more piling on to a bad news story that is almost exactly a year old.

That would be a mistake. The warning letter should be a must read for all biopharma companies with products on the market (and all companies who hope to be so lucky as to have products some day). The letter does indeed add to GSK's headaches, but for the rest of industry it should serve as notice that the agency is likely to do a lot more enforcement of post-marketing study reporting requirements in the months and years ahead.

Congress, remember, has just handed FDA new enforcement authority over post-marketing trials, in the form of the ability to mandate Phase IV studies--and fine sponsors who fail to live up to their commitments.

The violations FDA cited in the letter to GSK predate enactment of the FDA Amendments Act in 2007, but the agency is sending an unambiguous message: there is no excuse for failing to comply with basic reporting requirements that already existed in law.

According to FDA, the agency found that GSK failed to include updates on as many as 18 different post-marketing trials in its annual reports to the agency on Avandia. GSK notes that the missing reports were inadvertent and disclosed to the agency before the final safety labeling update on Avandia in November. FDA doesn't dispute that this is a case of mistakes rather than deliberate concealment. That, in fact is the point.

Here is the key part of the letter:

FDA's inspection revealed that your firm lacked appropriate knowledge of the studies associated with Avandia, resulting in the reporting deficiencies noted. Absent a clear explanation of the extent and cause of these deficiencies and an adequate plan to correct them, we are concerned that similar deficiencies in the postmarket reporting for your firm's other FDA-approved drugs may exist . We expect that your corrective actions will include a comprehensive evaluation of your firm's reporting of postmarketing studies for all drug products for which your firm holds an approved application.

In other words, it is not that GSK hid the data from FDA, it is that GSK did not have an appropriately rigorous process to ensure that it reported all the right data to FDA. In the new world of post-marketing oversight and regulation, expect the agency to make sure that every company gets that message loud and clear.

And in case you haven't read our analysis before, executives at all levels should bear in mind that the FD&C Act is a "strict liability" statute, meaning that top executives--starting with the CEO--can be held criminally accountable for violations they knew nothing about. (Indeed, as is FDA's policy, the letter to GSK is addressed to the CEO, JP Garnier.)

At this point, GSK is saying all the right things. “We take these findings seriously, and corrective steps to make sure we file periodic reports completely and promptly have been taken or are underway,” the company says in a statement. The company notes that many of the trials were in fact disclosed to FDA anyway, just not in the annual report as the agency says they should have been. And, the company adds, many of the studies were also publicly disclosed on the government's ClinicalTrials.gov website and through GSK's own on-line trial registry.

"GSK is committed to taking the appropriate steps to address the concerns raised by the FDA." The rest of the industry would do well to do the same.

FDA’s Risk Communication Advisory Committee: An Ineffective Beginning

If you’re an executive for a company with an FDA-regulated product, the agency’s inaugural Risk Communication Advisory Committee meeting had to make you a little nervous.

Granted this was the first time the group was brought together so you’d expect some wandering by the committee. Still, there was a lot of wandering. And the last thing the industry or the agency needs is more unknown variables thrown into the risk communication equation. From the hour-long introductions on the first day to the back-and-forth open public hearing portion of the meeting, the committee was like a Super Bowl half-time show gone bad. There appeared to be little focus on any particular area of discussion and much of the conversations between panelists lacked meaningful direction—a telltale sign of a bad committee.

Here’s the issue for biopharma companies: FDA typically follows advisory committee recommendations, although they certainly aren’t required to. With a committee this inexperienced and seemingly unfamiliar with FDA regulations, procedures and protocols, how will their opinions be interpreted into final risk communication decisions? How will the media report recommendations from a newborn committee that may be clearly out of whack with FDA standard procedures?

The Institute of Medicine’s report on drug safety called for the creation of a risk communication advisory panel similar to FDA’s other scientific drug review committees except focused on how FDA should best communicate safety and risk-related issues to the public.

In other words, how to alert the public without alarming them. To read our initial story on the new committee, click here.

What FDA, and the drug industry for that matter, really requires from this committee is a strong group of advisors to provide practical guidance to FDA on how to address risk concerns quickly, proportionally to the risk presented with new information emerging continuously. If the inaugural meeting serves as any guidepost, FDA won’t be getting that guidance.

The agency has had a mixed record recently dealing with these types of situations. In May, FDA was criticized heavily for reacting too slowly to the publication of meta-analysis data on GlaxoSmithKline’s diabetes drug Avandia showing more than a 40% increased risk of heart attack associated with patients using the drug. In fact, the House Committee for Oversight and Government Reform was able to announce a hearing before FDA could even respond to the analysis with a press release or conference call. We all know how that turned out.

Then there was a rather awkward “early communication” call in August with the media over potential cardiovascular risks linked to AstraZeneca’s blockbuster proton pump inhibitor Nexium found in two small studies. But after discussing the possible risks uncovered by the trials, the agency said on the same call there were no risks related to Nexium. “FDA has concluded preliminarily that these data do not suggest an increased risk of heart problems for patients treated with either of these products,” Center for Drug Evaluation and Research associate director for safety policy and communication Paul Seligman said.

