Analysis of Planned Review Timelines
4.1. Communication of Timelines in Filing Communication Letter
Exhibit 2. Timelines Included/Omitted by Review Division/Office
Division of Cardiovascular and Renal Products
Division of Neurology Products
Division of Psychiatry Products
Division of Anesthesia and Analgesia Products
Division of Pulmonary, Allergy, and Rheumatology Products
Division of Metabolism and Endocrinology Products
Division of Gastroenterology Products
Division of Dermatology and Dental Products
Division of Reproductive and Urologic Products
Division of Medical Imaging Products
Division of Nonprescription Clinical Evaluation
Division of Anti-Infective and Ophthalmology Products
Division of Antiviral Products
Division of Special Pathogen and Transplant Products
Division of Drug Oncology Products
Division of Hematology Products
Division of Biologic Oncology Products
Formal training was offered in both CDER and CBER prior to rolling out the planned review timelines requirement. Although all cases of omitting planned review times from the Filling Communication letters were for applications in CDER, the proportion of RPMs interviewed who recalled receiving formal training on the new requirement was lower in CBER than in CDER. Of the RPMs interviewed, only 14% (1/6) of CBER RPMs indicated that they recalled receiving training, while 45% (5/11) of CDER RPMs received the training. Most reviewers who did not recall participating in training said that they learned of the requirement through informal processes such as mentoring, RPM meetings and team meetings.
Exhibit 3. Planned Review Timelines Formal Training by Center
The overall timing of applications received by month and compliance with including the planned review timelines in the filing communication reveals a clear pattern, shown in Exhibit 4. Planned review timelines were rarely omitted after the first three months of the new requirement: 5 of the first 11 applications (45%) failed to include the timelines, but only 1 of the remaining 33 applications (3%) failed to include the timelines in subsequent months. Three of the four RPMs interviewed about the non-compliance of their application with this activity indicated that they did not remember to include the dates because the letter template for the filing communication had not been updated to include the new language at the time they drafted the letter.According to the CDER Standard Templates committee, the planned review timelines language in the CDER template was included as of January 23, 2009. The filing communication letter template for CBER, in which all FY09 applications included the planned review timelines in the filing communication, was updated to include the planned review timelines as of February 1, 2008. In addition, CDER data systems were updated in July 2009 to prompt RPMs to enter the target dates.
Exhibit 4. Timelines Included/Omitted in Filing Communication by Month
Among the applicants interviewed about the planned review timelines, 54% (7/13) were aware of the new requirement for FDA to include the target dates in the filing communication letter and to meet those targets (Exhibit 5). Among those applicants interviewed who were aware of the requirements, half (3/6)  indicated that communicating the date in the filing communication letter was helpful. Specifically, these applicants noted that the timelines allowed them to plan and prepare for the labeling and PMR/PMC discussions, and to follow up with FDA if the date passes without hearing from the review team.
Exhibit 5. Applicant Awareness and Opinion of Planned Review Timelines Requirement
4.2. Adherence to Communicated Timelines
The Planned Review Timelines Manual of Policies and Procedures indicates that the “timeline for communication of labeling comments and PMR/PMC requests will be consistent with the GRMPs for NDAs and BLAs, taking into consideration the specific circumstances surrounding the individual application.”The GRMPs guideline is to initiate discussions three weeks before division sign-off, which would typically be six weeks before the PDUFA goal date. The range of timeframes for the planned review timelines that were included in the filing communication was between 14 and 44 days prior to the PDUFA goal date for CDER applications, and 28-30 days before the PDUFA goal date for the CBER applications.
Among the applications that were evaluated for compliance with adhering to these communicated planned timelines, 61% (11/18) failed to meet the date established to initiate communications regarding labeling and/or PMRs/PMCs. More than half of the applications (56%; 10/18) missed the target date for initiating labeling discussions, as shown in Exhibit 6. While 22% (4/18) of the applications failed to initiate PMR/PMC discussions on time, nine of the applications did not have any PMRs/PMCs in their action letter, so the proportion of applications with PMRs/PMCs that missed the communicated target date was 44% (4/9). Three of the applications that missed the labeling target date initiated communications within 15 days of the communicated deadline; however, no labeling discussions were initiated by FDA with the applicant for five applications. There was a wide range of time by which the PMR/PMC discussion target date was missed, and three of the four applications that missed this target date also missed the PDUFA goal date. The only exception was an application that received a major amendment that extended the goal date by three months.
A priority review designation may be granted to NDAs or BLAs that provide a major advance in treatment over currently approved products, and this designation provides for a shorter review cycle (6 months) than for a standard review (10 months). In spite of this compressed review timeframe, there was very little difference in the proportion of applications that met and missed the planned review timelines target dates between standard and priority review applications. As shown in Exhibit 8, the priority review applications met the target dates 38% (3/8) of the time, while standard review applications met the target date in 40% (4/10) of cases.
Exhibit 8. Target Date Compliance by Priority or Standard Review
AC meetings were held during the review cycle for half of the applications in the study cohort. These meetings require a significant amount of review team preparation and are often difficult to schedule, which can lead to timeframe compression for the downstream activities. As shown in Exhibit 9, 67% (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. Five RPMs of products that had an AC meeting and missed the target dates were interviewed, and three of them indicated that the advisory committee was a factor that led to missing the planned review timeline. More specifically, interviewees 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.
Applicants frequently submit amendments to the application throughout the review cycle, many times requiring additional review by discipline reviewers. This can potentially delay the completion of the primary review and impact the initiation of labeling and PMR/PMC discussions with the applicant. The number of amendments submitted, as well as the proportion that were submitted within the last 90 days prior to action, are shown for the cohort applications in Exhibit 10. There was no discernible pattern correlating the volume of amendment submissions to adherence with planned review timelines, as both the number of amendments submitted and the proportion submitted near the end of the review were similar for applications that met and did not meet the planned review timeline target date.