May 2005
Clinical Trial Directive from a Clinical Research Centre Perspective
Presented by Dr Leo James
ABSTRACT
The talk will use Inveresk as an example of a Clinical Research Organisation, with comparisons made between pre- and post-Directive. It will adopt the following format:
Introduction – Brief summary of Inveresk's clinical trials
Phase I
Description of Inveresk's practice pre-CTD
Study approval / Study complexity c Study drug
Termination / Serious adverse events
The Clinical Trials Directive as applied to Phase I
Aims / Scope / Competent authority
Key features for Phase I / Timelines
Ethics committee / Protocol amendments
Manufacturing / Adverse events
Inveresk's preparations for 01 May 2004
Immediate impact of CTD
Subsequent impact of CTD
Phase II-III
Status pre-directive
Countries affected
The Clinical Trials Directive as applied to Phase II-III
Trials in progress pre 01 May 2004
Summary and comparison with Phase I
Our speaker introduced himself as marathon runner which quickly saw a wave of guilt spread over the conference centre from those who had just helped themselves to one too many of the high calorie conference biscuits.
The first presentation of the day had finished with a discussion around how little the implementation of the Clinical Trials Directive (CTD) had impacted the ability to run phase I trials in the UK. This presentation looked at the additional actions that phase I units have had to implement since 1st May 2004 to ensure that this is the case.
An initial observation from the speaker was that the CTD outlines its objective as "to simplify and harmonise the administrative provisions governing clinical trials", but at no point attempts to make the running of trials easier for clinical trials units. The most major change in phase I was the need to seek approval from a competent authority (in the UK this is the MHRA) before a trial can be run. This was not only an additional process, running in parallel with the previous ethics committees, but also involved the completion of a 60 page form. In the phase I environment where numerous small studies are run this is a major additional administrative burden. There was concern early on that the MHRA review would see a traditional attraction to placing trials in the UK (quick start up) eroded away as the MHRA review period was initially up to 60 days. In reality this concern has not been born out, timelines experienced for MHRA review are around 21 days. Of more concern is the time currently taken to approve 'substantial' protocol amendments, which is currently running at greater than 30 days – longer than the length of an average study, or as the speaker put it 'a substantial amount of time'. The MHRA are however aware of this and a resolution is hoped for in the near future. Two other smaller administrative changes are the need to notify the MHRA within 90 days of the end of a trial, or 15 days if stopped early, and the need to prepare the final report within one year.
The other major shift in requirements for running phase I trials was the need for all phase I units to have access to a Qualified Person (QP) to ensure local adherence to GMP. Whilst at face value this sounds straight forward, these individuals are in short supply and the smaller/independent CROs have struggled to identify/train individuals to fill these roles.
All phase I units can also expect to be regularly audited by the MHRA and more details of this process were provided in the next presentation of the day by Tríona Coll.
On a positive note for data managers it was agreed that the directive has had a limited direct impact on data management, although one consequence of the directive is more vague and multi-part protocols which are impacting on resource planning.
At the UK level the initial impact of the CTD was a marked decrease in trials being run in phase I clinical trials units as sponsors predicted problems that never arrived. Whilst the market is slowly picking up, the directive combined with a weak dollar is still having an impact sufficient to see one phase I unit go out of business. Having succeeded in ensuring that there are no obstacles to running phase I trials in the UK it is now important that all involved in the industry spread the word that the UK phase I industry is business as usual...
Rob Nichols
Quintiles GDRU