The Nexium communication was followed by a January “early communication” briefing by FDA on Merck/Schering-Plough’s ENHANCE study of the cholesterol combo drug Vytorin almost two weeks after data from the study were made public by the companies and commented on at length by cardiologist Steve Nissen in the mainstream media.

On the call, FDA officials summarized the results already made public by Schering-Plough, and said it would review the data fully once it is submitted by the sponsor. To read a recap, click here.

The risk communication committee is supposed to help FDA avoid situations like that. What the agency appears to have on its hands, though, is a motley crew of experts with very different fields of expertise who don’t necessarily fit together or fit the purpose they were meant to serve—at least based on the initial two-day meeting.

The purpose of this first meeting was not to make specific recommendations on a specific product or issue but rather a more general discussion of risk communication. So there will be wandering. What should be alarming to drug companies, however, is how pronounced the absence of direction was during question and answer sessions and the level of inexperience displayed by individual panelists.

FDA senior risk communication advisor Nancy Ostrove explained in her overview presentation to the panel that this particular committee is supposed to be different. But in this case, different does not necessarily mean better.

The open public hearing encapsulated how the two-day meeting went. A free-lance reporter spoke endlessly (public speakers are generally given five minutes to make a statement during advisory committee meetings, this went way over) about how reporters used to be able to interact directly with FDA officials but now must go through the press office to seek permission to speak with an official and often aren’t granted access. Committee chairman Baruch Fischhoff, Carnegie Mellon, and other panelists engaged in a prolonged Q&A session with the speaker. It was painful.

Not everything was bad. FDA assistant commissioner for accountability and integrity William McConagha delivered a clear and important presentation on legal authorities and protections related to the First Amendment and communicating risk. One interesting suggestion to come out of the meeting from consultant Steve Gorelick, Hunter College, was that FDA hold a daily media briefing similar to the Pentagon.

All in all, though, the first risk communication panel meeting was a dud. Although it takes time for FDA advisory committees to develop personality and voice, this is one committee that won’t be afforded the time to do that. With arguably unprecedented public scrutiny of FDA and the next drug safety event around the corner, the agency will need to mine the expertise of the panel—sooner rather than later.

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.

JP Garnier's Farewell Address: The Lessons of Avandia (Part 2)

The Avandia disaster is probably not what JP Garnier imagined he would spend most of his time talking about in his swan song as CEO of GlaxoSmithKline.

But give him credit: Garnier is using GSK's setback to draw attention to some important trends that we think, at least, will indeed be ever more critical for the biopharma sector in the years ahead.

Earlier we laid out Garnier's argument that the drug safety pendulum will never swing back. So what is industry to do? Here is the outgoing GSK CEO's six-step program.

(1) If you have important new safety information, get it out as soon as possible (even if the regulator wants you to wait.)

“You should do the meta-analysis as we did with Avandia,” Garnier said. “But then you should absolutely demand that this would be issued and put in context by the appropriate authority. That didn’t happen in every country. That’s why we had a problem in the U.S. where the FDA wanted to do the work first.”

Indeed, one underappreciated benefit to industry from the new FDA safety law is that, by giving FDA the authority to mandate warning labels, it also creates deadlines that will help ensure that sponsors do get new safety information out sooner.

(2) Be proactive with payors.

“Payers don’t necessarily wait for the FDA,” Garnier said. “Think about it. If you’re an insurance company reimbursing Zetia and Zelnorm and products like this including Avandia, you will also get the phone calls from the patients. What you’re going to do? Say I’m waiting for the FDA, maybe in six months I will have an answer for you?”

“So we have seen payers jump in and take a stand while the dust has clearly not settled and before the body of scientific evidence has been really reviewed in appropriate way, and that is also something that needs to be managed very carefully. You could quickly lose formulary position for reasons which are not solid.”

GSK is hardly the only company to learn that lesson in 2007. (EPO anyone?)

(3) Don’t rely on labeling to communicate warnings to prescribers.

“Black boxes are becoming trivial. It used to be a very rare event to get a black box on your product, [but] they have tripled in the last four years. So now there is so many of them that frankly they don’t make the same impact with the medical profession, which is a pity, because sometimes we really need to warn our physicians.”

“We’ve already adjusted to this and we’re taking on now the role of communicating … to the physician who is not waiting for FDA. We have sent physician letters because in some cases we do want to alert them to what is likely to come out based on what we know about the products.”

(4) Expect to do more outcomes studies.

“There will be more demands for outcome studies. People are even questioning whether hemoglobin A1c is a good indicator for diabetes. It is very easy to say well why don’t you do outcome studies and show us that over five or six years you can reduce the rate of gangrene and heart attacks and the like. Well, if we have to do that, it is going to be a long time before the product can hit the market. So we’re going to have to deal with this issue.”

Once again, it is not just Avandia that supports that argument. Look at ENHANCE.

(5) Get ready for the “Progressive Blockbuster.”

