The Directive and the New Europe
Abstract
The accession of 10 new European States on May 1st 2004, coincidentally on the same day as the implementation of the Clinical Trials Directive, means new opportunities as well as pitfalls for companies undertaking clinical research projects.
This article explores the possibilities and issues with particular reference to clinical supply and examines whether the expansion of Europe will make it more or less attractive as a clinical research venue.
Concern has been expressed in recent years about the decline of clinical research in Europe.
A recent report from Cap Gemini Ernst and Young showed that growth in pharmaceutical Research and Development in Europe was only 50% of that in the US.¹
However, Europe continues to be the second largest pharmaceutical market worldwide with sales around 100 billion US dollars and an important clinical research base.
Will the accession of ten new member states improve the climate for research and how will the implementation of the Clinical Directive in Europe help or hinder that process?
A number of the accession countries have been used increasingly since the mid 1990s as attractive clinical research venues, in particular Poland, Czech Republic and Hungary.
More recently other countries such as Slovak Republic, Slovenia and the Baltic States have joined their ranks.
The reasons are well rehearsed; the prevalence of disease and the availability of drug- naïve populations, the treatment of patients in large outpatient clinics, the good standards of medical education and the high ratio of doctors per capita of population.
Movement of clinical supplies into these regions, however, has not always been easy and differing regulatory requirements, the need for import licences, and customs hurdles have sometimes proved difficult.
The Clinical Directive (Directive 2001/20/EC) "went live" on May 1st and is changing the conduct of clinical research in Europe.
Regulatory and ethics submissions for clinical trials are being harmonized both in terms of content and time to approval and the EUDRACT database will give authorities access to data on clinical research throughout the EU.
Some of the most fundamental changes relate to the manufacture and import of investigational products.
There is now a requirement that all IMPs should be manufactured to GMP but in addition to this, the Directive provides for the following:
that manufacturers or importers of CTM should hold a manufacturing authorisation. that a Qualified Person should be at the manufacturer's continuous disposal and should be responsible for ensuring that CTM has been manufactured to GMP as laid down in Directive 91/356. GMP/GCP inspection by the authorities of any site involved in clinical research, including manufacturers and packagers of CTM. requirements for clinical trial labelling.
The accession countries have been working for some years to prepare for the change in regulatory requirements for both IMPs and marketed product.
Since 1999 EMEA has led the Pan European Regulatory Forum "PERF", a preparatory training and exchange programme and since April 2003 the regulatory authorities of the candidate countries have been sitting as observers on the Agency's scientific committees and working parties.
A Joint Audit Programme has been established by the Ad Hoc Working Group of GMP Inspection Services whereby observed inspections can be carried out by experienced inspectors and experiences can be shared.
Importantly there is no transition period allowed for achieving compliance with the various Directives and guidelines.
Each country in the EU should, therefore, now be operating to equivalent standards of GMP with QPs in place who are able to perform release activities.
In reality of course there may still be considerable differences in the interpretation and application of GMP standards and third-party GMP/GCP inspections may highlight this.
It is difficult to say how many third party inspections will take place as most inspections will be carried out by the competent authority in the country of manufacture and release.
Additionally, Member States may request information from another Member State on GMP compliance and licence status of a manufacturer and there is a system in place for dealing with divergent opinions.¹
The Clinical Directive now requires that all labelling of IMPs should be in the local language of the country where the trial is to take place.
Whilst some companies outside the EU have generally used English labels in the past and are finding the change somewhat onerous, most companies in the EU have been using multi-language labelling for some considerable time.
The process of translation and back-translation is well established and causes little difficulty, particularly as the technology for booklet labels for clinical trials is improving all the time.
The Directive allows for free movement of materials inside the EU once IMPs have been imported and released by a QP and to date, the main manufacturing sites and flow of IMPs for global and multi-national studies has been from inside the EU to the former CEE countries or from the US or Japan to the EU and thence to the CEE countries.
Ease of communication and similar GMP systems have made this the most convenient route and it may remain so.
Furthermore, the manufacture and packaging of IMPs presents a different set of challenges from the manufacture of commercial batches and companies in the accession countries which do not have this experience might be reluctant to venture into this type of production.
However, cheaper development costs and harmonisation of regulatory standards may change the picture in the longer term as pharmaceutical companies may provide support in this area in an effort to reduce costs without increasing development lead times.
Free movement of materials also suggests that there may be fewer problems with bureaucracy and customs delays in the former CEE countries now that the Directive is in force.
In practice, problems have been reducing over the last four to five years as these countries become more "mainstream" in terms of clinical research but time will tell which countries will still apply a requirement for an import licence.
Clearly, the Directive and its impact have engendered some nervousness in pharma companies, particularly those outside the EU.
Nevertheless, pharma companies and contractors have been aware of those changes for some years and have been preparing in the background.
Due to this diligent preparation, the 1st May deadline caused relatively few problems in relation to investigational medicinal products.
The accession countries are of course keen to ensure that their good reputation for conducting clinical research continues.
Pharma companies and CROs will want to continue to build on this success.
It is business as usual - the new challenges lie with countries such as Russia, Bulgaria and Romania as the boundaries of clinical research expand in search of good (and rapid) data.
Author: Keren Winmill
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