[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]
Sci Transl Med. 2019 Nov 27;11(520). pii: eaaw1049. doi: 10.1126/scitranslmed.aaw1049.
A meta-analysis of clinical studies conducted during the West Africa Ebola virus disease outbreak confirms the need for randomized control groups.
Dodd LE1,2, Follmann D3, Proschan M3, Wang J4, Malvy D5,6, van Griensven J7, Ciglenecki I8, Horby PW9, Ansumana R10,11, Jiang JF12, Davey RT13, Lane HC14, Gouel-Cheron A3,15.
Author information: 1 Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. email@example.com. 2 School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa. 3 Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. 4 Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, Frederick, MD, USA. 5 Inserm, UMR 1219, Université de Bordeaux, Bordeaux, France. 6 Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France. 7 Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium. 8 Operational Centre Geneva, Médecins Sans Frontières, 1211 Geneva, Switzerland. 9 Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK. 10 Mercy Hospital Research Laboratory, Kulanda Town, Bo, Sierra Leone. 11 School of Community Health Sciences, Njala University, Bo, Sierra Leone. 12 Beijing Institute of Microbiology and Epidemiology, Beijing, China. 13 Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. 14 Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. 15 Anesthesiology and Intensive Care Department, Hopital Bichat-Claude Bernard, Assistance Publique-Hopitaux de Paris, Paris, France.
Recent Ebola virus disease outbreaks affirm the dire need for treatments with proven efficacy. Randomized controlled clinical trials remain the gold standard but, during disease outbreaks, may be difficult to conduct due to ethical concerns and challenging field conditions. In the absence of a randomized control group, statistical modeling to create a control group could be a possibility. Such a model-based reference control would only be credible if it had the same mortality risk as that of the experimental group in the absence of treatment. One way to test this counterfactual assumption is to evaluate whether reasonable similarity exists across nonrandomized control groups from different clinical studies, which might suggest that a future control group would be similarly homogeneous. We evaluated similarity across six clinical studies conducted during the 2013-2016 West Africa outbreak of Ebola virus disease. These studies evaluated favipiravir, the biologic ZMapp, the antimalarial drug amodiaquine, or administration of convalescent plasma or convalescent whole blood. We compared the nonrandomized control groups of these six studies comprising 1147 individuals infected with Ebola virus. We found considerable heterogeneity, which did not disappear after statistical modeling to adjust for prognostic variables. Mortality risk varied widely (31 to 66%) across the nonrandomized control arms of these six studies. Models adjusting for baseline covariates (age, sex, and cycle threshold, a proxy for viral load) failed to sufficiently recalibrate these studies and showed that heterogeneity remained. Our findings highlight concerns about making invalid conclusions when comparing nonrandomized control groups to cohorts receiving experimental treatments.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
PMID: 31776287 DOI: 10.1126/scitranslmed.aaw1049
Keywords: Antivirals; Favipiravir; Serotherapy; ZMapp; Monoclonal antibodies; Ebola; West Africa.