Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

The new Variation Regulation. A major step forward? ***

Dr. Susanne Lange (Abschlußjahr: 2009)

Language: English

The goal of the review of the variation Regulation is to make the system simpler, clearer and more flexible without compromising human and animal health. Further harmonisation of the regulatory environment is a key task of the European Commission. For the variation framework this means to widen the scope of the variation Regulation to include national marketing authorisations. The goal was to reach full harmonisation so that all variations to a marketing authorisation in the EU follow the same rules independently of the approval procedure for granting the marketing authorisation. This goal has been achieved for the vast majority of marketing authorisations so that harmonisation has been reached to a great extent. But so far it is not clear if all member states will implement the EU variation system.

The revision of the variation Regulations No 1084/2003/EC and No 1085/2003/EC should eliminate the weak points of the current variation system and include the scientific development. One of the weak points in the current system is that all variations regardless of their impact on the medicinal product are classified as type II when not defined in the Regulation as type IA or type IB variation. It has been shown in the past that a lot of variations had to be submitted as type II variations although they have only a minor impact on quality, safety and efficacy of the medicinal product. This is the reason why the definitions now have changed so that a variation which classification is undetermined is considered as type IB variation with the option to upgrade the variation to a type II variation. The classification of a variation is undetermined when the change is not defined in the Regulation and/or in the guidelines. Such variations are called unforeseen variations. For unforeseen variations the marketing authorisation holder can make a request for a recommendation of the classification. The recommendation is made public and will be included in the guideline at a later stage so that for a given variation the recommendation is only made once. It gives certainty for the marketing authorisation holder and the competent authorities regarding the classification of variations and ensures that new scientific developments are automatically included in the system which makes the system flexible. The weakness of the current system that minor variations have to be submitted as type II variation has been removed in the new system which reduces administrative burden.

Another weak point in the current system is the over regulation of type IA changes. Type IA changes have no or minimal impact on the quality, safety and efficacy of a medicinal product but in the current system it is not possible to implement such a change on the responsibility of the marketing authorisation holder. The marketing authorisation holder has to submit the change to the competent authority and has to wait at least 14 days until receipt of the acknowledgement of a valid notification before he can implement the change. In the new system a 'Do and tell' procedure is established so that the marketing authorisation holder can first implement the change and then submit the variation to the competent authority. It depends on the type of change if an immediate notification is required or if the submission can wait up to twelve months. The new 'Do and tell' procedure for type IA variations provides the marketing authorisation holder a lot of flexibility. The marketing authorisation holder can immediately implement a change without prior submission to the competent authority and can even wait with the submission up to twelve months when no immediate notification is required.

If within the twelve months further changes of type IA are implemented for the particular marketing authorisation the marketing authorisation holder can group these changes. For the submission of grouped variations within twelve months the term annual report has been established. In the current system grouping is only possible for consequential changes. Grouping in the new system is possible for all type IA variations concerning one marketing authorisation and is not restricted to one marketing authorisation. Even several changes to several marketing authorisations can be grouped as long as the changes and the relevant authority are the same. Grouping decreases administrative work by the marketing authorisation holder and by the competent authorities but it has to be done in the right way. Grouping for type IB or type II variations is not as flexible as for type IA variations in the new system. The cases where grouping applies are outlined in the new variation Regulation. They differ in a few cases from the current approach where only consequential changes can be grouped so that only little more flexibility is obtained. Apart from the cases outlined in the new variation Regulation it is also possible that the competent authority agrees to the grouping which brings more flexibility into the system so that it will depend on the competent authorities to which extent grouping will be possible in the future.

The worksharing procedure is a new approach which does not exist in the current system. The worksharing procedure applies for one marketing authorisation holder when a change or a group of changes concern several marketing authorisations with different relevant authorities. The impact on the individual medicinal product should be neglect able to have an advantage of the worksharing procedure. The idea of the worksharing procedure is to avoid double assessment of the same changes by the competent authorities. One reference authority is chosen to act on behalf of the others like this is the case in the mutual recognition procedure. The introduction of the worksharing procedure should reduce administrative burden by the competent authorities and the marketing authorisation holder has the advantage to have only one final opinion instead of several different opinions like this is possible when the assessment is done individually. Quality changes like a change to an ASMF (Active Substance Master File) are often not limited to one marketing authorisation holder but the change affects several marketing authorisations of different marketing authorisation holders. Although the change for all marketing authorisations is the same it is not possible to use the worksharing procedure due to the limitation to one marketing authorisation holder. The worksharing procedure is a very good element but in a broader scope it could reduce administrative burden even further.

Overall conclusion:
The revision of the variation system is a major step forward to make the system simpler, clearer and more flexible by developing the current system without establishing a complete new system. This means that the revision is an evolution but not a revolution of the variation system. There is still the need to simplify the system even further and a review of the classification of the variation will take place in 2012 according to Article 26 of the new variation Regulation.

Pages: 91, 1 Annex: pages: 2