gms | German Medical Science

Background/research question: Within the early COVID-19 pandemic, the established principles of evidence-based medicine were partly overridden since immediate actions were required to fight serious disease. Many critically ill patients were treated experimentally and the authors of treatment recommendations (guidelines and consensus statements) had to deal with a great level of uncertainty due to a lack of robust data from clinical trials. To evaluate how evidence was generated, we analysed the impact of studies from different evidence levels on treatment recommendations. In particular, we focused on data from non-randomised and observational studies and how they informed hypotheses and designs of RCTs during the early COVID-19 pandemic.

Methods: Based on current and archived treatment recommendations we identified considered and established pharmaceutical treatment options for critically ill patients with COVID-19. The body of evidence for these drugs (observational and interventional trials systematically identified) was described in terms of evidence grade, design, consistency, applicability, and limitations. We analysed variables that reflect the quality of the evidence resulting in specific treatment recommendations or changes in those over time.

Of particular interest were RCTs, which were initiated relatively quickly by public authorities and national institutes. We compared results and evidence from RCT to upstream/parallel non-RCT evidence to explain how non-randomised and observational studies influenced RCTs. Reasons for a possible lack of consistency between the studies were explored in in-depth analyses of the characteristics determining the quality of evidence.

Results: We found that international guidelines evaluated the evidence of drugs of following categories for the treatment of COVID‑19: anti-viral (e.g. remdesivir, [hydroxy-]chloroquine), anti-inflammatory (e.g. corticosteroids), and anti-thrombotic (e.g. anticoagulants). The well-designed RCTs such as SOLIDARITY (WHO), RECOVERY (UK), DISCOVERY (Inserm), and ACTT (NIAID) delivered robust evidence that had great implications for clinical care. Their design and conduct were largely informed by observations made in cohort studies.

Conclusion: The simultaneous coexistence of studies of different quality and evidence levels result in complex interactions and mutual influences. It is therefore important to systematically and critically review the various sources of evidence to learn how to deal with limited time and resources in future pandemics.

Competing interests:

Stefanie Wüstner und Sara Hogger:

Angestellt bei AMS Advanced Medical Services GmbH, die Aufträge von diversen pharmazeutischen Unternehmen erhält.

Friedhelm Leverkus:

Angestellt bei Pfizer Deutschland GmbH