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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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SOPP 8401: Administrative Processing of Biologics License Application (BLA)

Version # 7
Effective Date:  April 25, 2013

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Table of Contents
  
I.      Purpose 
II.    Scope 
III.   Background 
IV.   Definitions 
V.    Policy 
VI.   Responsibilities 
VII.  Procedures 
 Receipt of Application
 Amendments
 First Committee Meeting
 Filing Decision, including Deficiencies Identified
 Review Tasks Prior to Mid-cycle Meeting
 Mid-cycle Meeting/Communication Telecon
 Review Continued
 Late-cycle Meeting for Applications Subject to the PDUFA V Program
 Review Wrap-up
 Complete Response Actions
 Approval Actions
 After Action Activities
VIII.  Appendices 
IX.    References 
X.    History 

  1. Purpose
    This document provides policies and procedures to Center for Biologics Evaluation and Research (CBER) staff on the administrative processing of Biologics License Applications (BLA) and New Drug Applications (NDA).

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  1. Scope
    1. This standard operating policy and procedure (SOPP) applies to original BLAs and NDAs processed by CBER.
    2. This procedure does not apply to BLAs subject to the Medical Device User Fee Act (MDUFA) or Abbreviated New Drug Applications subject to the Generic Drug User Fee Act (GDUFA).
    3. Supplements and annual reports are not covered in this SOPP. 
    4. Non-user fee products will be reviewed under CBER’s Managed Review Process (MRP) adhering to the user fee performance goal timeframes as resources permit.  Some steps in the process will not apply to non-user fee products.

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  1. Background
    1. The Biologics License Application (BLA) is a request for permission to introduce, or deliver for introduction, a biologic product into interstate commerce.  A BLA is submitted by the manufacturer and must contain data derived from non-clinical laboratory and clinical studies which demonstrate that the manufactured product meets prescribed requirements of safety, purity, and potency.  (21 CFR Part 601.2) 
    2. The New Drug Application (NDA) is the vehicle through which applicants formally propose that a new drug be approved for sale and marketing in the United States.  (Federal Food, Drug and Cosmetic (FD&C) Act Section 505(b))
    3. The Prescription Drug User Fee Act (PDUFA) was enacted in 1992 and renewed in 1997 (PDUFA II), 2002 (PDUFA III), 2007 (PDUFA IV), and 2012 (PDUFA V).  It authorizes FDA to collect user fees from manufacturers of certain human drug and biological products.  Since the passage of PDUFA, user fees have played an important role in expediting the drug approval process. 
    4. On September 27, 2007 the Food and Drug Administration Amendments Act of 2007 (FDAAA) was signed into law authorizing legislation including, among other things, PDUFA IV and reauthorizing two other laws:  the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA).  Both the BPCA and PREA are designed to encourage more research into, and more development of, treatments for children. The Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 reauthorized both BPCA and PREA and made them permanent.
    5. The most recent renewed legislation under PDUFA V is meant to promote even greater transparency and improve communication between FDA review teams and the applicant. FDA established a review model for new molecular entity (NME) NDAs and original BLAs with the goal of improving the efficiency and effectiveness of the first cycle review process and decreasing the number of review cycles necessary for approval (herein referred to as the PDUFA V Program). 
    6. Products subject to PDUFA user fees include most human drugs and biological drug products.  Products exempted from PDUFA include the following:
      1. Whole blood or a blood component for transfusion
      2. Bovine blood product for topical application licensed before September 1, 1992
      3. Allergenic extracts
      4. Cord blood and peripheral blood stem cells separated from whole blood by physical or mechanical means for transfusion
      5. An in vitro diagnostic biologic product licensed under section 351 of the Public Health Service (PHS) Act.  (These BLAs are subject to MDUFA.)
      6. A biological product licensed for further manufacturing use only
    7. CBER developed the Managed Review Process (MRP) with the goal of providing a process to most effectively and efficiently review all user fee and non-user fee license applications and supplements. This process begins during the investigational phase which builds the foundation of information necessary to demonstrate safety, efficacy and capability of consistent manufacture of a drug or biological drug product and continues through the postmarketing phase.  The MRP incorporates Good Review Management Principles and Practices (GRMP) guidance, including incorporation of quality, efficiency, clarity, transparency, and consistency during the review process.  CBER’s MRP consists of all CBER regulatory SOPPs, job aids, checklists, and templates, including letter and review templates that help the review community carry out their review responsibilities.  GRMP is outlined in FDA guidance (see references).
    8. Complementary to the MRP during the review and decision making process are the independent advice and recommendations of Advisory Committees (ACs).  They provide independent advice and recommendations to the FDA on scientific and technical matters related to the development and evaluation of products regulated by the Agency.  FDA requests advice from ACs on a variety of matters, including various aspects of clinical investigations and applications for marketing approval of drug products.  Advisory Committee members are scientific experts such as physician-researchers and statisticians, as well as representatives of the public, including patients.  Although the ACs provide recommendations to the Agency, final decisions are made by FDA. 

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  1. Definitions
    1. Amendment – information submitted to a pending application, including additional information or reanalysis of data previously submitted to clarify, revise or modify the application as originally submitted.
    2. Complete Response (CR) Letter –a letter issued when the complete review indicates that there are deficiencies remaining that preclude the approval of the application at that time. Note: A CR letter stops the review clock.  The CR letter will summarize all of the deficiencies remaining, and, where appropriate, describe actions necessary to place the application in a condition for approval.
    3. Day-74 Letter – a letter notifying the applicant of issues identified during the filing review phase that were not communicated in the filing letter. Note:  if the issues were already identified in the filing letter it is not necessary to issue a Day-74 Letter (also known as the “Deficiencies Identified” letter).
    4. Discipline Review (DR) letter– a letter sent to an applicant during an application review to convey early thoughts on possible deficiencies found by a discipline reviewer at the conclusion of the review of all assigned areas of the BLA or NDA application. 
    5. Establishment Inspection Report (EIR) – the report issued at the conclusion of an establishment inspection that summarizes the inspectional findings.
    6. Filing Letter – a letter issued to notify the applicant that their application has been filed and will be reviewed.  Note: The filing letter also includes information stipulated by PDUFA V and may contain any identified filing deficiencies.
    7. Information Request (IR) communication – a communication sent to an applicant during an application review to request further information or clarification that is needed or would be helpful to complete the discipline review. 
    8. Late-Cycle meeting – a meeting held for applications subject to the PDUFA V Program with the CBER review team, CBER senior management, and the applicant to discuss the status of the review of the application late in the review cycle.  Note: This meeting is not intended to discuss the pending regulatory decision on the application.
    9. Letter Ready Comments - written comments formulated by the reviewer(s) of an application written sufficiently well (e.g., correct grammar, spelling, punctuation) to be readily included in a communication (not always a letter) to the applicant.
    10. Mid-Cycle Communication – a phone call to the applicant that generally happens within two weeks following the internal mid-cycle review meeting to provide the applicant with an update on the status of the review of their application. (PDUFA V)
    11. Primary Discipline Review – a written review containing a reviewer’s assessment and recommendations of all assigned areas of the original BLA or NDA application.
    12. Priority Review – a reduced review schedule compared to a standard review schedule to potentially allow the product to reach the market faster. Note: Products are eligible for priority review if they provide a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious or life-threatening disease. 
    13. Standard Review – all non-priority applications are considered standard applications.
    14. Review Memorandum Addendum – information appended to a previously finalized review memorandum.  Note: This addendum may include a written review of any amendments that have been accepted for review by CBER since the primary discipline review was completed and documented, any AC recommendations, and/or results or actions stemming from issuance of an Establishment Inspection Report (EIR).
    15. Summary Basis of Regulatory Action (SBRA) – a summary of all relevant and pertinent information from the review of a BLA or NDA. Note:  The SBRA documents conclusions from all review disciplines (clinical/statistical, CMC, pharmacology/toxicology, etc.) about the product, notes any critical issues and disagreements with the applicant and within the FDA review team and how they were resolved, provides recommendations for action and an explanation of any non-concurrence with review conclusions, and provides a detailed discussion of areas in which there were notable issues, unusual aspects or problems with the data or analysis, novel features of design or conduct of studies.
    16. Unsolicited Amendment – a submission of information or data from the applicant that the Agency has not requested.

