Phase 4 Studies

Phase 4 studies, by definition, are those studies that are performed after a new drug has been approved for marketing (Fig. 5.9). Phase 4 studies serve multiple purposes and comprise many different types. They also pose some unique challenges, which will be discussed below. The FDA often requests commitments from the NDA applicants to conduct r Post-approval studies r Multiple purposes

Multiple types r Unique challenges in design & conduct r Often very large studies r Simple design (IRB approvals)

r Failure to fulfill FDA requirements can result in withdrawal of approval

Fig. 5.9. Phase 4 Studies Overview r Compare to competitor drugs r Use to define mechanisms of disease (often investigator-initiated)

r Identify variables in existing indications r Identify new dosing schema r Explore "real-world" effectiveness (e.g., in the office) r Define effects in special populations (elderly, children) r Examine impact of concurrent diseases r Post-marketing surveillance r Drug interactions

Note: Phase 4 will overlap with 3b studies. Fig. 5.10. Phase 4 Studies: Possible Objectives postapproval studies [7]. In general, characteristics of phase 4 studies are that they can be very large and have a more simple study design. Although these studies were not deemed essential for initial approval, they provide additional data that could change the prescribing information or the use of the drug. A major challenge to consider with phase 4 studies is that failure to fulfill FDA requirements for more data, especially for adverse events and further efficacy information, can result in withdrawal of an already approved drug.

Objectives of phase 4 studies are manifold (Fig. 5.10); determining efficacy and safety compared with competitor drugs, defining mechanisms of disease that often are performed as investigator-initiated studies (see below), exploring "real-world" effectiveness (e.g., in the office), defining effects in special populations (e.g., the elderly, children, concurrent disease), providing postmarketing surveillance for unsuspected or low-frequency adverse events, further defining potential drug interactions, and possibly pharmacogenetic assessments (to be discussed below). Some objectives done during phase 4 period may require FDA agreement and may be classified technically as phase 3b or even phase 2 studies, such as new administration schema, significantly different doses, and identifying new and expanded indications.

Postmarketing surveillance studies are meant to substantiate safety in a larger, more heterogeneous patient population than is possible during the pivotal studies performed during phase 3 with their strict, often randomized placebo-controlled double-blind designs (Fig. 5.11). The patients often have r Safety (post-marketing surveillance) - substantiate safety in larger, broader patient populations r Efficacy and safety - in settings of widespread subpopulations and dosing schemas r Usage studies in varied and normal practice environments r Substantiate product quality and consistency Fig. 5.11. Phase 4 Studies: Types r Food / Drug /Disease Interactions r Investigator-initiated r Pharmacoeconomic - may be part of phase 3 plan as well r Pharmacogenetic - increasingly important to identify responders / non-responders and susceptibility to toxicity r Quality of life r Epidemiology

Fig. 5.12. Special Studies coexisting illnesses, greater or less severity of disease, longer or shorter duration of disease, more varied signs and symptoms of disease, or are taking medications that would have excluded them from the phase 2 and 3 studies. The studies may be open-label and relatively uncontrolled, but the protocols are IRB approved usually with patient consent obtained. Sometimes these studies are required by the FDA, and then they will approve the design as well. The protocols still will contain specific dosing, inclusion criteria, monitoring, and data requirements and then they must be of sufficient quality to be publishable, so that the medical community will accept the information. Their primary focus is on serious adverse events whose frequency may be too low to identify in phase 3 studies. Postmarketing surveillance studies may also provide additional evidence of efficacy and safety in the setting of widespread related but off-label use.

There is considerable overlap between phase 4 studies and studies done as part of phases 2b and 3b in objectives, potential investigators and sites, and many design features. The major differences are fourfold: the time at which the studies are performed in development; the size of the studies differ, that is, smaller studies predominating during phase 2b and larger studies during phase 4; whether they are within versus outside of labeling (package insert); and FDA approval is required for the design in phase 3b and exploratory phase 2.

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