8. Post-Approval

1. Renewals (except for MA under exceptional circumstances)

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• A new marketing authorisation is valid for five years. The MA may be renewed after five years on the basis of a re-evaluation of the benefit risk balance by the relevant authority.
• The MA holder shall provide the relevant authority with a consolidated version of the file in respect of quality, safety and efficacy, including the evaluation of data contained in suspected adverse reactions reports and periodic safety update reports submitted, and information on all variations introduced since the MA was granted, at least nine months before expiry of the MA.
• Once renewed, the MA is valid for an unlimited period, unless the relevant authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal. 
• If within three years of receiving a MA the product is not marketed or, after marketing, is no longer actually present on the market for three consecutive years the MA shall cease to be valid.
  • MAs under exceptional circumstances granted under Article 14(8) of Regulation (EC) No 726/2004 are also valid for 5 years. However, continuation of the authorisation shall be linked to the annual reassessment of the conditions under which the MA was granted.
  • Conditional MAs granted under Article 14-a of Regulation (EC) No 726/2004 do not fall under the above provisions. They are valid for 1 year and should therefore be renewed annually.

Legal basis: Article 24 of Directive 2001/83/EC; article 14 of Regulation (EC) No 726/2004

2. Variations

Throughout the life of a medicine, the marketing authorisation holder (MAH) is responsible for the product and to take appropriate action on any information which might influence the evaluation of the benefits and risks of the medicinal product concerned. 

The MAH is required:

• to continuously update the dossier to take account of technical and scientific progress and to introduce any change that may be required for the manufacture and control of the medicine.
• to ensure that the product information (SmPC, labelling, PL) is kept up to date with the current scientific knowledge.

Updating should be taken up through the variation procedure, and be reflected in the dossier and/or Overall Summaries and Overviews, as appropriate.

Legal basis: Article 23 of Directive 2001/83/EC:

2.1. Variation procedures

• Definition:      
  ‘Variation’ means any amendment to the terms of the marketing authorisation, and any conditions, obligations, or restrictions affecting the marketing authorisation, including the SmPC or changes to the labelling or the package leaflet
• Variations are classified in different categories depending on the level of risk to public health and the potential impact on the quality, safety and efficacy of the medicine concerned.
• Regardless of the legal basis of the initial MA, a MAH can submit an application in relation to further developments or uses of its medicinal product, including new therapeutic indications, in accordance with the provisions and requirements set out in Regulation (EC) No 1234/2008
• Any application by the MAH to vary a MA which has been granted in accordance with the legislation needs to be submitted to all relevant authorities*.

*‘Relevant authority’ hereinafter means:

• the competent authority of each Member State concerned;
• in the case of centralised marketing authorisations, the EMA;

Legal basis:      

Regulation (EC) No 1234/2008 (https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A02008R1234-20210513)‘concerning the examination of variations to the terms of marketing authorisations for medicines for human use and veterinary medicines and on the documentation to be submitted pursuant to those procedures’ (the ‘Variation Regulation’)

Of note: The following text refers to the Variation Regulation as legal basis unless otherwise noted

2.2. Categories of variations

• Type IA variations - minor variations ‘Do and Tell’ procedure.
• Type IB variations - minor variations ‘Tell, Wait and Do’ procedure.
• Type II variations - major variations.
• Extensions.

Guidelines on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicines for human use and veterinary medicines and on the documentation to be submitted pursuant to those procedures (2013/C 223/01).

2.3. Type IA variations – ‘Do and Tell’ procedure

Such minor variations have only a minimal or no impact on the quality, safety or efficacy of the medicine, and do not require prior approval before implementation.

A guideline clarifies the conditions which must be met.

These minor variations are classified in two subcategories:

• Type IA variations require immediate notification to the authority following implementation, in order to ensure the continuous supervision of the medicine.
• Type IA variations that do NOT require  immediate notification may be submitted by the marketing authorisation holder (MAH) in an annual report within 12 months after implementation.

Annex II of Regulation (EC) No 1234/2008

2.4. Type IB variations – ‘Tell, Wait and Do’ procedure

Type IB is a minor variation which is neither a Type IA variation nor a Type II variation nor an Extension.

• These variations must be notified to all relevant authorities by the MAH before implementation, but do not require a formal approval.
• The respective authority has 30 days in which to respond to the MAH that the notification has not been accepted.
• Upon acknowledgement of receipt of a valid notification, the MAH must wait for a period of 30 days to ensure that the notification is deemed acceptable by the relevant authority before implementing the change.

2.5. Type II variations

These major variations are defined as variations which are not an extension and which may have a significant impact on the quality, safety or efficacy of a medicine.

A Guideline clarifies the conditions which must be met.

The Variations Regulation and the Variations Guidelines set out a list of changes to be considered as Type II variations. In addition, any other change which may have a significant impact on the quality, safety or efficacy of the medicinal product must be submitted as a Type II variation.

Type II variations need to be approved before they can be implemented.

Type II variations can only be implemented once the MAH has been informed of the favourable outcome by the authority.

2.6. Extension

Certain changes to a Marketing Authorisation, have to be considered to fundamentally alter the terms of this authorisation and therefore cannot be granted following a variation procedure. These changes are to be submitted as ‘Extensions of marketing authorisations’. They are listed in Annex I of the Variations Regulation and comprise two main categories:

1. Changes to the active substance(s) where efficacy and safety characteristics are not significantly different.

2. Changes to strength, pharmaceutical form and route of administration.

Such applications will be evaluated in accordance with the same procedure as for the granting of the initial MA.

The extension can either be granted as a new MA or will be included in the initial MA to which it relates. It is important to remember that a completely new indication for a product already on the market requires a new MA.