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  1. Policy
    1. All new marketing applications for products subject to licensure under the Public Health Service (PHS) Act are handled as BLAs or supplements to BLAs. The procedures in this SOPP are not inclusive of all detailed procedures used to process applications.  This SOPP is to be used with other related SOPPs, such as SOPP 8412: Review of Product Labeling and others listed in the references section that describe administrative handling and review of license applications.  New Drug Applications (NDA) are managed in the same manner as BLAs where appropriate.  Differences in NDA handling are described in the procedure section of this SOPP as needed.
    2. A signed form FDA 356h should be submitted with all BLA/NDA-related applications and correspondences to CBER.  This information will aid in routing the application to the appropriate division for processing. The person who signs an FDA application form (e.g., Form FDA 356h) is presumed to have signatory authority for the company, and therefore should be considered an Authorized Official of the company when submitting a BLA. Accordingly, the signatory of the original application, or designee, should sign all amendments submitted to CBER.
    3. Certification of Compliance, under 42 U.S.C. § 282(j)(5)(B), with Requirements of ClinicalTrials.gov Data Bank (42 U.S.C. § 282(j)) (Form FDA 3674) should be included with all applicable submissions, i.e., originals and amendments. The applicant is to determine the relevance of the application for compliance with Title VIII of FDAAA and check the appropriate box on the form.  The applicant should also indicate on the form the National Clinical Trial (NCT) number(s) that apply.
    4. Applications filed over protest after a refuse to file decision will not be subject to the procedures of the PDUFA V Program, but will instead be subject to the six and ten month review performance goals for priority and standard applications, respectively.
    5. For products covered by user fees, the performance goals established in the most current user fees goals letter will be met.
    6. Applications for non-user fee products will not be subject to the procedures of the PDUFA V Program, but instead will be subject to the CBER Managed Review Process.  Differences in handling are described in the Procedures section as needed.
    7. Review Assessment and its documentation starts when the application is received and progresses throughout the review time line, such that the primary discipline review must be nearly complete, if not complete, by the target date in time for the Mid-cycle meeting.
    8. CBER’s policy is that under normal circumstances product lot(s) should be available for distribution at the time of approval of most BLAs and NDAs.  Exceptions will be made on a case by case basis. Please refer to SOPP 8408.1:Development of Testing Plans and Release of Lots as Part of the Approval Process, for detailed information.
    9. The original application submission is expected to be complete per 21 CFR 601.2 and 21 CFR 314.  
      1. For products subject to the PDUFA V Program, the FDA review committee members and the applicant may agree at the pre-submission meeting on minor application components that are allowed to be submitted not later than 30 calendar days after receipt of the original submission of the application.
      2. For products subject to the PDUFA V Program, the only components allowed to be submitted more than 30 calendar days after the original application include stability and clinical safety updates.  Dates when these are to be provided should be discussed at the pre-submission meeting.
      3. Incomplete submission of an application, including failure to provide agreed upon information within 30 days of receipt of the application, will be subject to a refuse to file decision. Please refer to SOPP 8404: Refusal to File Procedures for Biologic License Applications for additional information.  
    10. Review Timeline: 
      1. For products subject to the PDUFA V Program, the review timeline begins upon acceptance of the original application submission for filing, no later than 60 calendar days from the date that FDA receives the application.
      2. For products subject to PDUFA but not subject to the PDUFA V Program, the review timeline begins upon FDA receipt of the application.
      3. For non-user fee applications, the review timeline begins upon FDA receipt of the application.
    11. Filing Meeting:
      1. Filing meetings are expected to occur.  Filing meetings for non-user fee products, however, occur as needed when the application is incomplete or other issues are identified by the review team.
      2. Prior to the filing meeting each reviewer is expected to document in a review memorandum any potential issues with the application that could result in a refuse to file decision or be included in the Day-74 letter.
      3. The filing review memorandum may be a formal memorandum or take the form of an email, with the immediate supervisor copied.  It is up to the discretion of the reviewer and the supervisor to determine which documentation method is used.
      4. Regardless of the documentation method used (formal memorandum, email, etc), the documented filing review memorandum must be entered into the appropriate regulatory database and imported into CBER’s Electronic Document Room (EDR).
      5. The filing meeting summary is also entered into the appropriate regulatory database and imported into CBER’s EDR.
    12. Review of unsolicited amendments and responses to a Day-74 letter communication of deficiencies will be handled in accordance with the guidance “Good Review Management Principles and Practices” (GRMP) for PDUFA Products. 
    13. Mid-cycle meeting:
      1. By the Mid-cycle meeting, each reviewer is expected to document their review progress in assigned areas of responsibility in a draft primary discipline review memorandum that summarizes content, documents the reviewer’s assessment and identifies key issues identified to date.
      2. At the Mid-cycle meeting each reviewer is expected to discuss key findings documented in the draft primary discipline review memorandum.   A Reviewer’s Report that summarizes substantive issues copied from the draft primary review memorandum and a proposed plan to address these issues must be provided by email to the RPM in advance of the meeting.
      3. For non-user fee products, formal Mid-cycle meetings are encouraged and will be conducted on an as-needed basis.
      4. For products subject to the PDUFA V program, the Regulatory Project Manager (RPM) and chair will have a Mid-cycle communication telecon with the applicant within two weeks following the Mid-cycle meeting to provide an update on the status of the review.
    14. Late-cycle meeting for submissions that qualify under the PDUFA V Program:
      1. The following must be provided to prepare the Late-cycle review committee memorandum:
        1. If a discipline review letter is not issued prior to the Late-cycle meeting:
          1. Each discipline reviewer will develop a brief memorandum copied from the primary discipline review identifying substantive issues to date for inclusion in the review committee memorandum issued to the applicant.
          2. The discipline reviewer’s brief memorandum will undergo a secondary review prior to inclusion into the review committee memorandum.
        2. If a discipline review letter is issued prior to the Late-cycle meeting, the review committee memorandum that accompanies the Late-cycle meeting materials may be prepared by copying the information contained in the letter already issued after a review is performed to determine that the copied information continues to be relevant.  Management concurrence must be obtained on the content of the final Late-cycle review committee memorandum prior to issuance to the applicant.
        3. If a discipline review letter is issued prior to the Late-cycle meeting and additional substantive issues have been identified, the Late-cycle review committee memorandum that accompanies the Late-cycle meeting materials issued to the applicant should contain the information from the letter already issued and those additional substantive issues that have been identified.
      2. The Office Director and/or Deputy Office Director, review committee members, and team leaders or supervisors from disciplines with substantive issues must be present at the Late-cycle meeting.  The meeting must be rescheduled if the Office Director or Deputy Office Director cannot attend.
      3. See SOPP 8401.1: Issuance of and Review of Responses to Information Request Communications and Discipline Review Letters to Pending Submissions for additional information.
    15. Advisory Committee (AC) meetings:
      1. Should occur no later than three months (standard review) and no later than two months (priority review) prior to the user fee goal date.
      2. The Agency briefing materials will be sent to the applicant not less than 20 calendar days before the meeting.
      3. Final questions for the AC should be sent to the applicant and the AC at least two calendar days in advance of the AC meeting.
      4. If the AC is scheduled earlier than when the Late-cycle meeting occurs (due to AC scheduling outside the review team’s control), only the background materials for the AC meeting will be sent to the applicant.
    16. It is critical that the review committee members keep management, including Office and Center senior management, up-to-date with any significant review issues.  Additionally, all communications, including telephone calls and other informal communications are to be continuously entered into all appropriate regulatory databases in real time; all documents should be uploaded to CBER’s Electronic Document Room (EDR). All letters issued by CBER must use the most recent approved template found on CBER’s Review Letter Templates Intranet Web page.
    17. Defined dates used on CBER correspondence and entered into CBER databases are described in regulatory job aid JA 820.02: Dating of CBER Correspondence.  CBER correspondence includes letters, internal memoranda, meeting or telecon minutes, and internal or outgoing e-mails or facsimiles (fax).
    18. An internal post action meeting will be held with all members of the review team within 45 days of ending the first review cycle (i.e., issuing the first CR or approval) to discuss the review team dynamics, interactions with the applicant, basis of decisions, what worked well, and what didn’t work well during the review cycle.  The goal is to identify improvements that can be made within team dynamics and Center or Office procedures.  A summary of the meeting including specific recommended changes should be recorded and communicated to the Associate Director for Review Management (ADRM), who will disseminate as appropriate to other CBER staff.
    19. All CBER correspondence should be entered in the appropriate regulatory database and imported into the EDR prior to the final action (e.g., approval, withdrawn, refuse to file).  After the final action is taken, applicant amendments will be allowed to the submission for 14 calendar days. Changes to CBER communications/documents will be allowed for 30 calendar days.  After these timeframes, a lockdown will be initiated and no additional or revised documents will be added to the submission without approval.  Refer to regulatory job aid JA 910.08: Lockdown of Applicant Submissions and CBER Correspondence for Marketing Submissions posted on CBER’s Intranet for additional information.

