WHO COVID-19 therapeutic guidelines

In response to Nicholas White and colleagues,¹ we offer these clarifications. WHO guideline development methods are prespecified,² abiding by principles for producing trustworthy guidelines. The WHO COVID-19 Therapeutics Guideline Development Group (GDG) is composed of external experts, with geographical representation and gender balance, including COVID-19 survivors, ethicists, and methodologists who are vetted for potential conflicts of interest. The GDG prioritises outcomes and identifies subgroups to be considered for each recommendation, always including age and disease severity (using WHO COVID-19 definitions of non-severe, severe, and critical).³ As WHO guidelines need to be globally applicable, the GDG deliberately used these disease severity classifications, based on clinical indicators, to assess subgroup effects rather than stage of disease (viral and inflammatory phases). The GDG avoided using access to health care (inpatient or outpatient) to define patient subgroups because who is admitted to hospital, when, and how can differ substantially across jurisdictions.

The meta-analysis team did a network meta-regression based on the prespecified subgroup variables, focusing on within-trial rather than between-trial comparisons. The GDG assessed the credibility of results from the subgroup analyses using the Instrument to assess the Credibility of Effect Modification Analyses tool,⁴ which uses structured questions to derive an overall credibility rating. Regarding hydroxychloroquine treatment for COVID-19: after assessing results, the GDG concluded there was no credible subgroup effect for disease severity and thus issued a strong recommendation against hydroxychloroquine that applied across severities. Finally, WHO has issued separate guidelines for therapeutics² and prophylactic drugs,⁵ with separate analyses for these indications, thus never pooling efficacy estimates for drugs used to treat COVID-19 with estimates of effects to prevent the disease.

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BR was the methods chair of the WHO COVID-19 Therapeutics GDG that assessed hydroxychloroquine treatment. TA is a board member of the MAGIC Evidence Ecosystem Foundation, a not-for-profit organisation that provides methodological support to the GDG. JD is the network lead, WHO Health Emergencies chair, and is part of the WHO COVID-19 Therapeutics Steering Committee. LA is a member of the WHO COVID-19 Therapeutics Steering Committee and a scientist and methods lead in the WHO Department of Quality Assurance of Norms and Standards.