Original research article: Regulatory delays in a multinational clinical stroke trial European Stroke Journal DOI: 10.1177/23969873211004845
By Linxin Li1, Diana Aguiar de Sousa2
- Wolfson Centre for Prevention of Stroke and Dementia, University of Oxford, Oxford, UK
- Department of Neurosciences and Mental Health (Neurology), Hospital Santa Maria – CHULN, University of Lisbon, Lisbon, Portugal.
Randomised clinical trials (RCTs) are considered the gold standard to assess treatment effect of a drug or an intervention but conducting RCTs can be time consuming and costly.1 It is easy to assume that once the funding is secured, the trials can kick off imminently. Unfortunately, regulatory procedures are usually required and contracts need to be fulfilled before a research site can be opened. Such procedures are undoubtedly important and in an ideal world should be efficient and proportional to the perceived risk of the trial. However, previous studies, mostly qualitative, have commented on numerous regulatory barriers causing major delays in initiating RCTs.2,3 With the introduction of new regulations, such as the General Data Protection Regulation (GDPR) in the European Union in recent years, more impact of institutional or legal review on the delays of RCTs is likely.
Using the multicentre, multinational, academic PRECIOUS (PREvention of Complications to Improve Outcome in elderly patients with acute Stroke) trial as an example, de Jonge and colleagues meticulously quantified time to milestone dates along the whole regulatory pathway between the first submission to a regulatory authority to initiation of a trial site.4 The trial involved over 80 sites in 9 European countries and was funded by the European Union’s Horizon 2020 programme.4
They found that despite having a team with bespoke expertise to support the submissions and applications, the median time to initiation of any site was almost 2 years (698 days). Similar magnitude of delays was observed for academic vs. general hospitals (659 vs. 703 days). As expected, there was significant variation across countries. However, even in the country with the shortest delay, the median time to initiation of an original site was over a year (504 days). Numerous regulatory requirements at different levels were required for all countries participating in the trial, with some countries having to go through as many as 8 steps. The most time-consuming steps were the signing process of the Country Coordinator Agreement (CCA) and Clinical Trial Agreement (CTA), which took a median time of 201 and 194 days respectively. Consequently and perhaps not surprisingly, a longer waiting time for site initiation was associated with a lower patient recruitment rate in the first 6 months after initiation.
The authors are congratulated for carrying out an extremely timely study when regulations are becoming increasingly complex. This study offers quantitative real-world data on how regulatory procedures can create hurdles to the successful conduct of a carefully designed RCT. As the authors mentioned, the remaining question is whether effort can be joined to reduce the delay by developing a universally accepted template for national contracts and by adjusting regulatory requirements proportional to the risk of the study. International collaborations to support RCTs in stroke, such as the European Stroke Organisation Trials Alliance (ESOTA), can be an important step forward in that effort. Indeed, trialists will always welcome initiatives aiming at facilitating the development of RCTs, including formal education on regulatory and ethical requirements and advocacy for clearer legislation. Still, conquering regulatory barriers in conducing multicentre and multinational RCTs is likely to be a long journey, as de Jonge and colleagues have demonstrated well.
The full paper can be found at https://journals.sagepub.com/doi/full/10.1177/23969873211004845
- Woodcock J, Ware JH, Miller PW, et al. Clinical trials series. N Engl J Med 2016; 374: 2167.
- Duley L, Antman K, Arena J, et al. Specific barriers to the conduct of randomized trials. Clin Trials 2008; 5:40–48.
- Djurisic S, Rath A, Gaber S, et al. Barriers to the conduct of randomised clinical trials within all disease areas. Trials 2017; 8.
- de Jonge JC, Reinink H, Colam B, et al. Regulatory delays in a multinational clinical stroke trial. Eur Stroke J. DOI: 10.1177/23969873211004845