Generic Application Quality Showing Signs Of Improvement
Executive Summary
US FDA’s monthly refuse-to-receive numbers for ANDAs are down early in FY 2017, suggesting that sponsor have an increased understanding of the agency’s standards.
Usually a drop in FDA's generic drug metrics is a cause for alarm, but when it concerns refuse-to-receive actions, it may signal a breakthrough.
The agency's Office of Generic Drugs has reported significantly fewer refusals during the first two months of fiscal year 2017 than had been seen in past years. If the trend continues through the rest of the year, it could indicate that industry has finally figured out OGD's application quality standards, which the agency has complained for years is hindering reviews and approvals.
Through the first two months of FY 2017, OGD issued 17 refuse-to-receive actions, which are warranted when a preliminary check reveals the application is not substantially complete.
The average of 8.5 per month is well below the figures seen in the previous four years of GDUFA. In FY 2016, OGD issued 20.5 refusals per month, and in FY 2015, it issued 19.7 refusals per month.
Monthly Average Refuse-to-Receive Actions
- FY 2013: 12.5
- FY 2014: 14.4
- FY 2015: 19.7
- FY 2016: 20.5
- FY 2017 (two months): 8.5
Source: FDA Generic Drug Program activity report data
In fact, the November total of eight refuse-to-receive actions was the lowest monthly total since April 2014, when seven were posted (see chart below).
There likely is no one reason for the downturn, but one potential conclusion could be that industry is filing higher quality applications. That would mean that more ANDAs include all the information necessary to support a review from the start.
FDA said an increase in the "number and complexity" of controlled correspondence between FDA and industry over time likely contributed. "Effective communication between applicants and FDA during drug product development can result in better quality applications and increased approvals on the first review cycle," the agency said in an email to the Pink Sheet.
When GDUFA launched, agency officials warned that application quality had to improve for the program to meet its goals. (Also see "GDUFA Success Depends On Industry Changes As Much As Review Improvements, FDA Says" - Pink Sheet, 4 Nov, 2013.)
The agency implemented a number of new policies when GDUFA launched, including formal ANDA review goals. But while sponsors now can receive an approval or tentative approval within a specific timeframe, if the application is not complete or of high quality, it also could receive a complete response or refuse-to-receive action, forcing another review cycle.
Source: FDA Generic Drug Program activity report data
Indeed, many sponsors so far have not been able to take full advantage of the formal review goals due to first-cycle rejections. The first-cycle approval rate for ANDAs submitted during the initial year that goals were mandated was low. (Also see "Generic Drug First-Cycle Approval Rates Lagging Under GDUFA I" - Pink Sheet, 25 Oct, 2016.)
Many ANDAs require three or more review cycles before approval, which the agency would like to see reduced to two. (Also see "ANDA Reviews: First-Cycle Desired, But Two-Cycles OK?" - Pink Sheet, 27 Jul, 2015.)
Is FDA Relaxing RTR Policies?
Robert Pollock, senior advisor and outside director to the board of Lachman Consultants, said in an email to the Pink Sheet that OGD reviewers also could be preventing refusals by allowing more flexibility with some policies.
Pollock said OGD could be "now applying the seven-day allowance for responding to filing review issues more liberally." He also suggested that it is also possible OGD is letting more problems they find "be classified as review issues where in the past some of those might have translated into an RTR."
If a review is allowed to move forward despite the issues raised during the filing review, the sponsor may be allowed to fix them while the review clock is still running.
Pollock also suggested that another potential reason for refusals decreasing is that some sponsors have been successful in having an RTR overturned. It could have prompted OGD to review some of its practices and subsequently lead to fewer actions. Several refuse-to-receive challenges have been successful, and some in industry questioned whether FDA staff training was adequate. (Also see "ANDA Refuse-to-Receive Challenges Become More Common – And More Successful" - Pink Sheet, 20 Jul, 2015.)
OGD's revised RTR guidance has probably not affected the figures yet, Pollock said. The agency issued an updated final guidance in late December with additional clarifications and reclassifications. (Also see "US FDA Largely Stands Pat In Revised ANDA Submission Guidance" - Pink Sheet, 23 Dec, 2016.)
ANDA Quality Should Boost OGD Productivity
If industry is in fact improving application quality, it will bode well for OGD productivity as it moves toward GDUFA's reauthorization later this year.
GDUFA II includes a priority review pathway for generics that will allow eight-month goals for qualifying ANDAs, which could allow generics to reach the market faster. (Also see "ANDAs Can Get Priority, Eight-Month Reviews Under User Fee Deal" - Pink Sheet, 24 Sep, 2016.) Improved submission quality also will help FDA better handle the uptick in ANDAs being sent in recent months, partly to take advantage of the new 10-month review goal. (Also see "ANDA Submission Wave Continues; Is A Crest Near?" - Pink Sheet, 12 Dec, 2016.)