Waiting on Prasugrel: No News is Good News

Another NDA, another missed deadline.

This time around, it’s a product upon which Eli Lilly has hung much of its future, the anti-clotting drug prasugrel (Effient).

Lilly has already been on a rollercoaster ride on Wall Street over prasugrel once the risks associated with the drug surfaced (32% increased chance of bleeding). And time is not on Lilly’s side: the company is racing to establish the drug on the market before 2011, when Plavix generics will complicate the anti-clotting landscape.

Prasugrel has also been closely watched as another sign of how FDA will use its new risk management authorities under the FDA Amendments Act. The billion-dollar questions: would FDA agree that the bleeding risk associated with prasugrel could be appropriately managed by a REMS, or is more needed for approval? And is there any chance for a relatively clean label?

All that makes prasugrel the closest-watched drug approval this year. Indeed, between the September 26 prasugrel user fee deadline and the Wall Street bailout agreement, there were more than a few investors who were constantly refreshing their computer screens as Friday wore on.

While a bailout deal may be at hand, we’ll have to wait a little longer to find out about the fate of prasugrel. For now, Lilly’s not talking, except to say—in a press release that crossed the wires at 5 pm on Friday—that FDA would miss the deadline, that the review is “very far along,” and that Lilly “remains optimistic” that an approval is imminent.

Wall Street’s immediate reaction was not positive—the announcement drove Lilly shares down 3.9% to $45.01 in after-hours trading, and shares opened lower this morning. Les Funtleyder at Miller Tabak expressed his frustration in a research note: “This has become a bit of an unsettling trend at the FDA. The decision tree used to be pass or fail, now there is a third column, the ‘I don't know.’” (Hat tip to CNBC).

We think that pessimism is misplaced.

We told you three months ago why we think FDA will approve prasugrel, and that reasoning hasn’t changed. Indeed, the fact that the agency missed the user fee deadline bodes even better for the drug’s prospects, because it indicates—barring any last-minute surprises—that an approval is close at hand.

Here’s why: Since FDA’s drug review divisions were given the green light to start missing deadlines, most of the applications delayed by workload issues were eventually approved within weeks, based on a recent analysis in The RPM Report. (If you don’t already subscribe, you can sign up for a 30-day trial to access the story.)

For one recent example, look no further than Amgen’s Nplate, which cleared FDA a little over two months after the user fee deadline. GlaxoSmithKline’s Entereg was approved 10 days late. UCB Pharma’s Cimzia was three weeks late. And there are other examples of how small allowances for heavier workloads at FDA have led to product approvals.

There are many reasons for a missed deadline, and some (like finding enough members to staff an advisory committee) have led to months-long delays for new products. But that’s doesn’t appear to be the case with prasugrel: “This is a very large, complex submission, and it should not be surprising that delays occur,” Lilly said.

Given the much-ballyhooed size of that NDA package, perhaps it’s not surprising that it would take FDA extra (and then some more) time to read through it. The absence of an advisory committee meeting for prasugrel is also a positive sign, given that drugs without one have a greater chance for a first cycle reviews.

Sanford Bernstein analyst Tim Anderson agrees that no news is good news: “Our best guess at this point is that while the Effient review is not yet complete, a final decision by FDA is not likely to require that LLY/Daiichi-Sankyo generate new clinical data; the issue may be a smaller one like finessing the label, the risk management plan, etc.”

We couldn’t agree more.

FDA User Fee Deadlines: Jenkins Expands On Interview Comments

In a roundtable interview with top FDA drug officials, Office of New Drugs director John Jenkins said FDA was on track to meet 80%-90% of its prescription drug user fee act (PDUFA) goals. To read Part I and Part II of the roundtable interviews, click here and here.

Jenkins wrote in to clarify and expand on his comments related to user fee deadlines:

“In our recent interview with Ramsey Baghdadi and The RPM Report I made some comments about the status of our current performance in meeting PDUFA goal dates. Those comments have been widely reported and I feel that I need to alert readers to a clarification since I may have misspoke during the interview since I did not have the data in front of me and was working from memory.

What I should have said is the following:

For the FY07 cohort of applications (as of June 30, 2008, which is the most recent update I have and the one I was referring to when we did the interview) our actual performance on application goals is generally in the 80-90% range. For the same cohort for procedural and processing goals our performance is also generally between 80-90%. The FY07 cohort is mature enough to draw firm conclusions regarding performance.

For the FY08 cohort of applications, the numbers are very preliminary since many of the applications in this cohort have not yet achieved their first PDUFA goal date. Our potential performance for application goals and procedural and processing goals ranges from 80-90%. The actual performance to date (as of June 30, 2008) is below these levels in many areas, but the data are so immature that it is too early to make comments on actual performance. In the interview I was referring to potential performance, but I did not make that clear. It is possible that our actual performance for FY08 will be below the 80-90% potential performance level in some areas, but it’s too early to say.”

