Vaccines, Blood & Biologics

SOPP 8412: Review of Product Labeling

Version # 5
Effective Date:
January 28, 2016
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  1. Purpose
    This SOPP outlines the general operating procedures for Center for Biologics Evaluation and Research (CBER) staff to process draft and final product labeling submissions for human drug and biologic products.

     

  2. Scope
    1. This SOPP applies to the review of product labeling for drugs and biological products regulated under Biologics License Applications (BLA), New Drug Applications (NDA), Abbreviated New Drug Applications (ANDA), their respective supplements, and annual reports.
    2. It does not apply to medical devices, including IVDs regulated under BLA. Review of labeling for medical devices is covered in other device-specific SOPPs and/or Job Aids.

     

  3. Background
    1. Proper labeling of licensed and approved products is a requirement of the Food, Drug and Cosmetic Act (FD&C Act) and the Public Health Service Act (PHS Act). Labeling is reviewed as part of a BLA, NDA, ANDA, their respective supplements, annual reports or product correspondence (First Use notification only), when appropriate, to ensure the information is correct and that the product is not misbranded.
    2. The mechanism for reporting changes to labeling varies according to the type of change and the change's potential for having an adverse effect on product identity, strength, quality, purity, or potency as described in 21 CFR 601.12 and 314.70. The reporting categories allowed by these regulations include several different dministrative processes for labeling submission and review. For drugs and biologics subject to 21 CFR 314.70 and 601.12, respectively, changes to a product package label, container label, and package insert require either: (1) submission of a supplement with FDA approval needed prior to product distribution (Prior Approval Supplement (PAS)); (2) submission of a supplement with Changes Being Effected (CBE); or (3) submission of the final printed labeling in an annual report.
    3. On December 11, 2003, FDA published a Final Rule (68 FR 69009 - the Electronic Labeling Rule (ELR)), requiring the submission of content of labeling in electronic format for marketing applications beginning June 8, 2004. The requirements of the rule can be found in 21 CFR 314.50(l)(1)(i) for NDAs, 314.94(d)(1)(ii) for ANDAs, 601.14(b) for BLAs and 314.81 (b)(2)(iii)(6) for annual reports. Following publication of the Final Rule, FDA issued Guidance for Industry: Providing Regulatory Submissions in Electronic Format - Content of Labeling in April 2005. The publication of this guidance indicated that the electronic format by which content of labeling should be submitted is Structured Product Labeling (SPL), which utilizes Extensible Markup Language (.XML).
    4. In the Federal Register of February 26, 2004 (69 FR 9120), the FDA published a Final Rule requiring certain human drug and biological products to have on their labels a linear bar code that contains, at a minimum, the drug’s National Drug Code (NDC) number (21 CFR 201.25). Refer to Guidance for Industry: Bar Code Label Requirements Questions and Answers (August 2011) for additional information. This document also covers the requirements for machine-readable label requirements for blood and blood components.
    5. In January 2006, FDA issued a Final Rule (71 FR 3922 - the Physician Labeling Rule (PLR)), which required labeling for BLAs and NDAs to conform to 21 CFR 201.56 and 201.57 beginning June 30, 2006. For BLAs, NDAs, and efficacy supplements approved prior to June 2001, implementation of the PLR is voluntary. The PLR revised the existing labeling regulations to require that the prescribing information of new and recently approved human drug and biological products include a cross-referenced Highlights section and Table of Contents along with the Full Prescribing Information. It also established certain required content, the reordering of the label, and minimum format requirements. The intent of the PLR was to make the prescribing information more accessible and informative for practitioners to improve risk and benefit communications as well as risk management. Refer to Guidance for Industry: Labeling for Human Prescription Drug and Biological Products – Implementing the PLR Content and Format Requirements (February 2013) for additional information.
