Benefit of Using Markers in the Drug Development Process

1. Identification of Biological Sources of Variability in Drug Response: For rational drug development, it is important to understand the contribution of PK or PD variability to the overall population variability in drug response (for dose individualization and TDM).

2. Physiological Interpretation of PK/PD Parameters: Appropriate physiological interpretation of PK and PK/PD parameters early in the drug development (in-vitro, preclinical, phase I) allows appropriate interspecies scaling and informative "Go-No Go" decisions [8].

3. Identification of Relevant PK/PD Covariates: The PK/PD approach throughout drug development assists in anticipating and identifying important patient factors, e.g., age, gender, concurrent diseases, and comedications, that may require dose individualization/therapeutic monitoring in the target population (see Chapters 8 and 9).

4. Rational Optimization of Dosage Forms and Dosage Regimens: Understanding of the intrinsic PK/PD characteristics with an acceptable biomarker and sources of population variability permits better design of dose-finding studies in phase I and II as well as rational development of appropriate dosage forms. It may also be useful in selecting optimal backup compounds to the lead compound.

5. Rational Labeling Decisions: Appropriate PK/PD modeling with an acceptable biomarker helps assessing and interpreting the PK results of "equivalence" studies, i.e., food-effect, chronic renal and hepatic disease-effect, and drug-drug interaction studies, by allowing to define a target range of "no clinically significant PK difference" ("What-If" Scenarios).

It is the PK/PD information gained in the drug development process that drives the final clinical dosing-regimen recommendations (particularly dose individualization and therapeutic monitoring) in the product label.

6. Marketing Approval: PK/PD studies with an acceptable surrogate marker may provide supportive ("confirmatory") evidence for drug approval in lieu of an (second) adequate and well-controlled phase III clinical trial, particularly for extension into special populations (e.g., pediatrics) or new dosage forms. However, this is likely to occur only if the surrogate marker has been accepted after comprehensive evaluation and other drugs in the same class have shown benefits in clinical outcomes.

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