chapter  5
22 Pages

Development and Application of Interspecies Biomarkers in Nonclinical Safety Evaluations

By the time a drug candidate has evolved through the developmental pipeline to

submission for regulatory approval to begin phase I clinical trials, an average of

999 other candidates have been discarded. And the odds of that selected drug

ultimately receiving marketing approval are estimated at approximately one in

five [1]. A 20% clinical drug development success rate from that point suggests

that the interface created by drug development approaches and regulatory review

requirements being used over the past decades are in need of great improvement.

Unacceptable toxicities and safety concerns are cited to account for 20-40% of

the failures [2]. One factor for this may be that many of the assumptions implicit

in current practice may be flawed or that the data generated are insufficiently

informative. Once a compound has been selected to advance to the stage of

initiation of clinical trials, its fate has essentially been cast. The clinical stages of

investigation remain primarily to match the patient population to the indication,

establish optimal dosing and use, and demonstrate proof of safety and efficacy for

that selected molecule. The selection of the molecule is based on all of the study

information preceding clinical trial initiation-discovery data, mechanistic

studies, chemistry, biology, in vitro toxicology, and the animal toxicology study

findings.