Changing the labelling and package leaflet (Article 61(3) notifications)
HumanRegulatory and procedural guidance
This page lists questions that marketing-authorisation holders (MAHs) may have on Article-61(3) notifications. It provides an overview of the European Medicines Agency's position on issues that are typically addressed in discussions or meetings with MAHs in the post-authorisation phase. Revised topics are marked 'New' or 'Rev.' upon publication.
A PDF version of the entire post-authorisation guidance is available:
These questions and answers have been produced for guidance only and should be read in conjunction with the rules governing medicinal products in the European Union, volume 2, notice to applicants.
MAHs must in all cases comply with the requirements of Community legislation. Provisions that extend to Iceland, Liechtenstein and Norway by virtue of the European Economic Area agreement are outlined in the relevant sections of the text.
Article 61(3) refers to Directive 2001/83/EC in which a so-called “61(3) Notification” is defined as a change to an aspect of the Labelling and/or Package Leaflet (PL) text not connected with the Summary of Product Characteristics (SmPC).
In order for a 61(3) Notification to be valid:
- the change must affect only the Annexes IIIA (labelling) and/or IIIB (PL), with no changes to the SmPC and/or the Annex II. In addition,
- the changes must affect the English labelling and/or PL text, with consequential amendments to all other language versions.
Examples of changes falling within the scope of 61(3) Notification:
- Changes in the local representatives
- Minor changes to the labelling and/or PL
- Labelling: e.g. changes of abbreviation for the batch number
- PL: Harmonisation of wording used in the PL
- Updated PL after User Testing when the User Testing report and amended leaflet cannot be included in an upcoming regulatory procedure which affects the Annexes (e.g. Type II variation)
- Introduction of combined PL (after prior consultation with QRD)
- Change in Braille (inclusion/deletion/change)
- Change in instruction for use in the PL
The following examples do not fall within the scope of 61(3) Notification:
- Changes to SmPC or Annex II,
- Changes that only affect some languages but not all,
- Changes in overall lay-out, design, readability of labelling and/or PL with no changes to the text. In such case, the need for an EMA review of the proposed changes by means of the provision of specimens, should be discussed with EMA Medical Information Sector (muspecimens@ema.europa.eu), as outlined in “Checking Process of Mock-Ups and Specimens of outer/immediate labelling and package leaflets of human medicinal products in the Centralised Procedure” on the EMA website.
It is possible to introduce within a single 61(3) Notification, several changes to the labelling and/or the package leaflet, which do not affect the SmPC or the Annex II (e.g. submission of a change in the local representative and harmonisation of the wording used in the PL).
The Agency strongly recommends, that whenever possible, the marketing authorisation holder (MAH) includes minor changes to the labelling and/or PL as part of another on-going or upcoming regulatory procedure amending the Product Information (e.g. Type IA*, Type IB or II variation affecting the product information, renewal, etc.). Should the MAH have a query on changes that may fall under the scope of 61(3) Notification, they should contact the EMA Service Desk, selecting the tab “Business Services”, category “Human Regulatory”. The subcategory to be selected is “Post-authorisation - Human”, followed by the sub-option “Article 61(3) Notification queries”.
If you do not have an EMA Account, you may create one via the EMA Account Management portal. For further information or guidance about how to create an EMA Account reference the guidance "Create an EMA Account".
However, if submitted stand-alone, changes only affecting Annex III have to be submitted as a 61(3) Notification (i.e. not possible to submit as a variation).
Upon submission, the Agency will inform the marketing authorisation holder (MAH) within 90 days whether the proposed changes are accepted or not. The Agency will inform concomitantly the Commission in cases where the changes have been accepted (for information on the update of the Commission Decision see: How and when will the updated Annexes become part of the Marketing Authorisation?).
* Only changes for which no rapporteur involvement, nor linguistic review is needed (e.g. change to local representatives).
References
The Rapporteur is normally not involved in the review of a 61(3) Notification. However, the Rapporteur may be involved on a case-by-case basis depending on the changes requested (e.g. extensive PL revision following User Testing).
