Chapter 58: Phase-Appropriate GMP Requirements

The United States Food and Drug Administration (FDA) published a final rule in the Federal Register on “Current Good Manufacturing Practice and Investigational New Drugs Intended for Use in Clinical Trials,” effective September 15, 2008. This guidance takes into consideration the nature of phase 1 clinical studies. It recognizes that the studies are of short duration, in well-controlled clinical settings with healthy subjects; therefore, it exempts most phase 1 investigational drugs and the active pharmaceutical ingredients (APIs) for the Investigational New Drug (IND) from compliance with 21 CFR 210 and 211. FDA is considering guidelines on investigational drugs used for phase 2 and phase 3 clinical trials; however, until they are published, 21 CFR 210 and 211 continue to apply.

In Europe, the Clinical Trials Application (CTA) requires good manufacturing practices (GMP) for all clinical trial phases and focus on the quality of the end product, and places emphasis on the qualified person (QP) for oversight of product quality.

Clinical Trial Phases

FDA has five categories for describing the clinical trial of a drug based on the study’s characteristics, such as the objective and number of participants. The five phases are:

• Phase 0. Exploratory study involving very limited human exposure to the drug, with no therapeutic or diagnostic goals (for example, screening studies, microdose studies).

• Phase 1. Studies that are usually conducted with healthy volunteers (20 to 80 people) and that emphasize safety. The goal is to discover the drug’s most frequent and serious adverse events and, often, how the drug is metabolized and excreted.

• Phase 2. Studies that gather preliminary data (100 to 300 people) on effectiveness (that is, whether the drug works in people who have a certain disease or condition). For example, participants receiving the drug may be compared with similar participants receiving a different treatment, usually an inactive substance (called a placebo) or a different drug. Safety continues to be evaluated, and short-term adverse events are studied.

• Phase 3. Studies that gather more information about safety and effectiveness by studying different populations (1000 to 3000 people) and different dosages, and by using the drug in combination with other drugs.

• Phase 4. Studies occurring after FDA has approved a drug for marketing. These including post-market requirement and commitment studies that are required of or agreed to by the sponsor. These studies gather additional information about a drug’s safety, efficacy, or both.