This section consists of a discussion of the findings from the analyses of the planned review timelines requirements, as well as Booz Allen’s recommendations to improve compliance.
5.1. Communication of Timelines in Filing Communication Letter
In the first year following the implementation of the planned review timelines requirement, the vast majority (86%) of applicable filing communication letters were compliant with including the target dates for initiating discussions of labeling and PMRs/PMCs with the applicant. There did not appear to be any division-specific practices or policies that influenced compliance with this requirement, as the six non-compliant applications were distributed across five different divisions. The most significant factor influencing non-compliance with this requirement appears to be the close proximity in time of receipt of the application with the rollout of the requirement. Among the first 11 applications received after the requirement went into effect, 5 (45%) failed to include the timeline in the filing communication, while only 1 of the remaining 33 (3%) was non-compliant. Further evidence that the recent implementation of the requirement was the primary cause of non-compliance is that 5 of 6 non-compliant applications were the first application(s) received by the review division after the requirement went into effect. Interviews with RPMs provided additional evidence that this is the main cause. In addition to noting that they did not remember the new requirement, three out of four RPMs of non-compliant applications interviewed indicated that they did not include the timelines because the standard letter template had not been updated with the new language by the time the filing communication was drafted and sent to the applicant. Once the new template was developed and made available in January 2009, nearly all applications included the timelines in the filing communication letter.
Another possible contributing factor for failing to meet this new requirement is training. Relatively few RPMs interviewed (6/18, 33%) said that they remembered receiving formal training about this new requirement and the processes involved. Most indicated that they learned in team meetings, from mentors, or from seeing the new language in the updated standard letter template. However, the fact that the timelines were included in most of the letters, particularly those sent after the standard letter template was updated and more than three months after the new requirement went into effect, suggests that lack of training may have been a contributing but not primary cause. Additionally, while the proportion of RPMs that received training in CBER was lower than that in CDER, all the CBER Filing Communication letters were compliant with the new requirement. The high rate of compliance after the initial period suggests that no further action may be necessary by FDA for this requirement.
5.2. Adherence to Communicated Timelines
While compliance with including the planned review timelines in the filing communication letter was high, compliance with meeting the established dates was relatively low, with only 39% (7/18) of applications meeting the target date. A similar proportion of relevant applications missed the target date for labeling (9/18; 50%) and PMR/PMC (4/9; 44%) discussions. While compression of the review cycle with a priority review designation would appear to be a potential factor in the failure to meet any late-cycle milestone, in the study cohort there was virtually no difference in compliance between standard (40%) and priority (38%) review applications. Similarly, there did not appear to be any correlation with non-compliance and a large number of applicant-submitted amendments, nor the late-cycle submission of the amendments.
There were two factors in the analysis that appeared to impact compliance with adhering to the planned review timeline, and they were both affirmed during interviews with the application RPMs. The first is related to the action taken. For applications that received a complete response, 78% (7/9) failed to meet the communicated target dates, while only 44% (4/9) missed the target dates for approved applications. More specifically, among the seven missed target dates for complete response applications, five were non-compliant for not initiating labeling discussions at all. Typically FDA does not negotiate labeling with the applicant for applications receiving a complete response, so the data seemed to indicate that FDA may have continued to operate under this practice in spite of the new requirement. Indeed, four of the five RPMs of these applications indicated that labeling discussions were not initiated because a complete response action was imminent. According to CDER’s MaPP 6010.8, review divisions are to “communicate to the applicant no later than the target date, generally through the issuance of a discipline review letter, the deficiencies and its determination that the deficiencies preclude discussion of labeling or PMRs/PMCs.” However, there was only one instance in the study cohort of a discipline review letter issued notifying the sponsor that deficiencies would preclude these discussions.
The second factor revealed in the data analysis was the need for an AC meeting. Applications that had AC meetings had a lower compliance (11%) in meeting planned review timelines than those that did not have an AC meeting (67%). This finding seemed rational because AC meetings require a significant amount of preparation and can easily disrupt and delay the remainder of the milestones in the review cycle. Once again, interview responses from RPMs validated the finding in the data. Three of five RPMs interviewed that had missed this milestone for an application with an AC meeting indicated that the AC meeting played a role in the missed target date.
The failure to notify applicants that significant deficiencies preclude the discussion of labeling or PMRs/PMCs by the target date identified in the timeline could be addressed through training. Rather than continuing the former policy of not informing applicants that labeling reviews were not going to occur, compliance may improve if RPMs and discipline reviewers are trained on the correct policy to notify an applicant that significant deficiencies preclude the discussion of labeling or PMRs/PMCs by the target date identified in the timeline.
For applications that will require an AC meeting, RPMs should take advantage of the flexibility in the policy allowing them to take into consideration special circumstances with an application, and provide planned review timeline dates closer to the PDUFA goal date. This would provide applicants with more reliable expectations for when they will hear from FDA regarding labeling and PMRs/PMCs, and would enable the review team to plan their activities against a more realistic schedule, which would improve compliance with meeting the communicated dates This notification should generally occur through the use of a discipline review letter.