Effective Date: October 1, 2012
This Standard Operating Policy and Procedure (SOPP) describes the policies and procedures for Center for Biologics Evaluation and Research (CBER) staff for the acceptance and review of resubmissions of applications and supplements.
- This SOPP covers Biologic License Applications (BLAs) and New Drug Applications (NDAs) and the associated efficacy and manufacturing supplements regulated under the Prescription Drug User Fee Act (PDUFA), biosimilar biological products regulated under the Biosimilar User Fee Act of 2012 (BSUFA), and non-user fee submissions.
- This SOPP does not apply to BLAs regulated under the Medical Device User Fee Act (MDUFA).
- This SOPP does not apply to ANDAs regulated under the Generic Drug User Fee Act (GDUFA) program.
- The 1992 Prescription Drug User Fee Act (PDUFA) set goals for resubmissions of original BLAs and NDAs only. Subsequent reauthorizations added Class 1 and Class 2 categories for original applications and efficacy supplements. Manufacturing supplement resubmissions and labeling supplement resubmissions are excluded from category (class) designations.
- 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 also may be referred to as the Biologics Price Competition and Innovation (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. Biosimilar biological product applications will be submitted under Section 351(k) of the PHS Act.
- Resubmission - A complete response to an action letter addressing all identified deficiencies.
- Class 1 Resubmission - applications resubmitted after a complete response letter that include the following items only (or combinations of these items): Note: Biosimilar biological products and non user fee products do not have Class 1 or Class 2 designations.
- Final printed labeling;
- Draft labeling;
- Safety updates submitted in the same format, including tabulations, as the original safety submissions with new data and changes highlighted (except when large amounts of new information including important new adverse experiences not previously reported with the product are presented in the resubmission);
- Stability updates to support provisional or final dating periods;
- Commitments to perform Phase 4 studies, including proposals for such studies;
- Assay validation data;
- Final release testing on the last 1-2 lots used to support approval;
- A minor reanalysis of data previously submitted to the application;
- Other minor clarifying information (determined by the Agency as fitting the Class 1 category), and
- Other specific items that may be added later as the Agency gains experience with the scheme, and will be communicated via guidance documents to the industry.
An example of minor clarifying information could be a response to a CR letter that contained only compliance issues stating the applicant’s compliance status has changed to acceptable and requesting the clock be started for completion of review for the application or supplement.
- Class 2 resubmission - resubmissions that include any other items, including any item that would require presentation to an advisory committee or a re-inspection of facilities.
An example of a Class 2 resubmission could be one that includes a resubmission containing other than minor assay validation data.
- The classification (Class 1 or Class 2) of the resubmission for a PDUFA application or efficacy supplement is based on the information contained in the resubmission.
- The content of a resubmission submitted by an applicant near or at the time a complete response issues, may be considered in determining the completeness of the response to the complete response letter and the classification of the resubmission.
- CBER will review and act on Class 1 and Class 2 resubmissions for applications or efficacy supplements within the time frames specified in the current PDUFA goal letter.
PDUFA V timeframes:
- Class 1 within 2 months of receipt.
- Class 2 within 6 months of receipt.
- CBER will review and act on resubmissions for biosimilar biological product applications or supplements with clinical data within 6 months of receipt, as specified in the current BSUFA goal letter.
- CBER will review and act on resubmissions for manufacturing and labeling supplements within the same timeframe as the initial review cycle for the supplement (excluding any extension due to a major amendment of the initial supplement). 21 CFR 314.110(b)(1)(iii) applies for NDAs; CBER will use these same timeframes for PDUFA BLAs.
- The resubmission will be considered complete if the applicant responds to each question or issue in the complete response letter. The quality of the response will be evaluated during the review. Some responses by the applicant may be inadequate and will need to be addressed once the review is begun.
- For resubmissions of new applications and efficacy supplements (PDUFA) and supplements with clinical data (BSUFA), a letter will be issued to the applicant acknowledging the resubmission, stating the classification of the response, and giving the goal date for the review.
- Non-user fee products will be reviewed under CBER’s Managed Review Process (MRP) adhering to the performance goal timeframes as resources permit.
- For resubmissions of labeling or manufacturing supplements acknowledgement will be in the form of a telecon, email, or acknowledgement letter. All email acknowledgements must comply with SOPP 8119: Use of Email for Regulatory Communications.
- Refer to SOPP 8001.4: Review of CBER Regulated Product Proprietary Names for information on proprietary name resubmissions.
- Regulatory Project Manager (RPM)
- Ensure data for all submissions is entered in the appropriate regulatory database, including assignment of third level STN if appropriate.
- Determine initially whether or not the resubmission is a Class 1 or Class 2 Resubmission if the applicant indicates a Complete Response (CR) for a PDUFA application or efficacy supplement.
- Determine initially whether or not the amendment is a complete response if the applicant indicates a complete response for a biosimilar biological product submission, non user fee submission or any non-efficacy supplement.
- Ensure the applicant is notified when a submission is determined to be incomplete (and therefore not a resubmission). Ensure that the clock was not started and will not start until a complete response to the action letter is received.
