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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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SOPP 8401.1: Issuance of and Review of Responses to Information Request Communications and Discipline Review Letters to Pending Submissions

Version #2
Effective Date:  November 15, 2012

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  1. Purpose
    The purpose of this Standard Operating Policy and Procedure (SOPP) is to describe the policies and procedures for Center for Biologics Evaluation and Research (CBER) staff for issuing Information Request (IR) communications and Discipline Review (DR) letters for pending applications and reviewing applicant’s responses to such requests.

     

  2. Scope
    1. This SOPP applies to Biologics License Applications (BLAs), New Drug Applications (NDAs), including biosimilar biological products, non-user fee products and their respective amendments and supplements. 
    2. This SOPP does not apply to BLAs subject to the Medical Device User Fee Act (MDUFA).

     

  3. Background
    1. In commitments made in support of the 1992 Prescription Drug User Fee Act (PDUFA), FDA undertook to review and act on complete BLAs and NDAs within agreed upon time frames.  As part of this undertaking FDA instituted the use of two types of letters:  action letters and information request (IR) letters.  FDA used IR letters to ask for information that would assist reviewers during the course of the review, or to convey deficiencies identified in the application in advance of the issuance of an action letter.  The Agency continues to use IR communications (e.g., letters, emails) to request further information or clarification to allow completion of the review while a specific discipline review is in progress.
    2. In commitments made in support of reauthorization of PDUFA, the FDA agreed to notify applicants of deficiencies identified in a BLA or NDA as early as possible after a discipline review had been completed.  FDA identified these letters as discipline review (DR) letters.  DR letters were issued to applicants to convey early thoughts on possible deficiencies when a discipline review was complete.
    3. Refer to Guidance for Review Staff and Industry:  Good Review Management Principles and Practices for PDUFA Products (GRMP) for additional information.  (see references)
    4. In commitments made in support of reauthorization of PDUFA in 2012 (PDUFA V) an application is expected to be complete at time of submission.  For applications subject to the PDUFA V Program, FDA intends to complete primary and secondary discipline reviews of original BLAs and NDAs and issue DR letters in advance of the planned late-cycle meeting.
    5. Refer to Guidance for Industry:  Information Request and Discipline Review Letters under the Prescription Drug User Fee Act for additional information. (see references)
    6. The Patient Protection and Affordable Care Act (PPAC Act) signed into law in March 2010 amends the Public Health Service Act (PHS Act) to create an abbreviated approval pathway for biological products that are demonstrated to be “highly similar” (biosimilar) to, or “interchangeable” with, an FDA-approved biological product.  These new statutory provisions may also be referred to as the BPCI Act.  The Biosimilar User Fee Act of 2012 (BSUFA) authorized fees and set goals for the review of biosimilar biological product applications, including post market safety activities.

     

  4. Definitions
    1. Information Request (IR) - A communication sent to an applicant during an application or supplement review to request further information or clarification that is needed or would be helpful to complete the discipline review.  
    2. 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 submission.
    3. Primary Discipline Review - A written review containing a reviewer’s assessment and recommendations of all assigned areas of the BLA or NDA submission. 
    4. Secondary Discipline Review - A review by the Division Director and by intervening supervisory (i.e., Branch or Laboratory Chief) or nonsupervisory (Team Lead) reviewers of the primary discipline review memo.

     

