Postmarketing Clinical Studies

Before FDA approval, drugs and biological products must be tested in three phases of clinical trials to determine efficacy in humans. Increasing numbers of human volunteers will be used in the three phases to determine safety, and when feasible and ethical, under conditions that reflect the natural exposure or disease condition. Once the drug or biological product is approved, the FDA can require additional postmarketing clinical studies to determine whether there are safety issues that are revealed in larger populations than were tested in premarketing studies to ensure the quality and consistency of manufacturing and to gather more data on efficacy when the drug is used under normal clinical conditions. These postmarketing clinical studies are required for products that are approved under accelerated approval provisions. These provisions are for serious or life-threatening conditions; for marketed drugs approved in adults which have the potential for benefit in children; or more recently, for products that have been approved under the Animal Rule (21 CFR Parts 314 and 601 [2002]). In these cases, the FDA requires postmarketing commitments that outline the clinical studies that will be undertaken and the time frame under which they will be carried out. In addition, the agency can require postmarketing studies to determine whether there are reasons to withdraw the approval of the product; i.e., whether there is a known or potential serious risk related to the use of the drug. The FDA requires annual reporting of the status of the postmarketing studies until it determines that the commitments have been fulfilled (21 CFR Part 314.81(b)(2)(vii) [2011]).

For drugs and biologics approved under the Animal Rule, the FDA requires postmarketing studies or clinical trials to “verify and describe the drug’s [or biological product’s] clinical benefit and to assess its safety when used as indicated when these studies are feasible and ethical” (FDA 2002, p 37995, 37997). The FDA requires that applicants submit a plan or an approach, including the appropriate due diligence to identify opportunities to conduct these studies, and to carry out the clinical studies if and when it becomes feasible and ethical to do so. However, due to the nature of these products and the pathogens they are meant to counter, opportunities to conduct these clinical studies are rare and may only be possible under exposure to a chemical, biological, or nuclear threat. For some products, however, particularly for those used in the prevention or treatment of (emerging) infectious diseases, there may be particular environmental or natural conditions that provide an opportunity to collect human clinical efficacy data under natural exposure. In fact, the Animal Rule treats the use of a product approved under the rule in response to an exposure as a clinical trial from which essential data can be obtained (Walker and King 2011).

These clinical studies also offer the opportunity to evaluate the relevance and predictability of the animal models that were used in the approval process. These studies, therefore, represent important opportunities to refine the animal model systems, to evaluate the biomarkers identified and measured, and to correlate the clinical findings in humans to those seen in the animal models. By identifying and collecting data using the appropriate biomarkers4 and correlating clinical information to existing animal data, it should be possible to improve understanding of the relevance of the animal model to human clinical responses. Such data would be particularly informative to models developed with a product-neutral approach, which, by exhibiting a broader application profile, may be useful in “unknown-unknown” exigencies (see Chapter 2, p 30). Therefore, it would be useful for postmarketing

4 Biomarker is a biological characteristic that can be objectively measured and evaluated as an indicator of normal, pathogenic, or pharmacological responses or as the target of a therapeutic intervention. Biomarkers provide insight into disease progression, prognosis, and response to therapy.

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