This retrospective study examined the impact of the Food and Drug Administration's (FDA's) initiatives to improve the likelihood that applications would be approved by the agency during the first round of review ("first cycle review") for New Dug Applications, New Molecular Entities and Biologic Licensing Applications during the five-year period of the Prescription Drug User Fee Act ("PDUFA III"). A New Molecular Entity is an active ingredient that has never before been marketed in the United States in any form. The primary goal of this evaluation was to determine the factors that prevent applications from being approved on first review and that result in them being subject to more than one ("multi-cycle") review. The study did not evaluate the merit of the underlying science or quality of reviews (discipline reviews), but rather investigated process issues that might cause multiple review cycles. The analysis was based on data originating from FDA. Under the Prescription Drug User Fee Act, FDA committed to achieving specific performance goals to improve the effectiveness and efficiency of new drug application and biologics licensing application reviews.
Several goals sought to improve the review process that occurs between initial submission of an application and subsequent FDA action. Action Packages (product review documents including correspondence, meeting notes, discipline reviews, etc.) were analyzed relating to all new molecular entity drug and biologics licensing applications submitted during fiscal years 2002-2004 that reached the first step in agency action by December 1, 2004 (a total of 77 applications). These packages generally contained the critical information required for Office and/or Division Directors to decide whether to approve the application or whether it contains sufficient information to be either approvable or not approvable. Where feasible during the study, comments from FDA Regulatory Project Managers involved in the product reviews was solicited to fill in missing information. The factors that influenced the speed and effectiveness of reviews requiring multiple review cycles were found to include product and sponsor characteristics, quality of the design and execution of the drug development program, variations in review processes, and development of post-marketing commitments. One major finding was that priority and fast-track products had higher first-cycle approval rates. Beyond the unmet medical need however, increased regulatory and sponsor attention throughout the drug development and review process may have contributed to the timely identification and resolution of issues. Most products that failed to receive first-cycle approval had key deficiencies in only one or two categories, with an even breakdown between the categories of safety, efficacy, and chemistry.
FDA reviewer team members agreed that early on-going discussions with sponsors was the most important factor in order to identify issues and provided an opportunity for timely resolution, ideally before the first formal advisory letter was sent to the applicant ("first action"). Effective communication and responsiveness to FDA inquiries by applicants was prevalent in applications that were approved during the first-cycle reviews while persisting disagreements over issue resolution were associated with approval delays. FDA's Good Review Management Principles and Practices guidance (published on March 31, 2005) recommended specific timelines for New Drug/Biologics Licensing Applications review procedures. Further, early and open communication with the sponsors would allow sponsors to address/resolve issues in a timely manner, potentially within the first review cycle. A number of the suggested recommendations may have resource implications for the FDA and sponsors. The final step of the first cycle study is a prospective evaluation which began in 2006 and is expected to be completed by 2008.
Report Title: Independent Evaluation of the FDA's First Cycle Review Performance -- Retrospective Analysis Final Report http://aspe.hhs.gov/pic/fullreports/06/8313.pdf
Agency Sponsor: FDA, Food and Drug Administration
Federal Contact: Bobolis, Mary A., 301-827-5253
Performer: Booz Allen Hamilton; McLean, VA
PIC ID: 8313