The European Union’s clinical trials directive, 2001/20/EC, has done little to clarify or simplify the regulatory environment for non-commercial trials in the UK, a new study suggests.

Rather, the directive’s implementation into UK law has sown uncertainty, increased bureaucracy, delayed trials and dramatically pushed up costs, the study by Cancer Research UK found. Moreover, it has made clinical trials units reluctant to take part in international cancer studies due to discrepancies in the legal interpretation and regulatory application of Directive 2001/20/EC at member state level.

In the study published in the European Journal of Cancer, CRUK researchers Julie Hearn and Richard Sullivan interviewed directors and senior staff from six National Cancer Research Institute Accredited CTUs, plus the CRUK Drug Development Office and the Wales Cancer Trials Network. They asked a range of questions about the impact of the UK Medicines for Human Use (Clinical Trials) Regulations 2004, which incorporated the EU Directive into national law as of 1 May 2004.

All eight CTUs said the new regulations had made non-commercial cancer trials much more expensive, as well as more difficult to conduct. In particular, more time was taken up by a heavier burden of documentation. Three CTUs said they had been unable to open or participate in a trial because it was considered too difficult and expensive.

Stripping out direct costs such as fees payable to the Medicines and healthcare Products Regulatory Agency or ethics committees, the increased expenditure by CTUs derived mainly from additional staff resources needed at every stage of the trial process. These included new positions in quality assurance, pharmacovigilance and information technology, as well as contracts officers and extra administrative support to handle “large volumes” of paperwork and archiving.

Costs hurtling upwards

Of the two CTUs able to provide direct cost comparisons pre- and post-Directive for similar types of cancer trials, one reported that overall expenses had expanded from £171,173 to £282,409 per annum, while another said annual costs had jumped from 117,458 to £201,061. Among other costs assessments by the CTUs interviewed, staff reported it was taking up to six months longer for a trial co-ordinator to prepare the requisite Clinical Trial Authorisation, Investigators Brochure and Multi-Centre Research Ethics Committee submissions before filing for MHRA approval, equivalent to a staff cost of around £20,000 per trial.

Setting up and logging trial agreements between sponsors and all the participating centres was a new activity to which four CTUs had allocated a full-time staff member at a cost of up to £30,000 per unit. Additional staff and resource costs for starting up and running trials, such as the need to visit all centres and produce a written report, were estimated at £60,000 to £100,000 per study; extra administrative support and pharmacovigilance staff came out at roughly £50,000. In all, the researchers concluded, the new regulations had doubled the cost of running non-commercial cancer trials in the UK, a finding independently verified by the European Organisation for the Research and Treatment of Cancer.

The CTUs reported delays of between six and 12 months as a direct result of the EU Directive. There were also marked problems of interpretation, with all the units describing the quality of guidance and advice from the MHRA as either poor or very poor. Another major stumbling block was the absence of a national template for standard Clinical Trial Agreements between the host institution, sponsors and participating centres. This had led to substantial delays as individual National Health Service R&D offices sought legal advice on each of the agreements, resulting in “over-interpretation of the Directive by the lawyers, and furthermore multiple interpretations, all of which caused increased bureaucracy and delay”.

Timelines lengthening, costs escalating

Not only had these complications lengthened timelines and deepened costs, they had also dented morale. “In the absence of a single source of information, there was a strong feeling of disillusionment and acute anxiety by experienced staff, which had inevitably led to over-interpretation of the guidance and ‘regulatory creep’,” the authors commented. Further uncertainty and anxiety about varying implementation of the clinical trial Directive across the EU member states meant all but one of the CTUs that usually conducted or contributed to international studies had stopped doing so.

The study authors acknowledged that many of the stakeholders in non-commercial clinical trials – and the MHRA in particular – had “stepped up to the mark” to address the issues highlighted in the survey. For example, a number of useful initiatives had been launched through the UK Clinical Research Collaboration Regulatory and Governance Workstream, such as a single academic Clinical Trials Agreement and the recent ad hoc review of Research Ethics Committee processes. “In comparison to most EU member states the UK response has been excellent,” they noted.

But a number of serious problems remained, they warned. International recruitment to many CTU trials had stagnated, the increased cost of running public sector trials was “a real threat”, and fatigue with the EU Directive posed “the very real danger that further malignant regulations will come out of Brussels”. Public funding bodies across Europe must “work together to vaccinate fragile academic research from future regulatory threats”, the researchers urged. By Peter Mansell