In medicine, a clinical trial (synonyms: clinical studies, research protocols, medical research) is a research study.
Types of clinical trial
The most commonly performed clinical trials evaluate new drugs or medical therapies to patients in strictly scientifically controlled settings. The purpose of such trials is to determine whether one or more treatment options are safe, effective, and better than current standard care. They are designed to be ethical, they must involve the full and informed consent of participating human subjects and they are closely supervised by the appropriate authorities. They usually must be approved by an ethics committee before permission is granted to run the trial.
The most statistically significant, and therefore the trial that gives the best form of medical evidence, is the randomized controlled trial. Other forms of clinical trials such as the cohort study and the case-controlled trial are still useful but provide less compelling evidence than the randomized controlled trial.
Currently most drug trials are designed to be randomized, double-blind, and placebo-controlled. This means that each study subject is randomly assigned to receive one of the treatments, which might be the placebo. Neither the subjects nor scientists involved in the study know which study treatment is being administered to any given subject; and, in particular, none of those involved in the study know which subjects are being administered a placebo.
Most clinical trials require large numbers of participants and sometimes it is necessary to organize multicentre clinical trials. Often the centres taking part in such trials are in different countries (in which case they are termed international clinical trials).
The number of patients enrolled in the study also has a large bearing on the study-power of the trial. The larger the sample size, the greater the study-power. However, in designing a clinical trial, this consideration must be balanced with the greater costs associated with larger studies.
Phases
Drug clinical trials are commonly classified into four phases, and the drug-development process will normally proceed through all four stages over many years. If the drug successfully passes through the first three phases, it will usually be successfully approved for use in the general population.
Phase I
Phase I trials are the first-stage of testing in human subjects. Normally a small (20-80) group of healthy (usually male) volunteers will be selected. This phase includes trials designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of a therapy. These trials are almost always conducted in an inpatient clinic, where the subject can be observed by full-time medical staff. They are not blinded and there is usually no need for placebo control. The subject is usually observed until several half-lives of the drug have passed. Phase I trials also normally include dose-ranging studies such that doses for clinical use can be refined. The tested range of doses will usually be a small fraction of the dose that causes harm in animal testing. Phase I trials most often include healthy subjects. Other groups commonly tested include subjects who are renally or hepatically impaired.
Phase II
Once the initial safety of the therapy has been confirmed in Phase I trials, Phase II trials are performed on larger groups (100-300) and are designed to assess clinical efficacy of the therapy; as well as to continue Phase I assessments in a larger group of volunteers and patients. The development process for a new drug commonly fails during Phase II trials due to the discovery of poor efficacy or toxic effects.
Phase III
Phase III studies are large double-blind randomised controlled trials on large patient groups (1000-3000 or more) and are aimed at being the definitive assessment of the efficacy of the new therapy, especially in comparison with currently available alternatives. Phase III trials are the most expensive, time-consuming and difficult trials to design and run; especially in therapies for chronic conditions. Once a drug has proven satisfactory over Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to various regulatory authorities in different countries (such as the Therapeutic Goods Administration (TGA) in Australia, the European Medicines Agency (EMA) or the Food and Drug Administration (FDA) in the United States) for marketing approval.
Phase IV
Phase IV trials involve the post-launch safety surveillance and ongoing technical support of a drug. Phase IV studies may be mandated by regulatory authorities or may be undertaken by the sponsoring company for competitive or other reasons. Post-launch safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and timescale than was possible during the initial clinical trials. Such adverse effects detected by Phase IV trials may result in the withdrawal or restriction of a drug - recent examples include cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).
References
Rang HP, Dale MM, Ritter JM, Moore PK (2003). Pharmacology 5 ed. Edinburgh: Churchill Livingstone.