Clinical trial: Encyclopedia II - Clinical trial - Phases

Clinical trial - 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.

Before embarking on costly clinical trials, pharmaceutical companies will perform pre-clinical development to ensure that their investment is wise.

Clinical trial - Phase I

Phase I trials are the first-stage of testing in human subjects. Normally a small (20-80) group of healthy 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. 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 I trials of new cancer drugs are a little different. These studies are ususally carried out in patients with advanced (metastatic) cancer. These trials are usually offered to patients who have had other types of therapy and who have few other treatment choices.

There are two specific kinds of Phase I trials - SAD studies, and MAD studies.

SAD - Single Ascending Dose studies are those in which groups of three or six patients are given a small dose of the drug and observed for a specific period of time. If they do not exhibit any adverse side effects, a new group of patients is then given a higher dose. This is continued until intolerable side effects start showing up, at which point the drug is said to have reached the Maximum tolerated dose (MTD).

MAD - Multiple Ascending Dose studies are conducted to better understand the pharmacokinetics/pharmacodynamics of the drug. In these studies, a group of patients receives a low dose of the drug and the dose is subsequently escalated upto a predetermined level. Samples (of blood, and other fluids) are collected at various time points and analyzed to understand how the drug is processed within the body.

Clinical trial - 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.

Clinical trial - Phase III

Phase III studies are large double-blind randomized 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 (EMEA) or the Food and Drug Administration (FDA) in the United States) for marketing approval.

Clinical trial - 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).

Adapted from the Wikipedia article "Phases", under the G.N U Free Docmentation License. Please also see http://en.wikipedia.org/wiki