RCT vs. observational studies for COVID-19

For COVID-19, across the 211 treatments we analyze, there is no difference in results between RCTs and observational studies, RR 0.98 [0.92‑1.04]. Restricting to, or waiting for, RCTs provided no benefit.
Observational studies for COVID-19 do not systematically overestimate or underestimate efficacy when compared with RCTs, as found in previous research1,2, and they provided confirmation of efficacy 8+ months faster3.
RCTs aim to equalize study groups, but add their own biases. For acute diseases with strong benefits for earlier treatment, the typical increased treatment delay adds a major confounding factor. Both RCTs and observational studies span the bias spectrum, from minimal to extreme. Studies must be evaluated individually. While obsevational studies require greater expertise to analyze, the advantages in practicality, cost, time, and ethics are substantial.
0 0.5 1 1.5 2 Low-cost 0.99 [0.91-1.08] RR CI High-profit 0.93 [0.84-1.02] All treatments 0.98 [0.92-1.04] COVID-19 RCT vs. observationalresults from 6,000+ studies c19early.org November 2025 RCTs showhigher efficacy RCTs showlower efficacy
Treatment Total Test for overall effect: z = -0.67 ( P = .51 ) Test for subgroup differences: χ 1 2 = 0.94 ( P = .33 ) Low-cost treatments High-cost treatments Total Total Test for overall effect: z = -0.23 ( P = .82 ) Test for overall effect: z = -1.50 ( P = .13 ) Acetaminophen Alkalinization Andrographolide Antiandrogen Antihistamine H1RA Artemisinin Aspirin Azvudine Budesonide Camostat Cannabidiol Chlorhexidine Chlorpheniramine Colchicine Curcumin Dexamethasone Famotidine Favipiravir Fluvoxamine Hydrogen Peroxide Hydroxychloroquine Ibuprofen Indomethacin Ivermectin Lactoferrin Lopinavir/ritonavir Mebendazole Melatonin Metformin Montelukast N-acetylcysteine NaCl Nafamostat Nigella Sativa Nitazoxanide Nitric Oxide Phthalocyanine Povidone-Iodine Probiotics Quercetin Resveratrol Selenium Sodium Bicarbonate Spironolactone Sunlight Thermotherapy Vitamin A Vitamin B12 Vitamin B9 Vitamin C Vitamin D Vitamin K Zinc Amubarvimab/romlusevimab Bamlanivimab/etesevimab Bebtelovimab Casirivimab/imdevimab Convalescent Plasma Deuremidevir Ensitrelvir Molnupiravir Paxlovid Regdanvimab Remdesivir SA58 Sotrovimab Tixagevimab/cilgavimab Tocilizumab RR (95% CI) 0.98 [0.92; 1.04] 0.99 [0.91; 1.08] 0.93 [0.84; 1.02] 1.19 [0.84; 1.68] 1.33 [0.72; 2.45] 0.58 [0.28; 1.21] 0.52 [0.30; 0.89] 0.84 [0.32; 2.19] 0.77 [0.26; 2.28] 1.03 [0.90; 1.18] 0.85 [0.50; 1.46] 0.92 [0.46; 1.84] 1.72 [0.56; 5.30] 0.59 [0.04; 9.06] 0.55 [0.27; 1.12] 0.82 [0.40; 1.68] 1.26 [0.88; 1.80] 0.88 [0.56; 1.38] 0.77 [0.44; 1.35] 0.86 [0.60; 1.24] 0.93 [0.71; 1.22] 1.16 [0.57; 2.36] 0.69 [0.11; 4.28] 1.13 [0.92; 1.37] 0.47 [0.22; 1.03] 6.86 [0.62; 76.31] 1.39 [0.84; 2.31] 2.32 [1.05; 5.13] 0.92 [0.63; 1.33] 0.31 [0.02; 4.88] 1.48 [0.87; 2.53] 0.84 [0.50; 1.40] 1.10 [0.33; 3.60] 0.96 [0.61; 1.50] 0.98 [0.54; 1.78] 0.69 [0.14; 3.47] 0.98 [0.44; 2.21] 5.84 [2.07; 16.52] 0.72 [0.32; 1.59] 1.35 [0.41; 4.30] 0.93 [0.56; 1.54] 0.92 [0.66; 1.29] 10.71 [0.46; 250.39] 0.99 [0.10; 11.72] 1.01 [0.07; 14.61] 2.37 [0.90; 6.22] 0.80 [0.31; 2.04] 1.15 [0.62; 2.14] 0.93 [0.19; 4.55] 0.84 [0.35; 2.01] 0.35 [0.03; 3.83] 0.10 [0.03; 0.39] 1.02 [0.81; 1.28] 1.11 [0.86; 1.42] 3.49 [0.13; 93.95] 0.83 [0.54; 1.28] 0.42 [0.01; 15.37] 1.30 [0.43; 3.97] 2.69 [0.31; 23.17] 0.79 [0.33; 1.90] 0.85 [0.72; 1.02] 0.37 [0.01; 10.38] 0.68 [0.35; 1.32] 0.84 [0.59; 1.21] 1.08 [0.86; 1.36] 2.09 [0.19; 22.80] 0.90 [0.72; 1.12] 0.47 [0.06; 3.35] 1.18 [0.58; 1.97] 1.10 [0.56; 2.18] 0.98 [0.74; 1.30] 0.1 0.2 0.5 1 2 5 10 Ratio of RCT RR to observational RR RCTs show higher efficacy RCTs show lower efficacy
References