An analysis of preclinical efficacy testing of antivenoms for sub-Saharan Africa: Inadequate independent scrutiny and poor-quality reporting are barriers to improving snakebite treatment and management

Background The World Health Organization's strategy to halve snakebite mortality and morbidity by 2030 includes an emphasis on a risk-benefit process assessing the preclinical efficacy of antivenoms manufactured for sub-Saharan Africa. To assist this process, we systematically collected, standardised and analysed all publicly available data on the preclinical efficacy of antivenoms designed for sub-Saharan Africa. Methodology/Principal findings Using a systematic search of publication databases, we focused on publicly available preclinical reports of the efficacy of 16 antivenom products available in sub Saharan Africa. Publications since 1999 reporting the industry standard intravenous pre-incubation method of murinein vivoneutralisation of venom lethality (median effective dose [ED50]) were included. Eighteen publications met the criteria. To permit comparison of the several different reported ED(50)values, it was necessary to standardise these to microlitre of antivenom resulting in 50% survival of mice challenged per milligram of venom (mu l/mg). We were unable to identify publicly available preclinical data on four antivenoms, whilst data for six polyspecific antivenoms were restricted to a small number of venoms. Only four antivenoms were tested against a wide range of venoms. Examination of these studies for the reporting of key metrics required for interpreting antivenom ED(50)s were highly variable, as evidenced by eight different units being used for the described ED(50)values. Conclusions/Significance There is a disturbing lack of (i) preclinical efficacy testing of antivenom for sub Saharan Africa, (ii) publicly available reports and (iii) independent scrutiny of this medically important data. Where reports do exist, the methods and metrics used are highly variable. This prevents comprehensive meta-analysis of antivenom preclinical efficacy, and severely reduces the utility of antivenom ED(50)results in the decision making of physicians treating patients and of national and international health agencies. Here, we propose the use of a standardised result reporting checklist to resolve this issue. Implementation of these straightforward steps will deliver uniform evaluation of products across laboratories, facilitate meta-analyses, and contribute vital information for designing the clinical trials needed to achieve the WHO target of halving snakebite morbidity and mortality by 2030. Author summary Antivenom is the first-choice therapy for victims of snakebite envenoming. Currently there is very little robust evidence that the antivenoms currently being used in Africa are suitable or effective. Unusually for a human medicine, clinical trials are not a pre-requisite for antivenom approval, licensing and use in patients. This leaves a situation where nearly all the information of an antivenom's effectiveness is based on mouse assays assessing neutralisation of venom-induced lethality, so-called preclinical antivenom testing. Here we analysed all the publicly available preclinical data on antivenoms for Africa published in the last 20 years. Our results demonstrate that there is worryingly little publicly available information on the preclinical efficacy of antivenoms and that the efficacy of some products is seemingly very weak. We hope that the World Health Organization's antivenom assessment and listing scheme (independently and systematically testing antivenom efficacy and quality) will fill many of these crucial information gaps. Furthermore, the quality of the result reporting was highly variable across studies, making meaningful comparisons difficult and causing challenges for clinicians treating snakebites to rapidly decipher efficacy information. To remedy this, we have developed a reporting checklist to harmonise preclinical antivenom efficacy reporting across the globe.