Wolfe vs. Rappaport (Part 2): Embeda Warning Letter Raised During Abuse-Resistant Opioids Ad Comm

Advisory committees are always interesting, but you really have to expect the unexpected when Public Citizen Health Research Group Director Sid Wolfe is on the panel.

The last time the FDA Drug Safety & Risk Management Advisory Committee member participated in a panel discussion, he wanted to discuss a past off-label promotion settlement during a review of a pending application from Jazz Pharmaceuticals seeking an expanded label for sodium oxybate to treat fibromyalgia.

As we reported at the time, Wolfe was cut off by the committee chair and then chastised by Division of Anesthesia & Analgesia Products Bob Rappaport for bringing up a topic that was not relevant to the discussion—and for not at least bringing it to the agency’s attention in advance as something he wanted discussed. As we first reported, Rappaport then read into the record a statement essentially telling the committee to disregard the issue.

To us, it seemed like Wolfe had a point, that a discussion focused entirely on the appropriate method for marketing a drug like sodium oxybate should at least consider the question of whether the sponsor would or would not actually follow the pathway set down by the agency. Whether or not the committee agreed with Wolfe on that point, they agreed almost unanimously that Jazz needed to rethink its approach to managing this product in the post marketing setting, and voted overwhelmingly against approval. (The agency formally rejected the application this month.)

Wolfe is back on a panel today, part of a meeting to review post-marketing study requirements for opioids that are designed to be abuse resistant. The purpose of the meeting is to determine what standards FDA should set for demonstrating abuse resistance in the real world. (Read the preview in "The Pink Sheet" DAILY, here.)

That is a fascinating topic in itself; probably a glimpse of the future (or a potential future) for essentially all big drug classes.

But the meeting began with Rappaport pointing out an unusual late addition to the committee’s briefing materials: a copy of the warning letter FDA sent to King Pharmaceuticals in 2009, shortly after it launched the abuse-resistant product Embeda. The letter, Rappaport noted, is not the type of thing FDA typically gives to committees, but Wolfe emailed the agency yesterday to ask for it to be distributed. And so it was handed out at the meeting (even though, Rappaport stressed, it is a marketing issue and so not really relevant to a scientific discussion about post-marketing study designs).

The letter hasn't been mentioned since--but King doesn't present until tomorrow morning.

King’s management team told us in an interview earlier this year that the video news releases that prompted the warning were a mistake that it would not repeat. But—as we discussed here—it certainly sets a standard for getting off on the wrong foot with an important new product.

And Wolfe, at least, sees it as evidence that FDA cannot rely on sponsors to do things the right way when it comes to making sure new drugs are used appropriately. So far (the meeting is two days and things are just getting going), Wolfe is pushing for more of the research in the pre-market setting. That doesn't seem to be getting any traction with FDA.

Interestingly, Wolfe doesn’t seem to have asked for any materials to be shared on the other product directly affected by the ongoing meeting: Purdue’s Oxycontin. That company, of course, was prosecuted for misbranding, with the government claiming Purdue’s marketing helped contribute to the widespread abuse of the drug.

Since the entire FDA effort on abuse resistance essentially flows from the Oxycontin controversy, Wolfe apparently doesn't feel like he needs to do anything to draw that connection for the committee.

Belatacept Advisory Committee: One Sign of the Times

Bristol-Myers Squibb is, as our colleagues at "The Pink Sheet" pointed out, facing a bit of an uphill climb during today's advisory committee review of the transplant drug belatacept.

But one item in the preview materials posted by the Food & Drug Administration caught our eye as a sign of the times for advisory committees in general: FDA issued a formal conflict-of-interest waiver for Richard Mann, who heads the kidney and pancrease transplantation program at Robert Wood Johnson Medical School.

Under new rules set by the FDA Amendments Act, the agency is directed to review potential conflicts-of-interest of advisory committee members carefully, and issue waivers sparingly. (You can read more about this issue in The RPM Report, here.)

In this case, the agency wanted Mann to serve as a temporary voting member, but spotted a potential conflict: he was listed as a co-investigator on a trial involving "competing products to belatacept." The study drugs are not identified in the waiver document, but it does explain the circumstances.

Mann was listed as a co-investigator "as a matter of policy" by the medical school; he is not an active participant in the trial. In fact, he "has filed the appropratiate paperwork" to have his name removed from the study. Moreover, the size of the potential conflict is "$0-$50,000 per year."

