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FINDINGS: FDA Characteristics: Independent Evaluation of FDA's First Cycle Review Performance – Final Report

Table of Contents

Sponsor Characteristics

Booz Allen analyzed first-cycle approval rates by Offices (along with other factors) to identify best practices in application review.  Booz Allen also studied the number of applications by office, staffing changes and manufacturing inspections to determine their effects on first-cycle approval rates. These factors were analyzed independently without other potential factors that might affect first-cycle approval (e.g., application quality)

Approval by Division

Product approval was analyzed by review office to identify trends.  The total number of applications was analyzed as well as the total number of Priority and Standard review designated applications.  The first-cycle average approval rate by review office was analyzed and compared to the average overall cohort first-cycle approval rate.  Additional analyses of average first-cycle approval rates by office for Priority and Standard designations were conducted (Exhibit 44).

Exhibit 44. Cohort Applications by Office and Review Designation

Chart of Cohort Applications by Office and Review Designation

The analysis of application distribution by review offices revealed a range from 1 application to 40 applications per office over the FY2002-FY2007 cohort.  The Office of Antimicrobial Products (OAP) and the Office of Oncology Drug Products (OODP) had the largest number of applications (40 and 38, respectively). OAP and OODP also had the largest overall number of Priority-designated applications, with each having 26 applications.

The overall first-cycle approval rate by review office analysis showed that three of the four offices with more than 20 products in the FY2002-FY2007 timeframe had average approval rates lower than the overall cohort average of 50% (Office of Drug Evaluation(ODE) I, ODE II, OAP were lower, OODP was higher than average).  The highest overall first-cycle approval levels were found in OODP and Office of Vaccines Research and Review (OVRR), while the lowest were found in ODE I, ODE II, and Office of Cellular, Tissue, and Gene Therapies (OCTGT).

The average overall first-cycle approval rate for Standard applications was 36% for FY2002-FY2007; for Priority approval products it was 68%.  In general, the first-cycle approval rate in an office was correlated with the proportion of Priority review applications in the office.  The only notable exceptions were ODE III and OVRR, which had higher approval rates than would be expected based on the number of Priority applications, and OAP, which had a lower approval rate than would be indicated by the proportion of Priority applications.

FDA Workload

The number and timing of application submissions were evaluated as indicators of workload since FDA does not utilize 100% time reporting to track the duration of time spent reviewing a particular application and supporting activities.

Exhibit 45. Submission Timing and First Cycle Approval Rates

Chart of Submission Timing and First Cycle Approval Rates

Forty-four percent of all applications were submitted in the fourth quarter of the fiscal year throughout the cohort period, more than twice as many as the next highest frequency quarter (Exhibit 45). The first-cycle approval rate was also the lowest for applications submitted in the fourth quarter, and the only quarter that was below the study average (38% in the fourth quarter vs. 51% overall).  Examination of other factors (e.g., review designation, sponsor size, sponsor experience) did not provide any insight regarding the significant differences with these applications in comparison to applications submitted in other quarters.


FDA   Staffing Changes

Feedback in focus groups with FDA review staff suggested that staffing changes in the management or review team could cause inefficiencies in the review process.  This hypothesis was tested in the FY2002-FY2005 cohort, by analyzing first-cycle approval rates as a function of staff changes of Office leadership, Division leadership, Medical team lead, and RPM. [19] 

Exhibit 46. Staffing Changes Between Pre-Submission and Review

Chart of Staffing Changes Between Pre-Submission and Review

Chart of Staffing Changes Between Pre-Submission and Review

Across the cohort, the same staff member was generally involved with the application from pre-submission through the review. When staff turnover occurred the RPM was the most common position change (38% RPM change for applications where information was available).  Changes in staff between pre-submission and review did not seem to impact the first-cycle approval rate, except for the Medical team lead turnover (56% with no change, 38% with change).  Based on limited data, staff turnover did not impact first-cycle approval rates.

Manufacturing Inspection Process

Current Good Manufacturing Practice (cGMP) compliance is integral to the review process and action. For an efficient review, FDA reviewers stressed the importance of effective internal communication with divisions overseeing manufacturing compliance. Interviewees stated that delays in cGMP inspections can slow the review process and/or result in multi-cycle reviews.  Manufacturing deficiencies uncovered late in the review cycle may not allow sponsors sufficient time to correct issues before the Action Date. This concern was particularly pronounced for applications requiring inspections at foreign locations which, due to increased administrative requirements as well as field inspector resource constraints, generally have longer lead times.

There was no significant difference observed in the first-cycle approval rate between applications requiring foreign manufacturing site inspection and those with only domestic manufacturing inspections, as shown in Exhibit 47.

Exhibit 47. Impact of Foreign or Domestic Manufacturing Site

Chart of Impact of Foreign or Domestic Manufacturing Site

These data suggest that despite the potential for delay due to logistical challenges of foreign inspection, FDA manages this process efficiently, without significant delay that impacts first-cycle approval.  However, the long lead times for the planning and execution of site inspections (up to four months, with additional vulnerabilities for foreign inspections) can place single cycle approvals at risk for applications with Priority designation, which have compressed review times.  Among Priority review products, the first-cycle approval rate for applications requiring a foreign inspection was lower (60%) than for those with only domestic site inspections (76%), suggesting that the compressed review time may impact first-cycle approval when foreign manufacturing inspections are needed.  Indeed, either an inability to conduct or failure of a manufacturing site inspection contributed to the lack of first-cycle approval for one-third of the multi-cycle Priority review applications that required a foreign manufacturing site inspection. [20]