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Following preclinical and first-in-human (Phase I) studies, an investigational drug or device is studied in subjects who have the disorder of interest. This phase of development is commonly called Phase II or exploratory therapeutic development. Major goals of Phase II studies are to support the proof of concept or proof of mechanism identified during preclinical development and to show evidence of efficacy that will support future confirmatory trials (Table 7–1). Other objectives include defining the target population, exploring the pharmacodynamic relationship between dosing regimens and the effects on disease, determining the proposed dosing regimen for future trials, and providing preliminary estimates of drug effect to be used in calculating sample sizes for Phase III trials.

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Table 7–1 Objectives of Phase II Clinical Development
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The objectives of Phase II support a critical “go/no-go” decision with regard to further clinical development. Sponsors usually prefer to abandon ineffective drugs early rather than waiting for resource- and time-intensive Phase III trials to tell them that the therapeutic has failed. Proof of mechanism, proof of concept, and identification of a therapeutic dose range and regimen are desired as early as possible. An inability to define any of these delays the clinical development program and may ultimately “kill” the therapeutic. Thus, the Phase II program should support the predefined goals of the clinical development plan and the target product labeling. The critical decision points and the criteria for the go/no-go decision are often determined as part of the clinical development plan.

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Dividing the clinical drug development process into numbered phases implies a linear progression; in fact, Phase II activities regularly occur while pivotal Phase III trials are active. Such overlap with other phases is not uncommon, particularly when a drug is evaluated in understudied subgroups within a target population. In some cases, a well-designed Phase II dose–response study can serve as one of the pivotal studies to be submitted to regulatory agencies for marketing approval.

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Phase II trials are generally short, enroll a relatively small number of subjects (up to 300), and often use surrogate rather than clinical end points (1,2). Phase II is sometimes divided into Phase IIa and Phase IIb (or early and late Phase II) to indicate the shifting goals of this phase over time. Phase I and IIa activities collectively represent “completion of clinical trials that provide data on the relationship of dosing and response for the particular intended use (including trials on the impact of dose ranging on safety, biomarkers, and proof of concept)” (3). In contrast to Phase IIa trials, late exploratory therapeutic trials tend to last longer, have larger sample ...

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