Biomarkers have to be identified early during the drug-discovery process and evaluated/validated systematically throughout the subsequent drug-development process:
1. Discovery: Potential biomarkers/surrogate makers should be selected based on the current mechanistic understanding of the pathophysiology of the disease and proposed mechanism of action of the drug candidate based on theoretical considerations and/or experimental evidence. Additional thought should be given to potential toxicity markers not associated with the known MO A (e.g., other drugs in the same pharmacological class, known toxicities in disease, known biomarkers in the disease).
2. Preclinical Development: The in vitro binding of the drug candidate to receptor/enzyme and/or in vivo or ex vivo functional testing (enzyme activity or receptor intrinsic activity) should be evaluated for feasibility as markers across various species, including humans. Ex vivo or in vivo challenge paradigms based on the MOA should be considered. As part of the preclinical workup, ER relationships for potential markers of efficacy/toxicity should be established. This will allow interspecies scaling and optimal selection of starting dose and dose-escalation increment or even a PD-guided study design for phase I for the first time in human studies.
3. Clinical Development: In phase I, in vivo testing/challenge paradigms in healthy volunteers should be considered to establish the ER relationship in low-population-variability setting. In phase II, demonstration of changes of biomarkers in the expected direction may serve as proof-of-concept (POC) suggesting clinical efficacy of the drug candidate, and help in making important Go-No Go decisions. Throughout the phase II stage, biomarkers should be correlated with short-term clinical outcomes in the target patient population; attempts should be made to establish ER relationships for biomarkers/short-term clinical outcomes. This correlation between biomarker and accepted (approvable) clinical outcomes should be quantitated in the phase III program, and important clinical covariates affecting outcome and marker should be identified. If necessary, the surrogate marker can be used for therapeutic monitoring of postmarketing in clinical practice. Demonstrated ER relationships with biomarkers or surrogate markers will also be useful in phase IV to assess new dosing regimens, dosage forms, and special populations (namely pediatrics).
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