Phases in Clinical Trial

Clinical trial is needed to support effectivity and safety claims of a medicine, and also to support data for approval need by regulatory system. Before a clinical trial is conducted in human, a compound (experimental medicine) is tested to animals first, to show whether the compound gives benefit or not. Animal study is using several dose level, from small to large doses. This is needed to determine how high is lethal dose, how low is an effective dose, how high is safe dose, and how wide/narrow is the safety margin, etc. When the animal trial data would be extrapolated into propose human trial with same agent, dose should be calculated by scientist so that human dose is much smaller than animal dose.

There are four phases of clinical trials: phase I, II, III, and IV. Phase I-III are called experimental trials, and phase IV is postmarket study.



Phase I is needed to confirm effective dose and toxicity (more about its pharmacokinetic). This phase is only involving about 15-50 people. Subjects with certain illness are needed to confirm effectivity, and healthy subjects are needed to confirm safety. Researcher is trying to figure out what is the best way to give this treatment and the highest safe dose. Due to small number of subjects, researcher should monitor them closely and adjust the dose carefully until the balance of maximum effectiveness versus minimum adverse effect is reached. Once the dose is determined, the next phase should keeping use this dose.

Phase II trial is needed to confirm how effective the new medicine is. How many the medicine given is based on phase I trial result. The subject number is about 25-100 to 300 people with illness. Usually there is no comparator medicine used in this phase.
There are two kinds of phase II trials: IIA to confirm the effectiveness of new medicine; and IIB to confirm the adverse effects of new medicine. If the medicine "passes" phase II trial successfully, i.e with benefit/effectiveness and acceptable side effects, this medicine should go on to phase III trial.

Phase III trials are needed to confirm whether the new medicine is better than previous/existing medicines used for a condition; with secondary endpoint of safety concerns. Usually use a comparator medicine/treatment. This phase is considered as the most important part of clinical trial. This phase usually is involving more patients; about thousands of subjects. The trial should be designed as double-blinded and randomized. If it is necessary, researcher creates interim analysis to watch out how the medicine affects subject's body carefully.
Phase III trial is important as a condition to pass regulatory system, to clear the medicine for market purpose. It is needed at least 2-3 positive-result phase III trials for this purpose.

Phase IV trial is needed to confirm effectiveness and safety for other conditions or an off-label indication (legal indication expansion purpose). The other purpose of phase IV trial is to assess benefit-risk balance and postmarket adverse effects. Blackbox warning addition, label revision, or withdrawal process are usually based on a phase IV trial.

References:
Phillips T.  The Stages of Clinical Trial, available from http://biotech.about.com/b/2009/01/01/221.htm (last modified on January 1, 2009)
What are the different stages/phases of clinical trials (http://www.breastcancer.org/treatment/clinical_trials/phases.jsp, last modified on February 17, 2009)