WoE Analysis and Key Risk Factors in Preclinical Development of Medicinal Products: A Review

INTRODUCTION. In recent years, the Russian Federation and the Eurasian Economic Union have included the concept of ‘weight of evidence’ (WoE) in regulatory documents. International regulators place great emphasis on data transparency in documenting and assessing the WoE, and their position is reflected in the relevant regulatory documents. However, the Russian Federation has faced the absence of consistent Russian-language terminology in this area, the lack of a clear vision of WoE assessment principles, and the need for a sound understanding of applied WoE methods for pharmaceutical development and regulatory review of preclinical study results. These gaps require collated information on WoE assessment and practical guidance for its use.

AIM. This study aimed to analyse regulatory documents as well as scientific and methodological publications on the WoE concept and assessment methods in order to investigate the opportunities and practical applications of WoE analysis in the development of medicines and the regulatory review of study results.

DISCUSSION. This article covers documents by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), the Organisation for Economic Co-operation and Development (OECD), the European Chemicals Agency (ECHA), and other organisations. Using these documents and taking into account Russian terminology, the authors clarify the WoE as a concept and explain its assessment. Furthermore, the article classifies the key risk factors that must be considered in WoE analysis, with examples drawn from immunotoxicity, reproductive toxicity, and carcinogenicity studies. Analysing such data is critical to the design of preclinical studies, interpretation of their results, and safety evaluation of medicines. This article provides examples of WoE assessments conducted to consider the need for additional preclinical studies in juvenile animals in the development of small molecules and monoclonal antibodies for paediatric use.

CONCLUSION. The WoE assessment algorithms and criteria described in this article may be implemented by preclinical study initiators, their research teams, and regulatory experts evaluating medicines.

1. Meek ME, Boobis A, Cote I, Dellarco V, Fotakis G, Munn S, et al. New developments in the evolution and application of the WHO/IPCS framework on mode of action/species concordance analysis. J Appl Toxicol. 2014;34(1):1–18. https://doi.org/10.1111/j.1539-6924.2005.00699.x

2. Linkov I, Loney D, Cormier S, Satterstrom FK, Bridges T. Weight-of-evidence evaluation in environmental assessment: review of qualitative and quantitative approaches. Sci Total Environ. 2009;407(19):5199–205.https://doi.org/10.1016/j.scitotenv.2009.05.004

3. Weed DL. Weight of evidence: a review of concept and methods. Risk Anal. 2005; 25(6):1545–57. https://doi.org/10.1111/j.1539-6924.2005.00699.x

4. Martin P, Bladier C, Meek B, Bruyere O, Feinblatt E, Touvier M, et al. Weight of evidence for hazard identification: a critical review of the literature. Environ Health Perspect. 2018;126(7):076001. https://doi.org/10.1289/EHP3067

5. Dekant W, Bridges J. A quantitative weight of evidence methodology for the assessment of reproductive and developmental toxicity and its application for classification and labeling of chemicals. Regul Toxicol Pharmacol. 2016;82:173–85. https://doi.org/10.1016/j.yrtph.2016.09.009

6. Ågerstrand M, Beronius A. Weight of evidence evaluation and systematic review in EU chemical risk assessment: foundation is laid but guidance is needed. Environ Int. 2016;92–93:590–6. https://doi.org/10.1016/j.envint.2015.10.008

7. Dekant W, Bridges J. Assessment of reproductive and developmental effects of DINP, DnHP and DCHP using quantitative weight of evidence. Regul Toxicol Pharmacol. 2016;81:397–406. https://doi.org/10.1016/j.yrtph.2016.09.032

8. Engalycheva G.N., Syubaev R.D. Development of paediatric medicines: key risk factors and non-clinical research programmes. Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. Regulatory Research and Medicine Evaluation. 2023;13(1):14–26 (In Russ.). https://doi.org/10.30895/1991-2919-2023-500

9. Hoberman AM, Maki K, Mikashima F, Naota M, Wange RL, Lansita JA, Weis SL. Alternatives to monkey reproductive toxicology testing for biotherapeutics. Int J Toxicol. 2023;42(6):467–79. https://doi.org/10.1177/10915818231200859

10. Bourcier T, McGovern T, Cavaliero T, Ebere G, Nishikawa A, Nishimura J, et al. ICH S1 prospective evaluation study: weight of evidence approach to predict outcome and value of 2-year rat carcinogenicity studies. A report from the Regulatory Authorities Subgroup. Front Toxicol. 2024;6:1353783. https://doi.org/10.3389/ftox.2024.1353783

11. Bassan A, Steigerwalt R, Keller D, Beilke L, Bradley PM, Bringezu F, et al. Developing a pragmatic consensus procedure supporting the ICH S1B(R1) weight of evidence carcinogenicity assessment. Front Toxicol. 2024;6:1370045. https://doi.org/10.3389/ftox.2024.1370045

12. Avila AM, Bebenek I, Bonzo JA, Bourcier T, Davis Bruno KL, Carlson DB, et al. An FDA/CDER perspective on nonclinical testing strategies: classical toxicology approaches and new approach methodologies (NAMs). Regul Toxicol Pharmacol. 2020;114:104662. https://doi.org/10.1016/j.yrtph.2020.104662

13. Vahle JL, Dybowski J, Graziano M, Hisada S, Lebron J, Nolte T, et al. ICH S1 prospective evaluation study and weight of evidence assessments: commentary from industry representatives. Front Toxicol. 2024;6:1377990. https://doi.org/10.3389/ftox.2024.1377990

14. Rosen EM, Ritchey ME, Girman CJ. Can weight of evidence, quantitative bias, and bounding methods evaluate robustness of real-world evidence for regulator and health technology assessment decisions on medical interventions? Clin Ther. 2023;45(12):1266–76. https://doi.org/10.1016/j.clinthera.2023.09.010