    6. In July 2006, the Institute of Medicine (IOM) published a report entitled Preventing Medication Errors, which cited labeling and packaging issues as the cause of 33 percent of medication errors. Product name confusion, as well as confusing packaging and labeling, contribute to these medication errors. Given the critical role of the label and prescribing information in the safe use of drug products, CBER relies on four major labeling reviews to ensure accurate information is provided in a manner understandable to physicians and patients. These reviews include the content of the prescribing information, the proper (established) name, the proprietary (trade or brand) name, and the format of carton and container labels.
    7. On September 27, 2007, the Food and Drug Administration Amendments Act (H.R. 3580 FDAAA) was established. In conjunction with the reauthorization of Prescription Drug User Fee Amendments Acts (PDUFA), the FDA agreed to meet specific performance goals. These performance goals are described in PDUFA Reauthorization Performance Goals and Procedures. For these performance goals, CBER agreed to develop review procedures and timelines for its staff (i.e., how to notify applicants of planned review timelines for original NDA/BLA applications and efficacy supplements). Although non-user fee products are not subject to User Fee performance goals, CBER strives to meet these review timelines for non-user fee products, as resources allow.
    8. A Circular of Information for the Use of Human Blood and Blood Components (the “Circular”) has been developed by the major industry organizations representing blood establishments and is reviewed by FDA to ensure compliance with 21 CFR 606.122. CBER announces in guidance that a particular version of the "Circular" is an acceptable standard and that it complies with the requirements and thereafter a copy of the Circular does not have to be submitted or reviewed with each submission if the accepted version is in use. After CBER’s announcement of acceptance of a Circular in a guidance document, firms may report the use of the accepted Circular in their annual reports if there are no changes made to the accepted version of the Circular.
    9. In December 2014, FDA issued a Final Rule (79 FR 72064 - the Pregnancy and Lactation Labeling Rule (PLLR)), amending its regulations governing the content and format of the “Pregnancy,” “Labor and delivery,” and “Nursing mothers” subsections of the “Use in Specific Populations” section of the labeling for human prescription drug and biological products. The final rule requires the removal of the pregnancy categories A, B, C, D, and X from all human prescription drug and biological product labeling. For human prescription drug and biological products subject to the Physician Labeling Rule (71 FR 3922, January 24, 2006), the final rule requires that the labeling include a summary of the risks of using a drug during pregnancy and lactation, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy and lactation. The intent of the final rule is to create a consistent format to provide useful information about the risks and benefits of a prescription drug and/or biological product for prescribing decisions in pregnant women, in nursing mothers, and in females and males of reproductive potential. Refer to Guidance for Industry: Labeling for Human and Prescription Drug and Biological Products – Implementing the PLLR Content and Format Requirements (December 2014) for additional information.
      1. Implementation Schedule:
Applications Required to Conform to New Pregnancy/Lactation Content Requirements (includes NDAs, BLAs and efficacy supplements)Time by Which Labeling with New Pregnancy/Lactation Content Must Be Submitted to FDA for Approval
Applications submitted on or after effective date of final rule (June 30, 2015)Time of Submission
Applications pending on the effective date of the final rule4 years after the effective date of the final rule (June 30, 2019) or at the time of approval, whichever is later