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  1.  Responsibilities
    1. Review Committee Chair (Chair) - discusses and assures resolution of scientific issues and associated regulatory interpretations in concert with management. Specific responsibilities include ensuring that all sections of the application have been assigned for review, drafting of the SBRA, and bringing scientific issues to the attention of management and facilitating resolution and consensus.  The chair works closely with the RPM in executing these duties. (Note: The CDTL as referred to in the PDUFA V Program is considered the chair within CBER.)
    2. Office Director, Deputy Office Director - the Signatory Authority who signs action letters and concurs or does not concur with the reviewer’s assessments and recommendations.
    3. Document Control Center(DCC) –processes all incoming submissions, including loading electronic applications into CBER’s Electronic Document Room, routing paper applications, processing, jacketing and storing approved applications, and filling document/file requests.
    4. Office Electronic Submissions Coordinator (ESC) - reviews electronic applications for “readability” and ensures reviewers have appropriate access to data files.
    5. Regulatory Project Manager(RPM) –responsible for the overall management of the review.  Specific responsibilities include scheduling review committee meetings, ensuring regulatory and administrative actions are completed on time, notifying management when timelines are not met, reviewing assigned sections, performing quality control checks, capturing review committee communications, ensuring regulatory databases are updated, and ensuring the file is administratively complete.
    6. Review Committee Members – each member of the committee performs a review of all assigned areas of submissions, participates in review meetings, and documents the review by writing a review memorandum, entering the review memorandum into the appropriate regulatory database and uploading documents to CBER’s EDR. This review should be scientifically sound and follow Good Review Management Principles and Practices.
    7. Supervisors – ensures the overall content of reviews are appropriate, all administrative processing steps are completed, including database data entry, and all deadlines are met.  Reviews and approves employees review memorandums and other submission documents per CBER policies and procedures.

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  1. Procedures
    1. Each step in the procedure section is chronologically listed where practicable.  It is permissible to accomplish steps out of sequence when appropriate.  Some steps in the process will not apply to non-user fee products.
    2. Application reviews are completed using the following process.  Each individual process is detailed in the following sections of this SOPP.
    3. Review assessment and its documentation starts when the application is received and progresses throughout the review time line, such that the primary discipline review must be nearly complete, if not complete, by the target date in time for the Mid-cycle meeting.

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    1. Receipt of Application
      1. Receive, process, log into CBER’s Document Accountability and Tracking System (DATS), and route to the appropriate Office all paper applications and extra reviewer copies. [DCC]  Note:  DCC will route the application based on the product name as reported by the applicant on the Form FDA 356h following current DCC routing procedures.
      2. Process electronic applications and notify the appropriate Electronic Submission Coordinators (ESCs) per DCC Procedure Guide 22: Procedure for Processing, Routing, and Storing Electronic Submissions[DCC]
      3. Maintain the original copy of the application (paper and/or electronic) in DCC as an uncirculated record copy. [DCC]
      4. Review electronic applications for “readability” (e.g., structure, format, presence of bookmarks, hyperlink functionality, etc.) throughout the entire application. [ESC]
      5. Ensure Office specific mailboxes for electronic applications are monitored and load notifications are triaged. [RPM, ESC]
      6. Determine the user fee status and send a copy of the PDUFA User Fee Cover Sheet, Form FDA 3397, to CBER PDUFA Staff[RPM]
      7. Ensure the information on the PDUFA User Fee Cover Sheet is accurate. Enter user fee identification number and payment date into the appropriate regulatory database for products subject to user fees. [CBER PDUFA Staff]
        1. Notify the applicant and inform the review committee members to halt review if user fees are not received within five (5) calendar days of the CBER receipt date. [RPM]
        2. Ensure “unacceptable for filing” paragraph is included in Submission Tracking Number (STN) assignment/acknowledgment letter if user fees are not received.  [RPM]
      8. Screen the application to confirm all the sections are present and consistent with the Table of Contents (TOC).  Notify the applicant of inconsistencies. [RPM]
      9. Ensure Form FDA 3674 (for clinical trials) was submitted, all information necessary was provided, and the information is included in the regulatory database. If the form was not submitted, contact the applicant to request it. [RPM]
      10. Ensure that an STN is assigned for an original BLA/NDA and all data are entered in the appropriate regulatory database (all necessary fields are completed, including the short summary). [RPM]
      11. Identify other submissions: [RPM]
        1. Identify any submissions referred to by the application (Form FDA 356h and within application).
        2. Enter these referenced submission numbers into the appropriate regulatory database.
        3. Request a copy of any referenced Drug Master Files to be routed to appropriate reviewers as a reference.
      12. Check for Study Data Tabulation Model (SDTM) or Analysis Data Model (ADaM) data and, if present, notify CBER’s Clinical Data Interchange Standards Consortium (CDISC) representative.  [RPM]
      13. Determine if PREA is triggered and notify the office Pediatric Review Committee (PeRC) representative if appropriate. [RPM]  Note:  PREA is triggered when an application for a drug or a biological product is submitted for:
        1. a new indication
        2. new dosing regimen (any change in a single dose, maximum daily dose or dosing interval)
        3. new active ingredient (including a new combination)
        4. new dosage form (e.g., vial to transdermal patch)
        5. a new route of administration (e.g., subcutaneous to intramuscular)
      14. Notify the appropriate supervisors of receipt of the original BLA/NDA application requesting assignment or confirmation of review committee members, including the following as applicable: [RPM]
        1. Clinical Reviewer
        2. Clinical Pharmacology Reviewer
        3. Pharmacology/Toxicology Reviewer
        4. Developmental Toxicology Reviewer
        5. CMC Reviewer
        6. CMC – Analytical Methods Reviewer
        7. CMC – Instrumentation and Software Reviewer
        8. OCBQ
          1. DMPQ Reviewer
          2. APLB Reviewer
          3. BIMO Representative
          4. DBSQC or LIB Representative
        9. Statistical Reviewer of clinical data
        10. Statistical non-clinical Reviewer
        11. Postmarketing Safety Epidemiological Reviewer
        12. PeRC Representative (CBER product office)
        13. Consult Reviewer (other Center, Office; follow Intercenter Agreement procedures, as applicable)
      15. Request additional copies of pertinent volumes of paper application from the applicant as needed.  [RPM]
      16. Notify or confirm with the RPM and assigned committee members that they are part of the review committee. [Supervisor]
      17. Ensure access of the electronic application in the EDR for all review committee members. [ESC, RPM]
      18. Enter all committee members, including those in DMPQ, DBSQC or LIB, OBE, APLB, BIMO and consult reviewers in other Centers in the appropriate regulatory database. [RPM]
      19. Inform the Data Abstraction Team (DAT) the product reviewer(s) assigned for review of animal, biological, chemical component/information if applicable per SOPP 8401.5: Processing Animal, Biological, Chemical Component Information Submitted in Marketing Applications and Supplements. [RPM]
      20. Route application. [RPM]
        1. For electronic applications, ensure load notifications are sent to appropriate review personnel.
        2. For paper applications, route application to all committee members using the Routing Request application in RMS-BLA for BLAs and DCC Action Notice (DAN) for NDAs.
        3. Notify all identified review committee members, including consult reviewers, and their supervisors, as appropriate, by email of the routing of paper applications as a reminder to look for the application in their office.
        4. Route all available review copies in the priority order designated by the RPM. [DCC]
      21. Initiate review and determine if the application can be filed. See Filing and Review Section below for details. [Review Committee Members]
      22. Establish/confirm a draft review schedule, including: [RPM, Chair]
        1. first committee meeting
        2. filing meeting
        3. PeRC meeting
        4. Mid-cycle meeting
        5. labeling meetings
        6. Late-cycle meeting (for applications that qualify under the PDUFA V Program)
        7. Other meetings as necessary (i.e., Advisory Committee, CBER FDAAA Safety Working Group (SWG) if there are postmarketing requirements)
      23. Schedule all review meetings using Microsoft Outlook, inviting all review committee members, supervisors, and senior management as appropriate. [RPM]
      24. Send an email to both “NMEProgram” and “CBER ADRM Meeting” inviting the Eastern Research Group (ERG) and the Associate Director for Review Management (ADRM) to PDUFA V Mid-cycle communication and Late-cycle meetings. [RPM]
      25. Ensure all review committee members have access to all appropriate electronic systems, including eRooms. [RPM]
      26. Ensure a check is made with the Biologics Information Tracking System-Pre-Applications Module (BITS-PTS) and Biologics Investigational and Related Applications System (BIRAMS). [RPM]
        1. Applicable cross-references should be listed in the regulatory databases if appropriate.
        2. Ensure the BITS-PTS number is closed, if appropriate. Please refer to SOPP 8114: Administrative Processing of Documents Received Prior to Submitting Investigational or Marketing Submissions (Pre-Applications) for additional procedures.
      27. Ensure the STN acknowledgment letter is issued for the original BLA/NDA application. [RPM]
      28. Determine what pre-license or pre-approval Good Manufacturing Practices (GMP) and Good Laboratory Practices (GLP) inspections and/or BIMO inspections are necessary; write inspection waiver memorandum(s) if appropriate. [Review Committee Members]

