Phase I studies also evaluate drug metabolism, structure-activity relationships, and the mechanism of action in humans. These studies also determine which investigational drugs are used as research tools to explore biological phenomena of disease processes. The total number of subjects included in Phase I studies varies with the drug, but is generally in the range of 20 to 80.

In Phase I studies, CDER can impose a clinical hold (i.e., prohibit the study from proceeding or stop a trial that has started) for reasons of safety, or because of a sponsor’s failure to accurately disclose the risk of study to investigators. Although CDER routinely provides advice in such cases, investigators may choose to ignore any advice regarding the design of Phase I studies in areas other than patient safety.

Phase II Clinical Studies
Phase II includes the early controlled clinical studies conducted to obtain some preliminary data on the effectiveness of the drug for a condition. This phase of testing also helps determine the common short-term side effects and risks associated with the drug. Phase II studies are typically well-controlled, closely monitored, and conducted in a relatively small number of patients, usually involving several hundred people.

Phase III Clinical Studies
Phase III studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained in Phase II. In essence, these trials are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug. Phase III studies also provide an adequate basis for extrapolating the results to the general population and transmitting that information in the physician labeling. Phase III studies usually include several hundred to several thousand people.

In both Phase II and 3, CDER can impose a clinical hold if a study is unsafe (as in Phase I), or if the protocol is clearly deficient in design in meeting its stated objectives. Great care is taken to ensure that this determination is not made in isolation, but reflects current scientific knowledge, agency experience with the design of clinical trials, and experience with the class of drugs under investigation.

Accelerated Development/Review
Accelerated development/review (Federal Register, April 15, 1992) is a highly specialized mechanism for speeding the development of drugs that promise significant benefit over existing therapy for serious or life-threatening illnesses for which no therapy exists. This process incorporates several novel elements aimed at making sure that rapid development and review is balanced by safeguards to protect both the patients and the integrity of the regulatory process.

Accelerated development/review can be used under two special circumstances: when approval is based on evidence of the product’s effect on a “surrogate endpoint,” and when the FDA determines that safe use of a product depends on restricting its physical sign that may not be a direct measurement of how a patient feels, functions, or survives, but is still considered likely to predict therapeutic benefit for the patient.

The fundamental element of this process is that the manufacturers must continue testing after approval to demonstrate that the drug indeed provides therapeutic benefit to the patient. If not, the FDA can withdraw the product from the market more easily than usual.