 

Approved Applications Subject to the Physician’s Labeling Rule:Time by Which Labeling with New Pregnancy/Lactation Content Must Be Submitted to FDA for Approval
Applications approved any time from June 30, 2001, up to and including, June 29, 2002, and from June 30, 2005, up to and including June 29, 20073 years after the effective date of the final rule (June 30, 2018)
Applications approved any time from June 30, 2007, up to and including the effective date of the final rule4 years after the effective date of the final rule (June 30, 2019)
Applications approved any time from June 30, 2002, up to and including June 29, 20055 years after the effective date of the final rule (June 30, 2020)
      1. For labeling not subject to the requirements of the PLR (i.e., applications approved prior to June 30, 2001), the pregnancy label category is required to be removed by three years after the effective date of the final rule (June 30, 2018).

     

  1. Definitions
    1. Label - Display of written, printed, or graphic matter on the immediate container of any article, or any such matter affixed to any consumer commodity or affixed to or appearing upon a package containing any consumer commodity. (21 CFR 1.3(b)).
    2. Labeling - All written, printed, or graphic matter accompanying an article at any time while such article is in interstate commerce or held for sale after shipment or delivery in interstate commerce (21 CFR 1.3(a)). Note: Labeling includes the container labels, package insert (or professional labeling), the patient package insert, medication guides, instructions for use, risk management materials and promotional labeling.
    3. Content of labeling - All text, tables, and figures, such as contents of the package insert or professional labeling, patient package insert, and medication guide required under 21 CFR 201.100(d)(3). Note: The Physicians Labeling Rule (PLR) and the Pregnancy Labeling and Lactation Rule (PLLR) specify the format for the content of labeling.
    4. First Use Notification:
      1. Final Printed Labeling - Version (paper or SPL) of label or labeling (carton and container and accompanying matter) available immediately upon marketing of the product and submitted to CBER as product correspondence or in an annual report.
      2. Final Content of Labeling - All text, tables, and figures, such as contents of the package insert or professional labeling, patient package insert, and medication guide required under 21 CFR 201.100(d)(3) submitted in electronic format (Final SPL) and submitted to CBER as product correspondence. (21 CFR 601.14)
    5. Structured Product Labeling (SPL) - The electronic format by which content of labeling should be submitted. SPL utilizes Extensible Markup Language (.XML).

     

  2. Policy
    1. SPL formatted content of labeling (.XML file) and a Microsoft (MS) Word-formatted version (.doc file) should be submitted with original BLA/NDA/ANDA submissions, efficacy supplements, and all supplements that require review of labeling. An MS Word version is not required for changes reported in an annual report or for human blood and blood component products using an Instruction Circular.
      • Labeling negotiations for original and supplemental BLA/NDA/ANDA submissions are performed using the track changes (redline/strikeout) function in MS Word. Note: there may be instances that require explanatory text or separate annotation within the document or as a separate document.
      • A revised SPL is not required during the labeling negotiations.
      • SPL can accommodate both PLR/PLLR and non-PLR/PLLR formats, Medication Guides, Patient Package Inserts (PPIs) and Instructions for Use.
    2. Labeling revisions are subject to the provisions under FDAAA Section 901 for Safety Labeling Changes and FDAAA Section 501 for the Pediatric Research Equity Act (PREA).
    3. For approved products, changes to product labeling will be considered a supplement to the applicant's BLA/NDA/ANDA unless the change qualifies as reportable in an annual report (21 CFR 314.70 and 601.12).
    4. Labeling submitted to annual reports are only those types of changes outlined in 21 CFR 314.70(d) or 21 CFR 601.12(f)(3). These are usually minor/editorial-type labeling changes. Annual reports will be handled in accordance with SOPP 8411.1: Administrative Handling and Review of Annual Reports for Approved Biologics License Applications (BLAs).
    5. For human blood and blood component products, a revised instruction Circular should be submitted in the following situations:
      1. A firm may modify the “Circular” to contain facility specific information or to include additional products or cautions announced by the FDA. Depending on the type of information added, the submission of a modified Circular of Information may be a PAS, CBE or annual report.
      2. When a firm submits a supplement for a new product and provides an instruction circular or indicates that the “Circular” has been modified, the submission is categorized as a PAS. CBER review of the circular is to ensure the content is in compliance with the regulations or that the modified “Circular” is consistent with the accepted standard Circular of Information. Any modifications requiring additional review are identified. See Guidance for Industry: An Acceptable Circular of Information for the Use of Human Blood and Blood Components.
    6. At the time of First Use (at time of distribution or sale), the applicant must submit the following as product correspondence or in an annual report if its submission coincides with distribution:
      1. Final content of labeling (21 CFR 601.14) in SPL format.
      2. Final advertising and promotional labeling at the time of initial dissemination or publication, on Form FDA 2253 (21 CFR 601.12(f)(4)).
      3. Three original paper copies of the revised carton and container final printed labeling (21 CFR 601.12(f)). In addition, the applicant may submit images (.jpeg) of all revised cartons and containers in the SPL.
    7. For multiple supplements that include labeling revisions under review for the same product/same applicant, a coordinated review of all submitted label changes should be conducted to ensure coordination with all open submissions and include language of recently approved versions.
      1. Upon receipt of approved language from a CBER review committee, the newly approved language will be reviewed by other affected review committees to determine whether or not that language will impact their review.
      2. Labeling coordination should be performed by an RPM.
    8. Pending CBE safety language should not be included in another pending labeling supplement until after CBE approval. The RPM should make review committees for the same product/same applicant aware of pending safety information under review. The purpose of notification is to make review committees aware of pending safety information for consideration in their review.
    9. Labeling revision requests to the applicant should be as complete as possible. The applicant is responsible for revising and resubmitting proposed labeling for review if labeling revisions are necessary.
      • Note: An SPL file may include changes approved in more than one submission. Any approval to revised content of labeling must be reflected in all other open submissions (i.e., applicants of open labeling supplements should be asked to update the proposed labeling in an amendment). Thus, at any given time, the SPL that is approved (and posted publicly) reflects the most inclusive and up-to-date content of labeling. Refer to Regulatory Job Aid JA 900.02: SPL Content of Labeling for additional information.