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    1. Amendments
      1. Receive, process, log into CBER’s DATS, and route to the appropriate Office all paper amendments. [DCC]
      2. Process electronic applications and notify the appropriate Electronic Submission Coordinators (ESCs) per DCC Procedure Guide 22: Procedure for Processing, Routing, and Storing Electronic Submissions[DCC]
      3. If the request for the Proprietary Name Review (PNR) is received separate from the BLA/NDA, categorize the amendment, enter the information into the appropriate regulatory database and notify the review committee members, including APLB, that the amendment is ready for review.  [RPM]
      4. Enter short summary of the content of the amendment into the appropriate regulatory database. [RPM]
      5. Notify the appropriate review committee members that an amendment has been received and forward the amendment information. [Chair, RPM]
      6. Determine if the amendment should be classified as a major amendment.[Review Committee Members, Division Director]. If the amendment is designated as major:
        1. Create review memo stating the designation of major amendment and the justification. [Chair]
        2. Notify the applicant following the procedures in SOPP 8402: Designation of Amendments as Major. [RPM]
        3. Enter the information in the appropriate regulatory database to extend the review clock. [RPM] Note:  There is only one major amendment allowed per review cycle.
      7. Review the amendment. [Review Committee Members, Chair, RPM]

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    1. First Committee Meeting
      1. Verify that all the sections of the application are present and consistent with the Table of Contents (TOC).  Notify the applicant of inconsistencies. [RPM]
      2. Screen the application to confirm all consultant reviews necessary are identified and appropriate consult reviewers have been notified. [RPM, Chair]
      3. Conduct first committee meeting: [Chair, RPM]
        1. Ensure all review committee members are assigned as appropriate. [Chair]
        2. Ensure all review committee members have a clear understanding of their review responsibilities. [RPM, Chair]
        3. Ensure all review committee members have received the appropriate documents or electronic links. [RPM]
      4. Determine if an AC meeting is likely.  If not, per FDAAA, Section 918, the justification should be included in the meeting summary.  It should also be included in the SBRA. Note: FDAAA requires justification in the approval letter if AC meeting was not held. [Review Committee Members, Chair]
      5. Confirm the review schedule and all future meeting dates. [Review Committee Members]
      6. Confirm the filing meeting was scheduled via Microsoft Outlook and discuss expectations for the filing meeting. [RPM, Chair]
      7. Identify any potential issues found during the early review, including identification of data sets submitted incorrectly, use of data standards, problems encountered opening data tables, or absent datasets. [Review Committee Members]
      8. Confirm what pre-license or pre-approval inspections are necessary. [Review Committee Members]
      9. Identify BIMO sites requiring inspection. [BIMO, Clinical Reviewer(s)]
      10. Write first committee meeting summary and identify follow-up activities.  Enter meeting summary data into appropriate regulatory database and upload summary to CBER’s EDR.  [RPM, Chair]
      11. Perform review in preparation for filing meeting.  [Review Committee Members]

