As a compound moves from Phase I into Phase II and eventually into Phase III, the objectives of the clinical development program evolve from primarily safety and PK to safety and efficacy. The data collected during earlier studies are used to define a potentially efficacious clinical dose range and dosing regimen, identify any special patient populations, and guide selection of a drug product to be used in pivotal registrational clinical studies. As a result, the biopharmaceutics focus shifts from an exploratory to a registrational paradigm in which the objective is to establish consistency, robustness, and predictability of the formulations.
Considering the previous discussion of the dependency of efficacy on PK and dependency of PK on formulation, changes in critical properties of a drug substance or formulation may have consequences for a clinical study (Ahr et al., 2000). PK studies conducted in Phase I and II are used to establish a body of knowledge surrounding the intrinsic properties of the medicinal agent (e.g., clearance) as well as the dependency of the performance on the actual product used. Since the outcome of PK and clinical studies depends on the product used, any changes to that product must be adequately qualified to establish its acceptability for use in the clinic. The definition of "qualification" in this sense is consistent with much of the discussion here: it depends on the drug and the available body of knowledge about that drug and its formulations. If an IVIVC has been established, dissolution equivalence may be sufficient; for a Class I drug, demonstration of rapid and complete dissolution across the physiological pH range may serve to qualify a new dosage form. For Class II and IV drugs, qualification in a bioequiva-lence study prior to use in a large-scale clinical study may be necessary. The design of the study would be driven by the extent of clinical experience already gained with a given drug product and the extent of change to the product. Changing from a capsule to tablet dosage form is a significant change that would likely require a bioequivalence study, while addition of a non-functional coating for ease of swallowing may not be considered to be sufficiently impactful to affect the product performance.
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