However, FDA notes, the fact remains that his employer has an interest in competing products, and therefore Mann has an "imputed conflict of interest."

The agency considered 10 other transplant nephrologists for the committee. Four couldn't attend, one did not submit the paperwork for review, and the other five were "recused to conflicts of interest"--presumably more serious ones than Mann's.

In other words, Mann was the only transplant nephrologist available for the meeting who didn't have a direct conflict of interest. Waiver granted.

But that also means one less waiver for the agency to use later in the year. Under FDAAA, supplies of waivers are limited--essentially to a small percentage of committee members overall--so issuing this one means one fewer to use later on. And, as the standard applied to Mann shows, it will be hard to seat committees without using at least some of those precious waivers--especially for specialty products.

Fighting Like a Wolfe Against Johnson & Johnson

There are certain codes of conduct during advisory committee meetings. Come prepared having thoroughly read the briefing documents. Speak in turn. Don’t discuss the merits of the application over lunch.

Sidney Wolfe isn’t one to stand on protocol.

During the March 19 Cardiovascular-Renal Drugs Advisory Committee review of Johnson & Johnson’s anticoagulant rivaroxaban, Wolfe, the acting consumer representative, took the unusual step of calling out to an FDA drug safety reviewer—Office of Surveillance & Epidemiology associate director for science John Senior, who was sitting in the audience—to ask him point-blank the very question the committee was being asked to deliberate: whether rivaroxaban should be approved based on the available data.

It was clear from the start that Wolfe wasn't keen on a rivaroxaban approval, and he set up Senior to issue a negative opinion. Wolfe noted the divergent conclusions drawn by J&J and FDA on rivaroxaban’s liver toxicity profile, and the expectation that the drug could be used extensively off-label. Then he asked Senior: “You’ve been involved in this for some time … Do you think it is a good idea to approve now without waiting to see the results of much more data from much longer duration trials?”

The question was significant for a couple reasons. First, it demonstrated that Wolfe isn’t afraid to step outside the typical bounds of advisory committee meetings to make his point. As we’ve blogged before, Wolfe is not your average committee member, and he’s certainly no shrinking violet. And while there is no hard and fast rule against asking an FDA reviewer his or her opinion about an application, to put Senior on the spot was a bit unusual—especially since he was not part of the FDA team at the conference table.

Calling on Senior served another purpose: it was Wolfe's way of getting another public FDA opinion against the approvability of rivaroxaban. OSE was well-represented at the meeting: director Gerald Dal Pan was at the committee table, and medical officer Kate Gelperin delivered a compelling critique of rivaroxaban’s safety profile. But Senior’s reasoned evaluation of the NDA only fueled Wolfe's arguments.

Senior said that while he was “impressed” with J&J's early look of longer-term safety trials (known as the ATLAS study), “I'd like to see more.”

Senior then evoked AstraZeneca's failed anticoagulant ximelagatran (Exanta). FDA should “learn the lessons from ximelagatran,” Senior said. Exanta's heptotoxicity signal did not surface until longer-term studies were analyzed, he reminded the advisory committee. With Exanta, FDA issued a “not approvable” letter, and AstraZeneca's eventually discontinued development. Without reading much between the lines: FDA should take its time with rivaroxaban.

Senior added that only under one circumstance should rivaroxaban be approved without longer-term data: “If it can be shown that the drug is saving more lives than it is risking, then I would think reduction in mortality would trump the risk of liver injury. But I haven’t been convinced that those data are real. I think we need to see that.”

Those statements seem to sum up how FDA—or at least the drug safety office—is thinking about the NDA. As reported in “The Pink Sheet” this week, the good news for J&J is that those longer-term data are available: the six-month ATLAS study has concluded. But time is likely to run out: it is unlikely that J&J can submit the final report and FDA can review it before the late May user fee deadline.

In the end, Wolfe cast only one of two votes against approval. Sanjay Kaul, perhaps best known as the disinvited prasugrel committee member, also actively argued against rivaroxaban. Neither managed to convince the rest of the advisory committee to see things their way. But the Wolfe-Senior exchange still illustrated Wolfe's tenacity in making his point—and his savvy in understanding FDA politics. Like we said before, Wolfe is not your typical advisory committee member.

