Of the completed clinical trials for existing drugs that may be repurposed for COVID-19, 40.4% did not report results on either ClinicalTrials.gov or through academic publication (Table 2). This shows a large gap in the evidence base potentially regarding the adverse effects of these drugs, limiting attempts to comprehensively review their safety before potential global distribution for the COVID-19 pandemic. The 2238 (59.6%) completed studies with available results were comprised of 1172 (31.2%) with results on the registry and 1066 (28.4%) without results on the registry, but with results from a standardised search of the literature (Table 2). Furthermore, 2379 (63.4%) studies without registry results were outside of the 395 day timeframe for results publication as mandated by the FDAAA 2007 (10), although 1008 (26.9%) of these had results published in academic literature, they still failed to upload their results on ClinicalTrials.gov. Not all trials include in this study are covered by the FDAAA 2007, but the twelve month deadline remains an important benchmark for good scientific practice (26). With 40.4% of clinical trial results unavailable for potential COVID-19 treatments, the data for clinical decision making regarding the safety of these therapeutics are limited. If any drug with an incomplete evidence base is used during the pandemic, even in compassionate use programmes, there is a risk of avoidable harm being done because of missing adverse safety data. An evidence gap was revealed for drugs which have had extensive media coverage such as hydroxychloroquine (37.0% without results), favipiravir (77.8%) and lopinavir (40.5%) (28–30). These drugs are currently being used in COVID-19 patients and clinical trials across the globe, sometimes in novel regimens and doses (7, 31, 32). Clinicians currently have few treatment options available, but with greater transparency and proactiveness from trial sponsors regarding the posting of results, there would be less risk of unforeseen adverse outcomes, especially in the treatment of mild-moderate COVID-19 as in the PIONEER trial (31).
It is recognised that there are sources of safety data outside of clinical trial registries, for example pharmacovigilance registers, however these databases are not always free to access and publicly available. In contrast with clinical trial registries, there is often no obligation for all adverse events to be reported by trial sponsors. Public health decision-makers, guideline developers, clinicians, and patients therefore rely on clinical trial registries, systematic reviews, and meta-analyses to inform treatment decisions. Evidence gaps and publication bias therefore have the potential to influence clinical practice and drug usage worldwide, particularly in a treatment landscape as changeable as the COVID-19 pandemic. If clinical decisions are based on incomplete evidence, this can result in avoidable morbidity and mortality, especially if unsafe drugs or ineffective treatments are given on a large scale. Sponsors and researchers alike carry an ethical responsibility towards clinical trial participants, who consent to participate in research in order to contribute to scientific understanding and improved clinical practice, to make results publicly available (33).
Our study reveals an important evidence gap regarding existing pharmaceuticals potentially being repurposed for COVID-19. However, the proportion of studies with results available in the academic literature is an approximation and there are several limitations to our study. Firstly, our trial population was limited only to those registered on ClinicalTrials.gov. While ClinicalTrials.gov is the largest registry in the world, with over 340,000 registrations as of writing and an order of magnitude greater than the next largest journal, additional trials on these therapies may have been registered elsewhere. However, it is unlikely that these would be expected to report at a different rate than those registered to ClinicalTrials.gov. Secondly, our strategy for locating publications included only those listed on ClinicalTrials.gov and identified through searches on PubMed and Google Scholar, which are open-access resources that should cover a majority of published clinical research. While including proprietary databases like Scopus or Ovid may have located some additional publications, we do not believe this would have substantially impacted our overall results (34). Thirdly, we are aware that trials that were not registered at all or published in non-English language journals without inclusion of the NCT number would not have been captured by our methodology. Finally, searcher heterogeneity and difficulty identifying results publication in the academic literature limits accuracy in any manual publication search, however, our search strategy was standardised and produced a high level of agreement between assessors (83.6%) in a check of a 10% random sample. However, any discordance between reviewers only reveals the inherent difficulties in finding results for the drugs in question, especially if the trial identification number was not included in line with CONSORT standards (35).
Our findings add to the existing evidence of the dearth of clinical trial reporting on public registries. This analysis investigated clinical trials of existing drugs currently being considered for use for COVID-19. However, given the diversity of drug classes included in this report, findings are likely to be representative of many pharmaceuticals. This presents a major problem for researchers attempting to summarise safety and efficacy by pooling trial data (36). Since academic publications often summarise key findings only, secondary research efforts are impinged by the incomplete publishing of all trial outcomes. ClinicalTrials.gov, in contrast, provides a forum to share complete safety and efficacy data reports, as well as facilitating consistent data reporting in a timely manner (14, 15). Prior research has shown that results reported to ClincialTrials.gov were often more complete, especially for safety data, when compared to matched journal publications (16–18). However, the availability of this data depends on researchers registering trials and uploading results in a timely manner, within twelve months of the primary completion date.
The International Committee of Medical Journal Editors (ICMJE) and the editorial offices of medical journals could play an important role in improving the lack of timely results posting on clinical trial registries by demanding submission of a link to summary results on public registries before academic publication, although this may mean that the publication bias of positive, ‘publishable’ results may trickle down to reporting on public registries as well. Furthermore, public funders and institutional publication funds could demand that trial sponsors post their results before allocating funding for academic (open-access) publication. These funding bodies could also deny individual sponsors funding if they have in the past violated clinical trial reporting rules (37). At the very least, journals should conform to the CONSORT statement in ensuring that registry identification numbers are clearly indicated in the abstract, full-text, and meta-data of published clinical trials in order promote discoverability and record linkage between registries and publications (35). Finally, clinical trial sponsors, such as universities, hospitals, public research institutions, and pharmaceutical companies, should themselves work towards improving their institutional clinical trial reporting performance by making use of available resources that provide detailed step-by-step instructions as to how to go about this task (11). Especially during the COVID-19 pandemic, it is of great importance that trials sponsors release summary results on these registries retrospectively to inform decision making around existing treatments being re-purposed for COVID-19.