FDA’s workload estimates show the agency has been spending less time dealing with INDs, but with policy changes taking effect that will require more work with sponsors during that stage, that outlook should change.

Some of the agency time has shifted to NDAs and BLAs, as it faces more pressure to complete reviews faster.

FDA sets estimates for the anticipated workload for the next fiscal year based on averages of the past five years. However, as the new review practices created by the FDA Safety and Innovation Act (the new user fee law), are implemented, there likely will be dramatic changes from the practices of previous years.

The agency’s figures for FY 2013 indicate about a 5% reduction in average time devoted to INDs compared to FY 2012 figures, according to workload data in a Federal Register notice setting new drug application costs. The average time devoted to NDAs and BLAs increased more than 12% compared to the previous fiscal year.

Submission volume in both categories increased, though. Five-year averages of the number of active commercial INDs (those having at least one submission during the previous 12 months) have steadily increased since FY 2008. And after decreasing in FY 2012, the five-year NDA/BLA average number of submissions nearly returned to FY 2011 levels, which was the peak of the six-year period reviewed.

While the workload change could be considered another effect of the struggling drug development pipeline, it also may at least in part be a function of the increasing complexity of NDAs and BLAs and the increasing effort they command on the part of review staff.

FDA said in an Aug. 3 statement that more work has been done recently on NDAs and BLAs, but the figures are still “within historical norms” compared to data from the past decade. The agency also said there are many factors that go into the workload calculations and they are moving averages.

FDA is required to estimate the amount of work staff devotes to reviewing four types of submissions – NDAs/BLAs, active commercial INDs, efficacy supplements and manufacturing supplements – to help determine the amount of Prescription Drug User Fee Act revenue it will receive each fiscal year.

Averages are compared to historical figures to determine the workload adjuster, a percentage that in most cases increases the base user fee revenue amount. It is combined with an inflation adjustment to determine the final revenue amount, which is used to set application and other fees.

Dividing FDA’s Time

To help compute the PDUFA application fee each fiscal year, FDA determines the proportion of time it spends on four submission types: NDAs/BLAs, active commercial INDs, efficacy supplements and manufacturing supplements. The five-year average in each category helps the agency determine how much to adjust the total PDUFA revenue figure for workload.

Five-Year Averages of FDA Workload

Source: FDA data published in the Federal Register.

In the FY 2013 workload adjustment, FDA estimated that during the last five years, on average, 40.3% of the total portion of drug review time was spent on active commercial INDs and 39.6% was spent on NDAs and BLAs.

Spending a nearly equal amount of time on both types of submissions is a change for the agency. Estimates as far back as back as FY 2008 show the average trended toward FDA spending more time reviewing INDs (see chart).

In FY 2008 and FY 2009, the difference between the two categories was 9% in favor of INDs. The spread rose to 9.7% in FY 2010 and then 9.8% in FY 2011, according to data published in the Federal Register.

At the peak, FDA on average spent 43.7% of its time on INDs and 33.9% on NDAs and BLAs, according to the data.

The spread began to narrow in FY 2012, when the average time spent on NDAs and BLAs increased to 35.3%, while IND time decreased to 42.4%.

A Practical Shift?

Part of the reason for the increase in NDA and BLA time may be the increasingly complicated applications sponsors are sending. Some new drugs are requiring larger and more complex clinical trials, which require more work for reviewers.

Advocates also have complained that in some cases, FDA reviewers do not entirely understand some rare diseases or their treatments. The new PDUFA reauthorization will allow for reviewer rare disease training to help encourage flexibility and scientific judgment Also see "PDUFA Commitment Letter Formalizes REMS Standardization Schedule" - Pink Sheet, 1 September, 2011..

The workload change also could be simply practical. FDA has been under increasing pressure to make application decisions faster. By devoting more time to the full applications in its queue, productivity should improve. And with the PDUFA reauthorization making its way through Congress during FY 2012, it would not be surprising if the agency chose to devote more time to reviews and improve those metrics.

During PDUFA negotiations with industry, the agency also said it wanted to improve its rate of first-cycle approvals.

Both sides agreed to extend application reviews for new molecular entity NDAs and novel BLAs to give FDA 60 days after an application is received to ensure it meets all filing requirements. The agency also will conduct mid- and late-cycle meetings with sponsors during the review to talk about pending issues Also see "PDUFA V Commitment Letter Front-Loads Guidance, Meeting Milestones" - Pink Sheet, 5 September, 2011..

