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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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PDUFA V Program

Program for Enhanced Review Transparency and Communication for NME NDAs and Original BLAs
To promote greater transparency and improve communication between the FDA review team and the applicant, FDA will establish a review model (hereafter referred to as “the Program”) that will apply to all New Molecular Entity New Drug Applications (NME NDAs) and original Biologics License Applications (BLAs), including applications that are resubmitted following a Refuse-to-File action, received from October 1, 2012, through September 30, 2017.  (Note: The decision as to whether the application is included or excluded from the Program is distinct from FDA's determination as to whether the drug product contains a "new chemical entity," as defined under 21 CFR 314.108(a). Determinations regarding new chemical entity exclusivity are made at the time of approval of an application. ) The goal of the Program is to improve the efficiency and effectiveness of the first cycle review process and decrease the number of review cycles necessary for approval, ensuring that patients have timely access to safe, effective, and high quality new drugs and biologics. The Program shall be evaluated by an independent contractor with expertise in assessing the quality and efficiency of biopharmaceutical development and regulatory review programs. The parameters of the Program are as follows:

 

Pre-submission meeting: The applicant is strongly encouraged to discuss the planned content of the application with the appropriate FDA review division at a pre-NDA/BLA meeting

  1. The pre-NDA/BLA meeting should be held sufficiently in advance of the planned submission of the application to allow for meaningful response to FDA feedback and should generally occur not less than 2 months prior to the planned submission of the application.
  2. At the pre-NDA/BLA meeting, the FDA and the applicant will agree on the content of a complete application for the proposed indication(s), including preliminary discussions on the need for risk evaluation and mitigation strategies (REMS) or other risk management actions. This meeting will be attended by the FDA review team including appropriate senior FDA staff. The agreement and discussions will be summarized at the conclusion of the meeting and reflected in the FDA meeting minutes.
  3. At the meeting, the FDA and the applicant may also reach agreement on submission of a limited number of application components not later than 30 calendar days after the submission of the original application. These submissions must be of a type that would not be expected to materially impact the ability of the review team to begin its review. Any such agreement that is reached on delayed submission of application components will be summarized at the conclusion of the meeting and reflected in the FDA meeting minutes.
    1. Examples of application components that may be appropriate for delayed submission include updated stability data (e.g., 15­month data to update 12-month data submitted with the original submission) or the final audited report of a preclinical study (e.g., carcinogenicity) where the final draft report is submitted with the original application.
  4. Major components of the application (e.g., the complete study report of a Phase 3 clinical trial or the full study report of required long-term safety data) are expected to be submitted with the original application and are not subject to agreement for late submission.

 

Original application submission: Applications are expected to be complete, as agreed between the FDA review team and the applicant at the pre-NDA/BLA meeting, at the time of original submission of the application. If the applicant does not have a pre-NDA/BLA meeting with FDA, and no agreement exists between FDA and the applicant on the contents of a complete application or delayed submission of certain components of the application, the applicant’s submission is expected to be complete at the time of original submission.

  1. All applications are expected to include a comprehensive and readily located list of all clinical sites and manufacturing facilities included or referenced in the application.
  2. Any components of the application that FDA agreed at the pre-submission meeting could be submitted after the original application are expected to be received not later than 30 calendar days after receipt of the original application.
  3. Incomplete applications, including applications with components that are not received within 30 calendar days after receipt of the original submission, will be subject to a Refuse-to-File decision.
    1. Applications that are subject to a Refuse-to-File action, and are subsequently filed over protest, will not be subject to the procedures of the Program, but will instead be subject to the 6 and 10 month review performance goals for priority and standard applications, respectively, as described in Section I.
  4. Since applications are expected to be complete at the time of submission, unsolicited amendments are expected to be rare and not to contain major new information or analyses.
    1. Review of unsolicited amendments, including those submitted in response to an FDA communication of deficiencies, will be handled in accordance with the guidance “Good Review Management Principles and Practices (GRMPs) for PDUFA Products.” This guidance includes the underlying principle that FDA will consider the most efficient path toward completion of a comprehensive review that addresses application deficiencies and leads toward a first cycle approval when possible.

