key: cord-0906935-8j72mi5b authors: Pommier, V.; Abassi, H.; Lavastre, K.; Calderon, J.; Guillaumont, S.; Dulac, Y.; Auriol, F.; Ovaert, C.; Blondelon, A.; Hascoet, S.; Lecerf, F.; Jore, C.; Avesani, M.; Thambo, J.-B.; Amedro, P. title: Impact of COVID-19 disease on clinical research in pediatric and congenital cardiology date: 2022-04-20 journal: Arch Pediatr DOI: 10.1016/j.arcped.2022.03.004 sha: 3b0e6ff9b6d9d1645e31bde96f2ddf709365de00 doc_id: 906935 cord_uid: 8j72mi5b BACKGROUND: COVID-19 triggered an unprecedented crisis affecting society at every level. Research in pediatric and congenital cardiology is currently in full development and may have been disrupted. The aim of the study was to determine the impact of COVID-19 on pediatric and congenital cardiology clinical research and to analyze decision-making and adaptation processes, from a panel of ongoing academic and industry-sponsored research at the time of the pandemic. METHODS: This observational study was carried out in April 2020, from a CHD clinical research network involving five tertiary care pediatric and congenital cardiology centers. Investigators and clinical research assistants from each participating research center completed an online survey questionnaire, and each principal investigator underwent a 1-h web-based videoconference interview. RESULTS: : A total of 34 study questionnaires were collected, reporting that 18 studies were totally suspended. Upon the investigator's decision, after discussion on ethical issues and with facilitating support from health authorities, 16 studies were resumed. The rate of study suspension in interventional research (53%) was similar to that in non-interventional research (56%). Logistical problems were predominantly reported in both continued and suspended trials. Research protocols were adapted, largely thanks to telemedicine, which in some cases even improved the course of the study. CONCLUSION: The impact of the COVID-19 pandemic on clinical research in pediatric and congenital cardiology has been limited by a rapid adaptation of all research structures and an extensive use of telemedicine at all stages of the studies. Results: A total of 34 study questionnaires were collected, reporting that 18 studies were totally suspended. Upon the investigator's decision, after discussion on ethical issues and with facilitating support from health authorities, 16 studies were resumed. The rate of study suspension in interventional research (53%) was similar to that in non-interventional research (56%). Logistical problems were predominantly reported in both continued and suspended trials. From its first appearance in China in November 2019 to its evolution toward a worldwide pandemic from March 2020, COVID-19 disease has dramatically destabilized all areas of contemporary life [1] . While most countries have totally or partially confined their populations, healthcare systems have rapidly adapted to manage the influx of patients infected with SARS-CoV-2, and were simultaneously forced to prioritize their other usual work [2] . Apart from the aspects directly related to patient care, clinical research also had to face new challenges, in terms of follow-up of patients enrolled before the epidemic and of enrolment of new patients. Therefore, all actors involved in clinical research, i.e., regulatory health agencies, health authorities, ethics committees, clinical trial promoters, research center facilities, and clinical trial investigators had to determine, within a very short period of time, how to manage patients already enrolled in ongoing trials and to decide whether or not clinical studies should be modified, halted, or suspended [3] . Clinical research in pediatric and congenital cardiology has grown in importance over the past decade. Indeed, while congenital heart disease (CHD) is the predominant cause of birth defects worldwide, off-label use of drugs and devices has long been observed in patients with CHD, especially in children. Therefore, recent regulatory initiatives have modified the pediatric clinical trials landscape by significantly increasing capital investment and trial volume in pediatric cardiology [4] . As a result, advances in evidence-based medicine are progressively emerging in pediatric and congenital cardiology [5] [6] [7] and research protocols dedicated to patients with CHD are being increasingly published [8] [9] [10] [11] [12] [13] . To note, for children with the most severe conditions, such as pulmonary hypertension, being enrolled in a clinical trial may represent a real promising opportunity [14] [15] [16] . Thus, it is certain that the unprecedented global health crisis caused by COVID-19 disease has significantly disrupted the course of clinical research in pediatric and congenital cardiology. However, much less is known about the extent of this disruption as well as any mitigation strategies to overcome it. This study aimed to determine the impact of COVID-19 in pediatric and congenital cardiology clinical research, and to analyze decision-making and adaptation processes, from a panel of academic and industry-sponsored research ongoing at the time of the pandemic. This observational prospective study was carried out in March and April 2020, from a CHD clinical research network involving five tertiary-care pediatric and congenital cardiology centers in France: Montpellier University Hospital, Bordeaux University Hospital, Marseille-La Timone University Hospital, Toulouse University Hospital, and Marie-Lannelongue Cardiac Surgical Centre. We identified the principal investigators (PIs) in each research center, as declared to the national health authorities (https://www.ansm.sante.fr), and the ongoing studies registered on an international clinical trial registry, as defined by the World Health Organization [17] . All cardiovascular trials enrolling children with any cardiovascular condition, as well as adult patients with CHD, and currently recruiting patients