There are no recommended submission dates for 61(3) notification. Hence, the MAH can submit a 61(3) notification at any time.
The Agency strongly recommends that whenever possible the marketing authorisation holder (MAH) includes these minor changes to the labelling and/or PL as part of another on-going or upcoming regulatory procedure amending the Product Information (e.g. Type IA*, Type IB or II variation affecting the product information, renewal, etc.). Should the MAH have a query on changes that may fall under the scope of 61(3) Notification they should contact the EMA Service Desk, selecting the tab “Business Services”, category “Human Regulatory”. The subcategory to be selected is “Post-authorisation - Human”, followed by the sub-option “Article 61(3) Notification queries”.
If you do not have an EMA Account, you may create one via the EMA Account Management portal. For further information or guidance about how to create an EMA Account reference the guidance "Create an EMA Account".
* Only changes for which no rapporteur involvement, nor linguistic review is needed (e.g. change to local representatives) .
The submission of a 61(3) Notification should include:
1.Cover Letter indicating the product name:
- dated, signed by the official contact person,
- including a summary and / or explanation of the proposed changes
- including a list of on-going/upcoming regulatory procedures affecting the Annexes and including a confirmation that the proposed changes only affect Annex III).
- including a confirmation from the MAH that there are no other changes than those identified in the cover letter (except for those addressed in other variations submitted in parallel),
- present/proposed table of the changes (this can be a separate annex).
2. Product information:
- The revised product information ('complete set of Annexes' includes Annex I, II, IIIA and IIIB i.e. all SmPC, labelling and PL texts for all approved strengths and pharmaceutical forms of the product concerned) in all EU languages (incl. IS+NO)
- in Word format (highlighted) indicated via 'Tools – Track changes'
- in PDF format (clean) with all changes 'accepted'
- Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated PIs. This applies to the English version and all the translations. Please submit annotated PIs in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated PI submitted by the marketing authorisation holder.
The complete set of Annexes must be presented sequentially (i.e. Annex I, II, IIIA, IIIB) as one document for each official EU language. Page numbering should start with "1" (bottom, centre) on the title page of Annex I. The Annexes should be presented in strict compliance with the QRD Convention published on the EMA website. When submitting the full set of Annexes in PDF format, this should be accompanied by the completed Submission of day +25 /235 final product information annexes (human and veterinary) - QRD Form 2 and checklist, and MAHs should follow/pay attention to the User guide on how to generate PDF versions of the product information - human.
The Annexes should be presented on the latest CHMP approved version.
The Annexes provided should only reflect the changes introduced by the 61(3) Notification. However, it is possible for the MAHs to take the opportunity to introduce minor linguistic amendments in the labelling and/or the PL for all or some EU languages. These changes should be clearly mentioned in the cover letter. Any changes not listed in the Notification cover letter will not be considered as part of the 61(3) Notification. In addition, it is not possible for the MAHs to introduce minor linguistic amendments in the SmPC and/or the Annex II.
3. If applicable:
- Any supportive relevant documentation [e.g.: User Testing reports English and multi-lingual ('worst-case') colour mock-up of outer and immediate packaging for each pharmaceutical form in each container type (e.g. blister and bottle, vial and pen) in the smallest pack-size] to the 61(3) Notification, presented under the appropriate headings and numbering of the EU-CTD format.
Information is available on ‘Submitting a post-authorisation application’.
A dedicated Procedure Manager (PM) will be assigned to the procedure once your notification has been submitted.
Timelines:
The length of the procedure will vary depending on the need for Rapporteur’s involvement, linguistic review and the submission of revised information by the MAH when required. If the EMA 61(3) notification is not issued within 90 days following the introduction of the request, the applicant may put the change into effect.
- Upon submission of your 61(3) Notification, the PM will review the content of the documentation.
- When the documentation submitted by the MAH does not meet the requirements, the PM will contact the MAH. The MAH should then provide revised documentation within 5 days. Upon receipt of the revised documentation, the PM will review the information. Should the information provided by the MAH be incomplete or does not fall under the scope of 61(3) Notification, the PM will inform the MAH that the proposed change cannot be implemented.
