Submission of variation applications

The electronic application form facilitates the registration of the application in NOMA’s case management system. One application form should be used if the variation application concerns several pharmaceutical forms and/or strengths of the same product. Each variation should be briefly summarised in the “scope” section of the application form. Further it is important that the “present and proposed” section is completed. A fully completed application form provides a clear overview of the proposed variations.

The applicant should select the classification that best describes the variation. For Type IA and Type IB, the applicant must indicate which of the relevant condition(s) are fulfilled and which documentation is enclosed. If one or more of the conditions laid down in the classification guideline for Type IA are not fulfilled, the relevant variation must be submitted as a Type IB variation, unless the variation is specifically classified as a Type II variation. If the variation is not listed in the classification guideline, the applicant should tick “z, other variation” at the lowest possible level. If the variation is covered by an Article 5 recommendation, the Article 5 box should be ticked. 

For grouped variations, it is important that the applicant classifies each individual variation in the application form. In the “scope” section of the application form, the applicant should provide a brief description of each individual variation and justify the grouping. This also applies to applications containing several variations with the same classification; for example, the classification C.4 must be repeated four times when the application contains four C.4 variations. The documentation forming the basis for the variation may also be stated in the “scope” section of the application form.

Relevant guidance:

• European Commission guidance on the procedures, including the Annex with the Commission’s classification guideline specifying conditions and documentation requirements
• CMDh Article 5 recommendations on unclassified variations (also used for national variation applications)
• CMDh guidance documents relating to variations
• CMDh questions and answers on the Variations Regulation

National procedure (NP)

For products authorised through the national procedure, the Norwegian Product information (PI) should be enclosed if the variation application proposes any updates to the PI. The track changes function should be used to highlight the proposed updates. Updates to the product information assessed in parallell procedures should not be inlcuded in the submitted texts. It is not necessary to attest the product information.

If there is a need to update the PI in line with the current QRD template, the applicant may do so at the same time. If the update only concerns the package leadlet and/labelling, this should be classified as a 61(3) notification. 

Mutual recognition procedure (MRP)

For Type II variations in the MRP, the NOMA issues an email after the end of procedure with information on the submission of Norwegian PI. To ensure correct handling by the NOMA case management system it is important that this specific email is replied to without changing the subject line.

The SmPC, package leaflet and labelling text should be submitted as separate Word files with all proposed updates highlighter with track changes. Please use the correct version of the QRD template; see the information on templates.

When changes are made to the common labelling text the Norwegian translations will be reviewed. Mock-ups should be submitted if significant changes are proposed to to the design and/or layout. NOMA may request updated mock-ups where necessary.

Centralised procedure (CP)

Please refer to the European Medicines Agency for Norwegian product information. NOMA will implement changes continuously in its databases. There is no need to submit the most recently approved version of the Norwegian product information in Word format. For certain changes, DMP will request the information necessary to update the databases, for example in the case of new pack sizes.

Type IA and Type IB variations must include documentation in accordance with the requirements set out in the classification guideline.

Type II variations should be discussed in an expert report. The report should provide a critical review of the underlying data. References such as original articles and reports from relevant studies should be enclosed. Additional requirements may apply to certain Type II variations.

Relevant guidance

General information on the grouping of variations is available in Annex III to the Variations Regulation, Chapter 7 of the CMDh Best Practice Guide on Worksharing, and Examples of Acceptable and Non-Acceptable Groupings for MRP Procedures.

National procedure

Nationally authorised products may be grouped across products. All variations included in the grouping should concern all the included MAs and there should be no need for product specific assessment.

Identification of correct number of variations submitted under scope C 

One data set of supporting documentation (e.g. a clinical study) = one variation. The supporting documentation is the documentation or references used to determine whether information should be included in the product information. For example, an adverse reaction may be based on both spontaneous reports and two literature articles. Together, this is considered one data set of supporting documentation for the relevant variation.

