key: cord-0897043-4o8r1e92 authors: Rubio-San-Simón, Alba; André, Nicolas; Cefalo, Maria Giuseppina; Aerts, Isabelle; Castañeda, Alicia; Benezech, Sarah; Makin, Guy; van Eijkelenburg, Natasha; Nysom, Karsten; Marshall, Lynley; Gambart, Marion; Hladun, Raquel; Rossig, Claudia; Bergamaschi, Luca; Fagioli, Franca; Carpenter, Ben; Ducassou, Stephane; Owens, Cormac; Øra, Ingrid; Ribelles, Antonio Juan; De Wilde, Bram; Guerra-García, Pilar; Strullu, Marion; Rizzari, Carmelo; Ek, Torben; Hettmer, Simone; Gerber, Nicolas U.; Rawlings, Christine; Diezi, Manuel; Palmu, Sauli; Ruggiero, Antonio; Verdú, Jaime; de Rojas, Teresa; Vassal, Gilles; Geoerger, Birgit; Moreno, Lucas; Bautista, Francisco title: Impact of COVID-19 in Paediatric Early Phase Cancer Clinical Trials in Europe: A report from the Innovative Therapies for Children with Cancer consortium (ITCC) date: 2020-10-09 journal: Eur J Cancer DOI: 10.1016/j.ejca.2020.09.024 sha: 9f10d1da5d492a0225094cd468ec604a5ea5e25a doc_id: 897043 cord_uid: 4o8r1e92 INTRODUCTION: Data regarding real-world impact on cancer clinical research during COVID-19 are scarce. We analysed the impact of the COVID-19 pandemic on the conduct of paediatric cancer phase I-II trials in Europe through the experience of the Innovative Therapies for Children with Cancer (ITCC). METHODS: A survey was sent to all ITCC-accredited Early-Phase Clinical Trial Hospitals including questions about impact on staff activities, recruitment, patient care, supply of investigational products and legal aspects, between 1/March and 30/April/2020. RESULTS: Thirty-one out of 53 hospitals from 12 countries participated. Challenges reported included staff constraints (30% drop), reduction in planned monitoring activity (67% drop of site initiation visits and 64% of monitoring visits) and patient recruitment (61% drop compared to 2019). The percentage of phase I, phase II trials and molecular platforms closing to recruitment in at least one site was 48.5%, 61.3% and 64.3%, respectively. Additionally, 26% of sites had restrictions on performing trial assessments due to local contingency plans. Almost half of the units suffered impact upon pending contracts. Most hospitals (65%) are planning on improving organizational and structural changes. CONCLUSION: The study reveals a profound disruption of paediatric cancer early phase clinical research due to the COVID-19 pandemic across Europe. Reported difficulties affected both patient care and monitoring activity. Efforts should be made to reallocate resources to avoid lost opportunities for patients and to allow the continued advancement of oncology research. Identified adaptations to clinical trial procedures may be integrated to increase preparedness of clinical research to futures crises. Thirty-one out of 53 hospitals from 12 countries participated. Challenges reported included staff constraints (30% drop), reduction in planned monitoring activity (67% drop of site initiation visits and 64% of monitoring visits) and patient recruitment (61% drop compared to 2019). The percentage of phase I, phase II trials and molecular platforms closing to recruitment in at least one site was 48.5%, 61.3% and 64.3%, respectively. Additionally, 26% of sites had restrictions on performing trial assessments due to local contingency plans. Almost half of the units suffered impact upon pending contracts. Most hospitals (65%) are planning on improving organizational and structural changes. The study reveals a profound disruption of paediatric cancer early phase clinical research due to the We are also thankful to all the staff from the ITCC Clinical Trial Units at each site for their invaluable contribution to the advancement of research in paediatric cancer despite this very difficult situation. JV was supported by the 2019 ITCC-Fellowship grant. There was no other specific support for this study. J o u r n a l P r e -p r o o f The COVID-19 pandemic has led to a global healthcare crisis, affecting more than 28 million individuals and resulting in 917,417 deaths as of 14 th September 2020 [1]. All European States, although not equally affected, have been forced to make unprecedented adjustments to prioritize resources against COVID-19 [2] , [3] . While clinical research is key to advancing medical knowledge and improving patient care, priority has been given to COVID-19-related patient care during the pandemic. This has severely impacted essential clinical research in other fields, such as cancer research [4] , [5] . Coronavirus mitigation measures can affect the conduct of clinical trials in many ways, e.g. patient recruitment, completion of trial assessments, or provision of investigational medicinal products (IMPs) [6] . Furthermore, pharmaceutical companies have redirected their focus to developing diagnostics and treatments against COVID-19, thus neglecting other research areas [7] . To limit the downstream impact for patients and for the drug industry, the European Medicines Agency (EMA) [8] and several national agencies [9] , [10] , [11] have issued guidelines on the management of clinical trial activities during the pandemic. They are all aligned in the intention to maintain trial activity, while assuring patient safety and trial activities traceability, but no definitive recommendations have been provided, making it difficult to create a unified action plan. Across Europe, all parties (i.e. healthcare authorities, regulators, sponsors) have implemented different measures depending on the impact of the pandemic in their countries and their capacity to adapt. Particular attention should be given to patients in cancer clinical trials due to their remarkable vulnerability: cancer patients not only require timely evaluation and treatment that does not allow for