Accelerating clinical trial implementation in the context of the COVID-19 pandemic: challenges, lessons learned and recommendations from DisCoVeRy and the EU-SolidAct EU response group

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered new approaches in clinical research. These include the conduct of adaptive platform trials, such as RECOVERY [[1]Mullard A. COVID-19 platform trial delivers.Nat Rev Drug Discov. 2020; 19: 501Google Scholar], REMAP-CAP and DisCoVeRy [[2]Ader F. Discovery French Trial Management TeamProtocol for the DisCoVeRy trial: multicentre, adaptive, randomised trial of the safety and efficacy of treatments for COVID-19 in hospitalised adults.BMJ Open. 2020; 10e041437Crossref PubMed Scopus (29) Google Scholar]. Platform trials allow the study of several target treatments in the same disease context on a perpetual basis, with therapies being allowed to enter or leave the platform based on a decision algorithm [[3]Woodcock J. LaVange L.M. Master protocols to study multiple therapies, multiple diseases, or both.N Engl J Med. 2017; 377: 62-70Crossref PubMed Scopus (575) Google Scholar]. DisCoVeRy is part of a European project, EU-RESPONSE, originally set up in France as a WHO Solidarity trial add-on study [[4]WHO COVID-19 solidarity therapeutics trial. World Health Organization, 2021https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatmentsGoogle Scholar]. EU-RESPONSE is funded by the Horizon 2020 programme to allow the expansion of DisCoVeRy to other European/associated countries, and the launch of ‘EU-SolidAct’, a second-generation pan-European platform trial for coronavirus disease 2019 (COVID-19)/emerging infectious diseases, implemented to extend what was initiated by DisCoVeRy. These trials have faced multiple hurdles. Under the 2001/20/EC Directive, approval of multinational clinical trials in Europe requires parallel and independent submissions to the national competent authority (NCA) and ethics committee (EC) of each participating country. Since 2009, the European Medicines Agency has developed a Voluntary Harmonization Procedure (VHP) whereby a single application is sent to one reference NCA coordinating the response of all NCAs, before a national phase takes place in each country. Some Member States offer the involvement of ECs (VHP plus process). Whereas DisCoVeRy used multiple national applications (VHP not possible because the trial received initial approval in France), EU-SolidAct opted for the VHP. In DisCoVeRy, five countries were involved at the onset of the pandemic, in 2020. The median review times were 13 days (interquartile range (IQR) 7–17 days) and 17 days (IQR 15–21 days) for NCAs and ECs, respectively. In 2021, the new treatment arm required the submission of an amendment that applied not only to the countries already involved, but also to the eight countries that had started recruiting since the first approval. The median amendments review time was 47.5 days (IQR 34.25–63.5 days) for 10 of the 13 countries and 35.5 days (IQR 27.75–58.5 days) for 8 of the 13 countries, for NCAs and ECs, respectively. The shorter time frame observed in 2020 is related to the fast-track procedure implemented for all of these countries at the beginning of the pandemic. The fast-track procedure was withdrawn in 2021. Duplicate reviews of the protocol with similar questions/queries were requested from various countries (See Table 1).Table 1Assessment time (days) for (inter)national approval for DisCoVeRyCountryFirst submission (2020)Amendments (2021)ECNCAECNCAAustria2117pendingpendingBelgium15132816Czech Republicpending aSome local regulations require approval by the national competent authority before submission to the ethics committee.98France031733GreecependingpendingHungary2732Ireland10856Luxembourg17192842Norway4938Polandpending aSome local regulations require approval by the national competent authority before submission to the ethics committee.66Portugal41743§67Slovakiapending aSome local regulations require approval by the national competent authority before submission to the ethics committee.53Spain87pendingMedian (IQR)17 (15-21)13 (7-17)35.5 (27.75-58.5)47.5 (34.25-63.5)Abbreviations:EC, ethics committee; IQR, interquartile range; NCA, national competent authoritya Some local regulations require approval by the national competent authority before submission to the ethics committee. Open table in a new tab Abbreviations:EC, ethics committee; IQR, interquartile range; NCA, national competent authority For EU-SolidAct, the VHP and VHP + assessment took 56 days. However, the duration of the subsequent national phase varied from a few days to several months. The median review time was 20.5 days (IQR 12.5–43.5 days) for 14 of the 16 countries and 35 days (IQR 29–42 days) for 9 of the 16 countries, for NCAs and ECs, respectively. The time frame for substantial amendments, including adding a new arm, is expected to be 50 days (See Table 2).Table 2Assessment time (days) for (inter)national approval for SolidActCountryInternationalNationalVHPVHP+NCAECAustriax21PendingBelgiumx2PendingCzech Republic4427Francex196Germanyx134PendingGreece14Hungaryx4242IrelandX383ItalyX12LuxembourgX9136Norwayx529Portugalx3384SlovakiaX2030Spainx4835SwitzerlandXTurkeyMedian (IQR)20.5 (12.5–43.5)35 (29–42)Abbreviations:EC, ethics committee; IQR, interquartile range; NCA, national competent authority; VHP, voluntary harmonization procedure Open table in a new tab Abbreviations:EC, ethics committee; IQR, interquartile range; NCA, national competent authority; VHP, voluntary harmonization procedure The aim of these clinical trials is to urgently obtain clinically relevant results and propose therapeutic and preventive solutions. Prolonged evaluation times are therefore obstacles to finding these solutions and to the subsequent rapid development of best clinical care for patients. In comparison, in the UK, where the conduct of clinical trials seems to have been more successful, with the support of the competent authorities, COVID-19 studies were swiftly revised to accelerate the approval process during the health crisis. The National Institute for Health Research established a single UK-wide process to