Professional Egos, Cultural Norms Clash At Xarelto AdComm

Let’s be honest – we look forward to some FDA advisory committee meetings more than others. Some meetings, such as those convened only because a product is a new molecular entity but with no controversial safety or efficacy issues attached, can be a bit of a yawn from a newsgathering perspective.

Give us a drug that has hit some regulatory bumps in a hot and highly lucrative therapeutic area, and it raises our journalistic antenna.

So, when we saw the FDA staff’s strongly negative review of the atrial fibrillation claim for Bayer/J&J’s Xarelto (rivaroxaban) – a review that went so far as to recommend a “complete response” action – we knew we were in for an interesting meeting of the agency’s cardio-renal committee on Sept. 8.

Couple that with the revelation that there were going to be some big names participating in the proceedings (Rob Califf! Steve Nissen! Sanjay Kaul! Tom Fleming! – none of whom could be accused of being afraid to share their views on a subject), we were practically salivating.

Our giddiness was further heightened when we saw FDA’s draft questions, which spanned six pages. FDA wanted to know whether rivaroxaban’s efficacy was appropriately studied against warfarin in the ROCKET AF trial, or whether the drug’s efficacy is best viewed against that of Pradaxa (dabigatran), Boehringer Ingelheim’s oral direct thrombin inhibitor that was approved last October.

Most of the committee members – and FDA’s cardiology guru himself, ODE I Director Bob Temple – were pretty clear in their views that the Xarelto sponsors shouldn’t be required to show rivaroxaban’s efficacy against that of another drug on the market for less than a year. (This week’s issue of “The Pink Sheet” offers in-depth analysis of how FDA might continue to use its “as effective” standard.)

Thanks to these views, drug developers appear to have escaped the potential calamity of having to go back to the drawing board to compare their late-stage compounds to the newest kid on the block for FDA approval. (Reimbursement is another story, but we digress.)

Nonetheless, the discussion over the appropriate comparator for rivaroxaban raised the lingering problem of how well clinical trials mimic real world use when it comes to establishing efficacy against another drug, and whether it’s wise to attempt to mimic actual medical practice when that offers a comparison that is far from ideal.

While warfarin may be the appropriate comparator in the eyes of most committee members and top FDA brass, a debate over how well warfarin is used in clinical practice and in the ROCKET AF trial led to a clash of egos and a lesson in cultural norms at the meeting.

One key issue before the committee was how well anticoagulation control with warfarin was managed in ROCKET AF, as gauged by International Normalized Ratio time in therapeutic range (TTR).

In their briefing documents, FDA reviewers took the ROCKET AF investigators to task for what they considered to be the less than “skillful” use of warfarin when compared to other anticoagulant studies.

The mean time in TTR was 55% across the ROCKET AF program, compared with 64% for dabigatran’s pivotal RE-LY trial. The lower TTR in ROCKET so distressed the agency reviewers that they used the word “skillfully” 16 times in their briefing document as they sought to drive home the point that it is difficult to ascertain rivaroxaban’s true efficacy when compared against warfarin that is well managed.

But some in the meeting room didn’t take too kindly to FDA’s characterization of unskillful use of a drug that has been a standard of care for stroke prevention in atrial fibrillation patients for years.

Duke University Vice Chancellor of Clinical Research Robert Califf, appearing on behalf of the sponsors and the study’s executive committee, maintained that the average TTR of 64% for North America was better than U.S. practice in general and comparable to the North American results in other anticoagulant studies.

“This is hardly a result that should be attributed to unskillful clinicians,” Califf said. “I have to say on behalf of the executive committee and over 1,000 investigators, we don’t think we’re unskilled. We think we’re pretty good.”

Califf maintained that the lower overall mean TTR in ROCKET AF was due in large part to the geographical diversity of the study population and the inclusion of patients at higher risk of stroke than in other anticoagulant trials. More than 38% of the patients were enrolled in Eastern Europe, where TTR was 49.7%. Another 15% came from the Asia-Pacific region, where TTR was only slightly better, 52.4%, according to FDA’s calculations.

Regional variations in how quickly patients were brought back for INR assessment resulted in an “artificial” lowering of TTRs in areas where there was a longer delay, such as in Asia-Pacific and Eastern Europe, Califf said.

Warfarin dosing was managed at each site according to local standards, and there was no centralized protocol for managing patients who fell outside of therapeutic range. Site investigators were educated on the importance of keeping INR within the 2.0-3.0 target range.

The geographical distribution of patients, coupled with the absence of a single warfarin dosing protocol, touched off one of the more interesting debates of the day between Califf and Cleveland Clinic’s Steven Nissen, a temporary voting member on the panel.

