Pharmaceutical companies are increasingly using biomarkers (biological markers) in early clinical drug development (phase I) to enable early proof-of-concept studies and to better predict the dose range for phases II and III. The average success rate from first-in-human (also called "first-in-man") to registration was about 11% for all therapeutic areas during a ten-year period for ten of the big pharmaceutical companies.1 A major cause of attrition in the clinical phases in 2000 was a lack of efficacy, and there is obviously a need to provide better and more meaningful data to assess the efficacy of compounds in early clinical development.

Biomarkers play an important role in decision making during the early phases of clinical drug development. Many biomarkers are used to assess the safety of a drug; others are used to study the pharmacologic effects related to the mechanism of action. The pharmacodynamic (PD) biomarker data can be used with the pharmacokinetic

(PK) data to show a relationship between the drug concentrations and the drug effects or side effects as measured by the PD biomarker. The PK/PD relationship can then support decision making regarding dose and dose regimen.

Very few biomarkers, e.g., HIV plasma viral load, blood pressure, and cholesterol, have reached the level of surrogate end points substituting for clinical end points.2 There is currently no regulatory guidance for method development and validation of the "research"-type of biomarkers, i.e., the nondiagnostic biomarkers. Nor is there any guidance for the appropriate use of research biomarkers in drug development. Most of the PD biomarkers used in early clinical drug development belong to this class, and many challenges are associated with using PD biomarkers in early clinical drug development. Validation (performance assessment) of the biomarker methods is only part of the challenge; choosing the right biomarker or set of biomarkers is another. Biomarker results in early clinical drug development are mostly used for internal business decision making, with limited regulatory guidance. The level of validation of the PD biomarkers and their associated methods is basically up to each user to define. The intended use of a biomarker or a set of biomarkers in early clinical drug development will, therefore, to a great extent, dictate the validation of the biomarkers and associated methods.3 To successfully use PD biomarkers in early clinical drug development, it is imperative to have cross-functional biomarker teams define the purpose for each individual biomarker or set of biomarkers.

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