October 2004
The European Clinical Trial Directive
A UK Phase I Clinic Perspective
Venturing in to unknown territory can often induce more anxiety than thrill of anticipation, particularly when there seems to be no real advantage of going there.
Phase I contract research organisations (CROs) within the United Kingdom had no choice but to make a journey into the unknown starting on May 1st 2004, the consequences of which have yet to be fully revealed.
Prior to May 1st 2004 the United Kingdom held the enviable position of being the first choice in the world for conducting rapid Phase I clinical development programmes. This enabled a reputation to be built of expertise in conducting first in human programmes, attracting business from around the globe and from the full range of industry clients.
Our preparation for the Clinical Trial Directive (CTD) began in 2002 at a senior management level, however much was speculation at this time because the fine detail was yet to be ironed out by the Medicines Control Agency (soon to become the Medicines and Healthcare Products Regulatory Authority (MHRA)). For those involved operationally in study conduct, the impact of the changes and how we would have to adapt, started rolling out in June 2003. The objective was to be ready in good time, to minimise the impact of any changes on our business and to promote our preparedness as vigorously as possible.
Forward planning at our clinic was extensive and involved the following activities:
Employment of a Qualified Person
Rebuilding the pharmacy as a GMP facility
Obtaining a manufacturing licence for Investigational Medicinal Products (IMPs)
Establishing the provision of a legal representative for non-EU clients
Establishing systems for obtaining the EudraCT number, IMPD preparation/ review, CTA preparation, submission, follow up with our regulatory affairs group
Liaising with the Independent Ethics Committee to implement the requirements of the CTD
Comprehensive staff training
And much more besides.
At the beginning of 2004 activity was becoming frenetic, not only on our part but that of our clients too. They were racing to get studies finished before the May 1st deadline, after which regulatory approval in the form of a CTA would be required for all clinical trials, including healthy volunteer studies.
A client who wanted to conduct an exploratory study with a batch of drug nearing its expiry date approached us in April. The time from initial approach to study close out was achieved in 6 weeks and just before the 01 May deadline. For us, this study represented the end of an era.
Drug development is all about time; the duration of a development programme, time to publication, fast fail, beating the competition to market, etc. We have always been proud of our timelines for Phase I studies. Fortnightly Ethics meetings, a large clinic and experienced team means we routinely work to a 3-month cycle from client contact to study conduct. The reality of the Clinical Trial Directive is that this timeline has not been greatly affected.
The MHRA have been meeting their promise to undertake review of Phase I studies in a 14 to 21 calendar day timeframe. Ethics submissions can be made in parallel with the CTA, generic screening allows the identification of volunteers prior to approval and flexible protocols mean we don't have to issue amendments requiring regulatory approval.
This nimble approach, minimising regulatory involvement, has been endorsed by the MHRA. There is also the advantage of obtaining approval for the Investigational Medicinal Product (IMP) early as this can smooth the way for patient studies after Phase I is complete.
So what problems has the CTD actually caused for a Phase I CRO? The simple answers to this question are scheduling and client confidence.
Phase I clinics have to run at a certain bed occupancy to remain profitable. Space is reserved for studies, volunteers recruited to attend on given dates, study days staffed, equipment hired, etc. Prior to May 1st there was only the uncertainty of the Ethics Committee to overcome when scheduling a study and by and large CROs know their committees and how they are likely to vote. We now have to take into consideration the view of the MHRA and their far greater scrutiny of the Chemistry, Manufacturing and Control (CMC) of the IMP. The MHRA may ask questions following a CTA application that have to be resolved before the study can start.
This may lead to the study being postponed until issues have been resolved to the MHRA's satisfaction. Postponements cost money, both real (screening, recruitment and overhead) and virtual in terms of lost opportunity (the lost revenue on the bed space if the study ran when planned) and someone has to pay. We therefore have to spell out to our clients the financial risk associated with assuming a first time MHRA approval. It is up to our clients to decide if they wish to build some extra time into the review process or to take the risk and possibly incur extra costs if the study start is delayed due to MHRA queries.
However, the most significant impact of the CTD on Phase I studies in the UK, as we perceive it, is client confidence. It is as if the whole industry is holding its breath, waiting to see what will happen next. Undoubtedly the pressure of Phase I work must be building up against this dam but currently there is no sign of it bursting. The number of requests for proposal has dropped significantly when compared with the same period in 2003, and although there is some evidence of an upturn it is slow, hesitant and appears rather fragile.
Currently we feel that, due to the unexpected persistence of the downturn, it may be well into 2005 before we see a full recovery. Obviously our greatest concern is that in the meantime, clients are forming relationships with clinics in other countries and these clinics are building their experience, which may erode our competitive advantage
Undoubtedly the CTA process is here to stay, and we must make every effort to minimise the perceived negative impact of these new regulations. It is a concern that many feel a unique "UK plc" selling point has been lost and industry is left suffering the consequences. Whilst it is true that compliance with the Directive has introduced additional bureaucracy, our greatest worry of studies taking significantly longer to achieve first dose has not come to fruition.
Consequently, as the UK still has the expertise to perform high quality, efficient Phase I studies and timelines are not being significantly impacted, we should be able to retain our position as the country of choice for Phase I. We must now wait for the global Pharma Industry to give us the opportunity to prove this claim.
Steve Andrew, Senior Client Services Manager
Covance Clinical Research Unit, Leeds