Overview of Current Drug Discovery and Development with an Eye towards the Future
M. Izet · InTech eBooks · 2011
IntroductionDrug discovery and development process aims to make available new pharmacological interventions to prevent, treat, mitigate, or cure disease in a safe and effective manner.It is a slow, complex, multi disciplinary and costly process.Drug development starts with a target identification and validation, followed by drug candidates (hits) discovery, and lead drug (compound with favorable pharmaceutical, safety, efficacy, and pharmacokinetic profile) selection and optimization.Preclinical (non clinical) efficacy, pharmacology, toxicology, and mechanistic studies may include in silico (computational) methods, use of in vitro animal or human tissues (including cells and subcellular fractions), and in vivo animals.The studies rely on models that are thought to be predictive of the subsequent preclinical or clinical effects.Guidances (government-regulated standards of normal expectations) for different steps are readily available from the regulatory agencies (http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/default.htm).The required toxic ology studies must be performed according to the Good Laboratory Practice (GLP) guidelines.Medicinal chemistry and pharmaceutics also play a crucial role from the beginning of the drug discovery and development process, involving chemical synthesis (including compliance with current Good Manufacturing Practice, cGMP), characterization, purification, chemical alteration, stability determination, and formulation of the drug candidate.The first-in-human (FIH) doses are based on the No-Observed-Adverse-Event-Level (NOAEL) values obtained in the relevant and more sensitive toxicology specie (rodent and non-rodent, commonly rat and dog), interspecies dose extrapolation, and a selection of an appropriate safety factor.Subsequent to preclinical evaluation, an Investigational New Drug (IND) application is submitted to the regulatory agency (e.g.United States Food and Drug Administration, FDA or European Medicine Agency, EMEA) summarizing all preclinical data (chemical, pharmaceutical, efficacy, toxicology and other) along with a rationale for the proposed clinical study and a clinical study protocol.Clinical drug development can commence after review of the IND by the regulatory agency and a clinical study approval by a local Institutional Review Board (IRB, a committee of scientists and non-scientists overseeing the clinical research).Phase 1 studies commonly use human volunteers to determine human safety and pharmacokinetics.Frequently, these studies also include biomarkers of efficacy as secondary endpoints.Drugs with acceptable safety profiles then enter Phase 2 for efficacy evaluations.These include the proof-of-principle studies to demonstrate effects on disease-relevant biomarkers and the proof-of-concept studies to www.intechopen.com