  5. Policy
    1. An IR communication or DR letter is not an action letter and does not stop the review clock.  These communication types do not represent a complete review of the submission.
    2. “Letter-ready” means 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.
    3. Information Request (IR) communication
      An IR communication may be used to request further information, including a clarification that is needed to complete the discipline review of an original BLA or NDA and their respective amendments and supplements.  Note:  More than one IR communication may be sent during the review cycle; however, excessive IR communications should not normally occur.
      1. An IR communication is issued while the discipline review continues. 
      2. Information requested in an IR communication should be information that is necessary or would be helpful to complete the review and, as such, is intended to be reviewed during the review cycle in which the communication was issued (if the response is promptly received).  Note:  IR communications should not be sent late in the review cycle.
      3. For simple clarification (e.g., asking to clarify contradictory information; where information is located), the reviewer may contact the applicant.  If the reviewer contacts the applicant, the reviewer is responsible for documenting the request in the appropriate database, importing the document into CBER’s Electronic Document Room (EDR), and notifying the regulatory project manager (RPM) and the review committee chair (Chair).
      4. IR communications other than clarifications are handled through the RPM.  
      5. An IR communication can be issued by telecon, fax, email or letter.
      6.  The Chair reviews IR communications before they are issued.
        1. IR communications other than clarifications issued by telecon, fax, or email may be sent by the RPM or Chair. 
        2. An IR communication issued by letter is signed by the Chair.
      7. An IR communication does not necessarily reflect upper-level supervisor (i.e., Division or Office Director) concurrence.
      8. Supervisor concurrence needed to send an IR communication is as follows:  
        1. IR communications meant to clarify information do not require supervisor concurrence.  
        2. IR communications (other than for clarification) require concurrence from the discipline reviewer’s immediate supervisor.
        3. The supervisor may grant permission to individual reviewers to forward IR communication comments to the RPM without immediate supervisory concurrence for specific files if the reviewer has demonstrated sound judgment based on experience.  The RPM and Chair should be notified by the supervisor when this permission is granted. 
        4. Supervisory concurrence, when needed, should be documented.
        5. Each Office should determine how immediate supervisory concurrence is obtained and documented.
    4. Discipline Review (DR) letter
      CBER intends to issue DR letters to convey deficiencies found at the conclusion of the discipline review of an original BLA or NDA, including those for non-user fee products if sufficient resources are available and submission quality allows.  DR letters are not expected to be generated for BLA or NDA supplements.
      1. The DR letter will be based on the review of the information submitted in the complete original application.  The DR letter may or may not include review of all responses to previous IR requests.
      2. In general, each discipline reviews a different section of the BLA or NDA. These disciplines may include but are not limited to:  the clinical review, chemistry, manufacturing and controls (CMC) review, non-clinical pharmacology toxicology review and the human pharmacokinetics and bioavailability review.  
      3. The DR letter will be generated following immediate supervisor review and concurrence of the primary discipline review memo(s) containing letter-ready comments.
      4. A single DR letter may contain comments from multiple discipline reviews when it is more efficient to do so.
      5. The draft DR letter will be circulated to the review committee (including consult reviewers) and their immediate supervisors. 
        1. Re-circulate substantive letter changes to appropriate members of the review committee. 
        2. Re-circulation will ensure concurrence of the comments by appropriate members of the review committee before sending the DR letter to the applicant.  For example, the statistical reviewer might want or need to address or clarify a clinical comment.
      6. A DR letter does not necessarily reflect upper-level supervisor (i.e., Division or Office Director) concurrence. 
      7. The DR letter is signed by the Chair. 
    5. Review of Responses to IR Communications and DR Letters
      1. Information requested in an IR communication is intended to be reviewed during the review cycle in which the communication was issued if the response is promptly received.
      2. CBER has no obligation to review information submitted in response to an IR communication or DR letter during the review cycle in which the IR communication or DR letter was issued. 
      3. An unsolicited amendment in response to a DR letter will be handled in accordance with the GRMP.  FDA will consider the most efficient path toward completion of a review that addresses application deficiencies and leads toward a first cycle approval if possible. 
      4. CBER may choose to review such information during the review cycle if time permits and it is determined that such review would not adversely impact the ability to meet the goal date for a first cycle approval.
      5. If the agency elects to review the response in the current cycle, the review committee will evaluate the responding amendment upon receipt to determine whether it constitutes a major amendment and extends the review clock.  Refer to SOPP 8402: Designation of Amendments as Major for additional information.
      6. If the review committee defers the review of a response, and a complete response (CR) letter is issued, the response will be reviewed during the next review cycle as part of the complete resubmission if the applicant references such response in the resubmission.

     

  6. Responsibilities
    1. Product Office Regulatory Project Manager [RPM]
      1. Responsible for overall management of IR communications. 
      2. Determines, along with the Chair, method of IR communication for requests other than simple clarification.
      3. Responsible for issuance of DR letters.
      4. Ensures IR communications and DR letters are documented in the appropriate regulatory database and imported into CBER’s EDR.
      5. Makes applicant response to IR communications or DR letters available to the appropriate reviewer(s).
    2. Reviewer
      1. Performs review of all assigned areas of the BLA or NDA submission and relevant amendments.
      2. May contact the applicant for simple clarification request.  If the reviewer contacts the applicant, the reviewer is responsible for documenting the request in the appropriate database, importing the document into CBER’s EDR, and notifying the RPM and Chair.
      3. Drafts letter-ready comments and/or questions for IR communications other than simple clarification requests; obtains appropriate supervisory clearance.
      4. Drafts and obtains immediate supervisory concurrence of letter-ready DR letter comments for all assigned areas of the BLA or NDA submission.
      5. Reviews and concurs on draft IR communication or DR letter prior to issuance.
      6. Reviews applicant response to IR communication or DR letter.
    3. Review Committee Chair
      1. Determines, along with the RPM, method of IR communication for requests other then simple clarification.
      2. Reviews letter-ready IR comments prior to issuance; may send IR communications issued by telecon, email or fax.
      3. Signs IR communication issued by letter.
      4. Reviews, concurs, and signs the DR letter.
    4. Immediate Supervisor
      1. Notifies the RPM and Chair when permission is granted to individual reviewers to proceed with comments for IR communications for specific files without prior approval. 
      2. Performs review and notes concurrence, or gives justification of non-concurrence, of draft letter-ready comments for IR communications, as appropriate, and DR letter. 
      3. Reviews the DR letter to ensure the final comments reflect what was concurred from primary discipline review memo.

