[Correspondence] WHO COVID-19 therapeutic guidelines

In response to Nicholas White and colleagues,White NJ Strub-Wourgaft N Faiz A Guerin PJ Guidelines should not pool evidence from uncomplicated and severe COVID-19. we offer these clarifications. WHO guideline development methods are prespecified,WHO
Therapeutics and COVID-19: living guideline. 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).WHO
COVID-19 clinical management: living guidance. 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,Schandelmaier S Briel M Varadhan R et al.Development of the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-analyses. 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 therapeuticsWHO
Therapeutics and COVID-19: living guideline. and prophylactic drugs,WHO
WHO living guideline: drugs to prevent COVID-19. 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.Figure thumbnail fx1

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.

References1.White NJ Strub-Wourgaft N Faiz A Guerin PJ

Guidelines should not pool evidence from uncomplicated and severe COVID-19.

Lancet. 397: 1262-12632.

Therapeutics and COVID-19: living guideline.

3.

COVID-19 clinical management: living guidance.

4.Schandelmaier S Briel M Varadhan R et al.

Development of the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-analyses.

CMAJ. 192: e901-e9065.

WHO living guideline: drugs to prevent COVID-19.

Article InfoPublication HistoryIdentification

DOI: https://doi.org/10.1016/S0140-6736(21)01331-3

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© 2021 World Health Organization. Published by Elsevier Ltd. All rights reserved.

ScienceDirectAccess this article on ScienceDirect Linked ArticlesGuidelines should not pool evidence from uncomplicated and severe COVID-19

The WHO Global Development Group guidelines on COVID-19 therapeutics are meant to provide evidence-based advice to all countries on the medical management of patients with COVID-19.1,2 The only small-molecule drug to show unequivocal benefit to date is dexamethasone. In the largest randomised controlled trial in patients who were admitted to hospital with COVID-19 (ie, the RECOVERY trial), dexamethasone at a low dose reduced mortality in the prospectively defined subgroups of patients requiring medical oxygen (rate ratio 0·82 [95% CI 0·72–0·94]) or being ventilated (0·64 [0·51–0·81]) but not in patients not receiving respiratory support at randomisation (1·19 [0·91–1·55]).

Full-Text PDF WHO COVID-19 therapeutic guidelines – Authors' reply

We thank Bram Rochwerg and colleagues for information on the WHO therapeutic guideline development process. Unfortunately, they do not address our main concern: the unjustified extrapolation of evidence from randomised controlled trials in severe COVID-19 to therapeutic guidelines for uncomplicated illness.1 Pooling summary data from studies with different severity definitions, deciding on inappropriate primary outcomes, and extrapolating from results in hospitalised patients to ambulant individuals with mild infections suggests a worrying lack of clinical judgement.

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