PDUFA Negotiations Focus On Review Delays; Firms, FDA See Different Causes

Industry appears to be showing its strongest hand as PDUFA V negotiations roll along, laying down the cards showing FDA's poor record of meeting user fee goals in recent years.

FDA has countered, however, that application quality and other issues aside from review inefficiency can cause a slow-down.

And while neither side is revealing what they will eventually accept in the design of the next round of the user fee program - which will go into effect in October 2012 - is seems clear that the structure of FDA drug evaluation will probably depend on whether the agency can persuade industry that any new initiatives can help improve review speed or whether firms will insist on a back-to-basics approach.

According to minutes of the most recent Prescription Drug User Fee Act reauthorization meeting on Aug. 9, industry has proposed that FDA optimize review process management to enhance predictability and add a mid-cycle review meeting with sponsors.

Industry also wants REMS discussions throughout the review cycle and a pre-advisory committee meeting with sponsors.

FDA has embraced review process efficiency through its Good Review Management Practices which aim to start consideration of post-marketing issues earlier in the process.

Where's The E-Vantage?

But the agency also wants funding in the next round of user fees for a project that would standardize electronic data in applications. (See chart: " ¹ User Fee Three-On-Three: FDA and Industry's Renewal Proposals ")

FDA's desire for a better way to handle electronic data is driven in part by the fact that so far, filling electronically has not conferred a review advantage to applicants.

Even though the agency automatically rates electronic applications as higher quality than paper-based ones, electronic submission alone was not found to have a statistically significant effect on review performance. But FDA said its ability to answer questions and investigate safety issues related to applications is hindered by the lack of electronic data standards.

One massive agency project just getting off the ground, Janus, is intended to allow reviewers to make easier data comparisons across applications (² (Also see "God Of Gateways: Will FDA's Massive Janus Database Drive Review Efficiency Or Comparative Effectiveness Research?" - Pink Sheet, 24 May, 2010.)).

The Data On Review Delays

At the meeting, the Pharmaceutical Research and Manufacturers of America presented an analysis of review times for new molecular entity applications submitted by their members from December 2007 through May 2010, which was termed post-FDA Amendments Act, meaning after the last renewal of the user fee program was enacted.

The analysis showed review times were longer during the 2.5-year period than previous years. A "considerable" proportion of NMEs were not reviewed by the user fee target date, according to the minutes.

It also concluded decisions on priority review applications tended to extend beyond the original user fee date and communications about risk evaluation and mitigation strategies as well as advisory committee meetings started late in the review cycle, making it difficult for FDA to meet PDUFA goals.

Advisory committees were held, on average, 1.5 months before the original user fee date for standard applications and more than a month before priority review goal dates.

Review Delays Already A PDUFA Topic

The complaint about review times was placed on industry's agenda when the reauthorization process began earlier this year. While neither organization stated the complaint specifically, both alluded to it.

When the PDUFA V process began in April, BIO submitted written comments stating data suggest the agency has struggled to meet performance goals. In FY 2008, FDA acted on 60 percent of priority NME or BLA applications within 6 months and 71 percent of priority NDAs and BLAs, well below the 90 percent goal, according to the comments.

BIO conceded the substandard performance may be because of the burden to implement FDAAA, but still said it was "troubled" by the review time trend.

"The dependability of FDA's good faith adherence to the established performance goals is one of the critical underpinnings to sustaining the PDUFA program," BIO said in its written comments.

PhRMA also said in a May written comment on the start of the PDUFA process it wanted to ensure the best use of agency resources through "enhanced management, governance and regulatory accountability" and said "the optimal review and approval process is one that is both efficient and judicious."

Office of New Drugs Director John Jenkins admitted problems with ramping up to new FDAAA requirements and in 2007 allowed drug review staff to miss PDUFA goals. Reviews were allowed to be delayed by up to two months and Jenkins reported staff listened. Late last year, Jenkins rescinded the directive (³ (Also see "The Good Old Days: FDA's Jenkins Instructs Reviewers To Meet Original User Fee Review Time Standard" - Pink Sheet, 7 Dec, 2009.)).

CDER Missed Nine NME Goals Last Year

An analysis by Pharmaceuticals Approvals Monthly found the Center for Drug Evaluation and Research hit nearly two-thirds of the NME and BLA user fee goals last year, even as Jenkins' directive allowing delays was in effect.

Nine of 25 NME and BLA approvals from CDER missed user fee goals, which was similar to the 2008 rate.

CBER's 2009 approvals were unique in that none of the new biologics were approved in the U.S. first. All nine applications had been approved overseas (⁴ (Also see "PDUFA Performance In The FDAAA Era: Over One Third Of Novel 2009 CDER Approvals Took Advantage Of Relaxed User Fee Goal Interregnum" - Pink Sheet, 1 Jan, 2010.)).

FDA Strikes Back With Own Analysis

FDA also came to the negotiating table with ammunition. According to the minutes, agency representatives questioned the accuracy of the industry study, saying it would be better if it accounted for user fee date extensions due to major application amendments submitted in the last 90 days of a review cycle.

The agency also produced its own analysis at the meeting of issues affecting review performance, looking at the complexity and quality of submissions. It said more complex and lower-quality applications correlated with a decrease in on-time performance.

The analysis - which looked at applications submitted from fiscal 2003 to 2009 in a single pool - defined complexity in terms of whether an advisory committee or REMS were necessary. Application quality was indicated by the number of information requests from FDA to sponsors, the number of filed application amendments, and whether the submission was in electronic or paper format.

The agency faces a two-fold challenge in using this data to help achieve its goals in the user fee negotiations. First, it has to convince industry that its definition of quality is a useful metric that firms can embrace to alter their applications and reduce their review times. As the example of electronic submissions illustrates, that might be a hard sell.

Second, FDA has to get sponsors to accept that issues ostensibly beyond their control - such as whether an application gets a REMS or an advisory committee - can result in review delays.

FDA declined to release the detailed results of the analysis, but it plans to subsequently publish the findings.

The Broader Picture On User Fee Renewal

Even as industry and FDA debate the best way to deploy resources to improve review times, both sides seem content to focus on the agency's traditional responsibilities rather than the more expansive approach undertaken in FDAAA (⁵ (Also see "PDUFA Old School: Industry Wants User Fees To Get Back To Basics" - Pink Sheet, 16 Jun, 2010.)).

They may not get their wish, however, especially if Democrats retain control of Congress. The legislative debate on the renewal of the user fee program could include efforts to add new limits on pharmaceutical advertising, increase FDA's oversight of foreign drug manufacturing, and - if it hasn't yet passed - new powers on food inspections.

Regardless of the political winds the PDUFA renewal proposal will eventually face, the process to finalize it continues. Process enhancement proposals will be discussed at the next industry-agency PDUFA meeting, scheduled for Sept. 13. Science and public confidence improvement ideas are the topic of a Sept. 27 meeting.

FDA also is meeting with other stakeholder groups to gather their ideas and proposals.

- Derrick Gingery ( ⁶ [email protected] )