     

  3. Responsibilities
    1. Review Committee
      1. Participates in the labeling review to ensure compliance with the content and formatting requirements per applicable regulations.
      2. Provides comments as appropriate in review memorandum.
    2. Regulatory Project Manager (RPM)
      1. Facilitates, as necessary, the coordination of label and labeling review activities, such as ensuring assignment of appropriate discipline committee members, scheduling labeling meetings, communication with the applicant, etc.
      2. Coordinates review of multiple pending supplements that include labeling revisions to ensure approved labeling includes all recently approved labeling revisions, as applicable.
      3. Serves as the primary point-of-contact with the applicant. The RPM should be included in all communications with the applicant.
      4. Ensures all bar code information submitted by an applicant is reviewed by appropriate reviewers. See Appendix A for 2D bar codes when applicable.
      5. Ensures National Drug Code (NDC) assignment(s) is accurate. See Regulatory Job Aid JA 900.08: National Drug Code and Bar Code Labeling Review for additional information.
    3. Clinical Reviewer
      1. Ensures accuracy of clinically relevant product information in the labeling and compliance with content requirements, i.e., PREA, PLR, PLLR, and all labeling regulations (see comprehensive list in the references section).
      2. Coordinates labeling issues during a review.
      3. Evaluates the Advertising and Promotional Labeling Branch (APLB) recommendation for Proprietary Name Review (PNR). Includes evaluation supporting or disagreeing with APLB recommendation for the proprietary name in the clinical review memo.
    4. Statistician
      Evaluates the accuracy of statistical clinical data included in the prescribing information relative to the information provided in the submission.
    5. Clinical Pharmacology Reviewer
      Ensures accuracy of mechanism of action statements, pharmacodynamics, pharmacokinetics, and information on the impact of age, gender, and race in the labeling
    6. Non-Clinical Toxicologist Reviewer
      Ensures accuracy of non-clinical toxicology product information relative to information provided in the labeling
    7. Chemistry Manufacturing and Control (CMC) Reviewer
      1. Ensures accuracy of chemistry and manufacturing product information relative to the information provided in the labeling (storage conditions, suitable expiry periods established, etc.).
      2. Reviews UNII (Unique Ingredient Identifier) Code request, in collaboration with FDA’s Substance Registration System (SRS), and concurs with the recommendation as appropriate. See Regulatory Job Aid JA 900.01: UNII Code for additional information.
      3. Ensures that the UNII codes and drug listing data elements in the SPL file are correct.
      4. Ensures all bar code information submitted by an applicant is reviewed by appropriate reviewers. See Appendix A for 2D bar codes when applicable.
      5. Ensures NDC assignment(s) is accurate. See Regulatory Job Aid JA 900.08: National Drug Code and Bar Code Labeling Review for additional information.
    8. Advertising and Promotional Labeling Branch (APLB) Reviewer
      1. Performs Proprietary Name Review (PNR), preparing a review memorandum that includes consultation with the clinical reviewer and/or chair.
      2. Provides consult to the clinical reviewer and/or chair on the content of the prescribing information labeling from a comprehension and readability perspective, ensuring that the labeling is not false or misleading to the target audience(s) (i.e., healthcare providers, patients, special populations) and ensuring consistency with the labeling regulations.
      3. Reviews labels and labeling for false or misleading promotional claims and representations.

