Table 1

Strengths and limitations of RCTs and meta-analyses for pandemic research

‘Quality’ features of RCTs and meta-analyses of RCTs	Reason why these designs are sometimes problematic in a pandemic
Randomisation, if successful, will ensure that comparisons between exposed and unexposed groups are fair—that is, that groups are effectively identical in all respects except for their exposure to the drug, vaccine or public health intervention in question. Clinical equipoise and informed consent helps ensure that a trial is ethical. Factorial, pick-the-winner, ring vaccination and other advanced RCT designs could potentially add helpful information about complexity and speed the generation of knowledge in a crisis. Meta-analysis allows objective and systematic assessment of individual trials and appropriate weighting by risk of bias. ‘Living’ systematic reviews can provide timely summaries of RCT evidence, as occurred with drugs and vaccines.	Because communicable diseases (by definition) spread through communities, it may be impossible to ensure that cross-contamination of arms does not occur. Even rapid RCTs take time to plan and execute; in most cases even a rapidly conducted RCT will generate less timely information than real-time analysis of observational data already in hand. It may be impossible to power trials adequately to evaluate the full range of interactions of interest. It may be unethical to avoidably expose study participants to a virulent pathogen RCTs are not the preferred study design for questions of aetiology (eg, ‘how does the SARS-CoV-2 virus spread?’) Meta-analysis involves subjective judgments by the reviewer about how rigorously an effect was measured and how well context and confounders were taken into account in primary studies. If the individual RCTs in a meta-analysis include unfair comparisons, or if their findings are incorrectly combined, flawed summaries, false reassurance and inappropriate policy could result.

‘Quality’ features of RCTs and meta-analyses of RCTs

Reason why these designs are sometimes problematic in a pandemic

Randomisation, if successful, will ensure that comparisons between exposed and unexposed groups are fair—that is, that groups are effectively identical in all respects except for their exposure to the drug, vaccine or public health intervention in question.
Clinical equipoise and informed consent helps ensure that a trial is ethical.
Factorial, pick-the-winner, ring vaccination and other advanced RCT designs could potentially add helpful information about complexity and speed the generation of knowledge in a crisis.
Meta-analysis allows objective and systematic assessment of individual trials and appropriate weighting by risk of bias.
‘Living’ systematic reviews can provide timely summaries of RCT evidence, as occurred with drugs and vaccines.

Because communicable diseases (by definition) spread through communities, it may be impossible to ensure that cross-contamination of arms does not occur.
Even rapid RCTs take time to plan and execute; in most cases even a rapidly conducted RCT will generate less timely information than real-time analysis of observational data already in hand.
It may be impossible to power trials adequately to evaluate the full range of interactions of interest.
It may be unethical to avoidably expose study participants to a virulent pathogen
RCTs are not the preferred study design for questions of aetiology (eg, ‘how does the SARS-CoV-2 virus spread?’)
Meta-analysis involves subjective judgments by the reviewer about how rigorously an effect was measured and how well context and confounders were taken into account in primary studies.
If the individual RCTs in a meta-analysis include unfair comparisons, or if their findings are incorrectly combined, flawed summaries, false reassurance and inappropriate policy could result.

RCTs, randomised controlled trials.