Clinical candidates selection

Lead optimisation is the synthetic modification of a biologically active compound, to fulfill all stereoelectronic, physicochemical, pharmacokinetic and toxicologic required for clinical usefulness (IUPAC). This phase begins with the first chemical lead or lead series selected for optimisation (i.e. the "lead series selected" milestone) and concludes with a decision for an optimized compound to enter preclinical development (i.e. the "pre-clinical candidate selected" milestone). This phase consists of testing of a compound to determine the chemical structure that has the optimum potency and selectivity for the target in question. The phase includes the search for backup compounds and may also include early ADME and toxicity evaluation. 

About the Economics OF Target and Clinical Candidate Selection... 

The industry average is that only 1 of 10 clinical candidates selected for entry into Phase I or entry into man (EIM) will reach the stage of approved drug that can be marketed. Some will fail early at low costs, but others may draw 300 million before the company knows that a drug did not make it. 

Navigating through the Clinical Candidate Selection Board at Big Pharma... 

Figure 10-1 Alignment of safety profiling, discovery toxicology, and pathology with the pre-clinical drug discovery process8. Profiling assays are implemented according to requirement of the phase, compound availability, and capacity. The complexity is increasing as projects progress toward clinical candidate selection.

Clinical candidate selection - characterize candidates and assess risk (induding regulatory requirements prior to clinical trials) of identified molecules... 

At lead selection and optimization false negatives are more tolerated (high specificity) however, at clinical candidate selection - in an ideal situation -neither false positives nor false negatives are allowed (high sensitivity - high specificity). 

Additional preformulation and physicochemical characterization of the candidate compound are performed and stress stability studies may be initiated. Ideally, the optimal solid state (polymorphic) and chemical (salt) form of the molecule are identified as part of clinical candidate selection. Selection of the most stable and bioavailable form will expedite subsequent development. The methods for testing the drug substance are refined and additional methods may be developed. 

Analytical documentation at the clinical candidate selection milestone may consist of the following items ... 

The phases of drug discovery are target finding, hit finding, hit to lead program or lead finding, lead optimization (sometimes pre-clinical candidate selection), and finally clinical candidate selection. 

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