New Directive – choosing the correct clinical trial service provider will prove crucial to non-EC sponsors



Mike Parker, Quality Assurance and Technical Director, Brecon Pharmaceuticals Ltd, Hay-on-Wye, UK

Summary
An EC Directive to be implemented in May 2004 will have a profound effect on the way clinical trials are carried out within the Community. There are three major changes: the use of a Qualified Person (QP) for release; the requirement for Investigational Medicinal Products to be manufactured, assembled and packaged in accordance with GMP guidelines; and the necessity for various authorisations before a trial can commence. The QP’s role in satisfying these regulations will be pivotal and sponsors will be required to have at least one QP “permanently and continuously” at their disposal. This will result in a substantial increase in the subcontracting of European clinical trial service providers by sponsors outside the EC. Many will be calling on these services for the first time and there are number of points to be aware of when choosing a service provider, not least the QP’s training, experience and availability.

Following implementation of Directive 2001/20/EC next May, new regulations will apply to the way clinical trials involving human subjects are carried out within the European Community. Prior to this point, there has been no coordinated legislation or control over clinical trials in the EC, with local legislation applying in most cases. However, Germany, France, Spain and Belgium have opted to implement the Directive early and are already conducting trials which abide by its requirements. It is likely too that other Member States will phase in the Directive before May 2004.

The overall objective of the Directive is to introduce the application of GxPs to clinical trials. Much of the Directive concerns Good Clinical Practice, but manufacturing, packaging, labelling and release are also affected. While the legislation will cover all clinical studies originating from within the Community, it will have particular impact on studies carried out by sponsors based outside the EC.

The most significant change for these sponsors will be the mandatory use of a Qualified Person for the release of the studies. This means that supplies manufactured, assembled or packed outside the EC will have to be QP released on entry after appropriate analysis and manufacturing site authentication. To comply with this requirement, sponsors must have at least one QP "permanently and continuously" at their disposal.

Another major change is that the Directive requires that Investigational Medicinal Products (IMPs) are manufactured, assembled and packaged in accordance with GMP guidelines and that new minimum labelling requirements are adhered to, as detailed in Annex 13 of the “Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2002”. The QP is responsible for checking compliance with all these requirements.

For products where manufacture, packaging and analysis take place outside the EC, and there has been no QP release, the only practical way for the QP to verify compliance with GMP is by site familiarisation. This requirement also applies to comparators and placebos, which means they will be subject to the same level of regulation and inspection if they are unlicensed in the EC.

The third significant change is that a sponsor company must have a trial authorisation – on which the release site must be specified – for a trial before it can commence supply of an IMP. If the IMP is to be imported into the EC, authorisation must also be sought for each individual trial import. In addition, a product specification file must be produced which should include manufacturing and product analysis details as well as ethics approval. Again, the QP will be responsible for checking compliance with these authorisations and with the product specification file.

The Directive contains a number of other changes concerning infringements or suspensions of the studies, reporting of adverse reactions and other guidance, but it is the three points outlined above – the necessity for QP release, adherence to GxPs and the various authorisations required – which will have the biggest impact on how trials must be conducted.

Clearly, sponsors outside the EC will need access to the services of a European QP if they wish to conduct trials within the Community. This will naturally result in an increase in the use of European clinical trial service providers and also reflect the importance of their role, as it is they who will take the weight of responsibility for authorisation compliance with respect to GMP.

The new Directive will consequently usher in a period where many non-EC organisations will seek to form relationships with European service providers for the first time and there are a number of considerations to be taken into account when choosing a partner.

QP Resource
The importance of the QP role in the authorisation process with regard to GMP compliance cannot be overemphasised. Ideally providers should be able to call upon a number of QPs with experience in all dosage form areas to ensure exclusive use of the provider for the duration of the trial. The broader the spectrum of QP experience, the greater the versatility that can be offered.

QP Training
The Directive requires QPs to undergo "appropriate training" with respect to experience, knowledge and formal education. However, there is still some debate as to what exactly constitutes appropriate training for clinical trials release. This will need careful formulating between sponsors, authorities and release/compliance personnel.

Whatever the outcome, ongoing in-house training to the highest standards will be of paramount importance. It is therefore essential to ensure the provider has the necessary infrastructure in place to support this, as well as an ethos which demands "best practice" training procedures are maintained.

Validation Experience
A service provider’s experience in validating processes, through the operation of commercial manufacturing or packaging activities, will also be critical. Validation, whether of machinery or an operative’s work, is a discipline which must be instilled in a company’s working procedures. Companies which already operate under GMP guidelines will be much better placed to ensure compliance with the Directive.

Knowledge of validation procedures will initially be particularly relevant to Phase III and Phase IV studies, where volumes will typically be inherently larger, and the validation requirements consequently higher. As time goes by, however, it is likely that the requirements for validation of stages I and II will be strengthened – the earlier processes are validated, the greater the potential savings in due course.

Quality System and SOPs
Standard Operating Procedures (SOPs) are an essential part of the provider’s modus operandi and an established contractor with commercial and clinical trials experience will have procedures that have been developed over a long period and draw on the experience of numerous audits. The SOPs will have been diligently scrutinised by both commercial and government agency auditors from around the world and developed accordingly – such excellence is difficult to come by any other way.

Auditing Experience
Audit experience and a keen knowledge of regulatory requirements are valuable commodities, as it is highly likely that the service provider will be called upon to provide an auditing service to ensure GMP compliance.

Labelling Issues
Direct experience of commercial packaging provides the contractor with an immediate benefit concerning the new labelling requirements. Although they are relatively straightforward, the requirements vary from country to country and it is important for the service provider to be able to comply with these, or offer the appropriate advice.

Breadth of Experience
It is advisable to consider a contractor with a full complement of capabilities and facilities which encompass import and release services – including analysis, process validation, method transfer and stability testing – together with appropriate storage and distribution and returns management. If required, experience of sourcing EC licensed comparators and placebos should also be checked.

The new Directive represents a radical change in the way non-EC sponsors must now approach and conduct clinical trials held in the Community, and sponsors should not delay in determining their future strategy. At a fundamental level, the Directive’s requirement to name the release site when applying for authorisation for a trial means that the whole life cycle of the trial will have to be considered at a very early stage. It will therefore be necessary to establish a relationship with the service provider and its associated QPs well before the trial is scheduled to begin. This is particularly relevant if the service provider will be required to conduct audits.

This is not a process to be rushed and by beginning now sponsors will be more likely to secure the services of a provider with whom they feel comfortable and in whom they have confidence.

First published in the Autumn 2003 issue of "Global Outsourcing Review"

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