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...

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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.)

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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.

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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.

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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.

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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.

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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.

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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.

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