key: cord-276092-4e4muqnu
authors: Dal-Re, Rafael; Mahillo-Fernández, Ignacio
title: Waste in COVID-19 clinical trials conducted in western Europe
date: 2020-07-07
journal: Eur J Intern Med
DOI: 10.1016/j.ejim.2020.07.002
sha: 
doc_id: 276092
cord_uid: 4e4muqnu

nan

both the scientific and ethical perspectives [2] . The quality of a trial relates to the design, conduct, analysis and reporting. The design is the only aspect that can be appraised in ongoing trials from the information reported in trial registries. Although the design can only provide a partial view of the trial's quality, it is relevant to assess the main design characteristics since illdesign trials will provide very limited useful information.

A cross-sectional analysis was carried out based on a series of searches conducted on May 20-21, 2020 looking for non-industry-sponsored, ongoing trials, aiming to assess medicines or convalescent plasma for the treatment of COVID-19 patients, in the 5 largest European countries and 2 regions (Benelux, Scandinavia). The searches were conducted on five registries (ClinicalTrials.gov, DKRS, EU-CTR, ISRCTN and NTR) with the terms 'coronavirus', 'covid' and 'covid-19'. So, three searches were conducted per registry and for each country. 'Country':

Belgium, Denmark, Finland, France, Germany, Italy, Luxembourg, Netherlands, Norway, Spain, Sweden, and the UK. On the searches on ClinicalTrials.gov, the following descriptors were also used: Study type: 'Interventional studies (clinical trials)'; Status: recruitments: 'Not yet recruiting', 'recruiting' and 'active: not recruiting'; Funder type: 'NIH', 'Other US Federal Agency' and 'All others (individuals, universities, organizations)'. Trials on special populations (e.g. cancer, diabetes patients, pregnancy, healthy volunteers, healthcare workers), or with special objectives (e.g. pharmacokinetics) or assessing prophylactic medicines (both pre-and post-exposure) or both prophylaxis and treatment, or assessing vaccines, or dietary supplements (eg, vitamins), or herbal preparations (eg Aesculus hippocastanum) were excluded. All phase 1 or phase 1/2 trials were excluded. Convalescent plasma and ozone trials were included.

The following information was extracted from each trial: single-arm or randomized controlled trial (RCT), blinding, and planned sample size; whether the trial was multicenter, had a control (standard of care) arm and a Data Monitoring Committee. All these features are associated, in principle, with robust designs. Randomization and blinding prevent selection, performance and detection bias. Large sample sizes help to eliminate known and unknown confounders. Singlecenter trials tend to provide larger intervention effects than multicenter RCTs. Being COVID-19 a life-threatening disease, DMC should be present in multicenter RCTs [3] . Since there are no approved drugs, all trials should have a Standard of Care (SoC) group.

Fisher's exact test was used for comparisons. A p<0.05 was considered significant (two-sided test).

There were 159 different trials, 141 (89%) RCTs and 18 single-arm trials. The findings (Table 1) showed that Italy was conducting 44% of all single-arm trials run in Europe and accounted for 38% of all trials conducted in Italy. France and Spain carried out between 3 and 5 times the number of RCTs run in the other countries/regions. The majority of RCTs conducted in Germany (63%) were masked, but only some 25% of those conducted in Benelux, France, Italy, Spain and the UK. Eighty-six percent of RCTs run in Scandinavia were multicenter, but only 54% of those carried out in Spain. No standard of care arm was only present in RCTs conducted in France, Italy and Spain (p=0.015). Data Monitoring Committee was differently present across multicenter RCTs in all countries/regions (p=0.019). There were few large trials ( Table 2) . Of special interest were SOLIDARITY, the World Health Organization-sponsored RCT, that was being conducted in five of the countries included in this study, and RECOVERY, the largest trial conducted in only one country (the UK) aiming to recruit 12,000 participants. Forty-two percent of all trials ─single-arm trials, RCTs recruiting ≤50 participants/arm and those with no standard of care arm─ were poorly designed.

This study shows that low-quality clinical trials were being conducted in all analyzed European countries/regions, which are among the territories of the world with the best clinical research.

Mediterranean countries (France, Italy and Spain) had higher number of single-arm and significantly more RCTs without standard of care arm than that of the rest of countries/regions, which resulted in a seemingly trend to higher percentage of low-quality trials than in central/northern Europe. Single-arm trials accounted for a similar percentage in this analysis (11%) and in a study that included 201 trials registered in any continent (14%) [4] .

Limited useful information should be expected from single-arm trials, RCTs recruiting ≤50 participants/arm and those with no standard of care arm. Some of these, however, could provide hypothesis-generating findings ─rather than hypothesis-supporting results─, that should be confirm in future adequate RCTs.

Since it should be expected that the absolute reduction on mortality should be limited [5] , many trials recruiting even hundreds of participants will end up with neutral/negative results.

Yet, some trials could show positive results, but this will likely happen in non-critical (but important) endpoints ─as occurred in an RCT with >500 participants/arm that found a shorter time to recovery with remdesivir compared with placebo, although non-significant difference was observed on mortality [6] . When reaching larger number of participants (>1500/arm), the benefit on mortality could be appropriately assessed as has been shown in the RECOVERY trial: dexamethasone has proven to be beneficial [7] whereas hydroxychloroquine did not [8] .

The main limitation of this study is that all the information has been captured from trial registries that are not always updated. So, for example, after recruiting 1059 participants the ACTT trial was early terminated [6] , soon before the searches on trial registries of this analysis were conducted, but it appeared on the registries as 'recruiting' (ClinicalTrials.gov) and 'ongoing' (EU-CTR), with a planned sample size of 800 participants. Also, the fact that EU-CTR is the only registry reporting on the presence of the RCT's Data Monitoring Committee limits its usefulness as a factor of robust design, since it was not available from trials that were only registered in other registries. However, it should be highlighted that it is rather surprising why some trials carried out in all the countries/regions included in this study seemed not to be registered on the EudraCT database (from which the EU-CTR obtains all the information), something that should be expected from all trials conducted with medicines in Europe. Since convalescent plasma is not a medicinal product and ozone could also be considered as such, trials assessing only these interventions could reasonably not be on EU-CTR; this, however, cannot be applied to other trials conducted with medicines that were being assessed on the treatment of COVID-19 patients (see Supplementary material).

So as not to waste the generosity from trial participants and the effort from investigators of all these trials, de-identified individual participant clinical trial data should be forwarded to two teams that are conducting living systematic reviews with network meta-analysis [9,10], that could report their results in a short period of time. This will be of invaluable benefit to clinicians and future patients. 

Waste in covid-19 research

Against pandemic research exceptionalism

Characteristics of registered clinical trials assessing treatments for COVID-19: a cross-sectional analysis

Randomized clinical trials and COVID-19. Managing expectations

Remdesivir for the Treatment of Covid-19 -Preliminary Report

2 different dosages

N: planned sample size

Trial conducted in other countries in addition to the ones considered in this analysis; (b) This trial is also run in Finland and Norway but with different number of arms (n=3), and thus with different ID