In conjunction with the authorization of the Prescription Drug User Fee Amendments of 2007 (PDUFA IV), the Food and Drug Administration (FDA) agreed to meet specific performance goals, described in PDUFA Reauthorization Performance Goals and Procedures. Under Goal X of the PDUFA IV goals, First Cycle Review Performance Proposal, FDA agreed to notify applicants in the Filing Communication letter of a target date for communication of feedback from the review division regarding proposed labeling and postmarketing commitments (PMCs)  that the Agency will be requesting. In fiscal year 2009 (FY09), the first year of the new requirement, only new molecular entity (NME) New Drug Applications (NDAs) and original Biologics License Applications (BLAs) were required to include the target date in the Filing Communication letter.
FDA developed policy manuals, revised existing letter templates, and provided training to introduce and implement the new requirements. The Center for Drug Evaluation and Research (CDER) released the Manual of Policies and Practices (MaPP) 6010.8 in June 2008, which established the procedures for communicating the planned review timelines for CDER staff. The Center for Biologics Evaluation and Research (CBER) established the policy with the release of Standard Operating Procedures and Policies 8401.3. In CDER, RPMs and review disciplines were provided training opportunities through the Office of Training and Communications, as well as videotaped versions of the class that could be viewed as needed. Both Centers facilitated implementation of the new requirement by creating filing communication letter templates that contained new language to communicate the planned review timelines to applicants.
As of September 30, 2009, performance data were available for 44 planned review timelines notifications for original NMEs and BLAs, and FDA met the commitment for 86% (38/44) of them. FDA committed under PDUFA IV to reporting its performance in meeting the planned review timelines for communication of labeling and PMR/PMC comments. As of September 30, 2009, data showed FDA had met the planned target date for 39% (7/18) of the applications that had reached the communicated date.
CBER’s Regulatory Information Management Staff and CDER’s Division of Business Analytics and Reporting provided Booz Allen with the identity of the applications in the cohort, as well as their success or failure in meeting the two planned review timelines milestones. Data on each application for the root cause analysis were gathered from FDA documents, RPM interviews and applicant interviews. FDA documents were the first source for basic information about product and review characteristics (e.g., priority/standard review designation, Advisory Committee (AC) meeting, number of amendments submitted, and approval or complete response action). These data were analyzed and hypotheses were developed regarding the explanation for failure to meet the planned review timelines milestones. Interviews with RPMs of cohort applications were subsequently conducted to identify root causes for non-adherence.
Inclusion of Planned Review Timelines in Filing Communication Letter
The six applications for which the planned review timelines were omitted from the filing communication letter were distributed across five review divisions, indicating that there was not any office- or division-specific practice or policy that led to the omission. Rather, five of the six non-compliant letters were issued for the first applications received by that division after the requirement for including planned review timelines was instituted, suggesting that failure to include the planned review timelines may have been due to slow adoption of a new policy. While 67% (12/18) of RPMs interviewed indicated that they did not recall participating in formal training about the planned review timelines requirement, most said that they learned of the policy through informal channels such as mentoring or team meetings.
Adherence to Communicated Review Timelines
FDA did not adhere to the communicated planned review timelines for 61% (11/18) of the applications that reached the communicated date. The two factors that seemed to explain the failure to meet the communicated target dates were an anticipated issuance of a complete response letter for an application (seven applications) and the need for an AC meeting (nine applications). For five of the seven applications that did not meet the target date and received a complete response, FDA did not initiate labeling communications with the applicant at all. Interviews with RPMs indicated that labeling discussions were not initiated because the previous policy was that they were unnecessary for an application that was going to receive a complete response. AC meetings were held during the review cycle for half of the applications in the study cohort. Two-thirds (6/9) of the applications in the cohort that did not have an AC meeting met the planned review timelines milestone date, while only 11% (1/9) of the applications that had an AC meeting were able to meet the target date. RPMs interviewed said that the additional time spent in preparation for the AC meeting caused delays for reviewers to work on labeling, and that FDA could not initiate labeling or PMR/PMC discussions until comments from the AC meeting were received. Neither priority review designation nor the number of amendments submitted during the review cycle appeared to impact the ability of FDA to meet the communicated target dates.
FDA compliance with including the planned review timelines in the Filing Communication letter was relatively high (86%) in the first year of implementation. Compliance was even higher (~97%) after the first three months, suggesting that adoption of the new policy was initially slow but has since been nearly universal. RPM interviews confirmed this, and suggest that FDA may not need to take additional action on this requirement.
By contrast, only 39% of the communicated planned review timelines were met. The primary drivers appeared to be a continuation of the prior policy of not communicating with the applicant on labeling or PMRs/PMCs for complete response applications, and the additional work and waiting time required from an advisory committee for an application. These challenges can be overcome by different measures. First, training on the planned review timelines should emphasize that the new policy is to communicate with the applicant about labeling and PMRs/PMCs by the target date in the Filing Communication letter, even if a complete response is anticipated. Second, FDA should provide target dates that are as close to the end of the review cycle as possible while still adhering to the GRMPs, for applications that will require an AC meeting, which will give a more realistic goal and allow for better FDA compliance.
1. Although PDUFA Goal X only mentions PMCs, PDUFA IV created an FDA authority to require postmarketing requirements (PMRs), which FDA includes in the planned review timelines notification.
2. In the event that deficiencies preclude the discussion of labeling or PMRs/PMCs, FDA can meet the requirement by communicating this to the applicant by the target date.
3. The data in this report are those published in the FY 2009 Performance Report to the President and Congress on the Prescription Drug User Fee Act. While this study report was in final preparation, the FY 2010 Performance Report was released, which included updated FY 2009 numbers, shown in Appendix B.
4. As of September 30, 2009, the date communicated in 18 of the 38 applications that included planned review timelines had passed. Among the remaining 20 applications, the communicated dates for 18 applications had not yet passed, and a major amendment extended the review clock for two applications.