Analysis of clinical and methodological characteristics of early COVID-19 treatment clinical trials: so much work, so many lost opportunities

Abstract

Background The COVID-19 pandemic continues to rage on, and clinical research has been promoted worldwide. We aimed to assess the clinical and methodological characteristics of treatment clinical trials that have been set forth as an early response to the COVID-19 pandemic. Methods First, we reviewed all registered clinical trials on COVID-19. The World Health Organization International Trials Registry Platform and national trial registries were searched for COVID-19 trials through April 19th, 2020. For each record, independent researchers extracted interventions, participants, and methodological characteristics. Second, on September 14th, 2020 we evaluated the recruitment status and availability of the results of COVID-19 treatment trials previously identified. Results In April 2020, a total of 580 trials evaluating COVID-19 treatment were registered. Reporting quality was poor (core participant information was missing in 24.1 to 92.7%). Between 54.0 and 93.8% of the trials did not plan to include older people or those with a higher baseline risk. Most studies were randomised (67.9%), single-centre (58.3%), non-industry-funded (81.1%), to be conducted in China (47.6%), with a median duration of 184 days and a median sample size of 100 participants. Core endpoints (mortality, clinical status, and hospitalization length) were planned to be assessed in 5.2 to 13.1% of the trials. Five months later, 66 trials (11.4%) were reported as “Completed”, and only 46 (7.9%) had public results available. One hundred forty-four of 580 trials (24.8%) either had the status “Not yet recruiting” or “Suspended”, and 18 (3.1%) trials were prematurely stopped (“Terminated” or “Withdrawn”) The number of completed trials and trials with results are much lower than anticipated, considering the planned follow-up. Conclusions Our results raise concerns about the success of the initial global research effort on COVID-19 treatment. The clinical and methodological characteristics of early COVID-19 treatment trials limit their capability to produce clear answers to critical questions in the shortest possible time.

Clinical Evidence Informing Treatment Guidelines on Repurposed Drugs for Hospitalized Patients During the Early COVID-19 Pandemic: Corticosteroids, Anticoagulants, (Hydroxy)chloroquine

“…Unmeasured confounders and residual confounding may lead to incorrect conclusions (85). Further points of criticism comprise poor quality of study reporting according to the guidelines of reporting observational studies [STROBE; (86)], or failure to include key clinical endpoints such as mortality or hospitalization duration as primary endpoints (87). Only large cohort studies using advanced methods to control for confounding were considered by experts and informed treatment guidelines (68,80).…”

Randomized controlled trials in patients with COVID-19: a systematic review and critical appraisal

“…High-quality evidence is always important, particularly in the context of a pandemic ( Raynaud et al, 2021 ). Evidence is emerging that many COVID-19 trials are of poor quality: reviews of registered COVID-19 trials (as opposed to fully published studies) have revealed that many are not blinded and have many other features associated with poor quality ( Jung et al, 2021 ;Karlsen et al, 2020 ;Mainoli et al, 2021 ;Mehta et al, 2020 ;Pundi et al, 2020 ;Zhu et al, 2020 ). Additionally, there is evidence that many studies of traditional Chinese medicine for COVID-19 are also at risk of bias Gao et al, 2021 ), and where risk of bias has been investigated in the context of specific treatments (e.g., hydroxychloroquine), concerns have been raised of the lack of high-quality studies ( Mazhar et al, 2020 ).…”

Methodological and ethical aspects of research on COVID-19

“…Сама отчетность зачастую скудна, выводы исследований и клинических испытаний, которые важны для пациентов и ЛПУ, не раскрыты. Например, 61,4% протоколов исследований не сообщили, были ли включены в исследование пациенты с риском смерти -они не были приоритетными в клинических испытаниях, среди которых лишь 11,4% завершились (на 19.04.2020) [5]. Как известно, чем меньше размер выборки, тем выше риск не обнаружить побочные эффекты, которые, несмотря на незначительную частоту, играют огромную роль в изучении фармакодинамики препаратов.…”