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    1. Filing Decision, including Deficiencies Identified
      1. Review the application for any refuse to file (RTF) issues.  The application should be compliant with 21 CFR 601.2 for BLAs and 21 CFR 314.101 for NDAs. The application should contain the information and data agreed to during the pre-submission meeting, except for applications under the PDUFA V Program.  Applications under the PDUFA V Program are allowed to submit stability and clinical safety updates not later than 30 calendar days after receipt of the original application. Follow SOPP 8404:  Refusal to File Procedure for Biologic License Applications. [Review Committee Members]
      2. Notify the chair and generate a review memorandum with management concurrence if a member of the review committee recommends the application should not be filed. [Review Committee Members]
      3. Alert the supervisory chain immediately upon discovering that a RTF recommendation may be made.  [Chair]
      4. Enter SDTM or ADaM eReview into appropriate database if appropriate. [CDISC Reviewer]
      5. Consult listing of individuals and firms per SOPP 8001.2: Accessing the FDA Lists of Disqualified and Restricted Clinical Investigators, Debarred Individuals, and Firms Under the FDA Application Integrity Policy. [RPM]
      6. Evaluate the information disclosed under §54.4(a)(2) about each covered clinical study in an application to determine the impact of any disclosed financial interests on the reliability of the study. [Clinical Reviewer, RPM]
      7. Hold filing meeting.  At the filing meeting, each reviewer is expected to discuss the relevant content of the application and present an overview that includes: [Review Committee Members]
        1. A summary of the submitted material;
        2. A description of any required material that may have been omitted from the application;
        3. Any substantive deficiencies or issues that potentially have significant impact on the ability to complete the review or approve the application;
        4. Comments on the status of the proprietary name review;
        5. A proposal  on whether the product would be subject to lot release, surveillance or exempt from lot release per SOPP 8408.1: Development of Testing Plans and Release of Lots as Part of the Approval Process;
        6. A discussion on the need for a RTF or deficiencies identified letter;
        7. A decision on filing, deficiencies identified or RTF;
        8. A decision regarding standard or priority review status; and
        9. A decision regarding need for an Advisory Committee.
      8. Document decisions in filing meeting summary. For non-user fee products without a filing meeting, document the filing decision in a filing memorandum. [RPM]
      9. Document the RTF decision, if applicable:
        1. Finalize RTF review memorandum and obtain management concurrence.  [Review Committee Members]
        2. Provide the memorandum to the RPM. [Review Committee Members]
        3. Enter all documentation in the appropriate regulatory database and import into CBER’s EDR. [RPM]
        4. Refer to SOPP 8404: Refuse to File Procedure for Biologics License Applications for additional procedures, including those on notifying the applicant. [Review Committee Members]
      10. Document the filing decision, if applicable:
        1. An email to the RPM with the decision is sufficient if the supervisor is copied.  [Review Committee Members]
        2. Enter filing meeting date or filing memorandum date in appropriate regulatory database. [RPM]
        3. Issue a filing letter using the appropriate letter template, upon concurrence of a filing decision.  Enter the letter date into the appropriate regulatory database and upload the letter to CBER’s EDR. At a minimum the filing letter must include the following: [RPM]
          1. The planned review timeline, including planned date for the internal Mid-cycle review meeting;
          2. Target dates for communication of FDA feedback on proposed labeling, postmarketing requirement (PMR), and postmarketing commitment (PMC) issues;
          3. Preliminary plans on whether to hold an AC meeting to discuss the application; and
          4. Any deficiencies identified at the time of the issuance of the filing letter.
      11. Ask the applicant if lots for testing could be available should the review committee members find a need to test the product in support of the application for products subject to lot release.  See SOPP 8408.1: Development of Testing Plans and Release of Lots as Part of the Approval Process. [Chair]
      12. Discuss with the applicant the need for an Advisory Committee if applicable. [Chair, RPM]
      13. Day-74 Letter:
        1. Document in a review memorandum with supervisory concurrence any potential issues that should be communicated to the applicant by Day-74 of the receipt of the application.  [Review Committee Members]
          1. This review memorandum may be a formal memorandum or take the form of an email, so long as the supervisor has been copied.  It is up to the discretion of the reviewer and supervisor to determine which documentation method is used. 
          2. Regardless of method used, the documented review memorandum must be entered into the appropriate regulatory database as a filing memorandum.
        2. Draft a deficiencies identified letter (Day-74 letter) that includes all issues identified during the filing review if the deficiencies were not identified in the filing letter. [RPM, Review Committee Members, Chair]
        3. Ensure the Day-74 letter is issued, the communication is entered into the appropriate database and the letter is uploaded to the EDR.  [RPM]

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    1. Review Tasks Prior to Mid-cycle Meeting
      1. Request that the applicant identify the lots that will be used for testing if not already stated in the application per SOPP 8408.1: Development of Testing Plans and Release of Lots as Part of the Approval Process.  Determine if any new instrumentation and/or testing personnel training is needed.  Communicate to the applicant the requirements for submission of samples and lot-specific data.  [RPM, Chair, DBSQC, and PRB]
      2. Confirm the Mid-cycle meeting is scheduled via Microsoft Outlook, the appropriate reviewers, supervisors and senior management, if appropriate, are available to attend, and provide the reviewers with Mid-cycle meeting expectations.  See Mid-Cycle Meeting/Communication section below. [RPM]
      3. Proprietary Name Review:
        1. Ensure the APLB consult proprietary name review (PNR) memorandum is finalized not later than Day 90 after receipt of the PNR request. [APLB]
        2. Notify the applicant regarding the proprietary name review decision, enter communications into the appropriate regulatory database and upload into CBER’s EDR. [RPM]
      4. Refer to SOPP 8001.4: Review of CBER Regulated Product Proprietary Names andJA 910.02: Proprietary Name Review (PNR) Processing for additional information.
      5. Confirm that the PeRC meeting is scheduled, as applicable. [RPM]
      6. Determine if CBER will conduct any testing of the product “in support” of the application.  See SOPP 8408.1: Development of Testing Plans and Release of Lots as Part of the Approval Process. [Review Committee Members]
      7. Discuss the potential of launch lots with the manufacturer per SOPP 8408.1.  [Chair]
      8. Determine the post-licensure manufacturer’s lot release protocol requirements for products subject to lot release or surveillance.  See SOPP 8408.1.[CMC Reviewer/Product Lead, Chair, DPQ or LIB, Product Release Branch (PRB), Statistician]
      9. Propose any post-licensure CBER confirmatory lot release testing. [CMC Reviewer/Product Lead and DPQ or LIB]
      10. Draft and circulate a Product Testing Plan for review. [DBSQC or LIB]
      11. Continue review activities in preparation for the Mid-cycle meeting. [Review Committee Members]
        1. Each reviewer is expected to document their review of assigned areas in a primary discipline review memorandum that summarizes content, documents the reviewer’s assessment, and identifies issues with information and data in the application to date.
        2. Prepare a Reviewer Report (information taken from the written primary discipline review) in MS Word. Refer to regulatory template T 910.06: Mid-cycle Meeting Summary for additional information.
      12. Route Reviewer Report by email to the RPM, Chair, and reviewer’s immediate supervisor (branch/laboratory chief) no later than four (4) business days prior to the meeting. [Review Committee]
      13. Compile Reviewer Reports into one document and distribute to attendees of the Mid-cycle meeting no later than two (2) business days prior to the meeting.  [RPM]
      14. Upload the consolidated Reviewer Report into the EDR. [RPM]

