An independent analysis of FDA's first-cycle review performance provides support for the agency's request for additional funding for pre-submission meetings.

The report, conducted by Booz Allen Hamilton, concludes that "milestone" meetings have a positive impact on the number of review cycles, particularly end-of-Phase II (EOP2) meetings.

FDA is calling for additional user fee funding for industry-requested meetings to be included in the reauthorization of the Prescription Drug User Fee Act (¹ Also see "PDUFA IV: FDA Stresses Burden Of Industry Meetings In User Fee Discussions" - Pink Sheet, 21 November, 2005., p. 3).

According to an FDA white paper prepared in advance of PDUFA IV negotiations, the agency held 2,131 industry-requested meetings in fiscal year 2004, compared to 1,555 meetings in FY 1999 - an increase that FDA claims has not been met by a corresponding increase in funding.

In FY 2005, there were more than 2,400 meeting requests from industry, FDA said in a press release accompanying the BAH report. Overall, "requests for consultations to review clinical milestones and next steps in the development process are up more than 60 percent over the past few years under PDUFA III."

Acting Commissioner Andrew von Eschenbach noted that such meetings "are very labor intensive and require adequate agency resources in order to sustain the current success."

Booz Allen Hamilton conducted the retrospective analysis of factors affecting first-cycle approval of NDAs and BLAs as part of the performance management initiatives of PDUFA III. The 2002 reauthorizing amendments called for an independent consultant to evaluate the product review process and impact of the Good Review Management Practices initiative.

The study looked at the 77 NMEs submitted in fiscal years 2002-2004 that had reached first action by Dec. 1, 2004. The analysis was based on FDA records and interviews with FDA officials. "Gaining the perspectives of sponsors on the root causes for multi-cycle reviews was beyond the scope of this study," BAH noted. "A planned prospective study will include an opportunity to solicit input from sponsors."

In the NME cohort as a whole, 47% (36) were approved on the first cycle. Another 23% (18) were multi-cycle reviews, and 30% (22) were pending at the end of the study.

"Drivers of multi-cycle reviews were found to include product characteristics, sponsor characteristics, quality of the design and execution of the drug development program, variations in review processes, and development of post-marketing commitments," the report concludes.

"Most products with multiple cycles had major deficiencies identified in only one or two areas," FDA noted. "Deficiencies in safety assessment were the most common reason for FDA requesting additional cycles, followed by efficacy and chemistry/manufacturing related issues."

The most significant factor in obtaining a first-cycle review was having an EOP2 meeting. "Increased regulatory and sponsor attention throughout the drug development and review process may contribute to the timely identification and resolution of issues," the report explains.

"Of 46 products with EOP2 meetings, 52% received first-cycle approval, versus only 29% for products that did not have such meetings," Booz Allen reported.

The value of increased early communication between FDA and sponsors is further demonstrated by the high first-cycle approval rate for drugs with priority and fast-track designations, which provide for greater pre-submission communication.

Of the 26 drugs with priority status, 62% were approved on the first cycle; only 34% of standard review drugs were first-cycle approvals. Fast track drugs had a 58% single-cycle approval rate, compared to 42% of non-fast track products.

Although the EOP2 meeting was associated with a higher proportion of first-cycle approvals, the report notes that "there seems to be room for improvement: of the multi-cycle applications that had an EOP2 meeting, 25% of these applications had the critical issue preventing first-cycle approval identified at this meeting, indicating a failure or an inability by the sponsor to resolve problems prior to submission."

"Pre-NDA/BLA meetings, while important, do not appear to have as beneficial an effect on first-cycle outcome as EOP2 meetings," the report continues.

Fifty-eight products had a pre-NDA/BLA meeting, with a first-cycle success rate of 47% compared with 33% for products without such a meeting.

The timing of pre-NDA/BLA meetings in the development process contributes to their lack of impact on first-cycle approval rates, the consultants suggest. "When issues are identified, there is often insufficient time to adequately address these as submission timelines are generally not delayed." Another possible reason is that "the content of the pre-NDA/BLA meeting is generally regarded as administrative, with a focus on application format considerations."

To further improve first-cycle approval rates, FDA should play a "much more proactive role" throughout the development process, the report recommends.

"Currently, sponsors are responsible for requesting pre-submission meetings to discuss specific issues. While the FDA can also raise questions at these meetings, most divisions do not have formal protocols in place to ensure all key areas are covered."

One way for FDA to become more proactive is to develop "an open and accountable communication system centered around issue resolution," the report advises. Under the proposed "check and follow up" system, the agency could actively follow up with sponsors after milestone meetings to ensure that issues have been adequately addressed.

Sponsors also need to take advantage of the opportunity afforded by early milestone meetings by taking action to remedy deficiencies, the report says.

The BAH report is one part of the first-cycle review initiative spearheaded in 2003 by then-Commissioner Mark McClellan (² Also see "FDA First-Cycle Approval Rate For NMEs Leaps To 50% In 2003" - Pink Sheet, 29 December, 2003., p. 39). The other aspects include the GRMP guidance, released in April 2005, and the "74-day letters" to alert sponsors to deficiencies with applications.

The retrospective analysis conducted by BAH will also be matched by a prospective study of the root causes of multi-cycle reviews, starting with submissions in FY 2005.

[Editor's note: This is the first in a series of stories on the first-cycle review report, which will continue in the Feb. 20 issue with an analysis of suggestions on how to improve FDA-sponsor early communication.]

Key To First-Cycle Approval Is To Meet Early And Often, Consultants Tell FDA

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