Lilly's Prasugrel Widens the Gap

The gap just got wider.

No, we’re not talking about the income inequality gap, or the gender gap, or the generation gap. We’re talking about the approval gap for new drugs and biologics between Europe and the United States.

Some critics of the Food & Drug Administration argue that FDA is more conservative than its counterparts in Europe. (This is what we think of as the “too slow” contingent. FDA is also criticized from other stakeholders—like Sid Wolfe and Chuck Grassley—of being too fast.)

FDA disagrees with both sides. As Office of New Drugs director John Jenkins said at FDC-Windhover’s FDA/CMS Summit for BioPharma Executives, “We review each application on its own merits—not against some goal that we will approve 25 applications this year. Those that meet the standards under the statute get approved; those that don’t, don’t get approved.”

But with last Thursday’s news that prasugrel—Eli Lilly and Daiichi Sankyo’s beleaguered blood thinner candidate that is still sitting at FDA—received a positive recommendation from the European Union’s Committee for Medicinal Products for Human Use, the noise from the “too slow” contingent is likely to get louder.

In an effort to discredit those critics, Jenkins presented data at the FDA/CMS Summit from a preliminary analysis of new molecular entities reviewed by FDA and the European Medicines Agency between January 2006 and October 2008. What Jenkins found was that EMEA approved slightly more novel products than FDA, but that the agencies had a similar approval rate.

Jenkins then looked at new molecular entities that were reviewed by both the Food & Drug Administration. Of those 29 products, FDA approved two that the European Medicines Agency has not, and EMEA approved seven that FDA has not. (Once Lilly and Daiichi receive final approval from the European Commission—which should come in two or three months—prasugrel would make that eight.)

Jenkins argued that the numbers are too small to support any conclusions that FDA is more conservative than its counterparts in Europe—especially given that one of the EMEA-approved drugs (Sanofi-Aventis’ weight loss drug rimonabant) has already been withdrawn from the market.

Pointing to the list, Jenkins said: “Here’s where all the statements about the EMEA being faster are coming from.” But some investors still see the data as a troubling trend. The prasugrel approval in Europe is only likely to feed those beliefs. (You can read all about that debate in the latest issue of The RPM Report.)

So what's up with prasugrel at FDA?

As we’ve reported, FDA is looking at February 2009 for an advisory committee meeting. Assuming that happens, an answer isn’t likely much before March 2009—which would double prasugrel's review time to 12 months. The user fee deadline was initially set for March 2008, but on two occasions was pushed back three months—most recently to September. Since then, it has become just one of a number of missed deadlines at FDA.

Cleveland Clinic cardiologist Steve Nissen, who has accused FDA of being both too fast and too slow, thinks Lilly and Daiichi deserve an answer one way or the other. What do you think? Is FDA more conservative than EMEA? Or is the difference too small to draw any conclusions?

Photo courtesy of flickr user StevenBulman44.

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

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.”

Setting the Record Straight on Suicidality

FDA Office of New Drugs Director John Jenkins wants to correct a misperception about testing requirements for psychiatric adverse events. Contrary to reports by certain media outlets, FDA is not putting in place a blanket request for suicidality studies.

“That’s simply not true,” Jenkins says. Rather, “it’s being done in a targeted manner, wherever it seems to be appropriate based on what we’ve seen from other products in the class, the pharmacology of the drug itself, or other studies of that same drug.”

Granted, the potential for certain drugs to cause mood disorders or suicidal thoughts has been in the news lately—especially given FDA’s recently aired concerns with potential psychiatric risk profile of Merck’s Singulair, a popular asthma/allergy medicine. But that’s not to say that FDA is changing the game for all drugs across all classes.

In the case of Singulair, FDA is “still evaluating the case reports that are coming in from spontaneous reporting,” Jenkins says. “We’re not systematically asking every sponsor of an anti-asthmatic drug or an allergic rhinitis drug to include suicidality as part of their targeted assessments.”

To do otherwise would not be scientifically sound, Jenkins says. “We have to be careful not to over-generalize this and suggest that every trial has to have a specific rating scale for suicidality. You could start taking that to its logical extreme and have every trial have a rating scale for every possible adverse reaction, even though there may not be a reason prospectively to specifically be concerned in that setting.”

For certain drug classes, however, FDA has upped the ante and is asking manufacturers to either prospectively or retrospectively test for psychiatric adverse events. For more information—and for an interview with FDA’s Jenkins—you can check out the latest issue of The RPM Report online; non-subscribers can sign up for a free trial to access the story.

But here's the good news: there are FDA-sanctioned ways to test for psychiatric adverse events. So even for companies that are being asked to test for depression and suicidality, at least there's a process to get some clarity and predictability into the process.