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    1. Mid-cycle Meeting/Communication Telecon
      1. Conduct Mid-cycle meeting including the following information:
        1. Report and Discuss
          1. Reviewer Reports. [Individual Reviewer Committee Members]
          2. Agreement on the issues for discussion at the AC meeting. [Review Committee Members]
          3. Determine whether PMCs, PMRs or a Risk Evaluation Mitigation Strategy (REMS) are needed. [Clinical Reviewer, Chair]
          4. National Drug Code (NDC) assignments to product/packaging. [RPM or designee]
          5. Proper naming convention. [RPM, product reviewer]
          6. Status of inspections (GMP, BiMo, GLP) including issues identified that could prevent approval. [Facility Reviewer, Product Reviewer, BiMo Reviewer]
          7. Reach agreement on information to be included in the Mid-cycle communication with the applicant. [Review Committee Members, Management present]
        2. Confirm
          1. Components Information Table was obtained and notification was sent to the Data Abstraction Team (DAT) if discrepancies were found per SOPP 8401.5: Processing Animal, Biological, Chemical Component Information Submitted in Marketing Applications and Supplements. If not completed, indicate the date it will be completed.[CMC Reviewer]
          2. New facility information is included in the application, requiring implementation of regulatory job aid JA 910.01: Manufacturing Facility Data Entry. If not completed, indicate the date it will be completed.[DMPQ CMC Reviewer, RPM]
          3. Status of decisions regarding lot release requirements, such as submitting samples and test protocols and the lot release testing plan. [CMC Reviewer]
          4. Unique ingredient identifier (UNII) code process has been initiated.  See regulatory job aid JA 900.01: Unique Ingredient Identifier (UNII) Code for additional information. [RPM]
          5. PeRC presentation date is set; remind the review committee that PeRC forms have to be submitted two weeks in advance of scheduled PeRC meeting, and the clinical reviewer has addressed waiver/deferral/assessment of the PREA decision. [RPM, Clinical Reviewer]
        3. Review
          1. Major target mile stone dates from appropriate regulatory database. [RPM]
          2. The status of the review for each discipline and a target date for completing the primary reviews, inspections, EIR.  If any primary discipline reviews have not met the target date, provide the date the review will be completed. Include any consult disciplines. [Review Committee Members, RPM]
          3. Determine if any reviews will not meet the deadline, and if not, what date they will be completed. [RPM]
          4. Discuss pending dates of targets and milestones (e.e., late-cycle meeting, Advisory Committee, labeling discussion). [RPM]
          5. Establish a labeling review plan and agree on future labeling meeting activities [RPM, Chair]
        4. Follow FDAAA Implementation interim procedures located on CBER’s Intranet Webpage, FDAAA Implementation, if REMS or a PMR is identified. [Review Committee Members]
        5. Enter the meeting summary into the appropriate regulatory database for the internal Mid-cycle meeting and upload into CBER’s EDR. [RPM]
        6. Mid-cycle communication telecon:  [RPM, Chair]
          1. Mid-cycle communication telecons apply to applications that qualify under the PDUFA V Program.
          2. Hold the Mid-cycle communication telecon within two weeks following the Mid-cycle meeting to provide an update on the status of the review of the application. The attendees include the RPM, the Review Committee Chair, the Associate Director for Review Management (ADRM) or designee, and the contractors responsible for tracking the elements of the PDUFA V Program. Refer to regulatory template T 910.08: Mid-cycle Communication Telecon for additional information. [RPM, Chair] The communication includes:
            1. Any significant issues identified by the review committee members to date;
            2. Any information requests sent and not received;
            3. Information regarding major safety concerns;
            4. Any new information requests to be communicated;
            5. Preliminary review committee thinking regarding risk management;
            6. Proposed date(s) for the Late-cycle meeting (to occur not less than 12 calendar days before the date of any AC meeting);
            7. Updates regarding plans for the AC meeting; and
            8. Other projected milestone dates for the remainder of the review cycle, including changes to previous projected dates communicated.
      2. Document the Mid-cycle communication telecon discussion, ensuring the content is focused only on the status of the review and any agreements or decisions made using regulatory template T 910.08: Mid-cycle Communication Telecon. [RPM]
      3. Circulate the Mid-cycle communication telecon summary to the chair to ensure there is agreement on the content. [RPM]
      4. Finalize the Mid-cycle communication telecon summary and send to the applicant. [RPM, Chair]
      5. Enter the information for the Mid-cycle communication telecon into the appropriate regulatory database and upload into CBER’s EDR. [RPM]

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    1. Review Continued
      1. Send Information requests as needed to facilitate review per SOPP 8401.1: Issuance of and Review of Responses to Information Request Communications and Discipline Review Letters to Pending Submissions. [RPM, Review Committee Members]  Note:  Per SOPP 8401.1, IR communications should not be sent late in the review cycle.
      2. Coordinate with CBER’s FDAAA Safety Working Group (SWG) executive secretary to schedule internal meetings, including a CBER FDAAA SWG meeting and meetings with the applicant if clinical PMC/PMRs or REMS and/or PeRC presentation are required.  [RPM, Chair]
      3. Prepare and submit PeRC forms, including: [Clinical Reviewer, Chair]
        1. Pediatric Page
        2. Pediatric Template
        3. Pediatric Assessment (as appropriate)
        4. Pediatric Waiver (as appropriate)
        5. Pediatric Deferral (as appropriate)
        6. Pediatric Plan (must be included with deferrals)
        7. Draft labeling
        8. Draft action letter language stating the pediatric disposition
      4. Participate in PeRC presentation. [Clinical Reviewer, Chair]
      5. Ensure the clinical reviewer has addressed the waiver/deferral PREA determination and the basis for the decision is reflected in the final clinical review memorandum. [Clinical Reviewer, Chair]
      6. Notify the safety working group (SWG) office representative of any FDAAA 505(o) & Food and Drug Modernization Act (FDAMA) 506B studies needed. Refer to SOPP 8415: Procedures for Developing Postmarketing Requirements and Commitments for additional information. [RPM, Chair]
      7. Notify Center SWG executive secretary of any FDAAA 505(o) & FDAMA 506B studies needed. [Office SWG Representative]
      8. Ensure draft Product Testing Plan is completed. [DBSQC Chair, CMC Reviewer]
      9. Ensure Pharmacovigilance Plan is adequate, if applicable. [OBE Epidemiological Reviewer]
      10. Ensure establishment inspection waiver memorandum(s) have been completed, as needed. [Review Committee Members]
      11. Ensure categorical exclusion or environment assessment memorandum is completed. [DMPQ]
      12. Prepare REMS Development Guide and REMS Memorandum, if appropriate. [Clinical Reviewer, OBE Epidemiological Reviewer]
      13. Continue review, documenting the primary discipline review in a review memorandum or review addendum. [Review Committee Members]
      14. Perform inspections if not already completed. [Review Committee Members, Inspection Team.]
      15. Send appropriate sections of the EIR to the inspection lead and finalize the report.  [Review Committee Members/Inspection Team]
      16. Lot release:
        1. Request a Lot Release Protocol template from the manufacturer per SOPP 8408.1: Development of Testing Plans and Release of Lots as Part of the Approval Process. [Chair]
        2. Identify post-licensure lot release protocol review(s) per SOPP 8408.1. [CMC Reviewer]
        3. Develop Protocol Review Worksheet and Data Monitoring Plans.  See regulatory job aid JA 900.07: Protocol Review Worksheet - Example and SOPP 8408.1. [Lot Release Protocol Reviewer(s)]
        4. Enter Protocol Review Worksheets and Data Monitoring Plans into appropriate database. [DPQ or LIB]
      17. Schedule labeling meeting(s) as needed. Refer to SOPP 8412: Review of Product Labeling for additional information. [RPM]
      18. Prepare labeling meeting summary and enter into appropriate regulatory database as needed. [RPM]
      19. Communicate with applicant regarding labeling decisions. [RPM]
      20. Schedule and conduct review committee meetings as appropriate. [RPM]
      21. Issue discipline review letter as appropriate per SOPP 8401.1.  [RPM, Chair]
      22. Perform secondary discipline review:  [Division Director, Team Lead, Supervisor]
        1. Review the primary discipline review memorandum(s).
        2. If the decision is to concur with the recommendation, a signature on the primary discipline review memorandum is sufficient.
        3. If the decision is to non-concur, document the decision and the reasons in a separate review memorandum.