delays [12] , but also they may be vulnerable to COVID-19-related serious events [13] , [14] . The European Society of Medical Oncology [15] and international paediatric Oncology Societies [16] have developed guidelines to mitigate the deleterious effects of the pandemic on the treatment of cancer patients. However, data regarding real-world impact on cancer clinical research during COVID-19 are scarce [17] , [18] . In this study, we evaluate the impact of the COVID-19 pandemic on the early-phase clinical trial activity in paediatric haematology-oncology in Europe. We analyse the experience of the Innovative Therapies for J o u r n a l P r e -p r o o f 6 Children with Cancer consortium (ITCC), an academic consortium dedicated to improve the access to novel treatments for children and adolescents with cancer in 13 European countries [19] , [20] . Of the 53 ITCC sites, 31 (58.5%) responded, including 22 university hospitals, 6 cancer centres and 3 private hospitals. All responses were complete and could be included in the analysis. Participating sites accounted for 12 European countries, with a fair representation from Northern, Southern and Western Europe. Fourteen sites were exclusively paediatric, while 17 treated adults and children. Sixty-four different phase I (n=33) and phase II (n=31) trials, and 14 different molecular platforms were active and recruiting before 1 st March. Phase I and phase II trials, and molecular platforms were open in a median of four sites (Interquartile range (IQR) 1-7), three sites (IQR 1-9) and one site (IQR 1-3.25), respectively (Table 1) . Almost all units (28/31) managed to perform remote data entry, although 23% (n=7) were not adequately equipped for it and reported difficulties performing trial activities from home-based offices. Most units experienced cancellations of site initiation (SIVs, 65%) and monitoring visits (MVs, 87%). Sixty-seven percent (n=35) of planned SIVs were cancelled, while 29% (n=15) were performed remotely and 4% (n=2) on-site. The decision to postpone visits was taken by sponsors in half of the cases (49%), by institutions (25%) and by sponsors and institutions together (23%) Sixty-four percent (n=196) of planned MVs were cancelled, whereas 35% (n=109) were performed remotely and 1% (n=4) on-site. The decision to postpone visits was predominantly taken jointly by sponsors and institutions (45%) or by institutions alone (42%). The percentage of phase I and phase II trials, and molecular platforms that closed to recruitment in at least one site was 48.5% (n=16), 61.3% (n=19) and 64.3% (n=9) respectively. All units continued to perform on-site patient visits, but 48% (n=15) reported limitations in providing best care for patients. Eight units (26%), seven of which were located in mixed adult-paediatric centres, had restrictions on performing trial assessments due to local strategies (e.g. procedures requiring anaesthesia due to shortage of specialists, fewer slots due to prolonged inter-patient intervals or cancellation of outpatient visits in other disciplines). Out of 809 patient visits performed, 80% were conducted on-site (n=646), while 13% (n=104) were conducted by phone and 7% (n=59) in local hospitals closer to families' home. Only eight patient visits were definitively cancelled. Among patients begin actively treated, 10 experienced treatment delays because of COVID-19 related concerns: physician's decision to guarantee patient's safety (n=8), hospital organizational policy (n=1), parents' fear of COVID-19 (n=1). No patient on trial had study discontinuation due to COVID-19. Twenty-three potentially eligible patients could not be screened for trials due to COVID-19-related constraints. Of those, 83% (n=19) received other anti-cancer standard of care treatment and 17% (n=4) did not receive anti-cancer treatment at that time point. Almost half of the units (48%, n=15) suffered impact on administrative and regulatory aspects (e.g. delays in Ethic Committee submissions, review of trials budget), and the completion of 43 contracts was delayed. In nearly all units (94%, n=29), local protocols were created, and sponsors procured contingency plans for the management of COVID-19 issues. National regulatory authorities from 10 out of 12 countries surveyed (83%), developed specific guidance for the conduct of clinical trials during the COVID-19 emergency. Sixty five percent of sites foresee a similar recruitment in 2020 compared to 2019, whereas 35% lower. Most units (65%) are implementing changes to promote remote working and SIVs/MVs. considerations. Homogenously, they pointed out the proactive attitude from the site staff to develop strategies to minimize potential risks to patient safety and to assure compliance with trial procedures. All investigators agreed that this episode will make units better prepared for future crises 13 This study reveals a profound disruption of paediatric cancer early clinical research due to the COVID-19 pandemic across Europe. Healthcare adjustments were made initially assuming that the pandemic would be brief, but we have come to realise that the pandemic and its consequences are unlikely to dissipate soon. Since children with cancer have an unmet need to access innovative therapies [21] , now is the right time to think how to fulfil their needs in this "new normal" setting. With hospitals diverting resources to care for COVID-19 patients, personnel shortages were a major concern in most units. Physicians and nurses' activities are patient-centred and therefore more susceptible to be compromised by COVID-19 mitigation measures. Nevertheless, the efforts of healthcare workers to address the issues resulting from this crisis enabled continued care provision for most patients. Other professionals, such