Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

The end of an era: Implementing Variation Directive 2009/53/EC into German Drug Law ***

Dr. Verena Tautorat (Abschlußjahr: 2011)

Language: English

Change applications for marketing authorisations (MAs) granted solely in Germany follow separate procedures as do variations in European procedures such as MRP, DCP or CP. The national and European systems to applying for and implementation of changes to existing MAs evolved in parallel and rather independently for a long period of time. The legal basis is Section 29 of the Medicinal Products Act ("Arzneimittelgesetz", AMG) for national MAs and Regulation 1234/2008/EC (Variation Regulation) for MAs granted in European procedures, respectively.

Yet, the continued existence of separate provisions to conducting change procedures was regarded to be in blatant contrast to the harmonised rules to applying for an initial application for MA. With Directive 2009/53/EC amending Directives 2001/82/EC and 2001/83/EC relating to veterinary and human medicinal products, this deficit was addressed. Through said Directive, the European Commission was empowered to take appropriate measures to extend the scope of the Variation Regulation to purely national MAs also. In consequence, the national legislation as currently in place in Germany is to be substituted by the provisions pertaining to the conduct of variation procedures in the near future.

This represents a major shift in the practice of introducing changes to national MAs in Germany. A detailed comparison of the procedure types reveals similarities as well as subtle though decisive differences in the procedures. For instance, the procedure type to be followed by default can be approximated as Type IAIN nationally as opposed to Type IB for MAs falling under the scope of the Variation Regulation. This has far-reaching consequences since an approval prior to implementation of the change is not required for the majority of national changes in contrast to variation procedures. As a result, the time until implementation of the change is on average significantly longer for a variation.
This is intensified by the large number of changes listed in the 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 (Classification Guideline) that are classified as Type IB and Type II variations. In these variation categories, an implicit or explicit approval is required, respectively. In contrast, only for a select and small number of changes listed in Sections 29(2a) AMG, an application requiring prior implicit approval has to be submitted.

In practice, delays at different stages of the variation procedures, such as during validation or clock-stops are observed for variations thereby leading to unreliable time lines for the applicant. Currently, only an implicit approval and no clock-stop are foreseen for national change applications pursuant to Article 29(2a). This requires the national competent authorities to strictly adhere to the time line of 3 months.

Another distinctive feature of the national procedures is the absence of the possibility of its rejection for change applications requiring no prior approval. The opposite is the case for variations. For all the variation types there is the possibility of a rejection of the application. As a result of all the differences, current national procedures for applying for changes allow for higher reliability and predictability of the time lines as their counterparts on the European level.
Apart from the differences in the procedures per se, there are also quite significant deviations with respect to the classification of certain changes. As such, changes requiring the submission of anew MA application nationally may be treated within the scope of a Type II variation on the European level and vice versa. Cases in point are the addition of an indication outside the approved area of therapy and the conversion into a comparable pharmaceutical form. In this respect, harmonisation truly is to be welcomed.

As becomes clear from these examples, the expansion of the scope of the Variation Regulation as triggered by the provisions included in Directive 2009/53/EC will have far-reaching consequences for the conduct of change applications for purely national MAs in Germany. Yet, this may also be greeted as an opportunity in some instances. In particular, this concerns the facilitated application of indications outside the approved area of therapy and the introduction of the concept of the extension application. The latter is linked to a possible review of the restrictive national interpretation of the global MA. Furthermore, a procedural simplification and reduced fees are expected of an update of the safety-relevant sections of the SmPC and PIL following a PSUR Worksharing Procedure.

At the same time, the conversion into a comparable pharmaceutical form within the scope of an application requiring prior approval will no longer be possible if not included in the legislation at a later stage. Also, for the addition of safety-relevant information to the SmPC and PIL an approval will then have to be awaited instead of the current "tell and do" approach for national MAs.
On December 2nd, 2011 the first draft of the revision of Section 29 was published. In the scope of the proposal, the adoption of the variation system as laid down in the Variation Regulation was not included. Only certain aspects such as the annual report for a number of defined changes as well as extended requirements for the submission of changes in accordance with Section 29(2a) are included. It appears to be the intention to postpone the adoption of the variation procedures until the scope of the Variation Regulation is extended appropriately. Also, there is no implementation of deviating provisions for MAs for human medicinal products authorised before January 1st, 1998 as given in Directive 2009/53/EC forseen. Full harmonisation with the European variation system is aimed for.

Apart from these considerations, it is desirable not to fully abandon the benefits of the national "Änderungsanzeigen". This involves maintaining current administrative practices of the national competent authorities. Since they are not necessarily anchored in the AMG, they are not required to be changed with the legislative revision. This would include forgoing a formal validation phase and continuing to start the procedure directly following receipt of the application. Also, there is the possibility to preserve unlimited grouping as currently practiced. Such an approach would not contradict the provisions given in the Variation Regulation provided it is limited to national German MAs. Only the willingness to do so would need to be communicated. These two measures alone are predicted to shorten the processing time of applications involving national German MAs in relation to variation procedures as practised currently on the European level.

Aside from retaining such pragmatic administrative practices, the opportunity should be seized to refine the variation system by re-evaluating the appropriateness of variation classifications as listed in the relevant guidance. In the two years of experience with the provisions of the Variation Regulation, sufficient insights should have been gained as to which changes may be eligible to be downgraded. As an opportune time to do so the upcoming revision of the Variation Regulation slated for 2012 presents itself. At that time it should also be strived to establish certain concepts such as the comparable pharmaceutical form on the European level.

Pages: 54