SubscribeThe EU Clinical Trials Directive has been in operation since May 2004. It applies to all members of the European Economic Area (EEA), ie the 25 Member States of the EU plus Norway, Iceland and Liechtenstein.
It also applies to clinical trial supplies manufactured in these countries for trials conducted outside the EEA.
Trial sponsors and clinical trial supplies manufacturers have also had to modify their procedures to meet the new requirements. In particular, Phase I trials are now brought into the regulatory system, and the trial supplies must be made according to GMP and certified by a “Qualified Person.”
The intention of the Directive was to harmonise the regulations across the EU but some differences of interpretation have become apparent as it has been implemented in each Member State. This article summarises experiences of working with the new system over the past 18 months.
Regulatory
All clinical trials in the EEA, from Phase I to Phase III, now require approval from national regulatory authorities before they can begin. One approval will cover all centres in a particular country, but multi-national trials require separate approvals for each country.
The application must be presented in the “Common Technical Document” format, and details of the data required can be downloaded from http://pharmacos.eudra.org/F2/pharmacos/docs/Doc2003/april/cp-guidance-ca_230403.pdf. Not all of the headings will need to be completed for early-stage trials, but authorities would expect to see full information for a pivotal Phase III study.
Each trial also needs a unique EudraCT tracking number, which can be obtained online from www.eudract.emea.eu.int.
The trial sponsor can be a company or an individual (eg an investigator), and has overall responsibility for compliance with GCP and GMP during the trial.
Sponsors must therefore satisfy themselves during the set-up process that all investigators, CRO’s, contract manufacturers, analytical labs etc. have the staff and facilities to comply with the Directive’s requirements. Official GMP and GCP inspectors will expect to see evidence that the sponsor has carried out these checks.
The sponsor must be represented inside the EEA to allow prosecutions to take place for any breaches. Non-EEA companies can do this by delegating to an EEA-based CRO, or by setting up their own subsidiary within the EEA. The latter is probably the better option, as it is not very costly and allows the EEA representative to be directly responsible to the sponsor. There are companies that can help sponsors with this.
The application form asks for details of the arrangements for Qualified Person certification of the investigational medicinal products (IMP’s), and the QP is also required to make a statement in the application that any non-EEA manufacturers used have GMP standards at least equivalent to those in the EU. Sponsors must therefore ensure that they have organised the QP certification procedures, and the QP has carried out any GMP audits, before submitting the CTA application.
The Directive allows for a 30-day assessment period, at the end of which the trial is either approved or the sponsor receives a “Grounds for Non-approval” (GNA) letter. The sponsor has a further 14 days to respond to the GNA letter, following which the trial is either approved or formally rejected.
Ethics Committees
Each trial needs Ethics Committee approval before it can start. Again, the European Commission has issued a guideline, which summarises the information to be provided, and this can be accessed here. The information is very similar to that submitted for the regulatory approval.
One Ethics Committee approval covers all of the centres in one country, but multi-country trials need multiple approvals.
Product Specification File
Each IMP needs a Product Specification File (PSF). This contains all of the information necessary to draft the detailed written instructions on processing, packaging, quality control testing, batch release and shipping of the IMP.
There is no specific format or layout; it could consist of a binder, a filing cabinet or an electronic archive. Copies of the complete file must be available to the sponsor (inspectors will expect to see it) and the Qualified Person.
Manufacturers will need to see the parts of the file relevant to their activities. The PSF is likely to change during the trial as new information becomes available, or process improvements are made.
The trial sponsor must have a suitable change control procedure to ensure that every copy of the PSF (including those at external contractors) is updated.
Investigational Medicinal Product
This is one of the major areas of change under the Directive. All IMP’s must be manufactured according to GMP, and a Qualified Person must certify the finished product. IMP’s are defined as the test product and any comparator or placebo product. It does not include rescue medications.
All EEA-based manufacturers, packers, labellers or warehouses must have a specific IMP manufacturing authorisation, issued by their national regulatory authority. As a part of this authorisation, they must name one or more QP’s who could carry out finished product certification. It is also possible to have an authorisation that only covers importation and QP release of IMP’s, for materials made outside the EEA.
Non-EEA manufacturers must have GMP standards that are at least as high as those in the EU. Part of the QP certification of the finished product is to confirm, by review of the manufacturing documentation, that this is the case. The QP is also required to sign a statement to this effect in the CTA submission.
It is no longer possible for non-EEA companies to send IMP’s directly to clinics or patients in the EEA, unless the clinic has its own IMP manufacturing authorisation. An IMP manufacturing authorisation holder, who carries out the QP certification, must import clinical trial supplies. Once certified, the IMP can be despatched to centres in any EEA Member State.
