Where To Find Biosimilar User Fees In Alphabet Soup?

Industry is looking for a PDUFA, but could end up with a FDAAA as it searches for an acronym for the biosimilar user fee to join the lexicon of bureaucratic alphabet soup.

It is an important question, mainly because the series of letters likely will become the most-recognized method of referencing the program. (Of course, how the program might actually run is another important question, one explored in this week's edition of "The Pink Sheet.")

The Prescription Drug User Fee Act is the oldest user fee and PDUFA has long been accepted as a classic acronym.

The 2007 FDA Amendments Act elicited the opposite response. It was criticized shortly after passage for its awkward, A-filled acronym. One person at the time said FDAAA was among the worst acronyms in recorded history.

Many seemed to prefer an alternate title for the bill: the FDA Revitalization Act. It would have shortened to FDARA, a much more pronounceable acronym.

So where would the biosimilar user fee fit in the acronym vernacular? BUFA or BSUFA would continue the “UFA” naming concept.

Shorter acronyms are preferred and the user fee likely will not elicit its own legislation, so maybe the “A” should be dropped. That would leave BUF or BSUF, but both seem awkward-sounding.

Indeed, negotiators for the generic user fees that are expected to be created sometimes refer to that program as GDUF, but it's unclear if they are being serious.

Maybe the biosimilar user fee will require a break from tradition, just like the negotiating process FDA is employing to create the program, and employ no acronym. After all, biosimilars are similar, but not the same, as their reference products.

Patricia Knight, president of Knight Capital Consultants, and a former chief of staff for Sen. Orrin Hatch, R-Utah, one of the principal authors of the legislation, said crafting a title for it “was just horrible.”

“We could get through some of the hardest stuff, but we were stumped on the title,” Knight said May 4 during a conference on the future of biosimilars in the U.S.

“We were throwing out ideas and we decided to pay a tribute to the Drug Price Competition and Patent Term Restoration Act, so it would be parallel to the Biologics Price Competition and Innovation Act. Truth be known, that title was picked in a contest.”

Are you more creative than Congress? Take our poll below to vote for your favorite biosimilar user fee acronym or offer your own.

– Derrick Gingery










Photo by Flickr user woody1778a used under 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.

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.)

FDA’s “Roadside Bombs” and “Insurgents”

“Roadside bombs” and “insurgents” aren’t typically found in FDA’s regulatory lexicon. But that’s how FDA’s former drug center director Carl Peck described the situation the agency finds itself in right now.

Peck, speaking at the Food and Drug Law Institute’s annual meeting March 27, was referring specifically to a study making headlines today in the New England Journal of Medicine. The study, authored by well-known Harvard researcher Daniel Carpenter, looked at new molecular entity approvals between 1950 to 2005 and found that drugs approved close to the prescription drug user fee deadline ran a higher risk of being withdrawn and receiving a “black box” warning compared to those drug approved earlier in the cycle.

“The conclusion is that drugs approved just before PDUFA deadlines are less safe than those approved well before,” Peck pointed out after a solid criticism of “ambitious politicians” and “media competing for sales-enhancing headlines” (the IN VIVO blog is obviously not shackled by this particular criticism since the blog is free…remember that, people).

More specifically, drugs approved two months before the PDUFA deadline carry a 5.5 excess risk of being withdrawn and a 4.4 excess risk of getting a “black box” warnings. To read the NEJM abstract, click here.

FDA isn’t taking this one sitting down.

“FDA has tried to confirm the numbers that are in that article and we have been unable to,” Center for Drug Evaluation & Research deputy director Douglas Throckmorton commented at the FDLI meeting. “The numbers we have gotten are considerably different.”

The Wall Street Journal first reported that FDA was sending a protest letter to NEJM related to the study findings. To read the story, click here. Throckmorton says the discrepancy between FDA figures and Carpenter’s figures aren’t negligible. “We need to know what those numbers really are before we try to interpret them and we have a group within the FDA that’s working to try to understand where that difference is because it’s considerable.”

