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.1White NJ Strub-Wourgaft N Faiz A Guerin PJ Guidelines should not pool evidence from uncomplicated and severe COVID-19.Lancet. 2021; 397: 1262-1263Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar 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.2Guérin PJ McLean ARD Rashan S et al.Definitions matter: heterogeneity of COVID-19 disease severity criteria and incomplete reporting compromise meta-analysis.medRxiv. 2021; (published online June 4.) (preprint).https://doi.org/10.1101/2021.06.04.21257852Google Scholar The recent separate guidelines on COVID-19 chemoprophylaxis,3WHOWHO living guideline. Drugs to prevent COVID-19.https://www.who.int/publications/i/item/WHO-2019-nCoV-prophylaxes-2021-1Date: March 2, 2021Date accessed: March 11, 2021Google Scholar which contain judgements on mortality prevention derived from trials with no mortality, have only magnified concerns about the WHO assessments.4Bartoszko JJ Siemieniuk RAC Kum E et al.Prophylaxis against covid-19: living systematic review and network meta-analysis.BMJ. 2021; 373: n949Crossref PubMed Scopus (71) Google Scholar, 5Schilling WH Callery JJ Chandna A et al.The WHO guideline on drugs to prevent COVID-19: small numbers-big conclusions [version 1; peer review: 1 approved].Wellcome Open Res. 2021; 6: 71Crossref Scopus (4) Google Scholar The world looks to WHO for guidance and leadership in these difficult times. Therapeutic guidelines should be based on an understanding of the disease process, the health needs and health-system capabilities, the clinical pharmacology of the drugs, and the quality and weight of evidence. When advising on potential treatments, evidence from randomised clinical trials with patients who have severe COVID-19 should not be extrapolated to prevention and early treatment.6Paules CI Fauci AS COVID-19: the therapeutic landscape.Med (N Y). 2021; 2: 493-497Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar Despite the undoubted equitability, impartiality, and rigour of the WHO COVID-19 therapeutic guideline process, there is something fundamentally wrong with it. We declare no competing interests. Guidelines should not pool evidence from uncomplicated and severe COVID-19The 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 guidelinesIn 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). Full-Text PDF