FDASIA also included policy changes to help get drugs to the market faster, which could eventually push more work to the IND stage.

Among the significant additions to the bill was language aimed at encouraging more use of accelerated approval. It was intended to further clarify the pathway, but uses much of the existing language Also see "TREAT Act Wants Accelerated Approval Change, But Uses Existing Language" - Pink Sheet, 20 February, 2012..

The bill, which President Obama signed July 9, also included the new breakthrough therapy designation, which allows a drug candidate showing a dramatic improvement over existing therapy to conduct an abbreviated clinical development program Also see "“Breakthrough” Designation Another Harmonization Opportunity, Woodcock Says" - Pink Sheet, 9 April, 2012..

Using either approval pathway almost certainly would require increased discussions during the IND stage.

If FDA is successful at growing accelerated approval and creating interest for the breakthrough designation, the workload needle could again move more in favor of INDs over NDAs and BLAs.

While not a part of the PDUFA fee calculations, biosimilars also are expected to require significant agency work at the IND stage. Sponsors will pay a product development user fee as part of the program to help support those activities. It was announced at the same time as the new prescription drug user fee amounts Also see "FDA Sets Biosimilar Application Fees, But Is Silent On Volume Projections" - Pink Sheet, 31 July, 2012..

Decrease In Time For Supplements A Shortage Issue?

The shift of workload focus in the IND and NDA/BLA area also comes with a decrease in time devoted to manufacturing and efficacy supplements.

Efficacy supplements saw their average portion of the workload decrease to 9.5% in FY 2013 from 9.9% in FY 2012. Since FY 2008, however, FDA has been devoting more time to those submissions. They accounted for 7.4% of time on average in FY 2008 and FY 2009.

The five-year average portion of time devoted to manufacturing supplements was 10.6% in FY 2013 estimates, down from 12.4% in FY 2012. The fraction of time devoted to manufacturing supplements also dropped 19.7% between the FY 2008 and FY 2013 calculations.

Estimates of the average total number of manufacturing supplements received also decreased 1.2% between FY 2012 and FY 2013, according to the notice.

The statistics may provide some fodder for those who believe FDA could be doing more to prevent and alleviate drug shortages.

Congress included several mandates in FDASIA for FDA to deal with the growing shortage problem. It allowed FDA to expedite reviews of manufacturing and other supplements if they could help mitigate or prevent a shortage, although the agency claimed it already had the ability to do it Also see "Did PDUFA V Pass Too Quickly?" - Pink Sheet, 25 June, 2012..

Some House members have argued that FDA should take some blame for the increase in shortages. The Oversight and Government Reform Committee issued a report indicating the agency’s recent increase in enforcement was a cause of the shortages Also see "Drug Shortages Mostly FDA’s Fault, House Oversight Committee Concludes" - Pink Sheet, 15 June, 2012..

House members also heard testimony that FDA should approve supplements faster so new facilities can begin production quickly in a shortage situation Also see "Medicare Reimbursement Rate Targeted As Culprit For Drug Shortages" - Pink Sheet, 30 November, 2011..

FDA has said its inspection policies neither cause nor prevent shortages Also see "To Prevent Drug Shortages, Don't Look To Inspections, FDA Says" - Pink Sheet, 22 August, 2011..

NDA/BLA, IND Volume Increases

Interestingly, while the workload is shifting, average submission volume in both the NDA/BLA and IND categories continues to increase.

The average number of IND submissions tabulated by FDA increased to 6,724.2 in the five-year period ended June 30, according to the FY 2013 user fee notice. That was a more than 3.1% increase from FY 2012 figures.

The average number of NDAs and BLAs also increased about 2.8% from 130.8 in FY 2012 to 134.4 in FY 2013 calculations.

The IND average has climbed steadily, up 21.6% since FY 2008. The NDA and BLA average fluctuated during the same period, but is up about 8.6% overall.

The increase in the average number of NDAs and BLAs received could help explain the shift in time devoted to them. But it is unclear why the average number of INDs would continue to increase, while the time devoted to them decreased.

FDA also saw another decrease in fee-paying full application equivalents in FY 2011, which helped increase the user fee for an application requiring clinical data Also see "FDA Sees Another Submission Decrease In FY 2011, Increases Application Fees" - Pink Sheet, 6 August, 2012..

FDA Spending Less Time On INDs, More On NDAs and BLAs

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