Throckmorton also pointed out what everyone in the biotech and pharmaceutical industries already know: almost every single new drug approval occurs at or just before the user fee deadline date. “The small fraction of products that aren’t—it’s an important fraction to look at—but whether that’s a balanced representation of what we’re doing” is debatable.

The CDER deputy highlighted that this is one particular research question that has a “right answer” and isn’t up for interpretation.

In other words, this isn’t likely to be a study to go the route of Avandia and other drug safety issues that never produced a general consensus. Judging from Throckmorton’s comments, the agency appears confident that it has the right numbers, not the academics. If that’s the case, chalk one up to FDA. Finally.

The Memo to End All Memos

The wheels of FDA public affairs can sometimes turn a bit slowly, but we finally have an explanation from Office of New Drugs director John Jenkins on why he authorized the review divisions to miss PDUFA deadlines, due to resource constraints.

We reported on that story in an earlier post, but here's Jenkins' explanation in its entirety. Enjoy.

"Over the past several years the rate of growth in workload for OND has far outpaced our ability to increase our staffing. The workload growth has occurred in many areas, including the number of meetings conducted with sponsors, the number of requests for Special Protocol Assessments (SPA), work related to emerging safety issues and early communication, work related to responses to Congressional inquiries, etc.

This workload imbalance was one of FDA's primary areas of focus when we were discussing with industry the PDUFA III and PDUFA IV program, and the PDUFA IV program includes a significant increase in resources to FDA to help address the workload concerns through increased staffing and better IT systems.

More recently we are faced with the increased workload related to the implementation of FDAAA and FDA's Safety First/Safe Use initiative. In addition to the resource increases under PDUFA IV, FDA also saw increased appropriations for FY2008 to help meet the growing workload. The new resources will have a significant impact on our workload/staffing balance in the long term, however, in the short term CDER is approximately 550 FTEs below its ceiling for FY08.

While we are working hard to recruit and train the necessary new staff (including replacement of staff who depart CDER for various reasons), it will take several years to achieve full staffing and to have all the new staff fully trained and productive. In that interim, it will be necessary for CDER and OND to make careful decisions about our work priorities, and those priorities will be reflective of our stated goals under Safety First/Safe Use to ensure proper balance between our focus on pre-approval activities and post-approval safety issues.

To that end, I have granted permission to OND division and office directors to make decisions to bring their unit's workload into better balance with their existing resources. These decisions will be made on a case-by-case basis since the balance is not the same in all divisions or even the same over time in any given division.

We will still strive to meet our PDUFA goals whenever we can, however, in some cases we may not be able to meet PDUFA goals and managers have been given the discretion to make those decisions. We have actually failed to meet many PDUFA goals (e.g., goals related to meetings with sponsors) over the past few years, although we have generally been able to meet most of our application review goals.

In the short term our ability to meet PDUFA goals is expected to decrease. In some cases we may have to cut back on work by declining requests from sponsors for guidance (e.g., meetings, multiple cycle SPA reviews) and in other cases we may decide to go past the PDUFA goal date for review of an application. In cases where we decide to go past the PDUFA goal date the sponsor will be notified by the division management of that plan.

It is important to note that decisions to miss the PDUFA goal date are separate and distinct from a decision to extend the PDUFA goal date by 3 months, which is allowed in response to the submission of a major amendment during the last three months of the review cycle.

CDER faces significant challenges in hiring the 550 additional staff (plus replacements for staff who depart for various reasons) authorized in our budget for FY08.

First, we have to find qualified candidates for the positions. We are aggressively undertaking that part of the effort through various channels including extensive advertisements and the use of recruitment incentives. Once we have identified a qualified candidate they must navigate through the complex Federal/HHS personnel system before they can receive an official job offer.