Prasugrel Backlash Doesn't Deter Kaul

Sanjay Kaul doesn’t get discouraged easily.

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

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

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

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

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

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

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

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

Whoops! Did We--and Novo--Speak Too Soon?

Did we—and Novo—speak too soon yesterday about Victoza’s chances at the FDA advisory committee next month? We reported Novo’s confidence that its GLP-1 analog liraglutide won’t be required to comply fully with the new FDA diabetes guidance issued last December.

Today, however, Takeda tells us that FDA has said its new diabetes treatment, alogliptin, will indeed be subject to the December guidance, even though it, like Victoza, was submitted earlier. It appears that Takeda will require more data, and, according to JP Morgan analysts, “this provides absolute clarity that FDA will now apply its new guidelines to all new diabetes drug applications.” Oh dear. Misplaced confidence? (Certainly Novo’s investors think so: shares were off about 3% today.)

But Novo’s position hasn’t changed. “Today is no different than yesterday,” Novo’s CMO Mads Krogsgaard Thomsen told The In Vivo Blog this afternoon. Liraglutide’s clinical trial program is more than double the size of alogliptin’s. And they’re completely different drugs: alogliptin is a DPP-IV inhibitor, a class that isn’t shown to improve blood pressure or reduce weight, as Novo claims is the case with Victoza. It’s conceivable, therefore, that FDA might hold DPP-IV inhibitors up to the new guidance—but not GLP-1 analogs, at least, not quite so strictly.

Thomsen also re-iterates that the company has done its MACE analyses (of CV events) with good results—indeed, the JP Morgan analysts appear to interpret this as Victoza actually meeting the new guidance requirements, despite the statistical powering issues (we couldn’t check as they don’t talk to journalists.)

Victoza’s other potential advantage: it’s clearly differentiated from the only other drug in its class, Lilly/Amylin's Byetta, on both efficacy and conveniece. Takeda can’t say the same.

Good for Novo. Why not hold a brave face? If one thing’s clear, though, it’s that victory next month is not a foregone conclusion. But even if Victoza does stumble—and, as one of you kindly pointed out yesterday, pancreatitis is another possible hurdle, given Byetta’s story so far, although Novo doesn’t think it will be more than a labelling issue—Novo might not mind that much (not that it would ever say so.) As mentioned, any delay would likely stall Byetta LAR, too. Which leaves Novo playing in the field where it’s strongest: insulin.

image from flikr user Mel B. used under a creative commons license

Novo Confident of Victoza Victory at FDA in May

The odds might appear to be stacked against it, but Novo Nordisk sounds remarkably confident that GLP-1 analog liraglutide (Victoza) will get approval from FDA by the end of May.

OK, so it needs to be confident: even if it is approved as expected, the once-daily drug, already about four years behind schedule, will have barely a year to make its mark before Lilly/Amylin’s once-weekly version of the incumbent GLP-1 analog Byetta hits the market in 2010.

But Novo’s up against a very diabetes-resistant FDA, with strong memories of the Avandia fallout, that has recently changed its guidelines in this disease area to require more safety data among patients at high risk of cardiovascular disease. And this, as Novo’s CMO Mads Krogsgaard Thomsen acknowledges, is “just the reverse of how we’ve recruited patients into diabetes trials in the past,” including into the liraglutide Phase III trials.

Traditionally, companies have sought to prove their drug’s safety and efficacy in relatively clean patient populations first. Given the cv signal picked up from Avandia well after that drug was approved, it’s clear why the agency has taken a more severe stand.

Among the 6000 or so patients in the liraglutide Phase III trials, very few suffered cv-related events. That’s good for those 6000, but it’s less good as far as providing sufficient statistical power to convince an edgy FDA to wave the drug through. Worse still, since Victoza’s early April advisory committee meeting is widely expected to provide the test case for the new guidance, FDA will be keen to set examples, not make exceptions.

Still, Novo’s got its defense all lined up--and its fingers crossed. For one thing, argues Thomsen, the guidance relates only to drugs that were not submitted by the time it was published, late last year. (Novo submitted liraglutide in May 2008.) There's some controversy over this, but the guidance, as Thomsen underlines, specifically appears to refer to studies in the planning stage and studies completed before submission of the NDA/BLA. (See pages 3 & 4.)

