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

Table of Contents

FDA Characteristics

Booz Allen developed recommendations based on the analysis and findings for the Overall Study Cohort combined with insights gained during our interviews and focus groups with FDA and Sponsors.  In general, our recommendations can be classified as either those that are designed to improve the quality of the submission or those designed to improve the quality of the review process (Exhibit 48).

Exhibit 48. Summary Overview of Recommendations

Chart of Summary Overview of Recommendations

Pre-Submission 1. Meeting Focus: FDA should continue its recent shift in emphasis on Pre-NDA/BLA meetings to include content in addition to format of product application.

2. Quality Measures: FDA should develop application quality measures to encourage future submission quality by offering sponsors an application checklist.

During Review and Post-Action 3. Communications Protocol: Sponsors and FDA should develop and obtain agreement on an application review communication protocol upon submission (e.g., communication format).

4. GRMPs Implementation: FDA should continue to implement GRMPs activities and timeframes for application review.

5. Quality System: FDA should supplement the GRMPs guidance with a quality system approach to continuously monitor and refine the process.

Overall 6. Early Issue Communication: FDA should continue early communication of issues through pre-submission meetings (e.g., EOP2, Pre-NDA/BLA) and during review (e.g., information requests, 74-Day letter).

7. Tracking and Resolution of Issues: Sponsors should continue to take advantage of opportunities for FDA feedback on potential and actual application issues such as EOP2, Pre-NDA/BLA, and 74-Day Letter Review Issues; sponsors should actively track and resolve these issues prior to application submission.

8. FDA Outreach: FDA should proactively initiate workshops with sponsors to outline communication methods, guidances, and FDA tools available throughout product development.

9. FDA Website: FDA should display a prominent tab on the FDA home page that organizes critical information and guidance for sponsors of new drugs and biologics.

10. Documentation Manual of Policies and Procedures (MaPP): FDA should develop a MaPP outlining best practices for documenting internal meetings and sponsor interactions.

11. Documentation of Sponsor Interactions FDA should consistently document sponsor interactions that are likely to impact product approvability (e.g., information requests, pre-submission conversations).

12. Knowledge Sharing Tool FDA should develop/use an internal FDA knowledge sharing repository to assist reviewers with approaches to resolve review issues.

Note: Some Offices already have some of these concepts in place.


FDA provides many opportunities for sponsors to interact with and obtain feedback from FDA prior to and during the application review process. These interactions represent valuable opportunities for the sponsor to obtain feedback regarding potential issues.  Sponsors should continue to participate in these meetings. Booz Allen observed higher first-cycle approval rates in applications submitted within six months of having the Pre-NDA/BLA meeting for the FY05 – 07 cohort than in the FY02 – 04 cohort.  FDA should continue its shift in emphasis of discussing data, in addition to application format issues.

Developing approaches for improving application quality will be the next challenge for FDA and sponsors after structured review processes have been successfully adopted.  Activities such as developing quality measures based on post-action application assessment and development of a quality checklist for sponsors to self-evaluate prior to submission may improve application quality.

During Review

Based on the findings, there is a significant difference in the frequency of communication associated with first-cycle vs. multi-cycle applications.  However, interviews with FDA staff indicate many sponsors engage FDA in non-productive communication via phone and email to determine the status of application.  To improve the efficiency and the effectiveness of the review process, Booz Allen recommends that FDA and sponsors agree on an application review communication protocol during filing determination.  Such a communication protocol would set expectations for sponsors about appropriate methods (e.g., secure email) and timeframes for FDA communication.

Although GRMPs have not yet been fully implemented, preliminary findings indicate that application reviews with high levels of compliance with assessed GRMPs activities had high first-cycle approval rates.  As such, Booz Allen recommends that FDA continue forward with GRMPs implementation, ensuring adoption of important milestones and timeframes.  Based on an initial 2006 assessment of GRMPs adoption and ongoing implementation, the impact of GRMPs should be assessed after rollout is completed.  Additionally, GRMPs need a mechanism for process improvement and feedback through quantitative metrics and staff perception, which could be provided through a quality system approach.  The objective of the quality system is to develop the mechanisms needed to sustain and improve the GRMPs. The quality system would include methods to evaluate the effectiveness of the GRMPs and provide processes and procedures to monitor, maintain, and refine the GRMPs.


Pre-submission meetings identified significant issues that ultimately impacted application approvability. FDA should continue to encourage sponsors to request these meetings and resolve the issues prior to application submission.  Booz Allen findings indicate that the 74-Day Letter is an effective tool for FDA to communicate application issues.  As indicated previously, the presence and severity of application issues was a major factor in multi-cycle review.  The proactive identification of application issues through the 74-Day Letter allowed applicants in many cases to address application issues prior to action. The FDA should continue to use the 74-Day Letter as an effective tool to communicate application issues.

Sponsors should maximize the efficiency and the effectiveness of the review process by tracking and resolving the issues identified during pre-submission meetings (e.g., EOP2, Pre-NDA/BLA) prior to application submission and actively resolving those issues identified during the review phase to the extent practicable. Sponsors should continue to acknowledge and address the issues presented in the 74-Day Letter.  Further, sponsors need to recognize that the 74-Day Letter does not represent a comprehensive listing of all application issues identified previously (e.g., EOP2 or Pre-NDA/BLA) or those that may be identified subsequently during the review process.

Inexperienced sponsors were less likely to hold key pre-submission meetings and had fewer FDA interactions throughout the review.  These sponsors would likely benefit from FDA-initiated efforts to clarify review processes and delineate tools and guidances available from FDA during product and application development.  One way to obtain this information is to engage in early and open dialog employing FDA-preferred methods (e.g. appropriate forms and correct submission procedures), and develop processes to rapidly respond to FDA requests.  The FDA can facilitate these activities with workshops and updated and streamlined guidance portfolios, as well as improving the utility of the website, which includes sections targeted to these sponsors. FDA could also update their website to better organize tools and guidances needed by sponsors during product development. Implementing and maintaining these recommendations may require additional FDA resources, but the cost of these additional resources could be offset, in the long-term, by reducing the incidence of multi-cycle reviews.

Booz Allen recommends that FDA develop a structured approach in the form of a MaPP for identifying and documenting FDA-sponsor interactions.  FDA should consider using Customer Relationship Management (CRM) software to document interactions.  Based on the importance of issue resolution in achieving first-cycle approval, FDA should develop a knowledge repository or sharing tool to identify, collect, and share successful experiences where issues were resolved during review.  More disciplined internal documentation practices will help maintain the FDA’s knowledge of issues communicated and information requested regardless of staff transition or long product development timeframes (e.g., multi-cycle review).  Developing a knowledge sharing capacity (e.g., cross application search capability to quickly locate information, location for knowledge exchange forums) among review staff will assist reviewers with identifying tested approaches and effective communication methods for issues across therapeutic areas.  Many commercial off-the-shelf knowledge management products (e.g., Documentum, Vignette, and FileNet) offer a set of features (e.g., content authoring, content storage, publication management) that could meet FDA’s business needs.