prioritize COVID-19 research as Urgent Public Health Research early in the pandemic [5National Institute for Health Research (NIHR)– Written evidence (COV0041).https://committees.parliament.uk/writtenevidence/8275/pdf/Date accessed: October 4, 2021Google Scholar, 6Fast track review guidance for COVID-19 studies.https://www.hra.nhs.uk/covid-19-research/fast-track-review-guidance-covid-19-studies/Date accessed: October 4, 2021Google Scholar, 7Guidance clinical trials applications for coronavirus (COVID-19).https://www.gov.uk/guidance/clinical-trials-applications-for-coronavirus-covid-19Date accessed: October 4, 2021Google Scholar]. This enabled the implementation of a fast-track review or process by offering reviews by the Research Ethics Committee and NCA with the submission of one application reviewed and the issue of approval within days. There were challenges in drafting the information leaflet as well. The adaptation of each leaflet to local regulations, including the size of the document and the number of consents to be drafted per party required by ECs, led to numerous exchanges and submission extensions. Some hurdles are expected to be reduced by the new Regulation 536/2014 on clinical trials, which is to come into force in January 2022 (see Appendix 1). This regulation will ensure that rules for conducting clinical trials are identical throughout the European Union (EU) and will also allow a coordinated assessment of clinical trial applications and especially the protocol and the product between Member States [[8]European Commissionhttps://ec.europa.eu/health/human-use/clinical-trials/regulation_enDate: 2021Date accessed: October 4, 2021Google Scholar,[9]Regulation (EU) No 536/2014 Questions & Answers – draft July 2021.https://ec.europa.eu/health/sites/default/files/files/eudralex/vol-10/regulation5362014_qa_en.pdfDate accessed: October 4, 2021Google Scholar]. Nevertheless, it seems that the coordinated process under this regulation will not apply to all the steps of approval. For example, it will not apply to patient information and consent, which will continue to be dealt with at site level. We therefore suggest the following considerations when implementing this legislation (See Table S1).-For EU-funded platform trials during the pandemic, to reach a single decision the assessment involving NCAs and ECs must be mandatory for all Member States.-A protocol pre-submission review involving all relevant NCAs/ECs is needed, to discuss potential grounds for non-approval early on.-During the health crisis, enabling the implementation of a fast-track process by offering review by a research EC and an NCA, with submission of one application reviewed within 1 week.-Amendments must be subject to fast-track review.-Repurposing trials to test drugs with known safety profiles should be seen as low-risk trials, with shorter timelines. The definition of ‘low intervention trials’ under Regulation 536/2014 must include such trials. Here, we have focused on inpatient studies. One should acknowledge that outpatient trials in which the logistics are challenging (e.g. test turnaround time, contacting people with a positive test, quarantine limiting study visits) will be even more difficult to implement if national rules continue to be defined without any EU harmonization and without taking the need for trials into account. Negotiations of agreements between the trial sponsor and sites, and translations into local languages, represent a major bottleneck. Some sites insist on using their own templates, which requires valuable time and resources in order to understand regional legislation and its legal language. The flowchart shown in Fig. 1 illustrates these hurdles. Following this, we suggest the development of a pan-European site agreement template by the EC, which allows an electronic signature for all parties, and its translation into all European languages. Acceptance of this template by implementing sites/institutions could be an eligibility criterion for publicly funded multinational trials in the EU. Mention should be made on the information sheet of the sharing of individual participants' data by EU Member States participating in the trial for public health benefits. Immediate availability of sufficient funding is critical for the success of multinational trials in a pandemic. This pandemic has demonstrated that implementing an EU seed grant programme is critical when sponsored funding is not yet available but the problem demands immediate investigation [[10]Messersmith J. Stoddart-Osumah C. Lennon M. Wirtz D. Emergency seed funding for COVID-19 research: lessons from Johns Hopkins University.J Clin Invest. 2021; 131e14561Crossref Scopus (5) Google Scholar]. The substantial and ambitious seed grant will allow the research to start quickly. Bottom-up funding mechanisms based on competitive calls are too slow, and have resulted in duplication and fragmentation of trials. We propose:-A top-down decision mechanism established at EU level that promptly releases appropriate budgets, using funding mechanisms from the Horizon Europe budget and/or ERA4Health in coordination with the European Health Emergency Preparedness and Response Authority (HERA)-Subsequent funding of intervention arms from the same public sources, with levels of funding adapted to the nature of the trial-Safeguards to ensure public health relevance, independence and scientific excellence. Europe, despite its diversity, must be capable of responding unanimously and rapidly to any health crisis; establishing effective medical collaboration is key to responding to epidemics/pandemics. Regulatory, legal and financial hurdles have significantly slowed down the efficient conduct of clinical trials, which is unacceptable during an active pandemic. Adaptive, large clinical trials during pandemics should be considered a critical countermeasure, and the pace of regulatory approval should be consistent with the urgency of this situation. This is also applicable to non-emergencies and to multicentre clinical trials in general. There is a definite need to overcome these hurdles to prepare Europe for the next pandemic and to make United Europe of Research a reality.