     

  4. Procedures
    1. General Information
      1. Not all process steps outlined below apply to labeling reviews associated with human blood and blood component products. Refer to the following regulatory job aid for additional information: JA 910.05: Labeling Review for Whole Blood and Blood Components including Source Plasma and Source Leukocytes.
      2. Please refer to the following regulatory job aid for additional information regarding labeling reviews conforming to new requirements (as of June 30, 2015) for sections 8.1 through 8.3 of the full prescribing information: JA 910.14: Labeling Review- Pregnancy, Lactation and Females and Males of Reproductive Potential.
      3. Reviewer tools are available on the FDA Intranet.
      4. SPL resources are available on the Internet.
      5. Additional/companion submissions containing labeling may be found by searching the RMS/BLA database. See Regulatory Job Aid JA 910.03: RMS/BLA Database Search for Labeling Submissions.
      6. For information regarding labeling changes related to the issuance or reissuance of Biological Products Licenses refer to SOPP 8403: Issuance, Reissuance and Revocation of Licenses for Biological Products.
    2. Original BLA/NDA/ANDA
      1. Initial processing (refer to SOPP 8401: Administrative Processing of Biologics License Applications):
        1. Verify labeling (i.e. content of prescribing information, carton, and container labels) has been submitted, including an SPL (.XML) file and a MS Word (.doc) version, if applicable. [RPM]
        2. Request reviewer assignments for clinical, statistics, clinical pharmacology, toxicology, CMC, and APLB, and others as applicable. [RPM]
          Note: A clinical reviewer and an APLB reviewer are included on all submissions containing labeling revisions.
      2. Examine all labeling components and note any missing information at the Filing Meeting. [Review Committee Members]
      3. Determine the planned target date for communication or feedback regarding labeling to the applicant and include date in the Filing Letter. [Review Committee Members]
      4. For Proper (Established) name review, ensure compliance with naming conventions as established by US Adopted Name Council (USAN) or office-specific policies if no USAN name is available according to SOPP 8426: Assignment of Biological Product Proper Names. [RPM or designee]
      5. Confirm submission of the Proprietary Name Review (PNR) request in the application, record the proposed proprietary name in the appropriate regulatory database, and if PDUFA product, confirm PDUFA milestone data entry per Regulatory Job Aid JA 910.02: Proprietary Name Review (PNR) Processing. [RPM]
      6. Review proprietary name to ensure compliance with the regulations, document recommendation in a review memorandum, communicate findings to applicant and document in appropriate databases according to SOPP 8001.4: Review of CBER Regulated Product Proprietary Names and Job Aid JA 910.02: Proprietary Name Review (PNR) Processing. [APLB Reviewer, Product Office Designee, RPM]
      7. Ensure Unique Ingredient Identifier (UNII) Code request is submitted to CBER SRS. [RPM, CMC reviewer]
      8. Concur with the CBER SRS recommendation, as appropriate. Refer to regulatory job aid JA 900.01: UNII Code for additional information [CMC reviewer]
      9. Enter the communication(s) from the CBER SRS Team in the appropriate regulatory database Communication/Correspondence screen in the same manner as compliance check or lot release communications [RPM] Refer to regulatory job aid JA 900.01: UNII Code for additional information
      10. Ensure compliance with labeling requirements as described in 21 CFR Parts 201, 202, 606, 610, 640 and 660, as applicable. [Review Committee Members]
      11. Review labeling from a promotional, comprehension and readability perspective, including consideration of potential medication errors due to content and format issues. [APLB Reviewer]
      12. Ensure compliance with promotional labeling and advertising requirements as described in 21 CFR Part 202, Prescription Drug Advertising. [APLB Reviewer]
      13. Ensure accuracy of NDC and bar code information. If other information is encoded in Bar Code, consult with Review Management. [RPM, CMC Reviewer]
