SubscribeWith the 1st May 2004 deadline for implementation of the new EU Clinical Trials Directive (2001/20/EC) now behind us, the reality of what this means for sponsors wishing to conduct a clinical trial within Europe is gradually becoming evident.
Yet many are still relatively unfamiliar with the changes that have been brought about, aimed at harmonizing the conduct of clinical trials within Europe without hampering the discovery of new essential medicines. These changes also impact upon the manufacturers and importers of investigational medicinal products.
One significant change of particular importance for those importing clinical trial material into Europe for use in a trial is described in article 13 of this directive. It outlines the necessity for Qualified Person (QP) release of Investigational Medicinal Product, a regulatory requirement previously only associated with the release of commercial medicinal products in most European Countries. Awareness of all such changes is critical to the sponsor, not only to aid efficiency in the conduct of the trial but also to ensure compliance with the regulations.
Prior to May 2004, European countries had many different approaches to the conduct of clinical trials as a whole, and so it was agreed that a more harmonised approach was necessary. Subsequently a series of Directives were published which describes those items that must be considered by all Member States. Directive 2001/20/EC, commonly referred to as the Clinical Trials Directive was published in April 2001.
It is the prime directive required by all European countries to ensure clinical trials are conducted in a regulated manner and as with any EU Directive, it was published as ‘the result to be achieved’ in all Member States. A period of time was then defined to allow for the Directive to be translated into local national laws.
This transitional period has since run its course and on 1st May 2004 operational evidence of the intent of this directive became a legal expectation. Therefore it is important that companies wishing to conduct clinical trials are aware of the changes that the EU Directive has brought about to ensure compliance and prevent unnecessary delays which could otherwise be avoidable when time is at a premium.
In order to conduct a clinical trial in the EC, the sponsor must first submit a valid request for authorisation to the Competent Authority of the Member State where they propose to conduct the trial. This request is known as the Clinical Trial Application (CTA). The content of this application will then be assessed by the competent authority and/or the Ethics Committee to ensure that the anticipated therapeutic benefits to the patient justify any foreseeable risks before a favourable opinion is issued to allow the trial to proceed.
Following approval of the trial, provision has also been made to ensure that any serious adverse events that become evident throughout the trial are reported on and appropriately handled. This ensures that the trial subject is not exposed to any unacceptable risk, either foreseeable or unforeseeable. Such protection is crucial in the safeguard of public health.
The safety of subjects participating in a clinical trial is the main reason behind many of the changes brought about by the Directive and thus why the need for a common system of authorization has also come about. This requirement within the pharmaceutical industry was previously only applicable to commercial products. However, this change now means that all facilities used for the manufacture or import of Investigational Medicinal Products (IMPs) will be subject to an inspection by the competent authority.
This is to ensure that the principles of Good Manufacturing Practice (GMP) as led down in Annex 13 to the EU guide to Good Manufacturing Practice are being adhered to. On the basis of this inspection, they may become licensed by the competent authority. This authorisation takes the form of a Manufacturing Authorisation for IMPs or MA for IMPs.
Yet, one additional aspect must be fulfilled in order for a facility to be granted a licence. This is the need for the manufacturer or importer to have a Qualified Person (QP) permanently and continuously at their disposal. This person will be named on the licence and will be responsible for the release of batches of clinical trial material before they can be used in a clinical trial.
This is an important role, tightly regulated by a Code of Practice and Annex 16 to the EU guide to Good Manufacturing Practice as well as the individual’s personal and professional ethical considerations.
The necessity for QP release of commercial products in accordance with the manufacturing authorisation, is a concept we are well familiar with in Europe and have been for many years. However, the role of the QP in IMPs is somewhat different and the complexity of this activity is likely to vary depending on the product and the site of manufacture.
Several scenarios present themselves. The first one is when the IMP has been manufactured within Europe. This is no doubt the simplest case for the QP when discharging their duties. In order to release material of European origin, they must confirm that each batch has been manufactured and checked in compliance with GMP, the Product Specification File (PSF) and the request for authorisation to conduct the trial, i.e. the CTA.
The first step to verify compliance with GMP is relatively easy for the QP in this scenario, since the site of manufacture will have been licensed by the competent authority within that Member State. However, the second stage to ensure compliance with the PSF is potentially more complex, since maintenance of the PSF to verify that all information is current and up-to-date is often a cumbersome and difficult task.
Nevertheless, it is one of great importance, as the QP will, on the basis of the information provided within the PSF and knowledge of the other elements, assess the material to determine its suitability for release. The third step in the process is assurance that the product is in compliance with the CTA. The QP is required to release the lot of material based on the information contained in the CTA and in doing so they provide trust in the material to the competent authority. Therefore it is important that the QP is kept informed of changes so that they can assess the impact to ensure they remain in compliance.
These checks by the QP, prior to release of IMP into a trial remain constant, irrespective of the site of manufacture and so this activity becomes more complex whenever the IMP have been manufactured outside Europe. In this scenario, the QP must be satisfied that the IMP has been manufactured to GMP standards equivalent to European GMP. This is usually done by way of a site audit so that an assessment of the manufacturing and testing facilities can be made, without compromising the requirements imposed by local law.
In doing so an understanding of the production process can also be gleaned. This can prove to be very useful to the QP when performing release of subsequent batches, when further site audits may not be deemed necessary but review of associated batch documentation may be carried out to allow the QP to certify the batch. In addition to this, analytical testing of IMPs may be required on import to Europe.
Most Member States have taken the view that it is not necessary to perform repeat analytical testing on import, however, under such circumstances the QP must be satisfied that the original analysis was valid. This is the reason why the QP will commonly audit both the manufacturing and testing facilities when such activities are performed outside the EU.
Another scenario exists when a comparator product from outside the EU, with a marketing authorisation in that country is to be used as an IMP. Under such circumstances the QP can perform release, if documentation is available to certify its manufacture to standards at least equivalent to European GMP. However, in the absence of such documentation, the QP must ensure that each lot undergoes all relevant analyses, tests or checks to confirm its quality.
This can sometimes prove difficult and therefore it is important that the sponsor gives purchase of comparators due consideration. One piece of advice would be that, if possible, comparators should be sourced within Europe or from countries where Mutual Recognition Agreements are already in existence, such as Canada, Australia, New Zealand, Switzerland and Japan. These Mutual Recognition Agreements are based on trust and confidence and are therefore very useful when it comes to importing comparators, as they aim to remove barriers to trade and promote standardization of GMP.
With the 1st May 2004 deadline now behind us, it is interesting to note that we are still unaware of the status of the Directive in some Member States, and yet for others we can see evidence that it is pending or already implemented.
All such circumstances as well as the changes discussed, present many different challenges to the QP, promising interesting and yet challenging times ahead for all parties involved in the conduct of a Clinical Trial in Europe. Hence we embark on a new and exciting pathway, one step closer to harmonisation with patient safety at the forefront.