Plus, he adds, "we did not a receive any letter from FDA to say we would have to adhere to the guidelines with liraglutide, as we did for our [Phase II, not-yet-filed] once-weekly GLP-1 analog NN9535." His second point: when looking at risk factors like body weight, systolic blood pressure or biomarkers of cv events, “our data shows nothing concerning at all,” Thomsen told The IN VIVO Blog.

Sure, but FDA could always retort with: “Nor did Avandia’s. That’s the point of our guidance.” At this stage, Novo is hoping that its willingness to do a post-approval study looking specifically at cv outcomes will be enough to win the agency’s favor. “Even though the event numbers are small, we’ve done the [cv event] analyses that the agency asked for--the same ones it will now require going forward--and this convinces us at least why there’s a good case for not requiring a pre-approval study.” He goes on to say that liraglutide may even provide cv benefits.

Favorable trends aren’t enough, though. But whatever hoops Novo has to jump through, its competitors, BMS/AZ and Takeda, both with DPP-IV inhibitors currently under review and, more pertinently, Lilly/Amylin with Byetta LAR, will have to do the same. And whether Novo has to do its CV outcomes trial before or after approval, at least that data will help it make its case in the next—likely even tougher—regulatory challenge it faces with liraglutide: getting it approved for obesity.

image from flickr user samthsham used under a creative commons license.

Is Partial Agonism the Key to PPAR Success?

In case you haven't had your fill of TZD news this week, we bring you word that Dr Reddy's Labs and Rheoscience have dosed their first patient in what will be the first of several large Phase III studies of their partial PPAR gamma agonist balaglitazone.

Say what?

The timing of the trial's launch missed the Avandia circus by only a day and suggests there are companies out there willing to put in the time and money and Herculean effort to make their case for potentially differentiated products in a problematic class. Some senior industry executives think the odds are stacked against success.

Among those skeptics is Wyeth R&D chief Bob Ruffolo, who when interviewed by the IN VIVO Blog only six weeks or so ago, asked (rhetorically): "Who is going to bring a new, improved version of Avandia to market" given the regulatory mountain the FDA will surely make such a company climb?

And it's a fair question, particularly in light of the past few months' events. Let's review.

• GSK's Avandia, subject of everyone's favorite meta-analysis, though allowed to remain on the market for now, will get slapped with some stern patient- and doctor-scaring warnings. Takeda's Actos has avoided the whirlpool so far.


• The PPAR class hasn't exactly had smooth safety sailing prior to Avandia's snafu. Warner-Lambert's Rezulin kicked off the parade back in 2000 and so-called next-generation dual gamma/alpha PPAR agonists like AZ's Galida and Merck's MK-767 and Merck/BMS' Pargluva eventually followed.
  
• Clinicians and patients may be moving beyond the PPARs in any case. The RPM Report has reviewed the winners/losers: Actos may have seen a bump in the wake of the initial Avandia news, but that hasn't lasted. Merck's first-in-class DPP4 inhibitor Januvia is enjoying wild success in its first year on the market and observers are salivating over potential newcomers like Amylin's once-weekly Byetta and Novo Nordisk's liraglutide.

Nevertheless, Rheoscience presses on. If Actos is now the TZD safety standard bearer, it makes sense that to get to market now companies will have to prove their drugs as safe or safer than Takeda's (in fact, European drug regulators require such an active comparator to prove non-inferiority). Rheoscience is aiming to do just that. The first balaglitazone Phase III will be a European "six-month, double-blinded, randomized, placebo-controlled multicenter trial in which type 2 diabetes patients will be given daily doses of either 10 or 20 mg of balaglitazone versus the active comparator Actos (45mg/day) as an add on to stable insulin treatment," according to Rheoscience.

Our interest piqued, we got in touch with Rheoscience CEO Philip Just Larsen, MD, PhD. (For background on Rheoscience, check out our 2004 profile of the company.) Rheoscience's September 2005 deal with Dr. Reddy's got the Danish biopharma company European and Chinese rights to balaglitazone in exchange for taking responsibility for execution and costs associated with the drug's US/EU Phase III program and US regulatory submission (Rheoscience will also receive an undisclosed milestone payment if an NDA is approved and undisclosed royalties on US sales). Novo Nordisk once held rights to the drug, but returned them to Dr Reddy's in 2004, back when dual PPARs were still expected to dominate the class, says Larsen.

