New EU Variation Regulation: Commission Delegated Regulation (EU) 2024/1701

In the light of the practical experience acquired during these years applying the Variation Regulation No 1234/2008, regarding the examination of variations to the terms of marketing authorizations for medicinal products for human use, it is appropriate to simplify, clarify and improve the EU legal framework, without departing from the general principles on which the Variation Regulation No 1234/2008 is based.
It is important that the EU legal framework is finalized to increase the efficiency of the procedures for both the pharmaceutical industry and the competent authorities, and in order to guarantee the same level of public health protection.

On the basis of the above general considerations it was necessary issue the new COMMISSION DELEGATED REGULATION (EU) 2024/1701, amending the Variation Regulation (EC) No 1234/2008.
The new regulation is applied starting from 01.01.2025 and regulates the variation procedures of the registration dossier of medicinal products for human use.

Moreover, it is appropriate to constantly take account of scientific and technical progress and ensure that the EU variation classification is amended accordingly.
Additionally, based on the experience gained from the COVID-19 pandemic and the adaptations to the variation procedures to change the vaccine composition due to the multiple variant strains, it is appropriate to introduce similar procedures also for other vaccines to address a public health emergency.

The main news introduced from the new Commission Delegated Regulation (EU) 2024/1701 are:
1) The concept of grouping different Type IA variations is extended to the “super-grouping” concept.
The super-grouping allows to submit one application for Type IA grouping of variations related to different medicinal products (with different MA numbers) that belong to the same MAH. The condition is that the proposed changes must be the same for all the medicinal products involved in the super-grouping. The new Regulation details the cases where the super-grouping is allowed. The use of the super-grouping requires proactive planning for MAHs, but it is very useful if many MA numbers are affected by a change. It is advantage in terms of workload.

2) The annual notification becomes mandatory for Type IA variations.
The Type IA variations as grouping (one medicinal products) or “super-grouping” (different medicinal products) must be notified to the Authorities as annual update, submitting an Annual Report. The Annual Report offers an high level of flexibility because the submission date can be chosen by the MAH, as long as the 12 months deadline is kept, and can prevent workload and costs. For the MAHs this means have a consistent internal database to constantly monitor and control the changes and a reliable document management system.

3) The worksharing procedure becomes mandatory for Type IB and II variations.
All Type IB and II variations must be submitted with a single application as worksharing procedure, when related to different medicinal products (with different MA numbers) belong to the same MAH. Worksharing requires intensive planning for the MAH, but it is useful to maintain an harmonized dossier for the companies that increasingly work globally.

4) Human coronavirus vaccines.
The examination of variations concerning changes to the active substance for the purposes of the annual update is applied also to human coronavirus vaccine.
For annual updates of human coronavirus vaccines that procedure shall only apply after a public announcement of the Agency.

5) Public health emergency.
More flexibility for the authorization procedures of human vaccines. In case of a public health emergency in EU, the relevant authorities may, where certain pharmaceutical, non-clinical or clinical data are missing, exceptionally and temporarily accept a variation to the terms of a marketing authorisation for a human vaccine pertaining to the pathogen causing the public health emergency.

6) Not applicable to veterinary medicinal products.
The effects of the new variation regulation is applied to medicinal products for human use only, therefore no reference to medicinal products for veterinary use is applied.

7) Medical devices
The new Variation Regulation includes variations for medical devices according to the new requirements of the Medical Devices Regulation and the quality guidelines of medicinal products when used with a medical device.

Additional information:
1) The European Commission is also currently reviewing the guidelines on the details of the various categories of variations and operation of the procedures (Variations guidelines: Proposed amendments to the European Commission guidelines on variations categories and procedures) and an updated version is expected during 2025.

2) The previous Article 5 recommendations for unforeseen variations have been integrated into the proposed European Commission guidelines above mentioned.

3) During this transition period, from 1 January 2025 to the date on which the updated Variation Guidelines become applicable, the MAHs should continue to rely on the current classification of the Variations Guidelines and on specific procedural guidance available the CMDh website.

4) In the EMA website (https://www.ema.europa.eu/en/guidance-application-amended-variations-regulation-1-january-2025#anchor1) are available guidelines on the implementation of the new Variations Regulation to be applied from 01.01.2025.
The guidelines provides instructions on:
– the procedure for grouping and super-grouping of Type IA variations (“super-grouping” concept)
– the annual update for minor variations of type IA (Annual Report)
– the mandatory (same MAH) and voluntary (different MAHs) use of the work sharing procedure for type IB and II variations (Worksharing)
– the annual update of a human influenza or human coronavirus vaccine (Human vaccines)
– the variations to human vaccines for public health emergencies (Public health emergency)
– the amendments of the unforeseen variations submitted under the Article 5 procedure of the Variation Regulation No 1234/2008.

Conclusions:

The new regulation is advantage in terms of workload and costs for the companies, increases the flexibility in connection with regulatory submissions, and facilitates a further harmonization by guarantying a common outcome of the respective variation assessment throughout Europe, but on the other side requires intensive tracking and strategic planning for the companies and consistent internal database and a developed and reliable document management system.