“The development of new chemical entities and new biologicals is going to change,” Garnier says. “One way is to slice the patient populations, not to try to put the drug on the market for all the patients that could benefit, but focus on the easiest slice, the ones where they would be the least amount of controversy from a safety efficacy standpoint.”

Then you “get the drug on the market because there you will have … an easier file for the FDA to react to.” And “then build up your product as you would an oncology drug” by adding more and more slices of the potential patient population. “By that time you have developed a lot of knowledge about your drug anyway, so it becomes easier to do the right development.”

“You are not going to get instant blockbuster with this kind of technique, you are going to get progressive blockbusters.”

That, to us, seems spot on—though we would argue that there is also room for “minibusters,” products that never reach traditional blockbuster sales levels, but still generate healthy returns because they deliver high value to patients (and correspondingly high gross margins to the manufacturer) without requiring the conventional Big Pharma sales and marketing infrastructure.

(6) Innovate, innovate, innovate.

“If you had any doubts, with this kind of environment, we need not just new products, we need breakthrough new products. We need added value. We need best-in-class and first-in-class, nothing else. Line extensions are on the decline, there is no question about it.”

Once again, Garnier is hardly alone in stressing the importance of first in class products in Big Pharma pipelines. But we haven’t heard anyone in pharma say quite so clearly that line-extensions are passé.

We’ll give the last word to Garnier:

“In a fast changing environment, you can’t fight the government agenda. You can’t fight the environment. You have to fit to the environment, take advantage and ride the wave.”

JP Garnier’s Farewell Address: The Lessons of Avandia (Part 1)

“This is here to stay.”

“This” refers to what outgoing GlaxoSmithKline CEO JP Garnier sees as a vicious cycle of safety signals damaging blockbuster brands--the phenomenon that he says caused a $1 billion decline in sales of GSK’s Avandia. (See diagram.)

Garnier’s message: the safety-first regulatory climate of 2007 is not going away. “This is long-lasting. This is not a bad year and then the statistics even out.” And the need to adapt to that reality was a major theme of Garnier’s final year-end presentation as the company’s top exec on Februay 7.

Here is how Garnier sees the new reality:

“In the past these meta-analyses were conducted among scientists with not much interest from the media. Things have changed. Those kinds of desk researchers want their publications to get some play. So the news is then digested by the media, and I can’t expect the media to know the subtle points about hazard ratios and confidence intervals and the like.”

“If you think about Avandia, the signal was if you compare Avandia to placebo out of 10,000 patients, five more in the Avandia group will have some kind of cardiovascular event, versus not treating a patient—which is not exactly realistic. When you compare Avandia to other type 2 diabetes agents the signal goes away.”

“That is what the FDA put in the labeling.”

Nevertheless, “that signal was publicized by the newspapers in America as saying there is a 43% increase in the risk of heart attacks if you take Avandia.”

In case you missed it, that was a dig at Steve Nissen, the Cleveland Clinic Cardiologist whose meta-analysis triggered the Avandia safety scare, along with a healthy dose of blame-the-media, always a popular explanation for unexpected safety disasters.

But the more important point is Garnier’s assertion that, like it or not, the Nissen effect is not going away anytime soon. And as we wrote here, industry has no choice but to adapt.

Or, as he put it, “It’s always going to be with us, because as you can see the fundamental parts of mechanisms are with us now. And we better be ready as a company to deal with this.”

Check back later today for six lessons Garnier learned from GSK’s unwitting experience as the guinea big for the new meta-analysis driven safety model.

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...

Who's Sorry Now? Not Feeling So Good Edition

Nature reports today that a peer reviewer for the New England Journal of Medicine leaked to GlaxoSmithKline that big old Avandia meta-analysis that has been the bane of their existence since it was released in May 2006. (Our coverage of the Avandia debacle can be found here.)

University of Texas Health Science Center professor of epidemiology Steven Haffner, MD, explained to Nature: "Why I sent it is a mystery. I don't really understand it. I wasn't feeling well. It was bad judgement."

Brian Vastag writes in Nature that Haffner faxed the article 17 days ahead of publication to GSK's Alexander Cobitz, whom he had worked with on an earlier trial of Avandia. What happens from there is unclear--though it's not like GSK effectively got out in front of the news, the 17-days head start may have helped them provide a relatively prompt interim analysis of its RECORD study, which was published in the NEJM in June to try to stop the bleeding.

We will likely have more on this later, once the dust settles. For now, we bring you another edition of "Who's Sorry Now?"

• Steven Haffner to NEJM: Sorry I leaked the Avandia study, but i had a serious cold that day.


• Senator Grassley's office to Nature: Sorry we broke your embargo on the Avandia news today, but we aren't feeling so hot today ourselves.


• American Heart Association and American College of Cardiology to patients: sorry we forgot to disclose our potential financial ties to Merck and Schering-Plough, but there's a wicked flu going around the office.


• Phillies to Mets: Sorry you're spending all that money on Santana, but you're still not winning the NL East this year. Cough.

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.