in March 2020 were eligible for the study. For each study, the PI and the clinical research assistant (CRA) were asked to complete an online questionnaire, and then they underwent a web-based videoconference interview. The online questionnaire used the Google Forms ® tool to create the survey. The first part included general questions on the study and on the number of enrolled patients. The second part included questions on the impact of COVID-19 on the study, with a focus on the decision-making regarding study suspension, or on all the adaptations that made the continuation of the study possible. Study suspension was defined as a complete discontinuation in new patient enrollments, or the impossibility for participants enrolled prior to the outbreak to undergo the study intervention and/or follow-up, for any reason. Study pursuance was defined as any form of complete or partial continuation of the study (Table 1) . Then, each PI underwent a 30-min web-based videoconference interview, carried out by a pediatric cardiology research coordinator, previously trained in qualitative research studies [18]. All quantitative data were automatically generated and extracted from the Google Forms ® survey. The characteristics of the studies selected are presented using frequencies. Qualitative data were rearranged in terms of similar topics and analyzed by two investigators. The study was conducted in compliance with the Good Clinical Practices protocol and the tenets of the Declaration of Helsinki. It was approved by our Institutional Review Board on March 16, 2020 (IRB-MTP-2020-03-20200412) and registered on Clinicaltrials.gov (NCT04336384). All PIs (n=5) and CRAs (n=5), identified in the five clinical research centers, accepted to participate in the survey and completed a total of 34 questionnaires (i.e., one per study carried out in each center) in Bordeaux (n=13), Montpellier (n=9), Paris (n=6), Toulouse (n=4), and Marseille (n=2), respectively. As some studies were multicenter trials, a total of 23 different ongoing studies were identified when the pandemic was declared ( Table 2) . Academic studies (n=12; 52%) were promoted by a university hospital (n=8), or an academic society Overall, out of the 34 studies reported by the survey, 18 were halted for an undetermined period (no further enrolment, pause of all study procedures for the previously enrolled patients), and 16 studies were continued with substantial modifications ( Table 3 ). The rate of study suspension in interventional research (53%) was close to that in noninterventional research (56%). Out of the 18 suspended studies, we identified five drug trials, four cardiac device studies, three randomized controlled trials (RCTs) on cardiac rehabilitation, three CHD registries, two RCTs evaluating a relaxation therapy (i.e., sophrology), and one study on cardiomyocytes derived from humaninduced pluripotent stem cells (hiPSC). The PIs reported that the main reason for study suspension was, in order of frequency, logistical issues (n=12; 67%), sponsor's decision (n=3; 17%), patient safety (n=2; 11%), or health authorities' decision (n=1, 5%). Ethical issues were discussed but never mentioned as the main reason for study suspension. In greater detail, logistical problems were predominantly reported as the main reason for study suspension in intervention studies involving cardiac devices (interventional cardiac catheterization procedures), home-and center-based cardiac rehabilitation programs, or blood sampling for experimental research (stem cells in children with cardiomyopathy). Indeed, enrolled patients could usually not travel to the site because of the lockdown; furthermore, all research centers involved in this study were also healthcare facilities in charge of patients with COVID-19 infection. For example, Marie-Lannelongue Hospital, one of the largest cardiac surgical centers in Europe and located near Paris, an area greatly affected by COVID-19, totally stopped the QUALIREHAB-RCT during the pandemic. Similarly, some institutions, such as cardiac rehabilitation centers, decided to totally suspend their clinical activity, meaning that RCTs involving an intervention with cardiac rehabilitation were compromised. Suspended drug trials mostly involved children or young adults with severe cardiac conditions, such as pediatric pulmonary arterial hypertension in studies testing pulmonary vasodilator therapy (selexipag, macitentan), pediatric heart failure (sacubitrilvalsartan), or univentricular hearts (macitentan). Interestingly, the centers where the drug trials were totally suspended were also those where no patient had been enrolled before the pandemic. Moreover, the decision to suspend the drug trials came from the PI and not from the sponsor. As a result, for the same study, some centers allowed on-site study monitoring, while others completely suspended it ( Table 2) . Ethical problems were not identified as the major reason for study suspension. However, it was discussed in all suspended academic studies (n=5) by the PIs who feared that CHD patients could be at risk for severe forms of COVID-19. Therefore, they expressed that patient visits at the hospital for academic research in this context may not be ethical in this population. For instance, in the SOPHROCARE-RCT, all group sessions of sophrology were cancelled, as the PIs considered it unethical to have a group of adolescents and young adult in relaxation therapy in the same room in the hospital. Nevertheless, health authorities never asked for those studies to be halted. Nearly half of the studies (i.e., 16 out of 34 study questionnaires) were declared as nonsuspended ( Table 3) . Among them, we identified, in order of frequency, nine drug trials, three rehabilitation trials, and three noninterventional studies, which were national CHD registries, and one RCT on patient therapeutic education. In many cases, some studies have been continued, but new patient enrolments were