Missing clinical trial data: the evidence gap in primary data for potential COVID-19 drugs

Abstract

Background Several drugs are being repurposed for the treatment of the coronavirus disease 2019 (COVID-19) pandemic based on in vitro or early clinical findings. As these drugs are being used in varied regimens and dosages, it is important to enable synthesis of existing safety data from clinical trials. However, availability of safety information is limited by a lack of timely reporting of overall clinical trial results on public registries or through academic publication. We aimed to analyse the evidence gap in this data by conducting a rapid review of results posting on ClinicalTrials.gov and in academic publications to quantify the number of trials missing results for drugs potentially being repurposed for COVID-19. Methods ClinicalTrials.gov was searched for 19 drugs that have been identified as potential treatments for COVID-19. Relevant clinical trials for any prior indication were listed by identifier (NCT number) and checked for results and for timely result reporting (within 395 days of the primary completion date). Additionally, PubMed and Google Scholar were searched to identify publications of results not listed on the registry. A second, blinded search of 10% of trials was conducted to assess reviewer concordance. Results Of 3754 completed trials, 1516 (40.4%) did not post results on ClinicalTrials.gov or in the academic literature. Tabular results were available on ClinicalTrials.gov for 1172 (31.2%) completed trials. A further 1066 (28.4%) had published results in the academic literature, but did not report results on ClinicalTrials.gov. Key drugs missing clinical trial results include hydroxychloroquine (37.0% completed trials unreported), favipiravir (77.8%) and lopinavir (40.5%). Conclusions There is an important evidence gap for the safety of drugs being repurposed for COVID-19. This uncertainty could cause unnecessary additional morbidity and mortality during the pandemic. We recommend caution in experimental drug use for non-severe disease and urge clinical trial sponsors to report missing results retrospectively.

Challenges and Lessons Learned From COVID-19 Trials: Should We Be Doing Clinical Trials Differently?

“…Therefore, the vast majority of RCTs focused on testing the repurposing of already existing drugs that had been already approved or had been under investigation for other indications( 17 ) ( Table 1 ). This is based on the assumptions that there is substantial evidence on the efficacy and safety of these drugs ( 18 ). However, a review focusing on the reporting of clinical results for 19 potential COVID-19 drugs showed that 40% of the completed trials assessing those drugs, prior to the pandemic, did not report their results on ClinicalTrials.gov or in the scientific literature ( 18 ).…”

“…This is based on the assumptions that there is substantial evidence on the efficacy and safety of these drugs ( 18 ). However, a review focusing on the reporting of clinical results for 19 potential COVID-19 drugs showed that 40% of the completed trials assessing those drugs, prior to the pandemic, did not report their results on ClinicalTrials.gov or in the scientific literature ( 18 ). For hydroxychloroquine, 37% of the trials were unreported.…”

COVID‐19 vaccines and treatments: When speed is necessary and not enough

“…In particular, the duplication of effort has plagued COVID‐19 efforts, especially clinical trials; with, for example, 343 reported clinical trials of hydroxychloroquine as of the end of November 2020 3 . Moreover, across a range of drugs, many of the trials have been too small or poorly designed to answer rigorous questions—with too few being blinded, randomized, controlled trials—and a large proportion of the completed trials have not reported on ClinicalTrials.gov or in the academic literature (1516 of 3754 completed trials, 40.4%) 4 . The large number of vaccine candidates in clinical development is extraordinary, and although some of those multiple efforts are undoubtedly important to ensure success—and reflect an understandable urge to respond quickly to the pandemic—competitive forces have probably driven this number too high, resulting in a potential waste of effort and resources.…”

Lessons Learned from Cutting-Edge Immunoinformatics on Next-Generation COVID-19 Vaccine Research

“…A report shows that 3754 clinical trials had been completed for COVID-19. It has been noted that some of these clinical trial results had not been updated in trial repositories (Rodgers et al 2021). Quite a few therapeutics have given better results in clinical trials for severe COVID-19 patients Chiranjib Chakraborty and Ashish Ranjan Sharma contributed equally to this work.…”