Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning “the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products” (hereinafter, the “Variation Regulation”), entered into force on 1 January 2009 and became binding on 1 January 2010.
The Regulation, which lays down general rules on the types and classification of variations, aims to establish, in the light of practical experience gained with the previously existing legal framework (i.e. Regulations (EC) 1084 and 1085 of 2003), and without departing from the general principles established therein, “a simpler, clearer and more flexible legal framework, while guaranteeing the same level of public and animal health protection” (see n. 1 of the Regulation).
The Variation Regulation applies to all variations to the terms of marketing authorisations for medicinal products for both human use and veterinary medicinal products granted following a Mutual Recognition Procedure or Centralised procedure, as well as following a Referral procedure but not, in principle, to variations to the terms of marketing authorisations granted following a purely national procedure or for authorisations granted for homeopathic and traditional herbal medicinal products, which have undergone the simplified registration procedure.
In particular, according to the Variation Regulation, variations can be classified in different categories, depending on the level of risk to public or animal health and the impact on the quality, safety and efficacy of the medicinal product concerned. Certain changes which have the highest potential impact on the quality, safety or efficacy of medicinal products will require, therefore, a complete scientific assessment, the same as for the evaluation of new marketing authorisation applications (see further below).
Besides the Variation Regulation, other guidance documents on variations to the terms of marketing authorisations for medicinal products have been issued by the European Commission, which will be regularly updated, taking into account the recommendations delivered by the coordination group established according to Article 31 of Directive 2001/82/EC or Article 27 of Directive 2001/83/EC (hereinafter the “Coordination Group”), the EMEA, as well as scientific and technical progress (see Article 4(1)(a) and Article 4(1)(b) of the Regulation).
In particular, two specific guidelines were issued by the Commission in December 2009: the Communication from the Commission entitled “Guideline on the details of the various categories of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products” (hereinafter, the “Commission Classification Guideline”) and the Communication from the Commission entitled “Guideline on the operation of the procedures laid down in Chapters II, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products” (hereinafter, the “Commission Procedural Guideline”).
The Commission Classification Guideline provides details of the classification of variations into different categories (i.e. minor variations of Type IA, minor variations of Type IB, major variations of Type II) and provides further details on the scientific data to be submitted and how this data should be documented. The Commission Procedural Guideline provides details on the operation of the procedures laid down in the Variation Regulation (i.e. variations to marketing authorisations granted following a mutual recognition procedure and decentralised procedure; variations to centralised marketing authorisations; extensions of marketing authorisations, work-sharing procedure, pandemic situation with respect to human influenza and urgent safety restrictions, respectively), as well as on the documentation to be submitted pursuant to these procedures. Both guidelines aim to facilitate the interpretation and application of the Variation Regulation.
In particular, the Commission Procedural Guideline provides, for each of the categories of variations mentioned above, guidance on the submission, grouping and handling of these variations. In particular: (i) for minor variations of Type IA a “Do and Tell procedure” applies together with a 30-day ex-post review; (ii) for minor variations of Type IB a “Tell, Wait and Do procedure” applies together with a 30-day ex-ante silent-consent review; (iii) for major variations of Type II a “prior authorisation procedure” applies with a 60-day evaluation timetable (reducible to 30 and extendible to 90 days); (iv) for extensions to the terms of a marketing authorisation, as indentified on Annex I of Variation Regulation and for which will either be granted a new marketing authorisation or will be included in the initial marketing authorisation to which it relates, an evaluation equivalent to the procedure for the granting of the initial marketing authorisation to which it relates; (v) for Urgent Safety Restrictions (hereinafter, “USRs”) initiated by the Marketing Authorisation Holder, a 24 hours silent-consent will apply. In particular, if no objections are raised by the relevant authority or the Commission within 24 hours following receipt of such a change to the terms of a marketing authorisation, USRs will be deemed as accepted. In all cases of changes to the marketing authorisation following USRs, including changes imposed by the Commission or by the national competent authorities as the case may be, a formal variation application will be submitted to the competent authority as soon as possible within 15 days of the date that the USR started.
Finally, other significant provisions of the Commission Procedural Guideline relate to the annual update of human influenza vaccines applications and to work-sharing procedures. In particular, in relation to human influenza vaccines, a special two step “fast track” procedure is introduced, wherein the first step concerns the assessment of the administrative and quality data elements (i.e. summary of product characteristics, labelling and package leaflet, and the chemical, pharmaceutical and biological documentation) and the second step concerns the assessment of the clinical data and data concerning the stability of the medicinal product. As to work-sharing, the Guideline sets out the specific circumstances in which a marketing authorisation holder is entitled to submit in one application the same Type IB, the same Type II variation, or the same group of variations or to agree so with the reference Member State or the EMEA in order to have only one authority examining the variation on behalf of the other concerned authorities.
The basic principle of the new regulatory framework on variations is to ensure that the evaluation procedure is adapted to the level of risk, having in mind also the limited capability of EU authorities to cope with the increased regulatory workload. In particular, while a risk based approach was already in place under the previous regulatory framework (e.g. changes were classified as minor -Type IA/B- or major -Type II- depending on the impact to product quality, safety and efficacy), significant flexibility was felt to be necessary to fill gaps existing in the previous legislation. The new rules provide for a distinction between changes to active substance/intermediates/starting materials/reagents, the importance of the impact of variations on restricted parts of the ASMF, or on sterile products, as well as to the level of knowledge and understanding of the process/product concerned.
In conclusion, the new practice, which, as discussed, aims to establish “a simpler, clearer and more flexible legal framework, while guaranteeing the same level of public and animal health protection”, clearly offers advantages to companies and authorities in terms of the harmonisation of the regulatory system applicable to changes to the terms of a marketing authorisation, the speeding up of the administrative procedures necessary to do so and the reduction of the workload borne by the national competent authorities involved. However, it also introduces considerable burdens in terms of new regulatory requirements to be met. How well this balance has been struck remains to be seen.