Larsen stresses the benefits of balaglitazone's partial gamma agonist properties. "It doesn't take full agonism for full glycemic control," he argues, pointing out that Phase II studies of the drug as well as preclinical models suggest that 20mg of balaglitazone is comparable to 45mg of Actos in that regard.

What's more, he says, balaglitazone shouldn't raise the same safety concerns as other TZDs, since in vitro models and preclinical trials suggest it causes less fluid retention than Avandia and Actos and is less adipogenic than those drugs. The second Phase III trial for the drug is an international long-ranging study to generate a safety database; again that trial will use Actos as a comparator, but Larsen says he doesn't expect either drug to generate the same cardiac ischemia safety signals that have plagued Avandia.

"It's worth emphasizing that it's not the class as such that is under suspicion for inducing cardiac ischemia," he says. "Actos is not associated with cardiac ischemia," a notion backed by FDA's David Graham during Avandia's recent panel meeting, he says.

Nevertheless the series of trials required to get balaglitazone onto the European and US markets will be very costly (Larsen declines to say exactly how costly). Patients and clinicians may be wary of TZDs and hamper trial enrollment (a suggestion Larsen disputes, particularly in terms of European patient accrual). The future of diabetes treatment may indeed by combination therapy, but whether or not TZDs are a mainstay of those combos remains to be seen as newer drugs like the GLP-1s make progress. The regulatory environment--for all drugs, it sometimes seems--is increasingly tricky. Larsen remains optimistic.

"I'm not worried about the regulatory environment. The advisory panel was in favor of drugs in this class, they're a necessary tool in the toolbox," he says. "Treating diabetics is a challenge and by limiting the options you put yourself in a difficult position, and these [TZD] products are quite efficacious."

As for the class' past failures, he points out that "the entire concept of pursuing the dual agonists was a blind alley, and it took those Phase III trials to show that is the case. That is how the selective PPAR agonists like balaglitazone were revitalized," and now shown that pursuing partial agonism could control the side effects related to full agonists like Avandia.

Rheoscience and Dr. Reddy's have competition. A second partial-PPAR gamma agonist in late stage trials belongs to Metabolex and Johnson & Johnson (we wrote about their innovative deal last summer). But don't expect any winners for quite some time. Balaglitazone's NDA won't be filed before late 2009 at the earliest.

FDA Advisory Committee Votes to Keep Avandia on the Market

FDA's joint advisory committee voted (22-1) to keep GlaxoSmithKline's diabetes drug Avandia on the market with a black box warning for patients at higher cardiovascular risk. All the votes came with the caveat for stronger warnings.

But they voted 20-3 that Avandia increases the cardiac ischemic risk in type 2 diabetes. What an odd vote.

We don't think it means very much and that Avandia, for all intents and purposes, is dead. See our previous post below. What do you all think?

The Nail in the Coffin on Avandia

It doesn't matter what the committee votes now.

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

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

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

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

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

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

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

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

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

Avandia and Rezulin: Parallels that Should Make GSK Nervous

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Evista Update

Lilly's response to my questions about the Evista press release (subject of a July 25 post):

"Following the July 24 meeting of the Oncologic Drugs Advisory Committee (ODAC), Lilly issued a press release containing factual information about the meeting’s outcome pertaining to Lilly’s osteoporosis drug.

'We believe that our actions were consistent with the laws and the consent decree,' said Anne Nobles, Vice President, Compliance and Enterprise Risk Management. 'Lilly takes very seriously our responsibility to abide by all the laws governing our business practices and are committed to ensuring our employees' actions reflect the highest legal and ethical standards of conduct.'"

Even Cancer Ain't Exempt

No drug is exempt from FDA’s ultra-conservative stand, it seems, even those, like GPC Biotech’s satraplatin (Orplatna), that allegedly improve survival among cancer patients with few if any treatment alternatives.

An oncology advisory committee (ODAC) yesterday recommended that FDA delay considering prostate cancer candidate satraplatin for approval until overall survival data from the company’s 950-patient SPARC study is available. This recommendation came despite interim analysis strongly supporting the efficacy and safety of satraplatin, which was granted priority FDA review in April 2007.