We have worked to gain permission to streamline that process as much as possible, however, in many cases it can still take months for the paperwork to make its way through the system before an official job offer is made. In some cases, candidates choose to take other positions before an official job offer from FDA can be made.

Finally, our pay structure often is not competitive to what qualified candidates can make in the private sector. We are working through existing authorities to make FDA's pay as competitive as possible in order to attract and retain the best candidates. As noted above, it is likely to take several years before CDER achieves full staffing and all the new employees are fully trained and productive. It can take 1-2 years, or more, for a new reviewer or project manager to be trained to do the complex work required at FDA.

We will be continuously assessing our workload and resources over time and make decisions on our priorities. There is no specific end date since I cannot predict when our resources will be in balance with our work. That is why there is no blanket policy but rather permission to reduce work as needed on a case-by-case basis."

image by flickr user oddsock used under a creative commons license.

The Beginning of the End of the User Fee Era?

In the 15 years since the Prescription Drug User Fee program was created, the biopharma industry and its investors have gotten used to a once-unthinkable proposition--that FDA would give a clear yes or no answer about the approvability of a new drug by a tight deadline.

That record of reliability now may be in jeopardy.

Given the agency's ongoing resource problems, Office of New Drugs Director John Jenkins has given overworked and overwhelmed review divisions the green light to do what was once unthinkable: miss PDUFA deadlines.

According to a story in BioCentury this week, Jenkins’ unofficial and unpublicized directive could result in FDA missing more than 10% of user fee deadlines this year. That may not sound too bad, suggesting only a minor slippage from the agency's official commitment under the PDUFA agreement to meet its goals for at least 90% of its applications.

But in reality, FDA's track-record on meeting deadlines has been very close to 100%.

What Jenkins is describing is a limited number of missed deadlines—only in cases when a division feels overwhelmed by its workload. But once you start missing deadlines, it becomes very difficult to get caught up. And it's not like FDA is being overwhelmed by new drug applications these days. Imagine what might happen if new drug applications were streaming into FDA like they were 10 years ago.

For industry, the beautiful thing about the user fee process is its predictability: on new drug reviews, FDA promises to give a sponsor an answer by a certain date. And if company executives ask for a meeting with FDA officials to discuss an application, they know they will receive one within a set period of time.

Up until now, user fee activities have historically been considered sacred cows at FDA: industry fees have increased at a healthy clip at each reauthorization of PDUFA. It’s been all the “extraneous” activities funded through congressional appropriations—like professional development and, until recently, post-marketing safety—that have suffered due to a lack of funding.

And these days, it seems like FDA is stretched to the limit. Between the inspections debacle, the FDA Amendments Act implementation, and the new “Safety First” postmarketing safety initiative, FDA “has more work on our plate than we can possibly accomplish,” Jenkins told BioCentury. “We are having to prioritize. We are having to set aside some things, hopefully on a temporary basis, until we can get adequately staffed.”

But hiring and training new staffers is no easy process, thanks to a lengthy and arcane procedure under current HHS guidelines. Mary Pendergast, a former deputy associate commissioner at FDA, discussed this exact dilemma during Windhover's FDA/CMS Summit in December.

“The FDA has to hire many additional people. But as any FDAer would tell you, the new rules imposed by the Department of Health & Human Services—which took away from the FDA the ability to hire its own staff—has caused a very difficult time for the FDA in terms of making new hires,” she said. “The system is so long that most competent people will have found a new job by the time the FDA tells them they want them to be hired.”

So far, Congress has turned a deaf ear to FDA’s resources woes, wanting promises of an agency overhaul before appropriating any more money. Capitol Hill has sent a clear signal on where it believes FDA’s priorities should lie, and it’s not in faster review times.

Congress wants FDA to hold advisory committess for all new molecules, or justify a decision not to in writing. The logistics of scheduling committee reviews within six- or 10-month deadlines make that a tall order. And the decision to delay an advisory committee review for Theravance's televancin demonstrates the real-world consequences of placing safety concerns (in this case, the integrity of the trial data) over PDUFA deadlines.