For Amgen's Nplate, No News is Good News

In case you didn’t have it circled on your calendar, July 23 was the user fee deadline for Amgen’s romiplostim (Nplate). And according to Amgen, FDA didn’t pick up the phone yesterday with a final answer on the platelet drug.

Without delving into specifics, Amgen says it was told by FDA that the agency will miss Nplate’s Prescription Drug User Fee Act deadline. The company says it is “optimistic that a final decision will be made soon,” but wouldn't speculate on exactly when the agency will be making an approval decision.

Maybe Amgen won’t speculate, but we will. We think the delay is actually good news for Nplate, and signals that—barring any last-minute surprises—an approval is just around the corner.

Simply put, if FDA weren’t pretty confident of the approvability of Nplate, it would have issued an “approvable” letter outlining its concerns with the BLA. Amgen would need to address FDA’s questions, submit a response and wait to hear back. (We should note that starting August 11, FDA will start sending "complete response" letters for all rejections.)

In this case, the review group is taking advantage of a new policy giving them the discretion to miss PDUFA deadlines. And it is fairly easy to see why the final review might take a bit longer than expected: Nplate will have a mandatory Risk Evaluation & Mitigation Strategy, or REMS, a new feature of the regulatory process created by legislation enacted last year. FDA is setting precedents with every REMS, and the agency has already extended or missed several deadlines for products covered by that authority.

There is a major caveat: when it comes to drug time lines, industry is treading in somewhat unknown territory these days. So while past history would suggest that a missed deadline would mean that approval is imminent, there is always a chance that the agency will let the application hang for a while.

That is certainly happening with FDA’s Cardio-Renal division, which has missed user fee dates for at least three NMEs this year: two anti-arrhythmics—Cardiome/Astellas’ vernakalant (Kynapid) and Solvay’s tedisamil (Pulzium)—and The Medicines Company’s clevidipine (Cleviprex) for acute hypertension.

But the oncology group has no history of letting applications linger. Quite the opposite: FDA doesn't always approve applications for cancer and related therapies, but it almost always acts quickly.

One thing is clear: as last week's slip-up by Business Wire illustrates, Amgen is ready to issue the approval press release whenever FDA is.

FDA and Review Meetings: Getting By With Less Advice

If you are having more trouble than usual trying to schedule a meeting with FDA review staff on a new drug application, you’re not alone. The agency has been denying more requests for meetings as it adjusts to a heavier workload.

And it’s not going to get better anytime soon.

As we’ve reported previously, FDA has been forced to re-prioritize its drug review duties in light of new responsibilities, most significantly the implementation of the FDA Amendments Act and “Safety First” initiative. As a result, Office of New Drugs director John Jenkins has directed his review divisions to miss certain deadlines set up by the user fee program in order to accomplish other tasks.

With all the progress FDA has made in hiring new medical reviewers and the recent bolus of new cash from Congress, you might think the agency would be able to return to its historical Prescription Drug User Fee Act (PDUFA) goal rates soon—if not already. Unfortunately for drug sponsors, they're not even close.

During a “CDER Live” panel discussion at the Drug Information Association’s annual meeting, the question of when FDA would be able to return to its regular PDUFA review schedule was broached by industry representatives on several different occasions. At least by one account, the extra work has led the agency to deny requests for pre-IND and end-of-Phase II meetings—vital interactions with FDA reviewers for drug sponsors.

Jenkins acknowledged that his office was cutting back on certain meeting requests, noting that they tend to be quite labor intensive. (Meetings with FDA have risen exponentially in recent years, and a single meeting with a drug sponsor can be preceded with three or four internal “pre-meetings” among FDA officials.) “We’re not ignoring those meeting requests; we’re making strategic decisions about which ones we can grant and which ones we can’t grant.”

Jenkins isn't happy about the current situation, but there isn't much he can do about it. “Those meetings are valuable and very important,” he said. “The IND part of our work is, in many ways, the most fascinating and stimulating part of our work, and we don’t like that we have to cut back in those areas. But that’s the reality.”

That reality won’t change until FDA can right its workload imbalance. “We have a lot more work on our plate than we have people in our building to help us get the work done. So we’ve had to make some prioritizations; we’ve had to make some decisions about what we can and cannot do,” Jenkins said.

“Some of that has resulted in missing PDUFA goal dates. I cannot tell you when that will not be the case,” he said. “It’s going to change when we are able to recruit and staff and train so that we have adequate people to do the work that we have on our plate. I think that’s going to take some time.”

For drug sponsors, that means getting by with less advice from the agency—and that means lower-quality NDA submissions. For some idea as to how long it could be before things improve, consider this: It takes two to four years for FDA brass to train new reviewers.

And you thought approval rates were low now.

(Photo courtesy of Flickr user bhell13 via a creative commons license.)