Phases of a Clinical Trial
Clinical Trial Phase: Clinical trials are done in phases that have different purposes and help researchers answer different questions. Each phase of the drug approval process is treated as a separate clinical trial. The drug-development process will normally proceed through all four phases over many years. If the drug successfully passes through Phases 0, 1, 2, and 3, it will usually be approved by the national regulatory authority for use in the general population. The number of subjects in a trial is a critical factor in determining a drug’s efficacy, as well as influencing the study’s perceived credibility. While it may take only a few subjects to uncover major toxicities, many more participants are needed to determine conclusively that an agent works. With a small number of subjects, there is always the possibility that an outcome could be the result of chance rather than being a true effect of an experimental therapy. Researchers, therefore, try to include enough subjects in their trials so that the results will be considered statistically significant, or very unlikely to be due to chance alone. The ability of a study to produce statistically significant data is known as its power.
Per the FDA CFR, “An IND may be submitted for one or more phases of an investigation. The clinical investigation of a previously untested drug is generally divided into three phases. Although in general the phases are conducted sequentially, they may overlap. These three phases of an investigation are a follows:”
Phase I clinical trials test new treatments in small groups of people and are monitored very closely for safety and side effects (typically 15-30 participants). These studies evaluate a compound’s pharmacokinetics – how it is absorbed, metabolized, processed, distributed, and eliminated by the body. At this stage researchers also try to determine an optimal amount of the agent, the maximum tolerated dose (MTD) that will offer the most benefit without unacceptable toxicity or dose-limiting toxicity (DLT), a process known as dose-ranging (starting dose guidelines). The MTD is used as the recommending dose level for the Phase II study. Versus the DLT which in general is defined as unacceptable yet reversible severe organ toxicity.
Phase II clinical trials evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and further review these treatments for safety (typically less than 100 participants) to determine the common short-term side effects and risks associated with the drug. Once it is established that there are no major safety concerns, an agent is further tested to see whether it still appears safe in a larger cohort of people. These studies also provide preliminary data on a candidate’s efficacy (activity, or how well it works). Sometimes these trials are divided into Phase IIa (pilot studies) and Phase IIb (small controlled trials). The study period is longer than for Phase I trials, usually several months to two years. In an effort to speed the development process, trial stages are sometimes combined (Phase I/II or Phase II/III). This stage is where most drug candidates are weeded out; only about one third of experimental agents successfully make it through Phase II studies.
Phase III clinical trials use larger groups of people to confirm how well treatments work, further examine side effects, and compare new treatments with other available treatments (typically 100 to several thousand participants). They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling. Phase 3 trials include large numbers of people to make sure that the result is valid. These trials usually last at least a couple of years, and often considerably longer. The most rigorous type of study is the prospective, double-blind, randomized, controlled trial (described in detail below), which compares a candidate drug against either a placebo (dummy drug) or a currently available therapy. During this stage, researchers continue to monitor the agent’s safety, since some toxicities may become apparent only after a drug is used in larger groups or over longer periods. Data from the final Phase III studies — called pivotal trials — may be submitted to the FDA as part of a New Drug Application (NDA) to be considered as evidence for approval.
- There are also very early (phase 0) and later (phase 4) phase clinical trials. These trials are less common. Phase 0 trials are very small trials that help researchers decide if a new agent should be tested in a phase 1 trial. Phase 4 trials look at long-term safety and effectiveness. They take place after a new treatment has been approved and is on the market to see how well it works under “real world” conditions and to determine whether its efficacy is durable, or long-lasting. Importantly, post-marketing studies also look for uncommon or long-term toxicities that did not show up in earlier trials. Over time, more information may be revealed about interactions with other drugs and use in different populations, such as people with coexisting conditions.