FDA's Jenkins Sounds Off on Incomplete NDAs

Earlier this week, FDA issued a Refuse to File on Merck-Serono's cladribine application, meaning the agency felt the NDA was sufficiently lacking that it didn't want to begin a review yet.

The topic of Refuse to File letters came up today at Windhover's FDA/CMS Summit. No drug or company was mentioned by name, however; the discussion was prompted by an audience question and warmly embraced by FDA Office of New Drugs director John Jenkins.

FDA, Jenkins said, has for the most part held up its end of the bargain created 17 years ago by the industry-FDA agreement known as PDUFA. "Most of the time," he said, FDA reviews drugs in the appropriate time window. But too often industry is developing the drug on FDA's review clock. If industry really expects FDA to stick to that model, he said, applications need to be complete so that questions won't arise just before the PDUFA date because information is still coming in from drug sponsors during the review process.

If industry's complete response letters were released, "would you make sure your application is complete before you submitted it?" asked Jenkins. Would senior executives wake up to regulatory realities? Jenkins suggested that companies "do the math some time." Delaying an NDA a few months until it's truly complete can save double that time on the extended review process that results from incomplete applications.

We can't be sure why FDA dinged Merck-Serono's application; that information is, for now, secret. In a recent feature about potential orally available multiple sclerosis therapies we duly noted that Merck Serono's chances with its first-to-NDA oral therapy cladribine weren't a 'slam dunk'. The drug's efficacy looks great in one Phase III trial in relapsing remitting MS patients, and side effects in this therapeutic space are navigable, for sure (just ask Elan and Biogen Idec). But that's just one trial, as we also noted, and the drug hasn't been tested against an active comparator. It was never clear how FDA would react to that.

FDA's rebuttal might have been due to some other deficiency unrelated to the lack of a confirmatory Phase III trial (which will take the company many more than just a few months, given the time frames for large MS trials). For its part the company has stated that it will get together with FDA as soon as possible to discuss the issue and other Phase III studies of oral cladribine which are ongoing in different forms of MS.

image from flickr user wilhei55 used under a creative commons license

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.”

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.

Prasugrel: Signs Point to FDA Approval

[Update: Well, it looks like Lilly will have to wait on the champagne, at least for now. FDA extended the review of prasugrel by three months after receiving "supplemental information" during the review. "We will continue to work closely with the FDA throughout the review process and continue discussions to determine if any requirements under the new FDA Amendments Act (FDAAA) will apply," Lilly VP-global regulatory affairs Jennifer Stotka said in a statement. To read the full release, click here.]

There’s nothing like a ticking clock as a deadline approaches to ratchet up the drama behind an FDA decision. Remember Provenge? On June 26, or possibly before then, Eli Lilly will find out whether its novel blood thinner prasugrel (Effient) will be granted approval, delayed or rejected.

We think Lilly may want to get the champagne ready. Here’s why:

1) The Data: When it comes to FDA approvals, it’s all about the data. No question. In Lilly’s Phase III 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 clopidogrel (Plavix). By any standard, that’s a compelling result.

There’s been a lot of finger pointing regarding a more cautious FDA when it comes to new drug approvals and we’re not going to dismiss that here. However, sometimes the cases used as evidence to make that argument were for drugs that missed their primary endpoints or made it by the skin of their teeth and had important safety questions.

Those expecting an FDA decision to delay the application point to the statistically significant 32% increase in minor and major bleeding. That’s a strong point against approval in today’s regulatory environment. But when you consider the primary endpoint, those bleeds didn’t lead to deaths, heart attacks or strokes. To read more about our coverage of prasugrel, click here.

2) Priority Review: We think a lot of the hard work on prasugrel was done prior to the priority review designation. Here is what FDA says warrants that designation:

“A priority review designation is given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists....The distinction between priority and standard review times is that additional FDA attention and resources will be directed to drugs that have the potential to provide significant advances in treatment.
Such advances can be demonstrated by, for example:

a) evidence of increased effectiveness in treatment, prevention, or diagnosis of disease;

b) elimination or substantial reduction of a treatment-limiting drug reaction;

c) documented enhancement of patient willingness or ability to take the drug according to the required schedule and dose; or

d) evidence of safety and effectiveness in a new subpopulation, such as children.