 

Day 74 Letter: FDA will follow existing procedures and performance goals (see Section III) regarding identification and communication of filing review issues in the “Day 74 letter.” For applications subject to the Program, the timeline for this communication will be within 74 calendar days from the date of FDA receipt of the original submission. The planned review timeline included in the Day 74 letter for applications in the Program will include the planned date for the internal mid-cycle review meeting. The letter will also include preliminary plans on whether to hold an Advisory Committee (AC) meeting to discuss the application.

 

Review performance goals: For NME NDA and original BLA submissions that are filed by FDA under the Program, the PDUFA review clock will begin at the conclusion of the 60 calendar day filing review period that begins on the date of FDA receipt of the original submission. The review performance goals for these applications are as follows:

  1. Review and act on 90 percent of standard NME NDA and original BLA submissions within 10 months of the 60 day filing date.
  2. Review and act on 90 percent of priority NME NDA and original BLA submissions within 6 months of the 60 day filing date.

 

Mid-Cycle communication: The FDA Regulatory Project Manager (RPM), and other appropriate members of the FDA review team (e.g., Cross Discipline Team Leader (CDTL)), will call the applicant, generally within 2 weeks following the Agency’s internal mid-cycle review meeting, to provide the applicant with an update on the status of the review of their application. Scheduling of the internal mid-cycle review meeting will be handled in accordance with the GRMP guidance. The RPM will coordinate the specific date and time of the telephone call with the applicant a) The update should include any significant issues identified by the review team to date, any information requests, information regarding major safety concerns and preliminary review team thinking regarding risk management, proposed date(s) for the late-cycle meeting, updates regarding plans for the AC meeting (if an AC meeting is anticipated), and other projected milestones dates for the remainder of the review cycle.

 

Discipline Review (DR) Letters: The FDA review team will follow existing guidance on issuance of DR Letters.

  1. Since the application is expected to be complete at time of submission, FDA intends to complete primary and secondary discipline reviews of the application and issue DR letters in advance of the planned late-cycle meeting. In cases where a DR letter is not issued in advance of the planned late-cycle meeting, substantive issues identified to date from that discipline will be communicated in the brief memorandum described in 7(b)(1).

 

Late-Cycle meeting: For all applications included in the review Program, a meeting will be held between the FDA review team and the applicant to discuss the status of the review of the application late in the review cycle.

  1. FDA representatives at the late-cycle meeting are expected to include the signatory authority for the application, review team members from appropriate disciplines, and appropriate team leaders and/or supervisors from disciplines for which substantive issues have been identified in the review to date.
  2. For applications that will be discussed at an Advisory Committee (AC) meeting, the late-cycle meeting will occur not less than 12 calendar days before the date of the AC meeting. FDA intends to convene AC meetings no later than 3 months (standard review) or no later than 2 months (priority review) prior to the PDUFA goal date.
    1. The Agency briefing package for the late-cycle meeting will consist of the Agency’s background package for the AC meeting, which will be sent to the applicant not less than 20 calendar days before the AC meeting, any discipline review letters issued to date, current assessment of the need for REMS or other risk management actions, and a brief memorandum from the review team outlining substantive application issues including potential questions and/or points for discussion for the AC meeting. FDA intends to provide final questions for the AC to the sponsor and the AC 2 calendar days in advance of the AC meeting.
  3. For applications that will not be discussed at an AC meeting, the late-cycle meeting will generally occur not later than 3 months (standard review) or two months (priority review) prior to the PDUFA goal date.
    1. The Agency background package for the late-cycle meeting, which will be sent to the applicant not less than 12 calendar days before the meeting, will consist of any discipline review letters issued to date, current assessment of the need for REMS or other risk management actions, and a brief memorandum from the review team outlining substantive application issues.
  4. Potential topics for discussion at the late-cycle meeting include major deficiencies identified to date; issues to be discussed at the AC meeting (if planned); current assessment of the need for REMS or other risk management actions; information requests from the review team to the applicant; and additional data or analyses the applicant may wish to submit.
    1. With regard to submission of additional data or analyses, the FDA review team and the applicant will discuss whether such data will be reviewed by the Agency in the current review cycle and, if so, whether the submission will be considered a major amendment and trigger an extension of the PDUFA goal date.

