The way to get to faster approval times is to take longer to review an application.

If that sounds like an oxymoron to you, you’re not alone. But that’s precisely what Food & Drug Administration officials and many in industry believe can happen under the fifth reauthorization of the Prescription Drug User Fee Act.

Should Congress sign off on the deal later this year as expected, a two-month “filing period” would run between the time that a sponsor submits an application and FDA officially starts the review clock. That new structure would essentially increase the review of a standard application to 12 months, and a priority review to eight months. Also see "PDUFA V: Final Recommendations Fund Proposals In Two Of Three Tiers" - Pink Sheet, 2 May, 2011.

It’s a trade-off that FDA and industry hope will lead to faster reviews.

“This is an experiment to see if we can improve the first-cycle approval rate for these applications without having too significant an impact on delaying access to those new drugs,” FDA’s Office of New Drugs Director John Jenkins, MD, said at The RPM Report’s FDA/CMS Summit for Biopharmaceutical Executives in Washington, D.C. on December 8.

“It’s a five-year program. We’re going to see how it works. There are evaluations that are included to see if this is successful in raising that level of per-cycle approval. And then we’ll evaluate it and decide whether it’s been successful or not.”

Under the FDA Amendments Act of 2007, FDA assumed additional responsibilities that consume much more of reviewers’ time—like implementation of Risk Evaluation & Mitigation Strategies and additional advisory committee meetings. “There are factors like that that have increased the workload for our staff in that compressed time frame,” Jenkins said.

At the same time, companies came into the PDUFA V talks wanting additional transparency, to limit last-minute “surprises” when FDA rejects an application that the sponsor believes is on track for approval. The PDUFA V agreement provides the agency with additional time to address not only the increased requirements under the Amendments Act such as REMS, but also to accommodate industry’s request for more transparency.

To FDA, the math is simple: applications that go past their user fee goal date without an official action are likely to get approved—the agency just needs a little more time to complete the review. Compare that to receiving a “complete response” letter and starting a review cycle all over again, and you start to see how a short extension can lead to faster approvals.

“Sometimes you need more time to get to an approval, and we only go past the PDUFA goal date,” Jenkins said. “It needs to be something important, because as you know, we get dinged for going past the PDUFA goal date. But if it’s an important drug that we think needs to get out there, we sometimes will miss the PDUFA goal date to get the issues resolved to get that drug approved in that cycle.”

Of course, FDA can’t do that for every product. “One of my favorite lines from companies that I hear all the time is, ‘We’ll give you permission to go past your PDUFA goal date.’ It’s not their permission to give,” Jenkins said. “We’ve made these commitments. They can’t give us permission to miss the PDUFA goal date. So, we brought that to the table, that we knew that sometimes having more time can get to approval.”

“The goal is that by taking a little bit longer, we can actually make the process more efficient. We’ll see if that works.”

Limiting Last-Minutes “Surprises”

In exchange for extended review times, industry will get what it wants: better and more frequent communication with FDA about an application under review.

An important provision under PDUFA V would add two required formal meetings to the review process to give sponsors an opportunity to learn about potential problems with an application earlier on—and perhaps address those issues before a “complete response” letter. Under previous user fee agreements, sponsors could request meetings during a review, but they were not required, scheduled events.

First, the user fee agreement includes a “mid-cycle” meeting between FDA and the sponsor to discuss significant issues with an application, information on major safety concerns and initial thoughts on risk management, and expected milestones for the remaining of the cycle, such as an advisory committee meeting. That could dramatically change some of the dynamics of the advisory committee itself. ([A#2011500123])

A higher-level meeting would then be held later in the review cycle, usually two or three months before a user fee deadline. The meeting would be attended by FDA signatory authorities and review team members to discuss any major deficiencies with an application, outline issues to be discussed at the advisory committee meeting (if planned), offer a current assessment of risk management actions and recommend additional information requests.

