Regulatory delays in a multinational clinical stroke trial.

Jeroen C De Jonge,Götz Thomalla,George Ntaios,Iris Alpers,Malcolm R Macleod,Bridget Colam,Iwona Kurkowska-Jastrzebska,Hendrik Reinink,Philip M Bath,Alfonso Ciccone,Janika Kõrv,Laszlo Csiba,H Bart Van Der Worp

doi:10.1177/23969873211004845

Abstract

IntroductionThe initiation and conduct of randomised clinical trials are complicated by multiple barriers, including delays in obtaining regulatory approvals. Quantitative data on the extent of the delays due to national or local review in randomised clinical trials is scarce.Materials and methodsWe assessed the times needed to obtain regulatory approval and to initiate a trial site for an academic, EU-funded, phase III, randomised clinical trial of pharmacological prevention of complications in patients with acute stroke in over 80 sites in nine European countries. The primary outcome was the time from the first submission to a regulatory authority to initiation of a trial site. Secondary outcomes included time needed to complete each individual preparatory requirement and the number of patients recruited by each site in the first 6 and 12 months.ResultsThe median time from the first submission to a regulatory authority to initiation of a trial site was 784 days (IQR: 586–1102). The single most time-consuming step was the conclusion of a clinical trial agreement between the national coordinator and the trial site, which took a median of 194 days (IQR: 93–293). A longer time to site initiation was associated with a lower patient recruitment rate in the first six months after initiation (B = –0.002; p = 0.02).DiscussionConclusionIn this EU-funded clinical trial, approximately 26 months were needed to initiate a trial site for patient recruitment. The conclusion of a contract with a trial site was the most time-consuming activity. To simplify and speed up the process, we suggest that the level of detail of contracts for academic trials should be proportional to the risks and commercial interests of these trials.

Highlights

The initiation and conduct of randomised clinical trials are complicated by multiple barriers, including delays in obtaining regulatory approvals
Randomised clinical trials (RCTs) and meta-analyses thereof are generally considered the best instruments to assess whether a specific diagnostic test or treatment is of benefit to patients or healthy persons,[1] but their initiation and conduct are hampered by multiple barriers
We provide a systematic overview of the time period required for each regulatory approval procedure needed to open an individual trial site and analyse its relationship with patient recruitment

Summary

Introduction

The initiation and conduct of randomised clinical trials are complicated by multiple barriers, including delays in obtaining regulatory approvals. Materials and methods: We assessed the times needed to obtain regulatory approval and to initiate a trial site for an academic, EU-funded, phase III, randomised clinical trial of pharmacological prevention of complications in patients with acute stroke in over 80 sites in nine European countries. Editorials and narrative reviews have reported lack of funding, increasing complexity of regulations, excessive monitoring, overinterpretation of privacy laws, and complex and overly bureaucratic trial procedures, often out of proportion to the conceivable risk to research participants, as important obstacles.[2,3,4,5] In addition, delays in obtaining ethical, regulatory, and legal approvals have been identified as major delaying factors in initiating clinical trials sites.[2] As a result of these and other barriers, it has been estimated that approximately half of the clinical trials fail to reach their target sample size within the planned timeline.[6]. Quantitative evidence on the true extent of the delays in RCTs due to institutional or legal review is scarce and limited to a specific part of the approval process, to specific countries and time periods.[5,7,8] New regulations, such as the General Data Protection Regulation in the European Union, have been introduced in recent years, which could have major consequences for institutional review and contractual governance

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