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U.S. Department of Health and Human Services

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

Table of Contents

Product and Disease Characteristics

In April 2005, FDA formalized GRMPs through the issuance of Guidance for Review Staff and Industry – Good Review Management Principles and Practices for PDUFA Products as agreed upon in the PDUFA III goals.  This guidance is intended for industry and review staff and focuses on good review management principles and practices as they apply to the first-cycle review of NDAs, BLAs, and efficacy supplements.  The GRMPs guidance is based on the collective experience of CDER and CBER with review of applications for PDUFA products.  The guidance is intended to promote the practice of good review management based on sound fundamental values and principles.  Adoption of GRMPs is intended to improve the quality, efficiency, transparency and consistency of the application review process. [10] The draft GRMPs guidance was published June 28, 2003, and the final guidance in April 2005.

The GRMPs divide the NDA/BLA review process into five distinct phases: filing determination and review planning, review, Advisory Committee meeting preparation and conduct, action, and post-action.  Within these phases, the guidance further identifies 42 review activities and associated timelines for completion within the phases of the review (Exhibit 12). 

 Exhibit 12. GRMPs Phases and Activities

Chart of GRMPs Phases and Activities

In 2006, Booz Allen analyzed the status of GRMPs implementation, the impact of GRMPs, and the sponsor perception of GRMPs on the review process (Appendix A: GRMPs Implementation Status, Appendix B: Sponsor and FDA Focus Group Findings).  For the FY2005 - FY2007 cohort, Booz Allen evaluated GRMPs compliance and impact by examining five key activities and their associated timelines as they applied to product application reviews: 

  • Hold filing meeting
  • Communicate filing review issues to applicant
  • Hold mid-cycle meeting
  • Complete primary review
  • Hold labeling discussions (for approval and approvable actions)

The choice of these five activities was based on the importance of the activity, as well as the availability of information to assess compliance with these activities. Specifically, these activities provided consistent documentation (e.g., meeting minutes, correspondence) to determine the timing and existence of these activities.  In determining compliance rates, Booz Allen assessed whether the activity was conducted within the timeframes.  For example, if a review team conducted three of the five assessed activities within the prescribed GRMPs timeframes, the compliance rate was captured as 60% (3 of 5 tasks).

We observed that applications that complied with most or all of the assessed GRMPs activities had the highest first-cycle approval rates (Exhibit 13).

 Exhibit 13. First Cycle Approval Rate by GRMPs Compliance

Chart of First Cycle Approval Rate by GRMPs Compliance

For the standard review products that had 20%, 40%, or 60% compliance, the overall first-cycle approval rate was similar (Exhibit 14).

 Exhibit 14. First Cycle Approval Rate by GRMPs Compliance and Review Designation

Chart of First Cycle Approval Rate by GRMPs Compliance and Review Designation

Booz Allen further examined first-cycle approval rates associated with increased GRMPs compliance to identify other factors (e.g., early communication, communication frequency) that may be related to or responsible for higher first-cycle approval rates.  However, the improved rates associated with GRMPs compliance could not be attributed to any specific aspect of GRMPs. With the limited data, Booz Allen did not perform a multi-variable analysis of GRMPs and other non-GRMPs factors that might affect first-cycle approval rates (e.g., application quality).

Compliance with assessed activities was not associated with earlier FDA communication with sponsors (Exhibit 15).  Overall, GRMPs compliance had no association with the frequency of communications between the FDA and the sponsor during a product review.  However, for Standard review designated applications, greater GRMPs compliance may have been associated with a slight increase in communication frequency.

 Exhibit 15. GRMPs Compliance and FDA-Sponsor Communication Frequency and Early Communication Timing

Chart of GRMPs Compliance and FDA-Sponsor Communication Frequency

While observing internal review meetings for the 41 FY2006-FY2007 products Booz Allen noted that review teams that captured post-meeting action items tended to spend less time revisiting issues in subsequent meetings, especially when action was needed by a discipline reviewer that did not participate full-time in the application review.  While the observed sample size was too small to generalize, the structured meeting and documentation practice appeared beneficial.  These observed activities were not required by GRMPs.  The activities included scheduling regular team meetings, briefly summarizing team meeting minutes and action items, and consistently documenting information requests sent to sponsors. 

Issues and Communication