Are clinical trials units essential for a successful trial?

Support at every stage

Experienced CTUs work with investigators to offer support at every stage of a clinical study, from defining the research question to preparing the final report. In particular, staff are likely to have an excellent practical understanding of relevant legal and regulatory issues, knowledge of necessary approvals needed, and extensive experience of data management and randomisation techniques.

Undoubtedly, many well conducted, high impact clinical studies have been done without CTUs. However, randomised clinical trials in 2015 and beyond are more likely to be large multicentre or multinational studies because these are the only way to achieve the numbers needed to detect moderate treatment effects. In this context, a robust study design, with adequate power and well planned recruitment, reliable intervention delivery, and adherence to follow-up is essential. Moreover, novel aspects of study design, such as interrogation of linked health records (with associated information governance challenges), registry based recruitment, or randomised trials embedded within a cohort study are increasingly popular strategies.

Health economic analysis, including intricate modelling studies, is a common component of randomised trials. In this rapidly evolving space, is it really feasible to conduct a randomised clinical study without the involvement of a CTU? The major funding bodies do not think so: CTU involvement is either mandated or strongly encouraged by the National Institute for Health Research, MRC, British Heart Foundation, and others.

Important safety net

Many clinical trials fail to deliver, often because of inadequate recruitment, poor delivery of the intervention, or losses to follow-up. In an evaluation of 114 multicentre studies performed up to 2003 (before modern CTUs), less that a third recruited the target population within the specified period.3 Although there may be genuine unforeseen explanations for why a clinical trial does not thrive, contingency planning and early recognition of problems are important to salvage the situation. Trial managers, statisticians, and other CTU staff with extensive experience of multiple clinical trials are best placed to anticipate difficulties and propose remedies.

In much the same way that high volume clinical centres are more likely to “rescue” a patient with complications, a high volume trials unit may be more likely to rescue a failing study. Unfortunately, poor research governance or even research misconduct may taint clinical trials. A recent report of US Food and Drug Administration site inspections found evidence of poor research governance in 57 trials over 15 years. Problems included falsification of data, poor record keeping, inadequate informed consent, and patient safety concerns.4

In an review of 2047 retracted articles, 1379 (67.4%) were withdrawn because of research misconduct.5 CTUs are not a panacea for all suboptimal research practices or trial failures, but the expertise of the team and inherent quality assurance processes may help minimise breaches from good clinical practice.

Ethical case

Perhaps the most compelling justification for CTU involvement is ethical. All clinical trials involve patients and are often funded by government or charitable grants. Modern clinical trials are enormously expensive (about £8000 per recruited patient in the UK6) and are therefore a precious resource, with a direct effect on the participants and, potentially, the wider patient population. It is an ethical imperative that researchers do everything to optimise study design, ensure appropriate sample size calculation, perform robust analysis, and report findings to published standards. The best way to achieve these goals is with the early involvement of an experienced CTU.

Is there anything to be lost by involving a CTU in all clinical studies? Critics may claim extra expense (around 5-10%), delays, and potential overcomplication of clinical studies. However, there would be no greater waste of money and time than proceeding with a poorly designed trial, ill suited to answer the research question. There is a strong and persuasive case for CTUs, and most public and charitable funding bodies strongly advocate their involvement. The units have been instrumental in maintaining the quality, credibility, and impact of clinical studies in recent years. Rather than questioning the importance of CTUs, the time has come for researchers to recognise their value in all clinical trials.

No guarantee of success

What is also clear is that the involvement of a CTU does not guarantee success. An analysis of 114 multicentre trials with CTU support funded by the NIHR and MRC showed that 45% failed to recruit 80% of the prespecified sample size. Less than one third of the trials recruited their original target number of participants within the time originally specified, and about a third required extended time and resources.3 Indeed, there are examples of trials with CTU support failing in clinical areas where trials without CTU involvement have succeeded.14 15 16 This may be because CTUs, especially with recent subspecialisation, become divorced from the patient and clinical communities.

The overwhelming majority of successful clinical trials do not have CTU involvement. CTUs are generally used only in phase III and IV trials. Far more phase I and II trials are performed than higher phase trials, so many successful trials do not involve a CTU.

The UK has only 45 registered CTUs, so it is currently impossible for a CTU to be involved with every clinical trial in the UK. Demand hugely outstrips supply. If all trials had to be managed by a CTU many important research questions would remain unanswered unless there was a large and rapid expansion of CTU numbers.

Adds considerably to cost

Finally, CTU involvement in a clinical trial adds considerably to the expense of a trial. The NIHR has given funding to CTUs to help them support NIHR funded projects and applications for research funding. These represent only a tiny percentage of the clinical trials activity within the UK, however. The expense associated with CTU involvement means that trials become too costly to go ahead and is a key reason why commercial research usually doesn’t use CTUs.

Many factors contribute to the success or failure of a clinical trial, and the involvement of a CTU is by no means a panacea. Indeed, if researchers were to adopt the mantra that clinical trials units are essential for a successful trial, a huge volume of valuable research would not be conducted, with considerable detrimental consequences to patients and at a huge loss to society.