The process of developing a novel drug is time-consuming and costly. To increase the chances of completing a clinical trial leading to the approval of a new drug, the choice of appropriate preclinical models is of utmost importance. Identifying a safe, potent, and efficacious drug requires thorough preclinical testing, which evaluates aspects of pharmacodynamics, pharmacokinetics, and toxicology in vitro and in vivo settings.
The purpose of preclinical studies is to provide information about the safety and efficacy of drug candidates before human trials. In addition, they can provide evidence of the biological effects of compounds, often including in vitro and in vivo studies. Understanding the dose and toxicity levels of the compound through pharmacokinetics, pharmacodynamics, and toxicology studies is essential to determine whether it is reasonable and safe to conduct clinical studies.
Fig.1 From basic research to an approved drug. (Jennifer, 2017)
The Ideal Preclinical Model Accurately Mimics Human Disease
Obtaining relevant results from preclinical studies with a high degree of generalizability requires appropriate preclinical models that are as comparable to the target population as possible. Typically, this involves a series of experiments using in vitro, in vivo, and more recently, also in silico models.
In vitro studies are a relatively rapid, simple, and cost-effective method for preclinical testing. These studies use cell, tissue, and organ cultures, or focus on specific cellular components, such as proteins or other biological macromolecules. While the in vitro models have the potential to provide mechanical insights, it is also limited by the fact that isolated cells may not behave as they do in vivo. Therefore, more sophisticated preclinical models are needed to establish the safety of investigational compounds before transitioning to clinical settings.
In vivo studies consider whole organisms based on various animal models. The selection of suitable animal models depends on numerous criteria and requires an understanding of species-specific physiological and target organ similarities, metabolic pathways as well as financial regulatory and ethical considerations.
Preclinical Research is Indispensable
Despite all efforts to identify relevant animal models to ensure a significant translational value, drugs often show different pharmacodynamic characteristics when administered to human subjects. Thus, merely one out of five investigational drugs tested in clinical trials eventually gains approval for clinical use. The fact that most anti-cancer drugs do not pass efficacy evaluation in Phase II and III studies suggests that currently used preclinical models fail at appropriately mimicking tumor heterogeneity, host factors, and drug resistance mechanisms. Adequate design of preclinical studies and careful choice of model systems are vital to ensure relevant results that translate into applicability in clinical settings.
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Jennifer, H. Preclinical research in drug development. Medical Writing. December 2017. Volume 26, Issue 4-Preclinical Studies.