Still, it wasn’t a complete surprise, at least since the rather negative FDA briefing documents released last week. These raised five “issues” including questions over the company’s assessment of pain progression, and, more importantly, over the definition and composition of one of GPC’s two key primary end-points used in the trial, progression free survival (PFS).

According to GPC’s “greatly disappointed” CEO Bernd Seizinger, GPC had communicated intensively with FDA throughout the application process and amended various aspects of the trials in accordance with FDA suggestions—including suggestions on what pain score to use. In sum, they’d done everything possible to make this work. (Listen for yourselves here.)

But FDA wasn’t having it. According to one analyst, “GPC walked into a complete stitch-up—FDA primed the advisory committee that they didn’t want this to happen.” Reading the briefing document, we’re inclined to agree.

Now, sources tell IN VIVO Blog that there’s no love lost between GPC and FDA—the ODAC meeting was “hostile and antagonistic,” according to one observer. Combine this with FDA’s overall caution (the last thing they want is to be hauled in front of the Senate for injudicious approvals) and you have a recipe for delay, if only temporary.

Still, GPC isn’t just an innocent victim here. Let’s go back to that issue of end-points. The briefing documents state that FDA had all along warned GPC that a PFS end-point may be problematic. Yet GPC failed to communicate this concern to the investment community.

That’s why analysts are so pissed—many had buy ratings on the stock, even after the review documents were released last Thursday. GPC shares fell 35% back then, and about the same again today. “Trust has been lost,” says one in London. “When it comes to the investment community, GPC are on their own.” (They can sulk in a corner beside Sanofi Aventis, which hasn't won any prizes for transparency among the investment community either, particularly with regard to Zimulti's rocky ride, on which we've reported extensively, including here.)

It’s a worrying time for the German biotech. All of a sudden, the overall survival data for satraplatin—which is the other primary end-point, alongside PFS--has become a make-or-break issue for the company. If it’s positive, the drug will probably still make it, although not in an accelerated fashion. If it’s not, the drug may not get onto the US market at all—which could prove fatal for GPC.

The rest of the sector has cause for concern, too, though (not to mention androgen-independent prostate cancer patients that have failed first-line therapy). This bleak little episode—besides showing up personal clashes between applicants and the agency, which, it seems, do matter—may mean that regulators’ caution is spreading beyond primary-care drugs like Avandia or the Cox-2s, where the main concern is safety.

Today, it seems, the tough hurdles can come from anywhere--including from non-safety-related issues like how pain is measured. Some might call this nit-picking.

Lilly’s Evista for Breast Cancer Prevention: Vindication or Provocation?

It looks like Eli Lilly & Co.’s raloxifene Evista is poised for approval for reduction of the risk of breast cancer. A Food & Drug Administration advisory committee voted yesterday to support use of the drug for that use in post-menopausal women at high risk of breast cancer, and—more narrowly—to support use for breast cancer prevention in post-menopausal women with osteoporosis.

The agency itself has until September to make a decision on Lilly’s pending supplemental FDA. But all signs point to an approval that, whatever else it means, will feel like vindication for Lilly.

Just 18 months ago, the company paid $36 million to settle an investigation into its promotion of Evista. The drug has been approved for use in osteoporosis for a decade. But in 2005 Lilly pled guilty to a criminal misdemeanor charge that it promoted the drug for breast cancer prevention and cardiovascular risk reduction. The conduct involved occurred in 1998; the company simultaneously settled related civil claims dealing with conduct that continued into 2000, but Lilly did not admit guilt.

In addition to paying the fine, Lilly entered into a consent decree prohibiting it from promoting Evista for breast cancer prevention without formal FDA approval.

Not that you would know that from reading Lilly’s press release announcing the advisory committee vote. Underneath a headline announcing the advisory committee vote, Lilly includes what starts out sounding like a disclaimer but ends up sounding like a claim of effectiveness for the new use: “EVISTA is currently indicated for the prevention and treatment of osteoporosis and may provide an important option for postmenopausal women at increased risk for breast cancer.”

Now that sentence is surely unobjectionable on its face. But it definitely counts as bold talk from a company that just signed a court order saying it is “permanently enjoined from directly or indirectly promoting Evista for use in preventing or reducing the risk of breast cancer…unless and until it is authorized to do so by the FDA by the approval of a supplement to the New Drug Application for Evista.”