Jenkins is hopeful that the enhanced communications will lead to more first-cycle approvals, but he cautions that more meetings alone is not a panacea.

“We’ll see how much more we can squeeze out of the orange, as far as process improvements, to get more first-cycle approvals,” he said. “We’re hopeful that that will help us in some cases. But again, you can’t rescue an application that has a failed efficacy study through process improvements during the review process.”

Amgen Inc. VP-global regulatory affairs Steven Galson, MD, a former Center for Drug Evaluation & Research director, agreed that the deal strikes a fair balance.

“Review time is important, but predictability is also important. And there’s no way to argue that over the last 10 years, FDA’s task hasn’t become more complex,” Galson said. “When we looked at the things that we were getting in these discussions with FDA… we saw those as a real strong step forward. Yes, it’s balanced by that additional time, but we think it’s overall a better way to do things.”

Johnson & Johnson senior director of pharmaceutical global regulatory policy and intelligence Andrea Masciale said that anything that prevents a second review cycle is worth trying. “You can’t minimize the resource burden of a second cycle. Not only the company, but then the agency has to pick up that file again, and you have to start all over again. So the hope is to not only get those products to patients sooner, but also to alleviate the resource drain of having to go to a second cycle.”

A New Communication Conundrum

More meetings brings up another new issue for sponsors to consider: how best to communicate those discussions with investors and the media.

There are likely to be differences in how companies handle those meetings, with emerging companies more likely to share the details of the discussions (although, in some cases, viewed through rose-colored glasses), and larger pharmaceutical companies keeping those meetings private while a product is under review.

“When the company has that late-cycle meeting with the agency, they’re going to get the most information they’ve ever received to date on our thinking about the status of their application and what the issues are, and there’s going to be questions about communication of that publicly,” Jenkins said.

“So, we’ll have to see how that’s going to evolve—how much Pfizer may say about those meetings versus how much a venture capital-based company may say about those meetings.”

“It’s going to be quite interesting, the dynamic around public communication, around that sharing of information. Again, we’re going to be constrained in not being able to really respond to whatever the sponsor may want to communicate. But it is a window into our thinking that currently doesn’t happen most of the time, so we’ll have to see how that plays out.”

Facilitated Communications with FDA

Another important aspect of PDUFA V is the addition of a small liaison staff from FDA that would serve as a point of contact for sponsors who have general questions about drug development or who need clarification on which review division to contact with their questions. The liaisons would also help train CDER employees to improve their communication skills with sponsors. Also see "PDUFA V: Emerging Sponsor Communication Issue Resolved And Expanded" - Pink Sheet, 6 June, 2011.

The need for a little more handholding is especially important for smaller companies that are filing their first application—a group that FDA refers to as “emerging sponsors.” And as the number of emerging sponsors decline Big Pharma partnerships and adopt a go-it-alone strategy, that extra help is needed to reduce the burden on the review staff. Also see "An Emerging Approval Trend At FDA: More First-Time Sponsors" - Pink Sheet, 19 January, 2012.

“There are just times when a small question would help speed an application, and we understand that,” CDER Deputy Director Douglas Throckmorton, MD, said at the FDA/CMS Summit. “The challenge is, how to balance the informal nature of some of those communications and the desire for sort of things that you can go back to your boss and say, ‘I talked to the FDA about, and they said I’m going to get approved next week.’”

Throckmorton is a fan of the PDUFA V proposal to set up the liaison communications teams. “It gives the opportunity for that kind of interaction in a structured way, so that the reviewers don’t feel they’re getting badgered about things that they may not even have influence over; they may not even know there’s a dedicated place where those questions can get answered, especially when time is essential and when there’s been maybe breakdowns of communication.”

“So, I see that as a real opportunity for answering a lot of those questions, with enough structure that both parties get what they need out of it,’ he said. “I think it’s got a lot of potential.”

Time for Transparency: PDUFA V’s Big “Experiment”

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