Selection of clinical candidates

In the selection of clinical candidates to pursue, the company does take into account competitors in the traditional sense of those that would compete for sales and reduce the profit potential. Some drugs are dropped from development plans because they are expected to be poor competitors with established drugs, especially where the competitor has a more effective sales force in the therapeutic area. 

Selection of Clinical Candidates and Preclinical Development Production of Active Pharmaceutical Ingredients... 

The ex vivo methods lend themselves easily for the performance of mechanistic investigations. In order to optimize selection of drug candidates prior to further clinical development, it is important to decipher the contributive roles of permeation, metabolism, efflux, and toxicity. This will then make it possible to properly channel the optimization process, for instance, by permeation enhancement, mucoadhesion, modification of the physicochemical characteristics of the drug, or even change in the route of administration in case the drug and/or formulation turns out to be too toxic. Regarding permeability studies, it is possible not only to quantify passive diffusion but also to identify and characterize (compound)-specific carrier-mediated transport routes. These tools have been used to identify and characterize the relative contribution of... 

The expectation that HTS and combinatorial chemistry could by themselves improve the drug discovery process is now clearly erroneous,50 and effort is currently focussed on developing methods to decrease clinical attrition through early selection of drug candidates with the best chances of success. 

The scope of this book covers the entire clinical development continuum from selection of lead candidate to first-in-human studies to ultimate product... 

Once a company has selected its clinical candidate, it has to be made in bulk—in hundreds of kilogram quantities, which itself is not trivial, to prepare for entering clinical trials. It is important to understand the significance of the sequence of phases in clinical trials. The stages are ... 

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. 

Mohler, M.L., Nair, V.A., Hwang, D.J., Rakov, I.M., Patil, R. and Miller, D.D. (2005) Nonsteroidal tissue selective androgen receptor modulators a promising class of clinical candidates. Expert Opinion on Therapeutic Patents, 15, 1565-1585. 

Subsequently, either additional ion channel studies or more sophisticated voltage-clamp methods may be used in conjunction with in vitro APD studies to assess proarrhythmia liability. In vivo models may be used before selection of the candidate drug, but use is limited due to their low-throughput nature. Prior to first in human (FIH) studies in vitro APD and in vivo APD and QT interval assessments are usually undertaken to complement the early cardiac screening data, thus establishing a dataset used to inform an integrated risk assessment as described in the ICH S7A and ICH S7B guidelines (Anon. 2001, 2005). Almost no non-clinical safety work is conducted after FIH. 

---