Then there is the focus on the preapproval inspection process. When that program was created in 1990, the first impact was a delay in approval for a number of pending applications while the agency hustled to conduct inspections of the facilities. In the intervening years, FDA has developed a list of exceptions to the preapproval inspection policy--and Congress isn't happy about that. Another reason for delays.

The bottom line is that folks like Reps. Rosa Delauro and Bart Stupak or Sen. Chuck Grassley are less concerned about missing a few deadlines than when FDA inspects the wrong heparin facility in China. Indeed, they are clearly uncomfortable with the entire user fee model--a fact that should give the biopharma industry pause.

But what’s in it for me? Antibiotic incentives in FDARA

It’s not all bad news for drug developers. The Senate’s drug safety legislation emerged from that chamber on May 8th carrying some interesting drug development incentives tucked away among the added requirements for postmarket surveillance and marketing/communication controls.

We watch C-SPAN, so you don’t have to

The two most interesting incentives—which promise limited scope for faster drug reviews and longer product lives—both relate to anti-infective drug development.

The first incentive, suggested as an amendment by the odd pair of very liberal Ohio Democrat Sherrod Brown and very conservative Kansas Republican Sam Brownback, would offer a faster FDA review for any drugs of a sponsor’s choice (anything in a sponsor’s pipeline—not just anti-infectives). All a sponsor would have to do to get access to the faster review would be to develop and make commercially available a product for under-treated diseases prevalent in the developing world.

The second amendment, sponsored by Utah Republican Orrin Hatch, claims to expand research incentives for antibiotics and redress exclusivity issues created ten years ago in a previous Congressional effort to bring antibiotics under Waxman-Hatch exclusivity provisions.

The first measure, Brown said, would be built on awarding “a priority review voucher to any company that brings a neglected tropical disease treatment to market.” It derives from an early 2006 proposal from a group at the Duke Fuqua School of Business, “Developing Drugs for Developing Countries,” and proponents say it could be worth about 12 months of extra marketing time to a company: FDA is supposed to conduct priority reviews within six months compared to “the average time of 18 months” for standard FDA application reviews. What’s more, research-stage companies that earn such vouchers could sell them on to Big Pharma, creating an additional asset market that encourages investment in neglected diseases.

Skeptics argue that tying the vouchers to “priority” review—instead of patent life or market exclusivity--may not turn out to be a big incentive. A senior Merck policy executive, Ian Spatz, openly questioned the vouchers’ value shortly after the Duke proposal was published. The difference in approval times associated with standard and priority reviews is much shorter than a year, argues Spatz, and therefore much less valuable to big commercial sponsors. And major products, where a voucher might tend to be used, often qualify for priority review in their own right.

The Hatch antibiotic incentive amendment would confer five-year market exclusivity for antibiotics filed with FDA before November 1997 but not yet approved by the agency. Preliminary analysis of the provision also suggests that it would permit generic copies of some antibiotics approved before November 1997 and so-far protected from generic competition due to an obligation for the follow-on sponsor to show that all patented indications have expired.

Hatch is also calling for clearer orphan drug incentives for anti-infectives. The amendment calls for FDA to hold an open meeting to clear up what indications qualify for orphan protections, including market exclusivity. Currently, anti-infective sponsors—and even some FDA reviewers—do not know how indications are counted toward the orphan population limits. The open meeting is designed to make it clear whether a product can qualify for orphan incentives if it treats a subclass of an infection (such as pneumonia) caused by a specific pathogen.

The Hatch incentives also would offer exclusivity protections to new approvals for single enantiomer drugs with an enantiomer that was previously part of an approved racemic drug, if the enantiomer drug is in a different therapeutic class. That distinction would prevent evergreening of existing products in the same class as an existing product (we’re looking at you, Nexium) but offer an incentive for the development of enantiomer in a new therapeutic category.