Preclinical development consists of a series of tests that ensure the safety and efficacy of a new therapeutic compound before it is tested in humans. There are four main phases to this process. First, safety pharmacology tests are conducted to ensure the drug does not produce any acutely harmful effects. These tests examine parameters such as bronchoconstriction, cardiac dysrhythmias, blood pressure changes, and ataxia. Next, preliminary toxicological testing is performed to determine the drug's maximum non-toxic dose as well as examine potential genetic, reproductive, and carcinogenic effects. Animals are treated with the drug for a specified duration and closely monitored for adverse effects. Post-mortem examinations are conducted to detect any signs of tissue damage. Efforts have been made to reduce animal usage through in vitro methods and computer modeling, although their predictive value is still limited.
The third phase involves pharmacokinetic and pharmacodynamic (PK/PD) testing, which studies the drug's absorption, metabolism, distribution, and elimination in laboratory animals. These studies help establish the relationship between drug exposure and its effects. The fourth phase is chemical and pharmaceutical development, which focuses on synthesizing the compound on a large scale, assessing its stability, and developing a formulation suitable for clinical studies.
Approximately half of the identified drug candidates fail during preclinical development. For the remaining candidates, a detailed dossier called the "investigator brochure" is prepared along with study protocols for submission to regulatory authorities such as the European Medicines Agency or the US FDA. Permission from the regulatory authority is required to proceed with human studies. The authority may refuse permission or request further work before granting approval.