- Upon receipt of satisfactory documentation and in cases where the Rapporteur's input is needed (e.g. submission of user testing results), the Rapporteur will assess the MAH's proposal within 15 working days. Should the outcome of the Rapporteur's assessment be not satisfactory, the MAH will be requested to provide revised documentation within 5 days. Upon assessment of the MAH's responses, should the outcome of the Rapporteur's assessment remain unsatisfactory, the PM will inform the MAH that the proposed change cannot be implemented.
- Once the proposed changes have been agreed and the linguistic review is complete (when applicable), the MAH will receive a 61(3) notification via email that the changes have been accepted.
Possible outcomes:
In summary, the following outcomes may be envisaged for 61(3) notification:
- Changes are acceptable and an EMA 61(3) notification is issued within a maximum of 90 days.
- Changes are not acceptable (even after receipt of additional/revised information if required). The PM will inform the MAH that the proposed change cannot be implemented.
- The proposed changes do not fall under the scope of a 61(3) Notification (even after receipt of additional/revised information if required). The PM will inform the MAH that the notification does not fall under the scope of Article 61(3) and cannot be processed. The proposed change cannot be implemented.
There is no fee payable for 61(3) notification.
Mock-ups
In principle, no mock-ups are to be provided with 61(3) notifications, however, where the overall design and readability of the outer and immediate packaging and/or package leaflet is affected as part of the 61.(3) notification, the need for the provision of mock-ups should be discussed with the EMA (muspecimens@ema.europa.eu) on a case-by-case basis (e.g. mock-ups would be required when proposing a new corporate design of packs, use of different colours, major changes in layout, introduction of new text in the labelling in line with the SmPC).
In case the submission of mock-ups is required, the relevant example mock-ups would need to be included in the module 1.3.2 of the application dossier.
In case of comments on the mock-ups, the MAH should submit responses and/or updated mock-ups, as applicable, to the EMA (muspecimens@ema.europa.eu) prior to the specimens printing. EMA will discuss the best and feasible corrective action with the MAH, taking into account the nature and amount of issues identified. EMA will endeavour to provide such feedback as soon as possible and taking into consideration the production plan of the medicinal product, as applicable.
Specimens
Where the overall design and readability of the outer and immediate packaging and/or package leaflet is affected as part of the 61(3) notification, the need for the provision of specimens should be discussed with the EMA Medical Information Sector on a case-by-case basis (e.g. specimens would be required when proposing major changes in lay-out, use of different colours as part of the 61(3) Notification, but not e.g. when only limited text is added/revised in a PL section).
In case specimens are required, in principle only one relevant example (multi-lingual if possible) would need to be sent to the EMA at the latest 15 working days before marketing. However, depending on the nature and extent of the change(s) concerned, additional specimens may be required by the EMA. The EMA will perform a general check from the viewpoint of readability within 15 working days, and will check if any previous comments on specimens have been duly implemented. The MAH will be informed about the outcome of the check.
Note:
In case the MAH wishes to receive EMA feedback on their proposed new packaging in advance of the specimen review, the EMA could agree with the MAH on a case-by-case basis, to review draft mock-ups before specimen submission.
The above principles also apply to mock-ups for Iceland. The mock-ups should be sent to mockups@ima.is. See also http://www.ima.is
No mock-ups and specimens are required for Norway.
References
Upon finalisation of a 61(3) notification, the changes to the product information annexes will be reflected in the framework of the next regulatory procedure for which a Commission Decision will be issued. For example, the changes could be included with the Commission Decision of a subsequent Type II variation.
However, the agreed changes can be implemented upon receipt of the EMA 61 (3) notification without awaiting the update of the marketing authorisation through a Commission Decision, and the agreed changes should be included in the annexes of any regulatory procedure subsequent to the 61(3) notification. Additionally, if the EMA 61 (3) notification is not issued within 90 days following the introduction of the request, the applicant may put the change into effect.
The EPAR (published on the EMA website) will be revised to implement the outcome of the 61(3) notification, after issuance of the EMA 61 (3) notification.
References
Information is available on ‘Contacting EMA: post-authorisation’.