- Ensure a Resubmission Acknowledgement Letter indicating the new action due date is sent to the applicant once the submission is determined to be a complete response to a CR letter for an application or efficacy supplement. Refer to CBER’s Letter Template Intranet Web page for the most current letter template.
- Ensure labeling or manufacturing supplement resubmissions are acknowledged by telecon, email, or letter.
- Ensure all communications are documented in the appropriate regulatory database and imported into CBER’s Electronic Document Room (EDR).
- Review Committee Member
- Determine whether the resubmission responds completely to the complete response letter.
- Confirm or change the initial determination that the resubmission is a Class 1 or Class 2 for a PDUFA application or efficacy supplement.
- Complete the review and act on resubmissions of applications or supplements within the time frames specified in the current PDUFA and BSUFA goals letters.
- Regulatory Project Manager (RPM)
- Ensure cursory review of a resubmission to determine if the amendment is a proposed complete response or incomplete response to a CR letter.
- Ensure data for all submissions is entered in the appropriate regulatory database, including assignment of third level STN if appropriate. [RPM] Note: if the applicant designates the submission as a complete response, the review clock is started.
- Notify the review committee of receipt of a resubmission; forward to appropriate review committee members. [RPM]
- Confer with review committee to make certain the response for a resubmission is complete. [RPM]
- Determine if a resubmission is a complete or an incomplete response. [Review Committee Members] Note: The resubmission will be considered complete if the applicant responds to each question or issue in the CR letter. If the resubmission is determined to be complete, the adequacy of the response will be evaluated during the review.
- If the resubmission is incomplete: [RPM]
- Ensure the designation of the resubmission in the regulatory database is corrected to Incomplete Response to CR letter if the review team confirms that the resubmission did not address all of the issues identified in the CR letter.
- Notify the applicant by phone if the submission is determined to be an incomplete response.
- The data entry in the regulatory database should reflect receipt of an Incomplete Response to CR letter rather than a complete response.
- When the information in the database is corrected, the review clock is re-set to reflect the original action close date.
- If the resubmission is complete:
- Ensure the review clock was started upon receipt once the review team confirms that the resubmission is complete and the designation of “response to CR letter” is selected in the regulatory database. [RPM]
- Determine initially whether or not the amendment is a Class 1 or Class 2 Resubmission if the applicant indicates a complete response for a PDUFA application or efficacy supplement. Note: Class 1 or Class 2 designations do not apply to: manufacturing or labeling supplements, non user fee or biosimilar biuological products. [RPM]
- Confirm Class 1 or Class 2 category if the resubmission responds completely to an action letter for a PDUFA application or efficacy supplement. [Review Committee Members]
- Send a Resubmission Acknowledgement Letter for an original application within 14 calendar days of receipt and for efficacy supplements within 30 days of receipt, as resources permit, indicating the new action due date to the applicant. [RPM]
- Acknowledge a resubmission for a labeling or manufacturing supplement by telecon, email, or letter. [RPM]
- Complete the review, including supervisory concurrence, within the appropriate timeframe. [Review Committee Members]
- Document the review in the appropriate regulatory database and import into CBER’s EDR. [Review Committee Members]
- Ensure all communications are documented in the appropriate regulatory database and imported into CBER’s EDR. [RPM]
- Information on Biosimilars
- Biosimilar User Fee Act (BSUFA)
- Biosimilar Biological Product Authorization Performance Goals and Procedures Fiscal Years 2013 – 2017
- Prescription Drug User Fee Act
- PDUFA V goals
- SOPP 8001.4: Review of CBER Regulated Product Proprietary Names
- SOPP 8119: Use of Email for Regulatory Communications
- Guidance for Industry: Classifying Resubmissions in Response to Action Letters
|Written/Revised||Approved By||Approval Date||Version Number||Comment|
|Dixon||Robert A. Yetter, Ph.D.||Aug 14, 2012||4||Revised to include PDUFA V, Biosimilar and non User Fee procedures|
|Dixon, Padgett, Wilson, Joneckis||Robert A. Yetter, Ph.D.||Feb 10, 2011||3||Revised for new format and to include manufacturing supplements and PDUFA IV reauthorization|
|Leonard Wilson||Robert A. Yetter, Ph.D.||Aug 30, 2002||2|
PDUFA III changes
|Rebecca Devine, Ph.D.||Rebecca Devine, Ph.D.||May 20, 1998||1||Original|
- Information on Biosimilars
FDA holds public hearing on the Biologics Price Competition and Innovation Act Biosimilar User Fee Act (BsUFA)
- Biosimilar Biological Product Authorization Performance Goals and Procedures Fiscal Years 2013 through 2017 (PDF - 89KB)
Prescription Drug User Fee Act (PDUFA)
- PDUFA V Goals (PDF - 130KB)
SOPP 8001.4: Review of CBER Regulated Product Proprietary Names Effective Date: November 24, 2008 SOPP 8119: Use of Email for Regulatory Communications Effective Date: February 13, 2009
- Guidance for Industry: Classifying Resubmissions in Response to Action Letters (PDF - 76KB)