The CRASH-3 trial found that a low-cost, widely available drug reduces death after TBI by up to 20%, depending on the severity of injury.24 The CRASH-3 trial is the largest clinical trial in TBI and the first to identify a safe and effective neuroprotective drug. If widely implemented, TXA could prevent over 100,000 deaths each year worldwide. The CRASH-3 trial builds on the success of the CRASH-2 trial,17 which showed that TXA reduces deaths in traumatic extracranial bleeding. Based on the CRASH-2 trial results, TXA was included on the WHO Model List of Essential Medicines74 and incorporated into trauma treatment guidelines worldwide. The CRASH-2 trial was considered by RAND Europe as providing an excellent return on the research investement.75
Obtaining funding support for the CRASH-3 trial was not straightforward, with applications to the MRC and HTA initially rejected. Commissioners’ concerns, which in the authors’ opinion were unfounded, included the potential for bias in a study with many hospitals; the challenge of obtaining participant consent; value for money of initial proposals; and complexity of managing international trials. The authors believe that proper randomisation, placebo control, complete follow-up and objective outcomes (e.g. death) avoid bias and that unconscious patients with life-threatening emergencies are an exception to the general rule of patient informed consent. As regards value for money, the authors believe that providing reliable and definitive answers in a large adequately powered trial provides much better value for money than by conducting many smaller trials over a longer period. Fortunately, the successful international pilot phase involving over 1000 patients, funded by the JP Moulton Charitable Trust, demonstrated the feasibility of the CRASH-3 approach. The CRASH-218 and CRASH-3 trials show that early treatment with TXA safely reduces mortality in low-, middle- and high-income countries. There is no evidence that the effects of TXA vary by a country’s income level. NHS patients were the first to benefit from the results of these global trials. Even sooner than this, the British Army incorporated TXA into combat care treatment protocols, resulting in a demonstrable reduction in combat deaths.76 The authors believe that it is more efficient to conduct adequately powered international trials that provide reliable answers for patients everywhere than to conduct smaller or less efficient trials within the borders of the UK.
Although recruitment was rapid, we extended the trial for scientific reasons. New research had suggested that the recruitment window of 8 hours was too long and that it should be shortened to 3 hours. The protocol was amended accordingly. This substantially reduced recruitment; however, UK research nurses and international collaborators worked hard to ensure that few eligible patients were missed and that patients were randomised and treated urgently. Although UK research nurses were critical to the success of the trial, many hospitals have no research nurse cover at night and weekends, periods when trauma is most common, and this resulted in reduced recruitment.
Trials have become more expensive. The CRASH-218 trial (20,210 patients) cost approximately £2M; however, 10 years later, the CRASH-3 trial (12,737 patients) cost approximately twice this amount. One reason for this increase in cost is burgeoning clinical trial bureaucracy. To conduct a multinational trial, approval must be obtained from the competent authority and National Ethics Committee of each participating country. In the European Union (EU), the Clinical Trials Directive was introduced to simplify and harmonise the administrative processes around clinical trials.77 The Directive stated that each Member State should:
- require a standard list of documents for review of a trial
- accept the English language in their communications with applicants and for documentation that is not aimed at the public or the trial participant
- provide an opinion on the trial within a maximum of 60 days.
Hospitals from 15 EU countries expressed an interest in taking part in the CRASH-3 trial. Seven of these countries required documents that are not part of the EU Directive standard list. Six countries required the full application form in their local language (i.e. Croatia, France, Greece, Italy, Lithuania and Portugal) and seven countries required the Investigational Medicinal Product labelling in their local language (i.e. Belgium, the Czechia, Greece, Hungary, Latvia, Lithuania and Portugal). Of the seven countries where competent authority approval was obtained, Belgium and the UK were the only two that complied with the 60-day timeline. For the other five countries (i.e. Ireland, Italy, Romania, Slovenia and Spain), the review time ranged between 64 and 291 days.
Of the six countries in which national ethics committee review approval was obtained, only two complied with the 60-day review timeline (i.e. Spain and the UK). In the other countries (i.e. Ireland, Italy, Romania and Slovenia), the review times ranged between 114 and 293 days. The cost of ethical review varied widely, with the Czechia charging £1162 for up to 10 sites and £116 for each additional site. There was no charge in the UK.
The sponsor global insurance policy (a worldwide policy excluding the USA) did not meet with the requirements of some EU countries, including Belgium, Germany and Italy. As there was no budget for additional insurance, we could not run the trial in Germany. In Italy, the investigators institutional ethics committee (Comitato Etico della Provincia di Brescia) found and paid for insurance. In Belgium, the investigators’ institutional ethics committee (Ethisch Comite UZ Gent) suggested that we delegate the responsibility for insurance to it. These responses were commendable and show the commitment to patient-relevant research.
With the implementation of the EU Clinical Trials Directive, it was anticipated that the approvals process throughout the EU would be streamlined and standardised. However, the additional costs for translation and review, and delays in obtaining approvals added to the costs of the trial.
We are grateful to the UK taxpayer for the opportunity to conduct this trial. We believe that the results will improve the care of patients with TBI in the UK and worldwide and we sincerely hope that, like the CRASH-218 trial, the CRASH-3 trial will be seen as providing a good return on the research investment. The trial team will continue to work with policy-makers to ensure that patients benefit.