Regulatory Interactions and Learnings-RADIAL the Trials@Home Proof-of-Concept Trial on Decentralization.

This paper is part of a series of six publications presenting lessons learned during the setup, regulatory submission, and conduct of the proof-of-concept Trials@Home RADIAL trial. The three-arm RADIAL trial, comprising fully decentralized, hybrid, and conventional arms, is the first clinical study to evaluate the feasibility and acceptability of decentralized clinical trial elements across six European countries. In this paper, insights from multiple formal regulatory interactions related to the RADIAL trial, conducted between 2021 and 2022, are presented. These interactions included (i) a consultation with the European Medicines Agency's Innovation Task Force, (ii) a national Scientific Advice procedure, and (iii) the clinical trial application submission under the EU Clinical Trials Regulation (Regulation EU 536/2014). Given the novelty of the decentralized approach and lack of guidelines, many constructive comments and questions were received that supported the finalization of the protocol and conduct of the trial. It is important to acknowledge that clinical trials often span multiple countries and regulatory jurisdictions, creating complexity due to variations in complementary national legal and regulatory requirements. We conclude that early and continuous regulatory engagement is essential for the successful implementation of innovative trial designs. Although progress has been made in supporting decentralized clinical trials, persistent challenges related to legislative heterogeneity remain. Harmonized regulatory guidance and greater transparency through the sharing of regulatory experiences will be key to facilitating the broader adoption of decentralized approaches and advancing clinical trials in Europe.