Manual of Standard Operating Procedures and Policies

License Applications

Designation of License Application Amendments as Major

SOPP 8402

Version #3

February 12, 2009
  1. Purpose
    2.

    This document provides guidance to CBER staff on the procedures for assigning the designation of major amendments of Biologics License Applications (BLA)/Supplements or New Drug Applications (NDA)/Supplements, and communicating to the applicant the designation and the effect of the designation on the goal date.

  2. Definitions

Amendment

 An amendment is the submission of information to an unapproved application or supplement, including additional information or reanalysis of data previously submitted, to clarify, revise or modify the application/supplement as originally submitted.

Major Amendment

 A major amendment is an amendment to a pending application, efficacy supplement or manufacturing supplement containing one or more of the following:

  • a substantial amount of new data not previously submitted to, or reviewed by, the agency
  • a substantial amount of new manufacturing or facility information not previously submitted to, or reviewed by, the agency
  • a new analysis of studies previously submitted to the pending application or supplement

Unsolicited Amendment

 An unsolicited amendment is a submission of information or data that the agency has not requested.

Resubmission

 A resubmission is a complete response to an action letter on an original BLA, NDA, efficacy supplement, or manufacturing supplement addressing all the identified deficiencies.

Class 2 resubmissions are those that include items not included in Class 1 resubmissions, including any item that would require presentation to an advisory committee Class 1 resubmissions are defined in Appendix 1.

  1. Background
    2.

In commitments made in support of the Prescription Drug User Fee Act of 1992 (PDUFA), FDA agreed to the goal of complete reviews of license applications and supplements within specified time frames. As part of the PDUFA agreement, major amendments received near the end of the specified review “clock” for an application would extend the “clock” or goal date. As part of the re-authorization of PDUFA III, the clock is also extended when major amendments to efficacy and manufacturing supplements as well as major amendments to resubmissions of original applications and efficacy or manufacturing supplements when they are received near the end of the review cycle. Complete review comments are communicated to the applicant in an action letter, which stops the review clock.

Other comments not constituting a complete review may be transmitted in an information request (IR) letter, discipline review (DR) letter, deficiency letter, filing letter, or telecon. Neither an IR letter nor a DR letter stops the review clock. Responses to IR or DR letters and unsolicited information may be received from the applicant during the review of an application or supplement. These submissions are amendments to the pending file and could constitute major amendments. Refer to SOPP 8401.1: Issuance and Review of Responses to Information Requests and Discipline Review Letters to Pending Applications and the appropriate letter template located on CBER’s Intranet.

  1. Policy
    2.

It is CBER policy that:

  • All priority and standard license applications or supplements subject to PDUFA performance goals will be reviewed within established timeframes.
  • Non-PDUFA products will be reviewed under CBER’s Managed Review Process adhering to the performance goal timeframes as resources permit.
  • Amendments will be assessed for the purpose of designation as major or minor.
  • The review clock will only be extended, according to current PDUFA performance goals, for major amendments submitted to
    • Original applications, efficacy supplements, and any original Class 2 application resubmissions within three (3) months of the goal date, (extends the goal date by three (3) months).
    • Major amendments to manufacturing supplements submitted within two (2) months of the goal date, (extends the goal date by two (2) months.)
  • Only one major amendment is allowed for the
    • original application or efficacy/manufacturing supplement and
    • the review of a Class 2 resubmission.
  • Unsolicited amendments to applications and supplements are discouraged; however, in some cases (i.e., new adverse reaction, safety information, manufacturing information, etc.) such amendments may be necessary.
    • Normally, unless the amount and type of information is substantive or voluminous, or the amendment is received so near the action due date as to preclude adequate time for the review, the review of a clarifying IR letter response will occur during the current review cycle. IR responses do not extend the review clock.
    • If these amendments are to be reviewed, a designation of major must be made.
  • A response to a DR letter or telecon may be reviewed, if the review can be completed in the current review cycle (including the extension for a major amendment).
  • CBER will not usually review an unsolicited amendment or a response to a DR letter received after the review of the application or supplement is complete and the issuance of an action letter is imminent (i.e., the type of action letter has been decided and comments are being drafted).
    • The receipt of these amendments does not affect the goal date for the application or supplement. However, there may be cases, such as in a priority application, where the amendment may support an approval in that review cycle. In such cases, the reviewing office will determine whether the information should be considered prior to taking an action on the application.
    • If these amendments are to be reviewed, a designation of major must be made.
      • If an action letter is issued after receipt and review of a major amendment, subsequent amendments to that application or supplement will not usually be reviewed until CBER receives a response with all the requested information to the action letter.

This policy applies to PDUFA and non-PDUFA products reviewed under CBER’s Managed Review Process.

  1. Responsibilities and Procedures

Regulatory Project Manager (RPM)

  • Ensures that the potential major amendments or resubmissions are distributed to the review committee as soon as possible.
  • Consults the review committee, or other individuals as needed, to assign a designation to an amendment.
  • Ensures that the designation of amendments as majoris made within 14 days of receipt (or sooner if the action due date is less than 14 days). The designation and rationale will be captured in a review memo. The review memo will be entered as a communication in the appropriate regulatory database and imported into CBERs EDR.
  • Ensures that amendments are accurately entered in the appropriate regulatory database.
  • Updates the appropriate regulatory database with the designation (the database will automatically extend the review clock):
  • For major amendments to original applications and efficacy supplements received within three (3) months of the goal date, the review clock will be extended by three (3) months.
  • For major amendments to resubmissions of original applications or efficacy supplements received within three (3) months of the goal date, the review clock will be extended by three (3) months.
  • For major amendments to manufacturing supplements received within two (2) months of the action due date, the review clock will be extended by two (2) months.
  • Other amendments do not extend the review clock.
  • Informs the committee of new goal dates and committee meeting dates as appropriate and
  • If designated a major amendment, ensures that a letter is sent using the appropriate letter template informing the applicant of the designation and changed goal date.

Review Committee Members or Consultant

  • Evaluate the amendment in accordance with the above definition and recommend, with justification, a major designation to the Regulatory Project Manager.
  • Respond to the RPM with the designation recommendation request.
  • Continue with the review and complete it within established timelines.
  • Comments from the review of a major amendment, along with the comments from the original submission, will be included in the action letter.
  • Amendments received after a major amendment has been reviewed and an action letter issued will not usually be reviewed except as part of a complete response to an action letter. The applicant's response to the action letter may refer to this information.
  1. References
    2.

Prescription Drug User Fee Act of 1992

PDUFA reauthorization Goals Letter

  1. Appendix
    2.

    Appendix 1: Definition of Class 1 resubmission

  2. Effective Date
    3.

February 12, 2009

  1. History
Written By
Approved By
Approval Date
Version Number
Comment
Application Policy Task Force
Rebecca Devine
8/1/1995
1
Reissued as SOPP 8402 in 11/21/1996. No change to Guide content. Formerly OD-R-7-96
Gilliam B. Conley
Len Wilson
Robert A. Yetter, PhD
4/16/2001
2
Updated to reflect policy changes:
  • BLA replaces ELA & PLA
  • major amendment option no longer available for supplements
  • current milestone time frames

L Dixon for RMCC
Robert A. Yetter, PhD
2/9/2009
3
 Incorporate changes based on current PDUFA agreement, performance goals

 
Updated: February 12, 2009