 

Inspections: FDA’s goal is to complete all GCP, GLP, and GMP inspections for applications in the Program within 6 months of the date of original receipt for priority applications and within 10 months of the date of original receipt for standard applications. This will allow 2 months at the end of the review cycle to attempt to address any deficiencies identified by the inspections.

 

Quality System: As part of a quality system approach to managing review in the Program, FDA will implement a tracking system that will document review team performance of the key milestones for each of the applications reviewed under the Program.

  1. These milestones include: conduct of pre-NDA/BLA meeting and agreement on content of complete application; submission of any components of the application within 30 calendar days of original application submission (as per pre-NDA/BLA meeting agreement); issuance of the 74-day letter; completion of mid-cycle communication with sponsor; completion of primary and secondary reviews; DR letters issued; exchange of late cycle meeting package; and conduct of late-cycle meeting.
  2. The process tracking information will support review management, and inform the subsequent analysis to be conducted by an independent third party (see below). The performance information generated by the tracking system will also be summarized and reported in the PDUFA annual performance report.

 

Assessment of the Program
The Program described in Section IIA shall be evaluated by an independent contractor with expertise in assessing the quality and efficiency of biopharmaceutical development and regulatory review programs. The statement of work for this effort will be published for public comment prior to beginning the assessment. The assessments will occur continuously throughout the course of the Program. Metrics for the assessments will include adherence by the applicant and FDA to the current GRMP guidance, submission of a complete application at the time of original submission, number of unsolicited amendments submitted by the applicant, timing and adequacy of Day 74 letters, mid-cycle communications, provision of late-cycle meeting memorandum outlining potential issues and questions for AC meeting consideration and discipline review letters; specific milestones of the Program as described in Section IIA; time to approval; percentage of applications approved on the first review cycle; and the percentage of application reviews extended due to major amendments. Following issuance of an FDA regulatory action at the completion of the first review cycle, the independent contractor will assess the completeness and thoroughness of the submitted application, Day 74 letter, mid-cycle communication, discipline review letters and late-cycle meeting. This assessment will include interviews of the sponsor and members of the review team, as appropriate.

 

Interim Assessment: An interim assessment of the Program will be published by March 31, 2015, for public comment. By June 30, 2015, FDA will hold a public meeting during which public stakeholders may present their views on the success of the Program to date including: improving the efficiency and effectiveness of the first cycle review process; decreasing the number of review cycles ultimately necessary for new drugs and biologics that are approved; and helping to ensure that patients have timely access to safe, effective, and high quality new drugs and biologics. During the public meeting, FDA will discuss the findings of the interim assessment, including anonymized aggregated feedback from sponsors and FDA review teams resulting from independent contractor interviews. FDA will also address any issues identified to date including actions proposed to improve likelihood of success for the program.

 

Final Assessment: A final assessment of the Program will be published by December 31, 2016, for public comment. FDA will hold a public meeting by no later than March 30, 2017, during which public stakeholders may present their views on the success of the Program, including improving the efficiency and effectiveness of the first cycle review process and decreasing the number of review cycles ultimately necessary for new drugs and biologics that are approved. During the public meeting, FDA will discuss the findings of the final assessment, including anonymized aggregated feedback from sponsors and FDA review teams resulting from independent contractor interviews and discuss any issues identified and plans for addressing these issues.