The process of drug development involves non-clinical and clinical studies.
Non-clinical studies are conducted using different protocols including animal
studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During
the early pre-clinical development process, also known as Go/No-Go decision, a drug
candidate needs to pass through several steps, such as determination of drug
availability (studies on pharmacokinetics), absorption, distribution, metabolism and
elimination (ADME) and preliminary studies that aim to investigate the candidate
safety including genotoxicity, mutagenicity, safety pharmacology and general
toxicology. These preliminary studies generally do not need to comply with GLP
regulations. These studies aim at investigating the drug safety to obtain the first
information about its tolerability in different systems that are relevant for further
decisions. There are, however, other studies that should be performed according to
GLP standards and are mandatory for the safe exposure to humans, such as repeated
dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted
before the Investigational New Drug (IND) application. The package of non-clinical
studies should cover all information needed for the safe transposition of drugs from
animals to humans, generally based on the non-observed adverse effect level (NOAEL)
obtained from general toxicity studies. After IND approval, other GLP experiments for
the evaluation of chronic toxicity, reproductive and developmental toxicity,
carcinogenicity and genotoxicity, are carried out during the clinical phase of
development. However, the necessity of performing such studies depends on the new
drug clinical application purpose.
This review presents a historical overview of drug discovery and the non-clinical
stages of the drug development process, from initial target identification and
validation, through in silico assays and high throughput screening
(HTS), identification of leader molecules and their optimization, the selection of a
candidate substance for clinical development, and the use of animal models during the
early studies of proof-of-concept (or principle). This report also discusses the
relevance of validated and predictive animal models selection, as well as the correct
use of animal tests concerning the experimental design, execution and interpretation,
which affect the reproducibility, quality and reliability of non-clinical studies
necessary to translate to and support clinical studies. Collectively, improving these
aspects will certainly contribute to the robustness of both scientific publications
and the translation of new substances to clinical development.
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