FDA already may be nearing the peak of its ability to approve applications during the first review cycle, less than a year into use of a new review system intended for that purpose.

The agency’s first-cycle approval rate, which measures the portion of submitted applications successfully cleared before their first user fee goal date, is so high now that FDA is wondering whether it could continue improving.

The first-cycle approval rate appears to have increased before the new review model that was part of the new prescription drug user fee program went into effect. The implicit bargain of the new review model was that review times would increase by two months, but the change would produce more first-cycle approvals, saving sponsors time overall.

If the first-cycle approval rate does not continue climbing, however, there may be questions about whether adding more time for reviews actually is the key to improving FDA performance.

The agency has also pushed the rate higher despite not fully implementing requirements for common data standards, which eventually could save review time and promote predictability and thus allow more first-cycle clearances.

Theresa Mullin, director of the Office of Planning and Informatics in the FDA Center for Drug Evaluation and Research, said the agency first-cycle approval rate is about 80%.

“Actually [the first-cycle approval rate has] gotten so high I don’t know we’re going to see a lot more improvement in that,” she said April 29 during the Drug Information Association/FDA Statistics Forum.

Improving the first-cycle approval rate was one of the primary reasons for implementing the new review model. PDUFA V, which was enacted in 2012, extended standard and priority review times for new molecular entity NDAs and novel BLAs two months.

The agency was allowed a 60-day filing review period once an application was submitted before the review clock starts. In return, sponsors are allowed mid- and late-cycle communications with the agency to talk about issues that have arisen during the review Also see "Buying Time: Industry Sacrifices Early To Gain Later With PDUFA V Review Model" - Pink Sheet, 1 October, 2012..

Industry and FDA thought allowing more time during the review may cut the amount of overall review time by decreasing the number of applications requiring multiple cycles.

Ideally, sponsors could fix smaller problems without the agency issuing a “complete response” letter or learn about major problems earlier Also see "Late-Cycle Approval Predictions Not A Good Idea, FDA Says" - Pink Sheet, 1 October, 2012..

So far, a number of sponsors have applications moving through the review model and reaching the point where mid-cycle communications and late-cycle meetings are being conducted ([A#00130408004]).

However, some FDA officials have pointed out that many of the elements of the new review “program” under PDUFA V have already been in place (Also see "Will FDASIA Slow Things Down?" - Pink Sheet, 7 January, 2013. and Also see "A Regulator’s Perspective For 2013: FDA’s Temple Discusses FDASIA, Caronia, and Breakthrough Development" - Pink Sheet, 22 January, 2013.). Such elements, like the 74-day letter and early communication initiatives, could be expected to have a muted impact.

Perfect First-Cycle Rate Not Realistic

The first-cycle approval rate has increased dramatically in the last 10 fiscal years to reach its current level.

In FY 2001, only about 20% of priority and standard applications were approved in the first cycle, according to PDUFA performance reports. A turnaround began with the introduction of Commissioner Mark McClellan’s first-cycle review initiative Also see "FDA First-Cycle Approval Rate For NMEs Leaps To 50% In 2003" - Pink Sheet, 29 December, 2003..

By FY 2004, the standard review first-cycle rate was about 50% and the priority review rate was nearly 60%.

The standard review rate was less than 40% in FY 2007 and FY 2008, but increased in subsequent years to about 50% by FY 2010, according to preliminary figures in the most recent PDUFA performance report.

After FY 2004, priority review first-cycle approval rates surpassed 60%, before dropping below 60% in FY 2008. The rate was approaching 50% by FY 2010, according to the report.

Overall first-cycle approval rates were 74% in FY 2011 and 72% in FY 2012, according to CDER data through Nov. 30, 2012 Also see "Oncologics Drove FDA’s 2012 Novel Approval Count To 15-Year High" - Pink Sheet, 7 January, 2013..

The upward trend tracks with the introduction of previous initiatives, including the first-cycle review initiative and later the 21^st century review initiative. It is proof that making such things a priority does have an effect on the agency’s performance Also see "Good Review Principles Implementation Could Threaten Six-Month Priority Review Timeframe" - Pink Sheet, 4 December, 2008..

Mullin said there is no first cycle approval goal, but she also said FDA does not consider 100% realistic.

“We’re going to approve applications when they can be approved,” she said after her presentation.

Industry “Will Watch This Experiment Closely”

Jay Siegel, chief biotechnology officer and head of global regulatory affairs at Janssen R&D LLC, also acknowledged the first-cycle rate is high, but said it still will be something to track going forward.

“Approval times already tremendously improved in the second half of PDUFA IV, which has created a little bit of discussion about ‘well what’s the baseline’ and ‘I don’t know that they can go up from there.’ … It would be interesting to understand those causes, but we think that’s a sign of good faith and good management at the FDA,” he said.

“Industry and the FDA both will watch this experiment closely because there are hypotheses here. … We don’t know how well [it] will work out.”

The improved first-cycle review time also may be the result of FDA efforts to require complete applications at submission, which was an issue during PDUFA V negotiations Also see "PDUFA V: FDA Application Completeness Crackdown Continues" - Pink Sheet, 7 February, 2011..

Clinical Data Standards Under Development

FDA still is developing common standards for clinical data to be used in applications, which is expected to be another step in the path to predictability.

Standards are expected to be released by disease, but likely will include elements that will apply across diseases. Mullin said the agency expects to use standards already in the public domain to set the requirements.

They will be released through guidance to speed the implementation process. Two years after final guidance is issued, they will be required for submissions, Mullin said.

She also said the ultimate goal is to create common standards for all parts of a submission.

“We’re trying to build it so it’s a common model and we’re not duplicating or having conflicting pieces from one type of therapeutic area to another,” Mullin said. “Our goal is to standardize the whole application to maximize the value of it for regulatory oversight and really at the end of the day minimize additional reporting burden.”

The common standard will allow the agency to ask more detailed questions, in addition to finish reviews quicker Also see "FDA’s Data Format Standards Approaching Cost-Benefit Analysis Stage" - Pink Sheet, 15 August, 2012..

Sequester Affecting Progress

Efforts to write the guidances as well as complete other commitments and mandates in PDUFA V have been hampered somewhat by the budget sequester.

Mullin said the agency is proceeding with the issues despite the resource reduction, which included user fees along with budget authority.

FDA lost about $82 million in user fee revenue and about $209 million overall in FY 2013 because of sequestration.

The agency, unlike other federal agencies, said it would not have to furlough employees. It chose cuts to travel and training budgets to make the required reductions ([A#14130301008]).

FDA officials already have met with industry to talk about the problems implementing PDUFA V stemming from the sequester’s resource reductions, although FDA remains committed to meeting its mandates Also see "PDUFA Communications Hurt By Sequestration As Late-Stage Meetings Begin" - Pink Sheet, 8 April, 2013..

Members of Congress in both houses may be interested in allowing the agency to recoup the sequestered user fee revenue. During recent budget hearings, House and Senate members asked about the lost user fee revenue and already have given budget flexibility to other agencies to avoid sequester-related furloughs ([A#14130426007]).

First-Cycle Approval Rate Already High; Can PDUFA V Actually Boost It?

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