     

  7. Procedures
    1. IR Communications
      1. Determine level of supervisory review and concurrence needed for communication. [Reviewer/RPM]
      2. Preparation and Issuance of IR Communications with no Supervisory Concurrence
        1. Determine method of communication.  [Reviewer/RPM]
          1. Refer to SOPP 8104: Documentation of Telephone Contacts with Regulated Industry for additional information. 
          2. Refer to SOPP 8119: Use of Email for Regulatory Communications for additional information.
        2. Ensure communication is entered into the appropriate regulatory database and imported into CBER’s EDR.  [Reviewer/RPM]
      3. Preparation and Issuance of IR Communications with Supervisory Concurrence
        1. Determine method of communication (e.g., email, telecon, fax, or letter). [RPM/Chair]
        2. Prepare letter-ready comments and/or questions for applicant.  [Reviewer]
        3. Forward draft letter-ready comments to RPM; include immediate supervisor for concurrence.  [Reviewer]
        4. Perform review and concurrence of draft letter-ready comments. Note: Offices may determine method of concurrence.  [Immediate Supervisor]
        5. Draft communication to applicant with proposed response date, as appropriate, and forward to reviewer, reviewer’s supervisor and Chair for review and concurrence.  [RPM]
        6. Review and comment on the draft communication within the timeframe requested by the RPM.  [Reviewer, Reviewer’s Immediate Supervisor, Chair]
          1. IR communication comments from more than one office will need review from all affected offices. 
          2. If the method of communication is a letter, refer to CBER’s Review Template Letters Intranet Web page for the most recent approved letter template.
        7. Sign IR communication letter. [Chair]
          Refer to SOPP 8116: Using Electronic Signatures for Investigational and Marketing Regulatory Document Concurrence/Signoff and JA 820.01: User Guide for CBER’s Electronic Signature Process for additional information.
        8. Issue communication to applicant.  [RPM].
        9. Ensure communication is entered into the appropriate regulatory database and imported into CBER’s EDR.  [RPM]
    2. DR Letters
      1. Preparation and Issuance of DR Letters
      1. Prepare letter-ready comments and/or questions for applicant.  [Reviewer]
      2. Forward draft letter-ready comments to immediate supervisor for concurrence as part of the primary discipline review memo.  [Reviewer]
      3. Perform review and concurrence of primary discipline review, with explicit clearance of draft letter-ready comments and forward to reviewer.  [Immediate Supervisor]
      4. Send draft letter-ready comments to the RPM.  [Reviewer]
      5. Draft letter to applicant with proposed response date, as appropriate.  Refer to CBER’s Review Template Letters Intranet Web page for the most recent approved letter template.  [RPM]
      6. Provide draft letter to all appropriate members of the review committee, consult reviewers and immediate supervisors for review and comment within a specified timeframe. [RPM]
      7. Review and comment on the draft letter within the stated timeframe.  [Reviewer(s), Immediate Supervisor(s)]
      8. Re-circulate substantive letter changes to the members of the review committee that contributed to the draft letter prior to finalizing the letter.  [RPM]
      9. Obtain concurrence and signatures, date and issue letter to applicant, ensuring concurrence page is removed.[Reviewer(s), Immediate Supervisor(s), Chair, RPM] 
        Refer to SOPP 8116: Using Electronic Signatures for Investigational and Marketing Regulatory Document Concurrence/Signoff and JA 820.01: User Guide for CBER’s Electronic Signature Process for additional information.
      10. Document the communication in the appropriate regulatory database and import into CBER’s EDR.  [RPM]
    3. Responses to IR Communications and DR Letters
      1. Review of Responses to IR communications and DR Letters
        1. Receive notification of response to an IR communication or DR letter and make the submission available to the appropriate reviewer(s).  [RPM]
        2. Perform initial review of response to determine if it can be reviewed within the current review cycle.  [Reviewer]

     

  8. Appendix
    N/A

 

  1. References
    1. References below are located on CBER’s Intranet Web page (unless otherwise noted)
      1. JA 820.01:  User Guide for CBER’s Electronic Signature Process
      2. Review Template Letters Web page
    2. Web links to the references below can be found in the list following the History Table
      1. Guidance for Industry: Information Request and Discipline Review Letters Under the Prescription Drug User Fee Act, November 2001
      2. Guidance for Review Staff and Industry: Good Review Management Principles and Practices for PDUFA Products (GRMP), April 2005
      3. Prescription Drug User Fee Act (PDUFA)
      4. PDUFA V
      5. Biologics Price Competition and Innovation (BPCI) Act of 2009
      6. SOPP 8104: Documentation of Telephone Contacts with Regulated Industry
      7. SOPP 8116:  Using Electronic Signatures for Investigational and Marketing Regulatory Document Concurrence/Signoff
      8. SOPP 8119:  Use of Email for Regulatory Communications
      9. SOPP 8402:  Designation of Amendments as Major 

     

  2. History
Written/RevisedApproved ByApproval DateVersion NumberComment
SOPP 8401.1 working groupRobert Yetter, PhDNovember 9, 20122Updated to implement PDUFA V commitments
Leonard Wilson, RMCCRobert Yetter, PhDJune 11, 20011Original Prepared to implement PDUFA commitments