The 2016 analysis by the Tufts Center for the Study of Drug Development estimated the average cost to develop and gain marketing approval for a new drug is ~ $2.87 bln. Drug development is not only costly; it is a lengthy, laborious and usually, sequential process. Discovery phase can take 2-10 years. A drug discovery projects initiate because there is a disease or clinical condition without suitable medical products available and it is this unmet clinical need which is the underlying driving motivation for the project. The initial research generates data to develop a hypothesis that the inhibition or activation of a protein or pathway will result in a therapeutic effect in a disease state. Compounds are created either in pharma discovery labs or collaborating universities and biotech labs. The major goal of discovery teams is lead compound. Lead compound is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful and has the potential of changing the course of the targeted disease. The lead compound may still have a suboptimal structure that requires modification to fit better to the target.
Non-Clinical & Pre-Clinical Development can last 2-6 years. Studies are performed in vivo and in animal models to establish drug candidate safety before the drug is given to humans in clinical studies. The goal of both preclinical and nonclinical research is to support the clinical trials that lead to product approval. While the strategic plan should include the “must have” studies in this area, it also wise to consider the “good to have” studies as part of product differentiation strategy.
Clinical Development is the process where drug candidates are tested on humans in phase I, II and phase III clinical studies. In the USA, clinical development starts with the submission of IND. Once the one IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials. During this time, FDA has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk. Phase I typically takes 1-2 years; it is 1st in a human test with 12 to 40 subjects or healthy volunteers. The primary purpose is to establish profile & dosing regimens, assess safety & tolerability.
The drug discovery process starts with an idea for a target. That idea can come from academia, clinical research and the commercial sector. Once a target has been chosen, the next step is to identify molecules which possess suitable characteristics to make acceptable drugs. This review will look at the late stages of the drug discovery; summarizing the processes necessary to advance the molecule from lead optimization to clinical development.
Lead Optimization is critical and an operationally diverse stage of the drug discovery process in which the chemical structures of compounds or biologics are modified to improve target specificity and selectivity, plus pharmacodynamics, pharmacokinetic, and toxicological properties to produce later a preclinical drug candidate. High-dose pharmacology, PK/PD studies, dose linearity and repeat dosing PK looking for drug-induced metabolism and metabolic profiling all need to be carried out by the end of this stage. This process requires detailed characterization of lead compound series and lead biologics, including data related to toxicity, efficacy, and bioavailability. Consideration also needs to be given to chemical stability issues and salt selection for the putative drug substance. If the molecule has acceptable toxicity profile and no mutagenicity, it has a potential for use as a lead molecule. Further optimization gives a better quality of lead molecules. These may subsequently be developed as a drug(s). All the information gathered will allow for the preparation of a target candidate profile which with together with toxicological and CMC considerations will form the basis of a regulatory submission to allow human clinical studies to commence. Discovery work continues even after identifying a lead, with two strategic goals in mind: identification of potential backup molecules and follow-up series, in case the compound characterization fails in the preclinical phase.
After the lead optimization, the molecule enters Exploratory Preclinical Development phase with the expectation of demonstrating beneficial therapeutic effect by at least one lead molecule. The beneficial therapeutic effect can be defined as modulation or activation of the target in the desired disease biology. If selected molecule meets those criteria, it can be declared a pre-candidate drug. Feasibility of formulation & manufacturing, along with commercialization potential should be assessed at this stage. Exploratory in vivo non-clinical safety pharmacology and general toxicology studies, as well as DMPK evaluations and analytical, clinical biomarker assay development.
In Confirmatory Preclinical Development, is the next phase of drug development with an objective to perform all activities required to enter clinical development for one, or more drug candidates, e.g. submit the first IND. Pre-candidate drug(s) is/are tested in disease-relevant, preclinical models. If there is a proof of beneficial therapeutic preclinical outcomes, relevant to the targeted human disease, the molecule gathers drug candidate status and will be progressed to the clinical development stage.
The table below summarizes the most critical activities in Lead Optimization to Confirmatory Preclinical Development phases.
|Molecule type||Lead Optimization||Exploratory Preclinical Development
Confirmatory Preclinical Development
|Molecule stage||Lead Molecule||Pre-Candidate Drug||Candidate Drug|
|New Chemical Entity (NCE)||Preliminary toxicology
Safety non-rodent PK
|Feasibility of formulation for human use
Metabolite activity check
14d pilot toxicology study
GLP toxicology study
Regulatory safety pharmacology
|New Biological Entity (NBE)||PK appropriate species
Optimization of sequence & manufacturability assessment
Modification/extension of half-life
Chimerization (applicable to monoclonal antibodies)
Production line starts for the lead molecule
14d pilot toxicology study
PK in proper species
Manufacturing cell line
Br J Pharmacol. 2011 Mar; 162(6): 1239–1249. doi: 10.1111/j.1476-5381.2010.01127.x
PMCID: PMC3058157 Principles of early drug discovery
JP Hughes,1 S Rees,2 SB Kalindjian,3 and KL Philpott3