stopped during the pandemic period (n=10; 62%), mainly because all physicians had suspended routine clinical outpatient follow-up to focus on cardiac and COVID-19-related emergencies. Nevertheless, all patients enrolled before the pandemic were able to undergo the follow-up as defined by the study protocol (n=15; 94%), at the cost of a protocol adaptation involving telemedicine (n=6), consultation in a hospital "COVID-19-free" area (n=4), or both (n=2). Despite the fact some studies could continue, significant logistical problems were reported (n=10; 63%), and most PIs and CRAs declared having drafted new organizational set-ups or processes to enable study continuation. Thus, many centers reported significant issues in organizing follow-up visits involving blood sampling, as in all drug trials from the survey (edoxaban, sacubitrilvalsartan, macitentan, selexipag). Therefore, with the sponsor's authorization, blood samples were sent to a local laboratory for analysis instead of to the central laboratory. For enrolled participants with the most severe cardiac conditions, such as in children with pulmonary arterial hypertension (macitentan, selexipag), a nurse was sent to the patient's home to take the blood sample and the tube was sent to the local laboratory. Another main issue in drug trials was about treatment delivery. All sponsors but one had the treatment delivered directly to the patient's home. In the study continuation group, the main adaptation during the protocol relied on telemedicine, which was considered by most PIs and CRAs as the major reason why study suspension did not occur. In many drug trials, most visits required by the research protocol were organized through teleconsultation, using medical websites approved by health authorities (Qare™, Doctolib™, Teleo™), or nonmedical videoconference software (Teams™, WhatsApp™, StarLeaf™, Whereby™, Zoom™). CRAs indicated they had to reach enrolled participants or their parents/legal guardians by telephone more frequently than usual, in order to organize drug delivery, blood samples, and teleconsultations with PIs. In the QUALIREHAB trial, an RCT evaluating the impact of a 12-week center-and home-based cardiac rehabilitation program in children and young adults with CHD, 54 participants were enrolled in the study when the outbreak was declared, of whom 26 were randomized in the intervention group. The coordinating center of the QUALI-REHAB trial managed to transform the center-based sessions into a full "web-workshop" including all sections of the program: medical follow-up with the PI using teleconsultation, patient education with a specialist nurse using teleconsultation, and interval training bicycle exercise sessions supervised by a physical education teacher, using a videoconference software. As a result, all patients enrolled in the intervention group (i.e., cardiac rehabilitation) from all participating centers in France were able to follow the intervention. Interestingly, no patient or parent/legal guardian expressed the wish to withdraw from any clinical trial. Moreover, CRAs reported that patients were reassured to have regular contact with the research center, which in all cases was also their referral tertiary care center. Interestingly, no ethical or legal issues with health authorities were reported in the study continuation group. Some investigators stated they had informed their IRB that they needed to modify the initial protocol (use of telemedicine) or to have a patient come to the hospital for study follow-up, despite containment instructions. Fortunately, the response of the health authorities was described as prompt and facilitating. Furthermore, when the investigator was also the referring doctor, all patients enrolled in a nonsuspended trial were satisfied with having a medical follow-up during the COVID-19 outbreak, whether as part of research or not. All research centers that participated in this study had to both face a health crisis of unprecedented magnitude, as all of them were also major tertiary care regional hospitals, and at the same time make quick decisions regarding clinical trials taking place at the time of the outbreak. [28] . Interestingly, in 1905 telemedicine took its first step in cardiology with Einthoven's telecardiogram [29] . The near future could bring medical follow-up and monitoring with free smart-phone application. Nevertheless, we must remain cautious, as this kind of technology may represent a threat for patient safety and data privacy. Such difficulties should eventually be overcome, and preliminary research on telemedicine prior to the epidemic will probably lead to further studies providing a higher level of evidence [30] . This study was based on a self-report survey web-questionnaire from a sample of the five most active research CHD centers in France (two out of four national referral centers, and three out of 21 regional referral centers), which therefore may not reflect the overall network of the national CHD centers. Unfortunately, we did not collect the enrolled patient's point of view, in any form of quantitative or qualitative analysis. The absence of patient withdrawal of consent observed in this study may reflect some degree of patient satisfaction of continuing the study; however, interviewing patients and their family would have been of great interest. The COVID-19 pandemic triggered an unprecedented crisis affecting modern society at every level. Interestingly, clinical research in this sample of pediatric and congenital cardiology studies was not as detrimentally impacted as we might have expected during the COVID-19 pandemic. Indeed, upon the PI's decision, and with facilitating support from health authorities, many studies were not suspended and research protocols were adapted, largely thanks to telemedicine, which in some cases even improved the course of the study (i.e., better retention and follow-up rates). 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