Phase 2 Studies

Phase 2 studies are performed to determine the initial effectiveness of an investigational drug or biologic in patients with the condition or disease of interest (Fig. 5.2). This phase of testing also helps determine the common short-term side effects and risks associated with the drug. Phase 2 studies are typically well controlled and closely monitored. A major focus is to find the appropriate dose(s) for the larger studies required in phase 3. The primary phase 2 studies are doseranging studies and are designed to provide proof of principle. One designs the studies such that the range of doses, typically four, includes an ineffective dose at the lower end and, at the upper end, a dose that does not add to the effect of the next highest dose. On average, 100 to 300 patient volunteers participate in the primary phase 2 studies. It takes approximately 2 years to complete these studies.

During these studies, one also begins to identify side effects and toxicity at doses to be used later in phase 3 studies and likely after marketing. Phase 2 studies of drugs that are being evaluated for chronic use are typically at least 4 to 6 weeks in duration and sometimes up to 6 months, which allows for observation of any later occurring side effects, the full action of the product to be produced, and possibly the assessment of tolerance or waning of a product's beneficial or toxic activities. Although there is a tendency to try to do as much as possible in these early phase studies, rather than focus on the essential questions, one should have a simple study design in order to maximize the probability of determining if the drug is effective and has acceptable toxicity. Many products fail at this stage and are killed, which is desirable as necessary before embarking on the very expensive and labor intensive phase 3 study program.

A feature of phase 2 studies is the use of relatively homogeneous patient populations with very tight inclusion and exclusion criteria. This is done to increase the likelihood of identifying a positive effect and minimizing confounding variables. On the other hand, the results obtained may not r Obtain additional information about drug for publications r Identify potential new uses (e.g., areas of unmet medical need)

r Examine follow-up clinical issues c dosing regimens o routes of administration c role of concomitant disease/drugs c effects on special populations

Fig. 5.3. Phase 2 Studies: Post Approval accurately reflect the effectiveness of the drug in the more typical heterogeneous patient population.

In addition to the phase 2 studies that must be performed as part of the drug approval process, other studies may be undertaken before the phase 2 studies have been completed and the data analyzed (Fig. 5.3). Studies may be performed for several reasons: to obtain additional information for publications, to identify potential other uses (e.g., new indications, areas of unmet medical need), to examine different dosing regimens, to explore new routes of administration, to define the role of concomitant drugs, and to determine the effects in special populations (e.g., the elderly, those with renal or hepatic disease, common comorbid conditions, pharmacogenetic variables). Caution should be exercised by management at companies in doing these types of trials before approval, as they may confound or slow the approval process by creating unexpected side effect data or just more data that the regulatory authorities need to review. As a result, these exploratory phase 2 trials often will be done postapproval.

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