The challenge to identify the correct number of variations often arise when submitting a grouped Type II variation application following a review of the company core data sheet (CCDS). It is important to note that marketing authorisation holders cannot include several updates in the CCDS and then submit one single variation to implement the information in the product information. The CCDS alone is not sufficient as supporting documentation, but it often provides references that may be used as documentation. If a separate assessment has been made as to whether an issue should be included in the CCDS, each such assessment must be regarded and submitted as one variation.

It is not acceptable for marketing authorisation holders of generic medicinal products to wait until the reference medicinal product (refMP) has implemented several text updates and then combine these into one single variation application to update the product information. For variation applications under category C.2, the marketing authorisation holder is expected to assess the likely number of data sets used in updating the reference medicinal product and group the application accordingly. See question 4.19 in the CMDh Questions and Answers on Variations.

Application form

The electronic application form facilitates the registration of the application in NOMA’s case management system. The applicant should use one application form if the variation application concerns several pharmaceutical forms and/or strengths of the same medicinal product. Each variation should be briefly described in the “scope” section of the application form and complete the “present and proposed” fields. A fully completed application form provides a clear overview of the requested variations.

The applicant should choose the classification that best describes the variation. The application form must indicate which condition(s) are fulfilled and which documentation is enclosed. If the variation results in consequential changes, these should be described in the application form. For grouped variations, it is important that the applicant classifies each individual variation in the application form. In the “scope” section, the applicant should provide a brief description of each individual variation and justify the grouping. This also applies to applications containing several variations with the same classification; for example, the classification G.I.4 must be repeated four times if the application contains four G.I.4 variations. The documentation forming the basis for the variation may also be stated in the “scope” section of the application form.

Administrative information in UPD

For VNRA variations, the following administrative information should be entered in the UPD:

• variation code
• affected product(s)
• submission comment with scope, email adress for communication and, if applicable, other relevant information such as present and proposed etc. 
• implementation date for the variation
• confirmation that the documentation requirements and conditions have been fulfilled

It is recommended to include a cover letter.  If one or more conditions or documentation requirements for a VNRA variation are not fulfilled, the relevant variation may be submitted as a VRA variation under an appropriate z-category.

For products authorised through the national procedure, the Norwegian Product information(PI) should be enclosed if the variation application proposes any updates to the PI. The Summary of Product Characteristics, package leaflet and labelling text should be submitted as separate Word documents. The track changes function should be used to highlight the proposed updates. If other variations are ongoing at the same time, the applicant should not include these in the text.

NOMA approves Norwegian labelling text when wording changes to the labelling text are applied for. In the case of changes to the design and/or layout, mock-ups must be submitted. NOMA may request updated mock-ups where necessary.

Updating the product information to the current QRD template should be submitted as a VRA G.I.18 variation. It is recommended that this variation be grouped with other VRA G variations. If only the package leaflet or labelling is to be updated, this is classified as a VRA G.I.15.z variation. If the change only concerns an update of the local representative in the package leaflet, the applicant may submit a VNRA C.10.a.

Both VRAs and VNRAs should include the relevant documentation, including documentation in accordance with the requirements set out in the classification guideline. For VNRA variations, the documentation must be uploaded to the UPD as a .zip file. A copy of the CMDv recommendation on the classification of the variation should be enclosed where relevant. 

VRA

VRAs should be discussed in an expert report. The report should provide a critical review of the underlying data. References such as original articles and reports from relevant studies should be enclosed. Exceptions to the expert report requirement apply to variations submitted to update the SPC following a subsequent recognition procedure, variations submitted solely to update the product information to the QRD template in accordance with Regulation (EU) 2019/6, and variations subject to a reduced (R) timetable as specified in Regulation (EU) 2019/6.

Grouping is only possible for VRA variations.

National variations may be grouped across products for VRA variations. General information on the grouping of variations is available in Regulation (EU) 2019/6, the CMDv Best Practice Guide for Variations Requiring Assessment, and the CMDv Best Practice Guide for Worksharing.