Methodological aspects of study design in preclinical drug development: A review

Introduction. Recent advances in molecular biology and computational science necessitate a revision of preclinical methodologies. Initiatives such as Tox21 program integrate traditional approaches with innovations, enabling new drug research strategies and transforming toxicology into a predictive science. However, the development of safe drugs through modeling requires the standardization of experimental and statistical approaches, while accounting for the characteristics of target populations.

Objective. To systematize methodological approaches toward unified statistical and experimental planning of preclinical drug studies.

Discussion. Analysis of the reviewed approaches shows that methodological rigor at the preclinical stage is a critical factor in the successful introduction of drugs into clinical practice. This paper proposes a tiered framework of study designs: ranging from exploratory and pilot studies that generate hypotheses to rigorous translational and pivotal trials intended for confirmation. Robust statistical planning is essential for ensuring both internal and external validity, thereby enhancing the reliability and translatability of research findings. Pilot and exploratory studies focus on effect size estimation and descriptive statistics, whereas confirmatory (pivotal) trials require rigorous a priori power analysis alongside strict randomization and blinding protocols. The presented classification of experimental units — whether single subjects, littermates, or repeated measures — is critical for ensuring statistical validity and preventing pseudoreplication. Unifying statistical designs for translational preclinical trials by analogy with clinical studies is the definitive strategy for ensuring reliable safety and efficacy predictions for pharmacologically active compounds prior to human trials.

Conclusions. The unification of statistical and experimental plans at the preclinical stage is necessary for obtaining reliable data on drug safety and efficacy. Adherence to unified methodological principles in exploratory, translational, and pivotal studies ensures data continuity and reduces the risk of erroneous predictions when extrapolating findings to human populations. The presented approaches can serve as a methodological basis for harmonizing preclinical and clinical strategies in medical and veterinary pharmacology.

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