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SARS-CoV-2 and its associated disease COVID-19 has presented a huge global challenge. To drive our response to the virus, researchers throughout the world have conducted and published an incredible amount of research in a very short amount of time. Much of this research is with a focus on either treating or finding potential treatments for this novel disease. This has resulted in an unprecedented number of clinical trials being planned and performed at speeds previously unseen.

Even before the current pandemic the rate of data being produced and published from clinical trials has been on the rise. The results of these are vital to determine clinical practice, with this often being influenced through the use of systematic reviews. As I discussed in a previous blog, there currently is a problem with how we conduct systematic reviews. They are an invaluable resource to assess all the available evidence on a given subject, but given the time they take to conduct, they often can be out of date very quickly following publication. As the evidence base around COVID-19 expands, systematic reviews will undoubtably be crucial for assessing potential therapies, the question is how can we keep up with the evidence?

Bridging the gap

Living systematic reviews (LSR) have been proposed as a solution to both prevent systematic reviews from going out of date and to keep up with rapidly moving fields. Cochrane suggest an LSR is appropriate when one of these three criteria are met:

1. The review is of priority to decision making
2. There is an important level of uncertainty in the existing evidence
3. There is likely to be emerging evidence that will impact on the conclusions

As an emerging viral disease, COVID-19 meets all of these criteria. High quality evidence on COVID-19 is clearly a priority to decision making, particularly around treatments. There have been issues with potential treatments being assessed using retrospective observational studies rather than randomized clinical trials or trials with small study populations. An LSR will not only allow the capturing of this evidence rapidly, but a pooled review of all the data, and assessments of the quality of the evidence can be performed using tools such as GRADE.

There is clearly a high level of uncertainty around the existing evidence around COVID-19. As an emerging infectious disease our understanding is rapidly and constantly changing, meaning our evidence base can shift daily. An LSR allows the monitoring and gathering of all available evidence by constantly screening the available literature.

Finally, and related to the previous two points, emerging evidence around COVID-19 will likely change the conclusion of any stand-alone systematic review. A LSR allows previous conclusions to be constantly validated, and where necessary, updated as the literature and evidence evolves. An emerging viral disease such as COVID-19 provides a rarity, a topic where all the theoretical reasons for performing a LSR are met.

So what evidence is available?

While hundreds of clinical trials have been formulated, started recruiting and in some cases have generated results, the majority have yet to produce any data or any publications. This means the traditional source of evidence in the form of published articles is not currently available for a systematic review. So how can we assess the current state of COVID-19 clinical trials?

The International Committee of Medical Journal Editors announced in a statement in 2004 that all member journals would require that any clinical trials submitted for publication would need to have prospectively registered their trial before starting recruitment. Given this, the vast majority of clinical trials are prospectively registered with clinical trial registries. This allows for the transparent reporting of clinical trials from their initiation through to completion. Trial registries therefore provide an alternative resource to gather data on clinical trials with data, such as interventions, study populations, funders and study status. The majority of these can also be easily searched using electronic search strings as you would with a bibliometric database. Given this requirement, there has been an explosion in trials registered related to COVID-19. This not only ensures the findings can be subsequently published in ICMJE member journals, but subsequently generates a rich source of data on COVID-19 trials in the absence of published results.

Putting theory into practice

Maguire et al. in their paper ‘Baseline results of a living systematic review for COVID-19 clinical trial registrations’ have taken the LSR methodology and applied to the best source of clinical trial data. The group from the Infectious Disease Data Observatory (IDDO) have conducted a review of COVID-19 clinical trials available from the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Additionally, and similarly to our LSR on F1000Research (See Figure 2 of Counotte et al.), the authors have applied technology to innovatively display their findings using an interactive visualisation of their results. The LSR has its own dedicated page on the IDDO website that links out to an interactive tool populated with the search results created using the Exaptive platform. This ‘Cognitive City’ is fully searchable and the results can be filtered by various features such as study design, country, recruitment status etc. This is not just a useful tool to present the studies data, but a poignant visual representation of the huge clinical and research response to COVID-19.

The baseline results found there were 728 study, with 109 pharmacological interventions or advanced therapy medicinal products covering 23 drug categories. It found that the majority of the early COVID-19 studies, as might be expected, were small studies that were likely to be underpowered. The authors have also identified some key areas that, while they were unable to analyse them in baseline review given the sparsity of data, will be important going forward. These included features such as medical product quality and the affordability interventions. This highlights the advantage of an LSR, as it provides the flexibility to identify key questions and address them as the evidence becomes available over the life-course of the study.

To highlight the rapid change in the evidence base for COVID-19, since the last search was performed for this LSR there has been progress in identifying therapies for the disease. In April a study published in the Lancet presented evidence that the antiviral drug Remdesivir was found to reduce time for  clinical improvement in patients, although this was not found to be statistically significant in the study group. More recently, the UK based RECOVERY Trial published an article in the NEJM demonstrating the steroid Dexamethasome reduced mortality in ventilated patients. Given the number of trials being conducted we can expect further results will become available in the coming months; this LSR will provide an invaluable resource to capture these as we progress through the pandemic.

When the theoretical becomes practical maybe it is time for change

The work of Maguire et al. has added validation to one established and one emerging practice. While trial registrations have been around for some time, the current pandemic has further demonstrated their necessity. They provide a platform for the transparent reporting of trial protocols and results in an open format. The open availability of this data made them an ideal data source for this study. Additionally, COVID-19 has provided a situation where all of the proposed scenarios for when a LSR might be performed apply. While LSR’s has been gaining traction they are still an emerging article type, but we currently have a situation where we can see theory become a reality, as Maguire et al. has demonstrated.

And finally, we must not forget the importance of open access in the current situation and going forward. COVID-19 research has been made openly available by a variety of publishers, although in many cases this a temporary arrangement. This pandemic has demonstrated the importance having research openly available to all to facilitate its validation and reuse. This is also of vital importance to LSRs. The dataset for the majority of LSRs is the literature and performing an LSR can only be made easier by ensuring that data is openly available. Equally, LSRs results benefit from being openly available. In the majority of cases these are performed when there is vital need for additional, accurate evidence on a given topic, to generate this information and then hide it behind a pay wall would seem to defeat the very purpose of an LSR – the rapid dissemination of up-to-date information.

Maguire et al. provides a demonstration of how initiatives to improve transparency and availability of clinical research have been successfully leveraged to address an evidence gap of vital importance. It is important that we learn from such examples as we continue through and emerge out the pandemic to improve how research is performed and disseminated.