Designation of a drug as “priority” does not alter the scientific/medical standard for approval or the quality of evidence necessary.”

FDA Office of New Drugs director John Jenkins is one of the most vocal advocates of the value linked to getting a priority review. He often cites the designation as the most telltale sign that a drug will receive a positive, first-cycle decision. It may be a leap, but we doubt such a high-profile drug in a treatment area with an established gold standard would have received a priority review without FDA having a strong idea of what they were going to do with it.

3) The (absence of an) Advisory Committee: This is another positive sign for Lilly, in our opinion. Why? Read this quote from former FDA drug center Steve Galson at a 2006 Stanford Research Group meeting in Washington:

“If it’s clear that the drug is very advantageous and helpful [then an advisory committee may not be necessary]…we’re just wasting everyone’s time because it’s obvious that this drug has to get on the market. On the contrary, if there’s some major drug safety issue that we know there isn’t any real disagreement...then we also don’t want to waste everyone’s time at a whole meeting.”

We think the former is the case with prasugrel when you pair it with the priority review. For example, if you look at Bayer/Onyx’ and Pfizer’s renal cell carcinoma drugs sorafenib (Nexavar) and sutinib (Sutent), respectively, both were priority reviews that resulted in timely approval without advisory committees. Both were viewed as significant advances in renal cell carcinoma therapy, an area that had been bereft of new treatments for years.

4) Sending a Message: Approving prasugrel by the PDUFA deadline would send a strong message to FDA stakeholders that the agency is willing to approve innovative drugs—that carry a pre-determined risk—in a timely fashion if the treatments demonstrate a real benefit to patients. Prasugrel appears to fall in that category. Moreover, a swift approval that meets the user fee deadline would allay many concerns over an FDA memo allowing reviewers to extend deadlines. To read more, click here.

5) Nissen Says Thumbs Up: Controversial Cleveland Clinic cardiologist Steve Nissen has been on record as saying prasugrel is “a good drug that should get approved.” Need we say more?

6) Bad Cordaptive Comparison: Drug company executives, the investment community, and FDA watchers highlight FDA’s decision to delay/kill Merck’s combo cholesterol drug niacin/laropiprant (Cordaptive) with a “non-approvable” letter in late April as a sign that prasugrel could get disappointing news. This is an apple and oranges comparison. Cordaptive was a standard review application in an area, cholesterol therapy, with an extensive number of effective treatments. Moreover, there appeared to be questions over the long-term risks of the anti-flushing agent laropiprant. When FDA reviews combo drugs there must be evidence that each component of the combination product makes a substantial contribution to the safety and/or efficacy of the combination product. In other words, the combination product has to be shown to be more safe and/or effective than either product alone. Clearly, FDA didn’t feel that was the case with Cordaptive.

Two key questions that will impact the decision and whether it will be made by June 26 are: 1) Who made the priority review decision?; and 2) Will prasugrel require an onerous REMS (risk evaluation and mitigation strategies) postmarket surveillance program?

If an office-level director, or Jenkins himself, signed off on the priority review, that bodes better for prasugrel’s chances of approval. It diminishes the chances of an intervention from a higher-ranking official to delay the decision.

We asked FDA who actually decides whether a drug is granted a priority review. Here’s what an FDA spokesperson says: “The decision on priority review designation is made by the OND division director based on a recommendation from the review team and based on the CDER standard as articulated in our guidance.”

The division director in this case is Norman Stockbridge, who reports into Office of Drug Evaluation I director Robert Temple.

As the decision relates to risk management, if a burdensome REMS program is required to monitor the bleeding risk, it could take a few extra months to work out the details.

In the end, based on the tea leaves, that FDA will approve prasugrel with a warning (not black-box) on bleeds and a REMS program that includes a prescribing MedGuide for patients, a physician education program and a postmarket study.

Now it's just a game of wait and see.

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.