as study coordinators or data-managers, may continue to perform home-based work more easily. In this regard, most units managed remote data entry, although 23% of them reported to not having the appropriate means to do so. Efforts should be made to implement homeworking solutions under the perspective of COVID-related restrictions expected throughout upcoming months. Although reallocation of staff to other areas to fight against COVID-19 is logical in this context, it has an undeniable impact on areas with highly specialized and multidisciplinary activities, such as clinical research. Our study shows drastic suspension of SIVs and MVs. The decisions leading to delaying SIVs are understandable due to the inherent complexity of early-phase studies. However, SIVs should be rescheduled as soon as possible to avoid lost opportunities for patients with no other therapeutic options. In our study, 15 SIVs were performed remotely, demonstrating the feasibility of this procedure. Regarding MVs, only 36% were performed. MVs ensure trial safety and data quality; their suspension may lead to unknown consequences upon the integrity of trials. Hence, it is necessary that sponsors implement alternative mechanisms to resume MVs in collaboration with research teams via reinforced remote communication. Potential impacts of weakening monitoring could be magnified by protocol deviations or delayed visits. Although sponsors provided guidelines to record deviations related to COVID-19 [22] , [23] , regulators should take a sensible approach when reviewing these deviations, especially as most would not compromise patient safety. More than 50% of the trials and 60% of the molecular platforms interrupted recruitment in at least one unit and 80% of the sites halted recruitment of at least one trial or molecular platform. The proportion of industry trials stopped is twice the proportion of academic trials, highlighting the key role that academic J o u r n a l P r e -p r o o f 14 researchers plays in times of crises and their commitment to cancer patient health over other considerations. Furthermore, patient recruitment during these two months was severely impacted with a 61% drop compared to 2019. The reasons for this drop cannot be explained by the halt in trial recruitment alone, but also by individual national lockdown strategies and institutional contingency policies, among others. All efforts should be made to resume recruitment as soon as possible, particularly for phase 2 trials or molecularly-driven studies that have higher chances of success [24] . In an attempt to minimize patient risk, 77% of sites performed remote patient visits in other healthcare institutions or by phone. While the general population was advised not to visit hospitals because of infection risk, this could constitute a major problem for patients receiving investigational treatments if adverse events do not receive the necessary medical attention or if they suffer treatments delays. Cortiula et al. [12] highlighted the negative implications of excessive focus on COVID-19 and of overshadowing other aspects of clinical practice, especially in cancer care. Fortunately, according to our data, no patient discontinued treatment due to COVID-19. Nevertheless, 23 potentially eligible patients could not be recruited due to COVID-19 related issues. It should be pointed out that whereas COVID-19 has a low mortality rate in children [25] , more than 90% of children with relapsed cancers will continue to die. Therefore, considering the safety profile and oral nature of the treatment for most novel anticancer agents, a risk-benefit assessment should be conducted, and cancer treatment continuation should be promoted. Moreover, the stalling process on experimental medicines may extend the already lengthy marketing process, meaning that some new medicines will take longer to reach the patients across the globe [26] . Several stakeholders are advocating seizing the opportunity to keep the positive clinical trial adaptations implemented during this pandemic permanently [27] , [28] , [29] . Doherty [27] recently suggested changes in trial design and trial implementation so that research units can better cope with future crisis. They settings [30] , [31] , there is minimal information that focuses specifically on repercussions on paediatric clinical trials sites [17] , [18] . The American Society of Clinical Oncology (ASCO) recently published an analysis of the impact of COVID-19 on the conduct of oncology clinical trials [17] . Although focused on United States research programs in adults, it reports numerous challenges with conducting clinical trials that we have also observed, including enrolment and protocol adherence difficulties or staff constraints. We acknowledge some limitations of this study. The rest of the authors declare that they have no conflict of interest. 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Nat Cancer COVID-19 transforms health care through telemedicine: evidence from the field Adapting to a pandemic -conducting oncology trials during the SARS-CoV-2 pandemic The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial and Hurricane Katrina: Lessons for managing clinical trials during and after a Mitigating the impact of disasters and emergencies on clinical trials site conduct: A site perspective following major and minor unforeseen events We are grateful to Carole Lecinse, ITCC project manager in Gustave Roussy, for her endless support and help to communicate with each ITCC site.We are also thankful to all the staff from the ITCC Clinical Trial Units at each site for their invaluable contribution to the advancement of research in paediatric cancer despite this very difficult situation. J o u r n a l P r e -p r o o f