      14. Hold labeling meeting(s) after mid-cycle to discuss proposed labeling revisions. [Review Committee]
        1. Complete a thorough review of the labeling before the labeling meeting. [Review Committee Members]
        2. Provide a draft clinical memorandum to the APLB reviewer to allow for the completion of the APLB Labeling Review memorandum. [Clinical Reviewer]
        3. Provide a formal APLB Labeling Review memorandum to the clinical reviewer, committee chair, and RPM with labeling revision recommendations based on the clinical review and labeling discussions, as appropriate. [APLB reviewer]
          • Additional consults with APLB are available on a case-by-case basis thereafter, but output that results from these further consultations may not be provided in an additional formal memorandum. These additional comments may be conveyed via meeting minutes, telecon minutes, or email communications.
        4. Collaboratively identify labeling requirements/revisions. [Review Committee Members]
        5. Summarize labeling issues identified at this meeting for inclusion in the Summary Basis of Regulatory Action (SBRA), as appropriate. [Committee Chair, RPM]
      15. Communicate labeling revision(s) to the applicant. Communications may include any revision requests previously communicated but not already addressed (i.e. Filing Letter, etc.). [RPM]
        1. This communication may occur anytime during the review; however, it most commonly occurs after the labeling meeting.
        2. If needed, labeling meeting(s) may be held with the applicant to resolve labeling disagreements or provide clarification. [Review Committee]
      16. Upon receipt of draft labeling revised as a result of labeling negotiations, confirm changes are consistent with requested changes. [RPM]
      17. Process revised draft labeling submitted as an amendment to the pending application and, if revised labeling is submitted outside the normal DCC procedures (i.e. email to RPM), assign a third level STN. [RPM]
        1. Note: if the amendment is submitted as part of an eCTD submission, the applicant must submit the amendment through the Agency’s Electronic Submission Gateway (ESG). Refer to CBER’s Internet Electronic Submissions Web page for additional information (see references).
      18. Document in the review memorandum any labeling issues that should be identified in the SBRA. [Review Committee Members]
      19. Notify applicant of acceptance of proposed draft labeling and request applicant to submit an amendment to the application that contains the final draft labeling. The approved labeling is either appended to or otherwise identified in the approval letter. [RPM]
      20. Ensure the approved final draft labeling is included in the Action Package for Posting according to SOPP 8401.7: Action Package for Posting [RPM]
    3. Labeling Changes Submitted After Approval of original BLA/NDA/ANDA (21 CFR 314.70 and 601.12)
      Process annual reports per SOPP 8411.1: Administrative Handling and Review of Annual Reports for Approved Biologics License Applications (BLAs).
      1. Determine if the proposed labeling change is classified under the correct change category (PAS, CBE, annual report). [Review Committee Members]
        1. Promptly notify the applicant by telephone and letter, if the category is incorrect, and inform them of the correct category. [RPM]
        2. Request reviewer assignments, as applicable, for clinical, statistics, clinical pharmacology, toxicology, CMC, and APLB. [RPM]
          • Note: A clinical reviewer and an APLB reviewer are included on all submissions containing labeling revisions.
        3. Provide submission link to the review committee along with a list of associated submissions that have open labeling for review. Additional/companion submissions with labeling may be found by searching the RMS/BLA database. See Regulatory Job Aid JA 910.03: RMS/BLA Database Search for Labeling Submissions. [RPM]
      2. Ensure the submission includes an SPL that reflects currently approved labeling in addition to the requested change for that submission. [RPM]