Especially when you consider that the DoJ investigation included, among other allegations, claims that Lilly promoted the off-label use through its press releases about Evista. (Read the Justice Department’s summary of Lilly’s conduct here.)

Of course, the consent decree includes other provisions, notably one stating that “nothing in this Decree shall be construed to limit or expand the rights of Eli Lilly under the First Amendment of the Constitution.”

When it comes to off-label promotion, that is precisely the question: what are the rights of drug companies like Eli Lilly under the Constitution? Free speech advocates argue that companies have the right to engage in scientific discourse about their products, even if they are talking about uses not approved by FDA. After all, if raloxifene works to prevent breast cancer, millions of women would benefit from knowing that as soon as possible.

Prosecutors see it differently: the FD&C Act prohibits promotion of unapproved uses of drugs, and they have gone after many companies for promoting their drugs beyond the label. There have been several recent settlements (with the Evista case one of the first) in which manufacturers have accepted that premise—explicitly or implicitly—rather than fight the charges in court.

In our next issue, The RPM Report will be taking an in-depth look at the current state of uncertainty in industry after the recent wave of settlements.

As the advisory committee vote indicates, Lilly’s statement that Evista “may be an important option for post-menopausal women at increased risk for breast cancer” is undeniably true. But it was undeniably true a decade ago too. And that didn't keep Lilly out of trouble.

Now, here’s a thought: Johnson & Johnson made headlines recently when it offered a money back guarantee to the UK National Health Service on its cancer therapy Velcade, promising to pay back the government if the therapy doesn’t prove cost effective.

Maybe Eli Lilly & Co. should take a page from that playbook. But instead of offering a refund to the US government, maybe Lilly should ask for its money back from the Department of Justice. Justice.

Rimonabant’s Risky Business

You know a weight loss drug doesn’t stand a chance when even morbidly obese patients are afraid to take it.

During the highly anticipated review of Sanofi-Aventis’ rimonabant by FDA’s Endocrine and Metabolic Drugs Advisory Committee yesterday, Lynn McAfee, the director of medical advocacy at the Council on Size & Weight Discrimination, told committee members that rimonabant was far too dangerous a drug to be allowed on the US market.

“This is a very scary drug,” she told the committee. “I lived through Redux and fen-phen and the calls in the middle of the night from dying people. Nobody wants to live through that again.”

Yikes. That’s a pretty damning statement from a group of people who are so desperate for weight-loss options that they spend nearly a $1 billion a year on dietary supplements—products that never cross the desk of an FDA medical reviewer.

But let’s be serious. As the IN VIVO Blog made clear in an earlier post, when a drug is linked not only to depression and suicidiality, but also a litany of neurological adverse events like seizures and multiple sclerosis, you don’t exactly have a slam-dunk on your hands. And did I mention the 50% chance of losing just 5% of your body weight?

So it should have come as no surprise that the advisory committee voted unanimously against approval. Frankly, the only folks that might have expected a different outcome were from Sanofi-Aventis—a company not exactly known for its sophisticated dealings with FDA. It’s common for a drug sponsor to become so invested in a drug that they can’t see the forest through the trees. But on rimonabant, Sanofi is in a totally different place—like la-la land.

That said, as far as advisory committee management is concerned, Sanofi did a surprisingly good job at trying to convince members that rimonabant deserved their seal of approval. Executives stressed no fewer than a half-dozen times that rimonabant was not for everyone, and totally inappropriate for those that have had or currently have psychiatric problems. And they proposed a pretty decent risk management program, including a controlled launch while they worked out the kinks.

But in the end, there’s only so much you can do with a risky drug. And rimonabant, unfortunately for all those obese patients out there, is a really risky drug.

Fat Chance for Rimonabant

Tomorrow is a big day for Sanofi-Aventis’ fat-buster rimonabant. FDA’s Endocrine and Metabolic Drugs Advisory Committee will scrutinize whether the drug’s beneficial effects on weight, triglyceride levels and cholesterol outweigh its side-effects, most significantly depression and suicidal thoughts.

The odds don’t look good for Sanofi. The timing is terrible—this review comes amid huge political controversy over FDA’s role in assessing drug safety, inflamed most recently by the cardio-vascular concerns raised around another drug the endocrinologist experts know well: GlaxoSmithKline’s diabetes drug rosiglitazone (Avandia).