It is up to the QP as to how they satisfy themselves of the GMP compliance status of non-EU manufacturers. However, most QP’s are carrying out on-site audits of non-EU manufacturers. The QP can outsource the audit to a contract auditor under his direct control, but authorities do not view it as acceptable to use an audit report provided directly by the manufacturer.
Inspectors would expect to see evidence of these audits, and would probably view it as a GMP deficiency if they had not been carried out. This applies even if the manufacturer has been inspected by an EU authority – there may be specific issues with the manufacture of the IMP that were not covered in the official inspection.
All IMP manufacturers, wherever they are located, are liable to inspections by EU authorities. Feedback from inspections so far has shown that areas of interest have centred on:
- Project management
- Handover arrangements from the development labs
-Protocol translation into manufacturing, packaging and labelling requirements
-Liaison between sponsor and contractor - Facilities
-Work flows
-Cross contamination
-Qualification and validation
-Environmental monitoring - Technical Agreements
- Product Specification File
- TSE
- Documentation control
- Standard Operating Procedures
- Randomisation/labelling
- Control of incoming materials
- Deviations/non-compliance/OOS reports
- Storage and distribution
- Complaints and recalls
There must be Technical Agreements between the trial sponsor and the manufacturers, detailing what specific quality responsibilities each has. This is particularly important where there are a number of manufacturers in the supply chain, to ensure that no areas are missed during transfer.
These agreements are essentially “Standard Operating Procedures”, so it is not essential that they are approved or signed by company legal departments or Chief Executives.
They must, however, be reviewed and signed by the QP, or similar, in each company. Again, inspectors will look for these agreements, and will view their absence as a GMP deficiency.
The QP is certifying that each batch of finished product complies with three criteria:
- Good Manufacturing Practice
- The regulatory approval
- The Product Specification File
The QP will therefore need to have access to the regulatory approval. Annex 13 of the EU GMP guidelines describes a number of other areas that the QP may need to take into account in certifying a batch, including process/equipment validation and stability results.
Many sponsors are finding it useful to involve the QP from the initial planning stages onwards, rather than simply expecting a final document review once the IMP has been manufactured.
Label texts must follow the requirements of sections 26 – 33 of Annex 13 to the EU GMP guidelines and be in the local language of the country of use. Failure to comply is an offence under the Directive.
Comparator Products
Comparator products come under the control of the Directive, and fall into one of three categories:
Product Marketed In The EEA
If the comparator product is obtained in the marketed pack, complete with an EU Marketing Authorisation number, the certifying QP for the clinical trial can accept that the product has been manufactured in accordance with GMP and the finished product specification.
If the product is repackaged for the trial, the QP needs to consider whether this will affect stability and shelf-life. It may be necessary to carry out a stability trial in the new pack. The QP should put together a rationâle for the decision and document it in the trial file.
If the product is obtained in bulk, the QP will need to satisfy himself that the product has been made and tested according to GMP, just as with the test product. It may not be possible to get this information from a competitor company.
Product Obtained From Countries With A Mutual Recognition Agreement With The EU
Again, if the product is obtained in the marketed packs, the QP will only need a Certificate of Analysis from the manufacturer. The QP will need to make the same decisions as for EEA marketed products for bulk or repackaged supplies.
Product Not Marketed In The EEA, And Obtained From A Third Country
The QP will need to be satisfied that the product complies with the specification, and that it was manufactured according to standards of GMP at least equivalent to EU. This may need a visit to the manufacturer and possible reanalysis. The QP should put together a scientific rationale of how the product should be released, including test method validation, and discuss it with the regulatory authorities. The release testing should then be included in the CTA submission.
The easiest option is to source comparator products from the EEA wherever possible. Whichever source is chosen, the sponsor must have a means of knowing if that batch of comparator has been recalled by the manufacturer, so that they can recall the clinical trial supplies.
Inspectors will be looking for this during their audits. The best plan is probably to draw up an agreement with the wholesaler that supplied the comparator that they will notify the sponsor if they are informed of a recall.
Summary
Overall, the changes brought about by the introduction of the Clinical Trials Directive have not been as great as were first thought. Most sponsors and manufacturers have been able to incorporate the new requirements with only slight changes to their working procedures.
Non-EU companies need to ensure that IMP’s are manufactured according to EU standards and are imported by a company holding a manufacturers authorisation. This will usually require audits of non-EU manufacturing sites by experienced EU auditors.
There is a greater need for advance planning now, both in terms of making regulatory submissions and in selecting and auditing manufacturers. Sponsors must ensure that all contractors used have suitable facilities, procedures and staff and that Technical Agreements are in place.
Many sponsors do not have the in-house expertise to identify the most appropriate contractors, audit them for GCP/GMP compliance, or draw up these agreements, and are finding it useful to employ specialist contractor selection and auditing companies to do this on their behalf.