        • Note: Pending CBE safety language should not be included in another pending labeling supplement until after CBE approval. The RPM should make review committees for the same product/same applicant aware of pending safety information under review. The purpose of notification is to make review committees aware of pending safety information for consideration in their review.
      3. Perform a comparison to the previous version of changes to approved labeling received in SPL format and document any differences. Refer to Regulatory Job Aid JA 900.09: SPL Comparison Instructions for additional information. [RPM]
      4. Examine all labeling components and note any missing information at the Filing Meeting. [Review Committee Members]
      5. Determine the planned target date for communication or feedback regarding labeling to the applicant for inclusion in the Filing Letter. [Review Committee Members]
      6. Ensure UNII Code request is submitted to CBER SRS, if applicable. [RPM, CMC reviewer]
      7. Ensure UNII Code is correct or concur with the SRS recommendation, as appropriate. Refer to regulatory job aid JA 900.01: UNII Code for additional information. [CMC reviewer]
      8. Enter the communication(s) from the CBER SRS Team in the appropriate regulatory database Communication/Correspondence screen in the same manner as compliance check or lot release communications [RPM] Refer to regulatory job aid JA 900.01: UNII Code for additional information
      9. Ensure compliance with labeling requirements as described in 21 CFR Parts 201, 202, 606, 610, 640 and 660, as applicable. [Review Committee Members]
      10. Review labeling from a promotional, comprehension and readability perspective, including consideration of potential medication errors due to content and format issues. [APLB Reviewer]
      11. Ensure accuracy of NDC and bar code information. If other information is encoded in Bar Code, consult with Review Management [RPM, CMC reviewer]
      12. Hold labeling meeting(s) after mid-cycle to discuss proposed labeling revisions. [Review Committee]
        1. Complete a thorough review of the labeling before the labeling meeting. [Review Committee Members]
        2. Provide a draft clinical memorandum to the APLB reviewer to allow for the completion of the APLB Labeling Review memorandum. [Clinical Reviewer]
        3. Provide a formal APLB Labeling Review memorandum to the clinical reviewer, committee chair, and RPM with labeling revision recommendations based on the clinical review and labeling discussions, as appropriate. [APLB reviewer]
          • Additional consults with APLB are available on a case-by-case basis thereafter, but output that results from these further consultations may not be provided in an additional formal memorandum. These additional comments may be conveyed via meeting minutes, telecon minutes, or email communications.
        4. Collaboratively identify labeling requirement/revisions. [Review Committee]
        5. Summarize labeling issues identified at this meeting. [Committee Chair, RPM]
      13. Communicate concerns raised during labeling comparison with applicant. [RPM]
      14. Communicate labeling revisions to the applicant. Communications may include any revision requests previously communicated but not already addressed (i.e. Filing Letter, etc.). [RPM]
        1. This communication may occur anytime during the review, however, it most commonly occurs after the labeling meeting.
        2. If needed, labeling meeting(s) may be held with the applicant to resolve labeling disagreements or provide larification. [Review Committee Members]
      15. Upon receipt of draft labeling revised as a result of labeling negotiations, confirm changes are consistent with requested changes. [RPM]
      16. Research concurrent open submissions with labeling for review to ensure coordination with all open submissions. [RPM]
      17. Notify the review committee(s) of any pending supplements for the same product/applicant so that the newly approved version of the labeling can be requested from the applicant, if the applicant does not amend the submission to include the newly approved labeling. [RPM]
      18. Notify applicant of acceptance of proposed draft labeling and request applicant to submit an amendment to the application that contains the final draft labeling. The approved labeling is either appended to or otherwise identified in the approval letter. [RPM]