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    1. Late-cycle Meeting for Applications Subject to the PDUFA V Program
      1. Prepare the Late-cycle review committee memorandum.  [Review Committee Members]
        1. If no discipline review letter has been issued:
          1. Draft a brief memorandum copied from the primary discipline review memorandum identifying substantive issues to date for inclusion in the review committee memorandum that accompanies the Late-cycle meeting materials issued to the applicant. [Review Committee Members]
          2. Perform a secondary review of the draft Late-cycle review committee memorandum to ensure the content is correct and current.  [Division Director, Team Lead, Supervisor]
          3. Finalize the Late-cycle review committee memorandum after receiving secondary review concurrence. [RPM, Chair]
        2. If a discipline review letter has been issued:
          1. Use the information contained in any discipline review letter already issued for the Late-cycle review committee memorandum.  If additional substantive issues have been identified, add those to the Late-cycle review committee memorandum issued to the applicant.  [RPM, Review Committee Members]
          2. Perform a secondary review of the draft Late-cycle review committee memorandum to determine that the copied information continues to be relevant.  [Division Director, Team Lead, Supervisor]
          3. Finalize the Late-cycle review committee memorandum after receiving secondary review concurrence. [RPM, Chair]
      2. Process meeting materials for applications going to an Advisory Committee, including:  [Chair, Office Director, RPM]
        1. Briefing materials for the AC meeting;
        2. Any discipline review letters issued to date;
        3. Current assessment of the need for REMS or other risk management actions; and
        4. Brief memorandum from the review committee outlining substantive application issues including potential questions and/or point(s) for discussion for the AC meeting.
      3. Send the Late-cycle meeting materials (excluding any AC briefing materials) to the applicant not less than 20 calendar days before the AC meeting. [RPM]
        1. If the AC is scheduled earlier than the last three months of the review cycle (due to AC scheduling outside the review committee’s control), only the briefing materials for the AC meeting as described in step 102(a) above should be sent to the applicant.
        2. In this case, the remaining documents listed in step 102(b and c) above should be sent to the applicant at approximately three months (standard) and two months (priority) before the user fee goal date.
      4. Process meeting materials for applications not going to an Advisory Committee (AC) including: [Chair, RPM]
        1. Any discipline review letters issued to date;
        2. Current assessment of the need for REMS or other risk management actions; and
        3. Brief memorandum from the review committee outlining substantive application issues.
      5. Send the Late-cycle meeting materials to the applicant not less than 12 calendar days before the Late-cycle meeting.  [RPM]
      6. Hold Late-cycle meeting
        1. Attendees for the internal pre-meeting and the Late-cycle meeting should include:
          1. Office Director and/or Deputy Director with signatory authority;
          2. All Review Committee Members;
          3. Supervisors from disciplines with substantive issues.
        2. Conduct internal, pre-meeting to prepare for Late-cycle meeting with applicant. [RPM, Chair,]
        3. Conduct the Late-cycle meeting with applicant to discuss the status of the review. Topics of the meeting should include the information contained in the Late-cycle meeting materials, additional data or analyses the applicant wishes to submit, and outstanding information requests.   This meeting is not intended to discuss the pending regulatory decision on the application. [Chair, RPM]
        4. Discuss with the applicant whether additional data or analysis that may be submitted 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 user fee goal date.  [Chair, RPM, Review Committee Members]
        5. Document the meeting discussion in the meeting summary, ensuring the content is focused only on the status of the review and any agreements or decisions made using regulatory template T 820.06: Meeting Summary.  At a minimum the following should be documented:  [RPM, Chair]
          1. Summary of discussion points;
          2. Owner of comments (FDA or applicant); and
          3. Agreements and disagreements.
        6. Circulate the draft meeting summary to all CBER/FDA Late-cycle meeting attendees and supervisors and ensure that there is agreement on the content. [RPM, Review Committee Members, Chair, Supervisors]
        7. Finalize the meeting summary and send to the applicant.  [RPM, Chair]
        8. Enter the information into the appropriate regulatory database, including the communication with the applicant and the meeting summary, and upload the meeting summary into CBER’s EDR. [RPM]

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    1. Review Wrap-up
      1. Communicate action letter timeline(s) to review committee members. [RPM]
      2. Prepare final review memorandum(s) or review addendums, as appropriate, and route to supervisory chain for sign-off. [Review Committee Members]
      3. Ensure REMS Memorandum and Notification Letter undergo CBER FDAAA SWG and Office of the Chief Council (OCC) review if appropriate. [SWG Executive Secretary]
      4. Consider possible press interest (may be needed for an important indication or a novel product) and contact the Consumer Affairs Branch (CAB), Division of Communication and Consumer Affairs (DCCA), Office of Communication, Outreach, and Development (OCOD) if necessary. [Chair, RPM]
      5. Verify with the chair which postmarketing requirements (PMR), if any, will be    included in the approval letter; communicate the PMRs to the review committee members. [RPM]
      6. Ensure CBER FDAAA SWG office representative is notified about any necessary PMR or clinical PMC. [RPM]
      7. Notify CBER FDAAA SWG regarding PMRs. [Office SWG Representative]
      8. Notify applicant of PMR or REMS, ensuring any REMS is communicated via REMS notification letter.  [Clinical Reviewer, Chair, RPM, OCC Reviewer]
      9. Ensure Components Information Table is included in review memorandum if appropriate.  See SOPP 8401.5: Processing of Animal, Biological, Chemical Component Information Submitted in Marketing Applications and Supplements.  [CMC Reviewer]
      10. Finalize postmarketing commitments (PMC), if necessary.  [Review Committee Members]
      11. Finalize review memorandum(s).  [Review Committee Members]
      12. Finalize EIRs, ensuring the narrative report, supervisory endorsement, and other communications are entered into the appropriate regulatory database and uploaded to CBER’s EDR.  [Inspection Team]
      13. Send Inspection Tab, including the EIR with exhibits and attachments, and any other paper communications and amendments, to RPM according to DCC Procedure Guide #11: Procedure for Filing Pre-License/Pre-Approval Inspection Material. [Inspection Team]
      14. Enter date(s) of field management directive (FMD-145) letters that were issued for closed inspections into the appropriate regulatory database. [OCBQ/DIS]
      15. Perform Complete Response (CR) or approval process per the process below. [Review Committee Members]

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    1. Complete Response (CR) Actions
      1. Provide review memorandum and CR letter-ready comments, approved by the supervisory chain, to chair and RPM. [Review Committee Members]
      2. Provide REMS information to RPM for inclusion in the CR letter, if appropriate. [Clinical/OBE Reviewers]
      3. Include any compliance issues and/or pending status of inspections in the CR letter.  [RPM, DMPQ]
      4. Draft and circulate CR letter for comment. [RPM]
      5. Perform final sign-off and issuance of CR letter. [Office Director, RPM]
      6. Ensure all documents or communications are entered into the appropriate regulatory database and uploaded into CBER’s EDR.  [Review Committee Members]

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    1. Approval Actions
      1. Ensure product dating was determined (expiration dates have been established). [Chair, CMC Reviewer]
      2. Ensure final labeling issues were addressed. [RPM]
      3. Ensure that the proprietary name re-evaluation outcome was provided to the applicant and outstanding issues were addressed, as appropriate.  [RPM]
      4. Draft a Summary Basis of Regulatory Action (SBRA) memorandum using regulatory template T 910.07: Summary Basis of Regulatory Action (SBRA). [Chair]
      5. Draft a press release and coordinate with OCOD/DCCA/CAB. [Chair]
      6. Draft approval letter: [Chair, RPM]
        1. Ensure lot release instructions are included as appropriate;
        2. Ensure inclusion of justification paragraph if there was no AC meeting; and
        3. Ensure PMCs/REMS/PMRs are addressed following the format outlined in the approval letter template.
        4. Ensure PREA is addressed in the approval letter, as appropriate. [RPM, Clinical Reviewer]
      7. Prepare action package for signature and circulate as appropriate. Perform quality control check on documents that were uploaded into CBER’s EDR. [RPM]
      8. Obtain lot release clearance. [RPM]
      9. Submit final Product Testing Plan to Office director for sign-off and enter final plan information into appropriate database. [DPQ or LIB, Chair]
      10. Obtain compliance check. [RPM, DMPQ]
      11. Obtain point of contact for Action Package for Posting requirement from OCOD/DDOM/EDT. Refer to SOPP 8401.7 for additional information. [RPM]
      12. Send final label revision to applicant (includes all final review committee member’s and Physician’s Labeling Rule (PLR) comments). [RPM]
      13. Email Officer/Employee list to review committee members using regulatory template T 910.02: Officer/employee List Email. [RPM]
      14. Respond to request of Officer/Employee list review. [Review Committee Members]
      15. Finalize SBRA memorandum. [Chair]
      16. Ensure all documents or communications were uploaded to the EDR and all other relevant information is entered into the appropriate database. [Review Committee Members] 
      17. Route approval letter and final action package for signature to all appropriate review office’s branch chiefs, division directors for concurrence. [Chair, RPM]
      18. Obtain final sign-off of approval letter and final action package. [Product Office Directors (OCBQ Director also approves if it’s an initial license for a new user fee product)]
      19. Prepare Action Package for Posting per SOPP 8401.7: Action Package for Posting and regulatory checklist C 910.01: Action Package for Posting. [RPM]
      20. Communicate approval to applicant. [Chair, RPM]
      21. Provide DMPQ/PRB and DIS with a copy of the approval letter so the lot release process may be completed.  [RPM]
      22. Ensure transmittal memorandum (regulatory template T 910.01: Transmittal Memo) is signed and forwarded to OCOD/DDOM/EDT. [RPM, Division Director, Office Director]
      23. Provide OCOD/DCCA/CTB with the approval letter, the package insert and SBRA [RPM]
      24. Provide Notification of Release to applicant for any Launch Lots as appropriate. [DMPQ review committee member]
      25. Assemble paper approval files for submission to DCC or send an electronic final action package (E-FAP) for electronic applications. [RPM]

