"From on high it is ordained
That the human mind be trained.
Not alone the ABCs
Elevate it by degrees;
Nor does writing competence
By itself make men of sense;
Nor will 'rithmetic in season
Satisfy aspiring reason:
Moral precepts, too, are needed -
To be heard with zeal and heeded..."

(Wilhelm Busch, Max und Moritz polyglott -
a story of two rascals in seven tricks,
Fourth Trick, München, DTV 2005,
19th edition)

The requirement of a preventive product control

While requirements for the registration of medicinal products in the EU were rather limited in the 1960s, the dramatic side effects and adverse reactions linked to the use of thalidomide caused a significant re-thinking process and a major change in data requirements. Directive 65/65/EC defined the terms of “medicinal product” and “medicinal product quality” for the first time in the EU. Even more important, it introduced the requirement of a preventive product control prior to access to the market. Following adoption of this directive, any medicinal product to be placed on the market in one of the EU Member States requires a marketing authorisation, which is subject to demonstration of the product’s safety, efficacy and quality to the competent authorities. Ever since then, the EU marketing authorisation procedures have been further developed and adapted to the needs of all stakeholders, e.g. the need for a quick access to medicinal products while ensuring patient safety, the need for the special requirements of advanced and emerging therapies and technologies, the need to consider the impact of globalisation of the pharmaceutical industry and of an enlarged EU.

The basis for a state-of-the-art legal framework for pharmaceuticals in the EU

Codification of the various pharmaceutical directives in 2001 and the review of the pharmaceutical legislation in 2004 together with the implementation of the Clinical Trials Directive 2001/20/EC today forms the basis for a state-of-the-art legal framework for pharmaceuticals in the EU. This framework offers different procedures to gain a marketing authorisation and takes into account the diversity of illnesses/therapies as well as of the pharmaceutical industry, e.g. small and medium sized enterprises aimed at predominantly national markets versus “big pharma”.

However, at the same time it has to be acknowledged that the EU pharmaceutical system is a complex one. At present, 40+ independent competent authorities of the 25 EU Member States and the three European Economic Area countries Iceland, Liechtenstein and Norway together with the European Medicines Agency (EMEA) form the network of EU/EEA licensing authorities for human and veterinary medicinal products. A variety of scientific committees and working groups is constantly working on a harmonised interpretation of requirements by drafting “points to consider”-documents and guidelines on an EU-level. The transparency rules newly introduced for all EU Member States with the review of the pharmaceutical legislation will additionally increase the understanding of the agencies’ decision-making processes and philosophies, thus further facilitating harmonisation between competent authorities.

The consequences for applicants/marketing authorisation holders

But what are the consequences for applicants/marketing authorisation holders? First of all, it is of great importance for the pharmaceutical industry to be aware of the historical development of the EU pharmaceutical legislation to understand today’s requirements of regulatory authorities. In order to be able to select the most appropriate licensing procedure for their specific products, it is vital for the industry to recognise the opportunities and constraints inherent to the national, the mutual recognition, the decentralised and the centralised procedure. In addition to being aware of the formal requirements for marketing authorisation procedures, the applicant should have a sound understanding of the scientific information necessary to demonstrate a medicinal product’s quality, safety and efficacy to the authorities. Once a marketing authorisation has been granted, the focus of the marketing authorisation holder turns to the life-cycle management of the product and its authorisation, covering a variety of aspects related to e.g. pharmacovigilance requirements and the various reasons requiring an up-date of the different parts of the dossier via variations up to the need for a timely submission of the renewal application. A large number of guidelines defines state-of-the-art requirements of the competent authorities. However, understanding authorities’ rationale for requesting specific information may help the applicant to judge whether a deviation from guideline requirements will potentially jeopardise the successful outcome of the application or whether it can be adequately and scientifically justified in the dossier and hence be accepted by the respective competent authorities. In addition to scientific understanding, application of ethics and good common sense will be of great value for the applicant.

A reference work for everybody involved in drug development and regulatory affairs

This Regulatory Affairs Guide provides substantial back-ground information on the legal framework for pharmaceuticals in the EU. It describes the structure and tasks of the EMEA and explains the different licensing procedures in detail. In addition to an overview of the formal elements of a marketing authorisation application, e.g. time-frames for the preparation of an application and documents to be submitted, it highlights the data requirements according to the structure of the Common Technical Document. In its holistic approach, it also covers the requirements for an Investigational Medicinal Product Dossier, “conditio sine qua non” for the initiation of any clinical trial in the EU, as well as for compliance and maintenance of the marketing authorisation. In an additional chapter, the Guide provides valuable information on specific product classes such as blood and blood products, advanced therapy products, radiopharmaceuticals, orphan medicinal and traditional products.

The Guide is meant to serve as a reference-book for everybody involved in drug development and regulatory affairs. It may equally serve to train both industry staff and assessors and inspectors in the regulatory authorities.

Susanne Keitel Bonn (Germany), September 2006