Solidarity trial
Solidarity is an international clinical trial launched by the World Health Organization (WHO) to help find an effective treatment for COVID-19 using repurposed drugs for this new indication. This platform trial is one of the largest international randomised trials for COVID-19 treatments, with an enrolment of almost 12,000 patients in 500 hospital sites in over 30 countries (latest update on 15 October 2020). An interim analysis in October 2020 showed that all four treatments evaluated up to that time (remdesivir (RDV), hydroxychloroquine (HCQ), lopinavir/ritonavir (LPV/r), and interferon beta-1a (IFN B1a)) had little or no effect on overall mortality, the initiation of ventilation, and the duration of hospital stay in hospitalised patients compared to the standard of care (see related NEJM.org article from 2 December 2020). In July 2020, the WHO accepted the recommendation from Solidarity’s International Steering Committee to discontinue the hydroxychloroquine and lopinavir/ritonavir trial arms (see the WHO’s website). This decision was also supported by the results of the RECOVERY trial, which is another large trial on COVID-19 treatments based in the UK. The discontinuation of the interferon beta-1a arm in October 2020 meant that patients could only be included in the standard-of-care or remdesivir arms. Other treatments strategies are now being evaluated in order to continue the search for effective COVID-19 therapeutics. So far, only corticosteroids have been proven effective against severe and critical COVID-19 (see NEJM.org article from 17 July 2020).
Swiss participation in Solidarity
On 16 March 2020, a few days before the peak of the first COVID-19 wave in Switzerland, the WHO contacted the Swiss National Science Foundation (SNSF) and the Swiss Federal Office of Public Health (FOPH) in order to start a Solidarity feasibility study in Switzerland. Very rapidly, many Swiss investigators from university and non-university hospitals showed high interest in participating. This momentum resulted in the creation of a Swiss consortium of 17 clinical sites (represented in green in Figure 1) on 26 March 2020. The CTU Lausanne was approached by the national coordinating investigator Dr Oriol Manuel to collaborate and provide support on all aspects of coordination, including budget preparation, project management, monitoring, pharmacovigilance, and regulatory duties. One of the first tasks was to set up a study budget, which allowed the consortium to be rapidly granted funding from the SNSF. Another priority was to validate the distribution of study responsibilities among institutions (WHO, FOPH, SNSF, and CHUV) since the WHO was requesting governmental commitment into co-sponsorship of the trial. Lausanne University Hospital (CHUV) was to act as the sponsor’s (WHO’s) representative in Switzerland and the SNSF as the funding body. The trial’s coordination was assumed by the CTU Lausanne, and close collaboration with the CTU Bern was set to ensure high-quality multilingual monitoring of German speaking sites. This collaboration between the two CTUs was established very rapidly since they experienced working together in the context of the Swiss Clinical Trial Organisation’s (SCTO’s) CTU network. The WHO independently mandated the CTU Bern to perform Central Data Monitoring, Data Management and Statistics. At the end of March, a race against time started that resulted in successful ethical and regulatory authorisations four weeks later as well as the inclusion of the first Swiss patient in the trial on 21 April 2020. This remarkable feat was accomplished thanks to the extensive expertise, exceptional collaboration, and great dedication of all parties involved. Table 1 summarises the main milestones in 2020 and at the beginning of 2021.
Challenges, solutions, and successes
One major challenge was obviously time pressure. Reorganisation within the CTU Lausanne was essential since the staff had to be rapidly reallocated to new tasks. The strategy was to create a pool of persons fully dedicated to the trial (at least in April 2020) to handle the high workload that Solidarity generated, while other CTU staff continued with some routine activities (e.g. those trials not suspended during the pandemic) and at the same time remained involved in an institutional task force coordinating more than 75 COVID-19 research initiatives. Another high priority for CHUV was the initiation of other key research on COVID-19, which required the CTU to allocate significant resources, including study nurses, coordinators, data managers, and regulatory support. Finally, how staff worked had to be reorganised since almost all the staff who were normally in the office worked remotely during the first COVID-19 wave. During the first lockdown, the uncertainties on the incidence of COVID-19 infections pushed the team to move forward with preparations as quickly as possible. Preparing study documents for 17 sites in three different languages required the coordinating team to be well organised. In terms of the regulatory aspects of the trial, the team chose to concentrate first on the approval of the documentation for the national coordinating site in Lausanne (the country-specific addendum to the master protocol, informed consent documents, site agreements, etc.) and then adapt the documentation for the other 16 sites. Preparing and signing off agreements was especially challenging due to work-from-home requirements in most hospitals’ administrative departments.
On the whole, the coordinating team’s successful strategy ensured a very quick and easy review and approval process with the lead and local ethics committees (ECs) and a rapid initiation of the trial at all Swiss sites. As shown in Table 1, both Swissmedic and the Swiss ECs usually reacted to the submitted dossier within 24 to 48 hours, even though the standard timelines (as per law) are 30 days (or 45 days for multicentre trials). Close phone contact with the authorities and the possibility of electronic submissions – both exceptionally authorised by Swissmedic during the COVID-19 pandemic – greatly simplified exchanges. Grouped and remote site initiation visits, a novel approach for monitors, allowed the very rapid activation of all 17 sites. Even though these efforts to initiate the trial at all sites as quickly as possible were successful, the incidence of COVID-19 rapidly decreased in Switzerland, which resulted in the inclusion of fewer than 10 patients at the end of the first wave (Figure 2). However, all these efforts were not vain since sites were ready to enrol patients when the second wave arrived in autumn. As a result, in mid-December more than 200 patients were included in the trial. Unfortunately, the discontinuation of most of the trial arms and a shortage of the remdesivir drug provided by the WHO resulted in a temporary suspension in the inclusion of patients in the trial in Switzerland until new drugs to be tested in Solidarity are selected by the trial’s International Steering Committee.
Lessons learnt and future perspectives
Because the COVID-19 pandemic is unfortunately not yet under control and the Solidarity trial is still running worldwide, it is not yet time to discuss the final lessons learnt. However, an interim picture can be formed. Looking back at 2020, we can proudly state that Swiss participation in Solidarity has been a success, and it definitely demonstrates that Switzerland is an attractive country for running clinical trials in emergency situations. Investigators, CTUs, ethics committees, and regulatory authorities are all able to rapidly adapt together to reach the same objective without sacrificing quality. As representatives of investigators from all parts of Switzerland and the Swiss CTUs, the authors would like to thank the authorities in particular and encourage them to keep their much-appreciated collaborative attitude, which contributes to reducing the gap usually felt between researchers and ethics bodies/the authorities. Requesting feedback within a few days is clearly unrealistic in the long term after this pandemic is over since all stakeholders have accumulated massive amounts of overtime. However, the scientific community would definitely appreciate the possibility to continue to make electronic submissions to Swissmedic. Finally, the CTU Lausanne and the CTU Bern also demonstrated their synergetic collaboration, which was undoubtedly built on previous exchanges within the SCTO network and will pave the way for future collaboration on clinical trials within the CTU network.
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