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

Table of Contents

Issues and Communication

Booz Allen investigated sponsor characteristics as factors for influence on first-cycle review rates.  Sponsors were characterized by their experience (e.g., prior approvals with FDA in general and in same therapeutic class), the size of the company based on market capitalization, the type of company (pharmaceutical or biotechnology only), and origin based on location of headquarters. Based on observations during the study, many of these factors tended to have a direct or indirect impact on the sponsor’s ability to respond to FDA information requests, either through resource availability or knowledge of FDA policies and procedures.  In turn, the sponsor’s ability to respond to FDA’s information requests can impact approvability.

Sponsor Experience

Sponsor experience with the FDA approval processes appears to contribute to first-cycle approvals.  Experienced sponsors had first-cycle approval rates of 55% compared to 38% for sponsors with no prior approved products (Exhibit 37).

Exhibit 37. Single-Cycle Approval Rate by Sponsor Experience

Chart of Single-Cycle Approval Rate by Sponsor Experience

For those sponsors that had prior experience, the first-cycle approval rate was greater if that experience was in the same therapeutic area (58%) than if it was in a different area (45%).  This result is consistent with feedback from FDA focus groups, which suggested that unfamiliarity with FDA regulations and the drug/biologic application process is a key problem for inexperienced sponsors and results in poor quality submissions.

Of sponsors with no prior FDA approval experience, 52% opted not to hold an EOP2 meeting compared to 28% of experienced sponsors.  For the Pre-NDA/BLA meeting, 20% of inexperienced sponsors did not have the meeting, compared to 14% of experienced sponsors. Despite lower overall approval rates, inexperienced sponsors did not take advantage of opportunities to meet with FDA, where they might have been able to learn and resolve key application issues prior to submission (Exhibit 38).

Exhibit 38. Sponsor Experience and Impact of Pre-Submission Meetings

Chart of Sponsor Experience and Impact of Pre-Submission Meetings

Booz Allen also examined the amount of communication based on sponsor experience.  Sponsors differed in the amount of documented communication they had with FDA throughout the review cycle, depending on their level of experience. 

Exhibit 39. Cumulative Average First Cycle Communications During Review Period by Sponsor Experience

Chart of Cumulative Average First Cycle Communications During Review Period by Sponsor Experience

Sponsors that had prior FDA approvals averaged more communications during the review cycle, with the increase occurring primarily during the last half of the review.  These findings are consistent with previous findings that sponsors with applications moving towards approval have more communication with FDA at the end of review to discuss labeling and postmarketing commitments.

Sponsor Size

Large sponsors have usually experienced a successful FDA application submission in the past, so it is not surprising that large sponsors had higher first-cycle approval rates.  Applications submitted by large sponsors (i.e., market capitalization greater than $5 billion) were more likely to gain first-cycle approval for both traditional pharmaceutical and biotechnology companies than were medium- or small-sized (i.e., market capitalization under $5 billion) pharmaceutical or biotechnology companies (Exhibit 40).  Booz Allen speculates that the larger companies have more resources and processes dedicated to supporting the FDA review process than smaller companies.

Exhibit 40. Approval Rate vs. Sponsor Type and Origin

Chart of Approval Rate vs. Sponsor Type and Origin

Overall, biotechnology companies in the study had higher rates of first-cycle approval for their products than did pharmaceutical companies.  This difference appears to be largely due to the fact that biotechnology companies in the Overall Study Cohort had a greater proportion of Priority review applications (55%) among their total applications than did pharmaceutical companies (40%).  The first-cycle approval rates were also slightly higher for US-based sponsors (54%) than foreign sponsors (45%).

While there were differences in review designations between pharmaceutical and biotechnology companies that impacted the first-cycle review rates, both large and small companies had approximately equal proportions of Priority and Standard review applications in the full cohort (Exhibit 41).

Exhibit 41. First Cycle Approval Rate by Review Designation and Company Size

Chart of First Cycle Approval Rate by Review Designation and Company Size

The approval rate for Standard review applications was similar regardless of company size (38% for large vs. 35% for small).  However, the difference in approval rate on Priority applications was much more significant (78% for large vs. 48% for small), and accounts for the greater first-cycle success for large companies.  Booz Allen speculates that this substantial difference may indicate that smaller companies have more deficiencies in their applications and have difficulty managing the compressed, six-month review timeframe of the Priority review, while larger companies with more resources are better able to respond to FDA concerns and issues in a timely fashion.

Further analysis of a company’s size and application deficiencies revealed a noticeable trend in the number of categories of deficiencies identified and documented in the first action letter of multi-cycle products (Exhibit 42).  Small company applications were divided nearly evenly between those with deficiencies in one, two or more than two categories.  Medium companies had deficiencies in two categories in just over half of their multi-cycle application Action Letters and did not have any action letters citing more than two categories of deficiencies.  Finally, nearly two-thirds of large company action letters of multi-cycle products had only one category of deficiency and there were no action letters with more than two categories.  This illustrates that within the Prospective Analysis Cohort, even among applications that were not approved in the first cycle, larger companies had fewer areas with significant outstanding issues, suggesting that they either had better quality submissions or were more successful at resolving issues prior to the Action Date.

Exhibit 42. Deficiencies in Multi-Cycle Products by Sponsor Size in FY2005-2007

Company Size One Category Two Categories More Than Two Categories
Small (n=11) 4 products
  • 3 Efficacy
  • 1 CMC
4 products
  • 2 Efficacy and Safety
  • 1 Efficacy and CMC
  • 1 Safety and CMC
3 Products
Medium (n=8) 3 Products
  • 2 Safety
  • 1 CMC
5 Products
  • 2 Efficacy and Safety
  • 2 Efficacy and CMC
  • 1 Safety and CMC
Large (n=22) 14 Products
  • 6 Efficacy
  • 6 Safety
  • 2 CMC
8 Products
  • 5 Efficacy and Safety
  • 3 Efficacy and CMC

When further examining the differences between small and large companies, there appear to be differences in the number of communications initiated by either FDA or sponsors.  Larger companies average more communications with FDA regarding their applications during the first-cycle review than either small or medium companies (Exhibit 43), particularly in the first half of the review cycle. 

Exhibit 43. Cumulative Average First-Cycle Communications During Review Period by Company Size

Chart of Cumulative Average First-Cycle Communications During Review Period by Company Size

In addition to the findings already discussed concerning end-of-review communication (i.e., labeling and PMC discussion), Booz Allen speculates that this greater amount of early communication may help larger companies respond to FDA concerns and resolve issues more rapidly.  Booz Allen hypothesizes that an increase in resources available to communicate with FDA may explain the higher rate of first-cycle approval observed for large companies than in small or medium companies.  In particular, Booz Allen speculates this may help facilitate better outcomes in compressed Priority review schedules, which is consistent with the higher first-cycle approval for larger companies with Priority applications.

FDA Characteristics