What’s more, Sanofi hasn’t been known for its smooth relations with FDA; nor, say analysts, was it fast to get endocrinologists on its side. The French group is said to have cosied up early on in its rimonabant campaign primarily to the cardiovascular experts it knew already through anti-platelet drug Plavix. (Don’t forget that rimonabant, an cannabinoid receptor antagonist, is one of these multi-faceted treatments that act on a number of pathways, making it both incredibly effective in addressing metabolic disease, says Sanofi, but also incredibly dangerous in terms of unknown or unwanted side-effects, say detractors.)

Small wonder, perhaps, that the FDA review document released yesterday has no qualms about washing rimonabant’s dirty linen in public. The document highlights a statistically significant increase in suicidal thoughts and behavior, a high drop-out rate in the rimonabant trials, in part due to depression side-effects, and reels off various neurological side-effects seen with greater frequency in patients taking rimonabant.

Now granted, the drug is already approved in Europe, as Acomplia, although Sanofi still faces marketing and reimbursement challenges (many European countries consider obesity treatments as life-style medications; a convenient excuse to avoid huge payouts). So won’t six-months’ worth of post-approval data from over 78,000 European patients help reassure the US gate-keeper?

Seems not. The FDA document lists over 2300 cases of adverse reactions in the UK and Germany, “frequent” reports of nervous system disorders “driven predominantly by dizziness”, and describes in detail a handful of individual cases including a man who attempted to strangle his daughter, and another who beat his wife while on rimonabant.

This degree of detail may very well be standard Advisory Committee meeting practice. The experts will know to consider these adverse events in the light of the thousands of patients using and potentially benefiting from the drug.

But rimonabant’s path to the US market has already been bumpy. Its sponsor’s ambition has been heavily clipped by US regulators: Sanofi submitted its NDA in May 2005 for three indications besides weight management (Type II diabetes, dislipidemia and metabolic syndrome), none of which were approved. Even for the obesity indication, FDA in February 2006 requested additional data—you guessed it, on adverse events. Even the Advisory Committee meeting was hurled at rimonabant at the last minute: back in 2006, it wasn't considered necessary. Not to mention the FDA's requested name-change: just to make life a little more challenging still for Sanofi, rimonabant will be known as Zimulti in the US.

If it gets there.

A June Wedding for Bristol/Sanofi?

Something tells me that talk of a potential acquisition of Bristol-Myers Squibb by Sanofi Aventis will heat up again in exactly one month.

The on again/off again speculation about a merger of the Plavix partners is decidedly off at the moment. And yes, yes, I know that my fellow IN VIVO bloggers think that Bristol's deals with AstraZeneca and Pfizer will make a Sanofi bid economically dumb. But two events coming up in mid-June could spur some desperate action.

For Richer, For Poorer

On June 15, BMS expects to be officially released from the terms of a deferred prosecution agreement it signed two years ago. The DPA has been the sword of Damocles hanging over Bristol, making it essentially untouchable for would-be-suitors—especially once Bristol ran into further trouble with its spectacularly misguided attempt to settle patent litigation over Plavix.

Bristol has now agreed to settle charges arising from that debacle—and says it has been assured that the deferred prosecution agreement will be released on schedule as long as it stays out of trouble between now and June 15. (That seems easy enough, but given Bristol’s history, its probably best not to count the chickens just yet…)

And, since “interim” CEO Jim Cornelius pulled off a Dick Cheney style CEO search—ending with himself as the new CEO—there is no reason to assume that Bristol is committed to independence for the long run.

But the real impetus for renewed speculation will probably come two days before June 15, when Sanofi Aventis’ much touted obesity therapy rimonabant goes up before an FDA advisory committee.

Sanofi insists the meeting is a good news event for the troubled application. Maybe. But given the company’s misreadings of FDA so far, Sanofi’s optimism probably shouldn’t inspire too much confidence. I think Kate Rawson has it right in the May issue of The RPM Report: Sanofi will be lucky if the drug gets even a strong minority support from the committee.

This does not seem to be a good time to take a big drug before an FDA advisory panel. Especially one with a safety signal. Perhaps most especially one with a safety signal (in this case depression) that dovetails with a major focus of congressional scrutiny. Did you see what happened to Arcoxia?

If rimonabant suffers a similar setback before the committee, Sanofi will be under even more pressure to make another move. So expect the merger speculation to heat up just before summer arrives.