“Given the fact that I think you guys knew that the TTR was going to be a critical factor in the approvability of the drug, I’m just puzzled why you didn’t make an effort to give sites, particularly Third World sites, some guidance about what to do,” Nissen said to the sponsors. “Basically, you sort of left them on their own, and my concern is that’s why you got such a low TTR” across the ROCKET AF study.

At this point, Califf embarked on a lesson in global diplomacy.

“Dr. Nissen I’m sure you didn’t mean to use the term Third World, because I don’t think that’s an appropriate term anymore, and in fact if you look at the news today you would find what you’re calling Third World actually owns most of our national debt,” said Califf, whose remarks were met with laughter in the room.

“I think the investigators around the world will be highly offended by the sort of American exceptional tone of some of the discussion, not you personally, but – ”

At this point, Michael Lincoff, Nissen’s colleague at Cleveland Clinic and acting chairman of the committee, attempted to redirect the discussion away from geopolitical issues and back to anticoagulants.

“Let’s focus on the subject,” Lincoff said, before he was cut off by Nissen.

“Rob, you showed us that those sites in those countries didn’t do a very good job of managing warfarin. That’s where all this comes from,” Nissen said to Califf.

“But these two concepts are related,” Califf responded. “It’s not that doctors do a lousy job. This is a really hard drug to use and it’s especially really hard to use in various social, economic personality characteristic circumstances. You know that as well as I do.”

“What we felt obligated to do was to do better than standard of practice given the heterogeneity of the practices in those centers,” Califf said. “We spent a lot of time at every site saying how do you do it? Let’s make sure what you’re doing is OK, but let’s not force you to use one specified algorithm. Let’s make sure you make the appropriate dosing changes. I showed you that it wasn’t that they weren’t making the appropriate dosing changes. They just brought the patients back when it was feasible to do it.”

With the sparring over lesser developed countries behind them, the committee continued with its questions and discussion, though later in the meeting other panel members felt the need to weigh in on the skillfulness issue.

TTR is “certainly a marker of skillful care” but is not an effect modifier, Cedars-Sinai cardiologist Sanjay Kaul maintained.

Yet, fellow panel member and cardiologist Darren McGuire, University of Texas Southwestern Medical Center, was quick to take offense. McGuire conceded the TTR rate at his institution is only about 54%, but he noted that numerous patient level characteristics, and not the treatment provided by a given physician, play a role in how well TTR is maintained.

“I will agree with Dr. Califf’s comment earlier. I take some offense at the term unskillful use, because it’s a little bit accusatory and it’s a complicated therapeutic strategy.”

Some committee members said they appreciated the lack of a standardized dosing protocol in ROCKET AF because it more closely mirrored how warfarin is used in clinical practice, which is imperfectly.

The issue of how well INR was maintained came up in the advisory committee review of Pradaxa as well. Boehringer was lauded for the level of control achieved for warfarin in RE-LY, which had an open-label design for that reason (though the trial design also drew criticism). But the INR variability also kept FDA from granting an outright superiority claim; the agency included cautionary language in labeling noting that the benefit was driven by centers where INR control was poor.

The back and forth at Xarelto review begs the question of whether better data is gained by mimicking real world use, though it may mean imperfect use of a standard of care, or if tightly controlled trial practice is a better comparator for convincingly demonstrating efficacy in the minds of regulators and payers.

While answers may not be quickly or easily forthcoming, it’s an issue that other anticoagulant sponsors should be prepared to address.

– Sue Sutter

Photo, "Triplets of Cap Hill," by Flikr user daniel spils, reproduced under Creative Commons license

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

Lilly Prasugrel Delay Could Extend Well Into 2009

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

RFP: Raise Temple's HDL

HDL-raising is a damaged surrogate. Or at least that's what FDA's Office of Medical Policy director Bob Temple says. And that should give some pause to any companies in the business of developing drugs to raise high-density lipoproteins or those making investments in those companies.

It's not that this class is dead in the water; FDA would love to see a major advancement in this area. But the burden of proof will be much higher and take longer compared to other classes of drugs.

Pfizer's investigational HDL-raising drug torcetrapib was supposed to be the next Lipitor and then some. But torcetrapib, which acts by inhibiting cholesterylester transfer protein (CETP), wound up getting scrapped because of too many deaths observed in clinical trials. That result cast a pall on the entire class.

Torcetrapib hasn't stopped other companies on betting that HDL-raising will be the next big thing. Merck is working on an HDL drug. Cerenis Therapeutics, founded by ex-Esperion executives, raised 25 million and 41 million Euros in 2005 and 2006, respectively, in its first two venture rounds. Cerenis, however, is investigating HDL drugs outside of CETP inhibition.

Pfizer, Roche and Resverlogix are all keeping their HDL hopes alive, looking at Apo-a-1, a major protein component of HDL in plasma.