     

  5. Appendix
    1. Bar Codes

     

  6. References
    1. References below are located on FDA’s Intranet (unless otherwise noted):
      1. CBER Regulatory Job Aids:
        1. 900.01: UNII Code
        2. 900.02: SPL Content of Labeling
        3. 900.08: National Drug Code and Bar Code Labeling Review
        4. 900.09: SPL Comparison Instructions
        5. 910.02: Proprietary Name Review (PNR) Processing
        6. 910.03: RMS/BLA Database Search for Labeling Submissions
        7. 910.05: Labeling Review for Whole Blood and Blood Components including Source Plasma and Source Leukocytes
        8. 910.14 : Labeling Review - Pregnancy, Lactation and Females and Males of Reproductive Potential
      2. SOPP 8426: Assignment of Biological Product Proper Names
    2. References located on Internet Web pages: Web links to the references below can be found in the list following the History Table
      1. 21 CFR
        Relevant sections are: Parts §201, §201.10( c), §201.56, §201.57, §201.80, §201.100(d)(3), §202.1, §299.4, §314.50(l)(1)(i), §314.70, §314.81 (b), §314.94(a)(8), §601.12, §601.14(b), §610, §606, 122, 640.84, 640.94 and 660.28
      2. Electronic Submissions Web Page
      3. Legislation:
        1. Food and Drug Administration Amendments Act (FDAAA), September 2007
        2. Prescription Drug User Fee Act (PDUFA)
        3. Pediatric Research Equity Act (PREA) December 2003
      4. Federal Register:
        https://www.federalregister.gov/
        1. Content and Format of Labeling for Human Prescription Drugs and Biological Products, Requirements for Pregnancy and Lactation Labeling (commonly referred to as the Pregnancy and Lactation Labeling Rule [PLLR]), December 2014. 79 FR 72064
        2. Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products, (commonly referred to as the Physician Labeling Rule [PLR]), January 2006. 71 FR 3922
        3. Requirements for Submission of Labeling for Human Prescription Drugs and Biologics in Electronic Format (commonly referred to as the Electronic Labeling Rule); December 2003. 68 FR 69009
        4. Bar Code Label Requirements for Human Drug Products and Biological Products; Final Rule; February 26, 2004 (Volume 69, Number 38). 69 FR 9120
      5. Guidances:
        NOTE: The General Labeling Guidances webpage is assessable at:
        http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm065010.htm
        1. Guidance for Industry: Providing Regulatory Submissions in Electronic Format- Content of Labeling (April 2005)
        2. Guidance for Industry: An Acceptable Circular of Information for the Use of Human blood and Blood Components (Nov 2013)
        3. Guidance for Industry; Contents of a Complete Submission for the Evaluation of Proprietary Names (February 2010)
        4. Guidance for Industry: Bar Code Requirements Questions and Answers (August 2011)
        5. Guidance for Industry: Labeling for Human Prescription Drug and Biological Products – Implementing the PLR Content and Format Requirements (February 2013)
        6. Guidance for Industry: Labeling for Human and Prescription Drug and Biological Products – Implementing the PLLR Content and Format Requirements (December 2014)
      6. SOPPs:
        1. SOPP 8001.4: Review of CBER Regulated Product Proprietary Names
        2. SOPP 8401: Administrative Processing of Biologics License Applications (BLA)
        3. SOPP 8401.7: Action Package for Posting
        4. SOPP 8403: Issuance, Reissuance and Revocation of Licenses for Biological Products
        5. SOPP 8411.1: Administrative Handling and Review of Annual Reports for Approved Biologics License Application (BLAs)

     

  7. History
Written/ RevisedApproved ByApproval DateVersion NumberComment
Monser, LSCChris Joneckis, PhDJan 18, 20165Revised to include Pregnancy and Lactation Labeling Rule
Dixon, PerkinsRobert Yetter, PhDMarch 21, 20124Revised to include Bar Code information
Rehkopf/RMCCRobert Yetter, PhDOct 13, 20113Update to new format and processes
L. Falk/RMCCRobert, Yetter, PhDMar 20, 20082Update to include Physician’s Labeling Rule; Submission of labeling in Structured Product Labeling Format
 Robert, Yetter, PhDDec 23, 20021Original version of SOPP

References: 21 CFR

Relevant sections are: Parts §201, §201.10( c), §201.56, §201.57, §201.80, §201.100(d)(3), §202.1, §299.4, §314.50(l)(1)(i), §314.70, §314.81 (b), §314.94(a)(8), §601.12, §601.14(b), §610, §606,122, 640.84, 640.94 and 660.28

References: Electronic Submissions Web Page

References: Federal Register

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