Trials directive highlights service providers' role
Choosing the right clinical trials service provider will become even more crucial following the implementation of the new EC directive, says Mike Parker, QA and technical director, Brecon Pharmaceuticals
Choosing the right clinical trials service provider will become even more crucial following the implementation of the new EC directive, says Mike Parker, QA and technical director, Brecon Pharmaceuticals
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 co-ordinated 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.
The most significant change for clinical trial sponsors will be the mandatory use of a Qualified Person for the release of the studies. This means that supplies manufactured, assembled or packed inside or 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.
GMP compliance
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 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, with the implementation of these new regulations, there will be a number of considerations that must be taken into account when choosing a clinical trials service provider.
• 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.
training procedures
• QP Training: The Directive requires QPs to undergo 'appropriate training' with respect to experience, knowledge and formal education. However, there is still a 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 that 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 that 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.
regulatory requirements
• 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 clinical trials held in the Community must be approached and conducted, 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.