So drug development in HDL is still alive and well. But FDA will want to see outcomes and long-term data.

Below is an excerpt from a roundtable discussion with FDA Office of New Drug director John Jenkins, Office of Surveillance and Epidemiology director Gerald Dal Pan and Temple (to see the full interview, click here for Part I and here for Part II).

The RPM Report: So low-density lipoprotein, LDL-lowering, you don’t need an outcomes study but if it were something else, you would ask for outcomes data?

Temple: It depends on what it is. If it were triglycerides, I don’t want to speak for that division—I don’t know what their decision on that is—but everyone is nervous about HDL because of the results of the single drug, torcetrapib.

The RPM Report: You discussed torcetrapib. Was this a drug you all were excited about?

Temple: Well, I was excited, my HDL is 30. I was looking forward to it. I was very disappointed.

Jenkins: I think that’s an example of an area where we might not have been excited about that particular drug but the idea of having drugs that can specifically raise HDL and hoping that would lead to a cardiovascular benefit, I’m sure there was a lot of surprise and disappointment internally and externally when that drug failed.

It’s important to distinguish between a torcetrapib finding and is that true of any drug that raises HDL? We don’t know that yet. But having laid that down as the first case, you’re probably going to want to see some good data before you start accepting that as a surrogate. That would require longer-term data before approval.

Temple: It’s a damaged surrogate.

Jenkins: It went against what everyone would have thought. Although I think the epidemiologic data haven’t been as strong for HDL-raising as they have been for LDL-lowering. Now you’ve got torcetrapib and it’s hard to ignore that finding, but it could be a drug-specific finding that other drugs that raise HDL may actually prove to be beneficial.

Temple: There were reasons to hope. For example, some of the LDL-lowering drugs in relatively normal people only worked in people whose HDL was low. So there were reasons to hope. I think everyone was quite surprised.

Temple and Comparative Effectiveness Standards Revisited

We told you to pay attention to the case of Vanda Pharmaceuticals.

To read our story, click here.

We haven’t changed our minds on the importance of FDA’s decision to reject the company’s atypical antipsychotic iloperidone and some of the regulatory and policy issues it brings to the fore.

We quoted comments from FDA’s Bob Temple at a July 30 Institute of Medicine meeting on evidence-based medicine. Temple heads up the office which regulates psychopharmacologic drugs and also serves as director of FDA’s Office of Medical Policy.

At the meeting, Temple said this:

“We have taken a couple of steps that I think are interesting. We’ve turned down new antipsychotic drugs because they didn’t seem as effective as the available therapy. I can’t remember if that ever happened before or whether we didn’t have the [courage] but we did. We decided that it wasn’t good if you’re an acute schizophrenic in the middle of an episode to be treated poorly.”

Our story has generated a number of comments, but we thought you’d be most interested in this one from Temple himself, who says we didn’t get it exactly right when analyzing his remarks at the meeting.

“Some of what I said is misinterpreted,” Temple said in an email. “At the IOM, I was explaining what I perceive drug companies to be perceiving and doing, not describing an FDA standard. That is what I was referring to when I said that ‘It’s getting harder to develop the third, fourth, fifth, and sixth member of a class of drugs because when there’s a generic available [within a class], people are inclined to use the cheap one.”

Our mistake. We thought we communicated that but after re-reading our story, it was confusing. Here’s the rest of Temple’s comments in their entirety. When Temple speaks, we always pay attention.

Temple: “Your next sentence said that comparative randomized studies ‘are the best, and maybe only, way to get drugs through FDA.’ That interpretation and conclusion are incorrect, and surprising, as your next sentence seems to recognize the commercial aspect of what I was saying: ‘To get anyone interested in the next member, you almost need to have some sort of advantage.’

It seems apparent that in my statement I was referring to my impression of what companies are doing to have a commercially viable product when there is a generic available for the drug class, and was not referring to any FDA requirement. In most settings, especially for symptomatic treatments, we do not get or ask for comparative data and are perfectly willing to approve a drug that is shown effective.

I did then go on to say that for antipsychotics (not naming a particular drug) we have rejected drugs that seemed clearly inferior to standard treatment because leaving someone with schizophrenia inadequately treated (which can take weeks to recognize) represents a risk. This is not so novel a position. We ask that new antibiotics, new anti-cancer drugs, new drugs intended to save lives or prevent bad outcomes (stroke, heart attack) have effects close to standard treatment for the same reason - importantly decreased effectiveness is not safe. We had not seen examples of anti-psychotic drugs that were markedly less effective than standard therapy; so I’m not sure you can really say that there's a new higher threshold.”

When looking at Vanda’s iloperidone, we still think there’s little room for negotiation on whether the company will have to do a head-to-head study against Risperdal. The company will have to decide whether it’s worth the money—and risk.