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    1. After Action Activities
      1. Ensure all documentation is in the appropriate regulatory database. [RPM]
        1. For communications not entered prior to the 30 day lockdown, prior approval from the immediate supervisor is necessary.
        2. Refer to regulatory job aid JA 910.08: Lockdown of Applicant Submissions and CBER Correspondence for Marketing Submissions for additional information
      2. Schedule an after action meeting via Microsoft Outlook with review committee members, others who were involved in the review process, and a representative from the office of the Associate Director for Review Management (ADRM). [RPM]
      3. Conduct informal meeting to analyze how the review process worked, recording the discussion in a meeting summary that should include: [RPM, Review Committee Members]
        1. Improvements that can be made to improve team dynamics;
        2. What processes and/or systems worked well during the review
        3. What processes and/or systems did not work well during the review; and
        4. Recommendations for how team dynamics, processes, and systems could be improved.
      4. Submit after action meeting summary to the ADRM. [RPM]

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  1. Appendices
    1. The PDUFA V Program
    2. SOPP 8401 Acronym List

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  1. References
    1. References below are located on CBER’s Intranet Web Page (unless otherwise noted)
      1. Document Control Center Procedures
        1. DCC Procedure Guide 8: Procedure for Filing Final Action Packages Containing FDA Correspondence for Marketing Applications
        2. DCC Procedure Guide 9:  Procedure for Filing Multiple Product Final Action Packages Containing FDA Correspondence for Marketing Applications
        3. DCC Procedure Guide 11: Procedure for Filing Pre-License/Pre-Approval Inspection Material
        4. DCC Procedure Guide 22: Procedure for Processing, Routing, and Storing Electronic Submissions
      2. Regulatory Checklists
        1. C 910.01: Action Package for Posting
        2. C 910.02: BLA/NDA Checklist
      3. Regulatory Job Aids
        1. JA 820.02: Dating of CBER Correspondence
        2. JA 900.01: Unique Ingredient Identifier (UNII) Code
        3. JA 900.07: Protocol Review Worksheet Example
        4. JA 910.01: Manufacturing Facility Data Entry
        5. JA 910.02: Proprietary Name Review (PNR) Processing
        6. JA 910.08: Lockdown of Applicant Submissions and CBER Correspondence for Marketing Submissions
      4. Regulatory Templates
        1. T 820.06: Meeting Summary
        2. T 910.01: Transmittal Memo
        3. T 910.02: Officer/employee list email
        4. T 910.07: Summary Basis of Regulatory Action (SBRA)
      5. Standard Operating Policies and Procedures (SOPPs)
        1. SOPP 8105: Submitting Documents for the CBER Web Sites
        2. SOPP 8301: Receipt and Processing of Master Files
        3. SOPP 8401.5: Processing Animal, Biological, Chemical Component Information Submitted in Marketing Applications and Supplements
    2. Web links to the references below can be found in the list following the History Table
      1. Statutes and Regulations
        1. Best Pharmaceuticals for Children Act (BPCA)
        2. CFR – Code of Federal Regulations Title 21
        3. Federal Food, Drug, and Cosmetic Act (FD&C Act)
        4. Food and Drug Administration Amendments Act (FDAAA) of 2007
        5. Food and Drug Administration Modernization Act (FDAMA) of 1997
        6. Food and Drug Administration Safety and Innovation Act (FDASIA)
        7. Generic Drug User Fee Amendments of 2012 (GDUFA)
        8. Medical Device User Fee Amendments 2012 (MDUFA III)
        9. Prescription Drug User Fee Act (PDUFA)
        10. Public Health Service Act
      2. Guidance Documents
        1. Guidance for Industry Information Request and Discipline Review Letters Under the Prescription Drug User Fee Act
        2. Guidance for Industry Providing Regulatory Submissions in Electronic Format – Biologics Marketing Applications (BLA, PLA/ELA, and NDA) November 1999 revised
        3. Guidance for Industry Good Review Management Principles and Practices for PDUFA Products
      3. Standard Operating Policy and Procedures
        1. SOPP 8001.2: Accessing the FDA Lists of Disqualified and Restricted Clinical Investigators, Debarred Individuals, and Firms Under the FDA Application Integrity Policy
        2. SOPP 8001.4: Review of CBER Regulated Product Proprietary Names
        3. SOPP 8101.1: Scheduling and Conduct of Regulatory Review Meetings with Sponsors and Applicants
        4. SOPP 8104: Documentation of Telephone Contacts with Regulated Industry
        5. SOPP 8114: Administrative Processing of Documents Received Prior to Submitting Investigational or Marketing Applications (Pre-Application)
        6. SOPP 8401.1: Issuance of and Review of Responses to Information Request Communications and Discipline Review Letters to Pending Submissions
        7. SOPP 8401.4: Review Responsibilities for the CMC Section of Biologic License Applications and Supplements
        8. SOPP 8401.7:Action Package for Posting
        9. SOPP 8402: Designation of Amendments as Major
        10. SOPP 8404: Refusal to File Procedure for Biologics License Applications
        11. SOPP 8405: Complete Review and Issuance of Action Letters
        12. SOPP 8406: Managing PDUFA User Fee Payments and Billing Activities
        13. SOPP 8407: Compliance Status Checks
        14. SOPP 8408.1: Development of Testing Plans and Release of Lots as Part of the Approval Process.
        15. SOPP 8410: Determining When Pre-License/Pre-Approval Inspections are Necessary
        16. SOPP 8411.1:Administrative Handling and Review of Annual Reports for Approved Biologic License Applications (BLAs)
        17. SOPP 8412: Review of Product Labeling
        18. SOPP 8413:Postmarketing Requirement/Commitment Related Submissions – Administrative Handling, Review, and CBER Reporting.
        19. SOPP 8415: Procedures for Developing Postmarketing Requirements and Commitments
      4. FDA Forms
        1. Form 356h: Application to Market a New Drug, Biologic or an Antibiotic Drug for Human Use
        2. Form 3397: PDUFA User Fee Coversheet
        3. Form 3674: Certification of Compliance, under 42 U.S.C. §282(j)(5)(B), with Requirements of ClinicalTrials.gov Data Bank (42 U.S.C. §282(j))

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  1. History
Written/RevisedApprovedApproval DateVersion NumberComment
Rehkopf
RMCC Working Group
Robert A. Yetter, PhDApril 18, 20137Revised to accommodate new user fee authorizations and updates from other SOPPs and to add NDAs
Linda DixonRobert A. Yetter, PhDApril 30, 20076Revised to include information on PTS.
RMCCRobert A. Yetter, PhDMarch 9, 20075Incorporates changes to describe lot release activities associated with product review and to include additional review activities
RMCCRobert A. Yetter, PhDMay 11, 20034Changes incorporating new SOPP 8104.3: Filing Action: Communications Options
RMCCRobert A. Yetter, PhDOct 2, 20023Changes accommodating PDUFA III and other updates
RMCCRobert A. Yetter, PhDFeb 22, 20002Incorporates changes necessitated by publication of BLA final rule (64 FR 56441) and Biostatistics & Epidemiology change from Division to Office
  Sept 10, 19971Original

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References- Standard Operating Policy and Procedures

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