The Food and Drug Administration (FDA) descriptions of the clinical trial of a drug are based on the study's characteristics, such as the objective and number of participants. There are five phases:
Types of Studies
Pre Clinical Studies
Pre-clinical studies involve in vitro (i.e., test tube or laboratory) studies and trials on animal populations. Wide ranging dosages of the compounds are introduced to the animal subjects or to an in-vitro substrate in order to obtain preliminary efficacy and pharmacokinetic information and to assist pharmaceutical companies in decisions regarding further development of the test compound, test item or test article.
Phase 0 is a recent designation for exploratory, first-in-human trials conducted in accordance with the Food and Drug Administration (FDA) 2006 Guidance on Exploratory Investigational New Drug (IND) Studies. Phase 0 trials are designed to expedite the development of promising therapeutic or imaging agents by establishing very early on whether the agent behaves in human subjects as was anticipated from preclinical studies. Distinctive features of Phase 0 trials include the administration of single subtherapeutic doses of investigational agent to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacokinetic and pharmacodynamic properties and mechanism of action.
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 (Pharmacovigilance), 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 so 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 volunteers, however there are some circumstances when patients are used, such as with oncology (cancer) and HIV drug trials. In Phase I trials of new cancer drugs, for example, patients with advanced (metastatic) cancer are used. These trials are usually offered to patients who have had other types of therapy and who have few, if any, other treatment choices.
There are different kinds of Phase I trials:
Single Ascending Dose studies are those in which small groups of patients are given a single dose of the drug while they are observed and tested for a period of time. If they do not exhibit any adverse side effects, and the pharmacokinetic data is roughly in line with predicted safe values, the dose is escalated, and a new group of patients is then given a higher dose. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the Maximum tolerated dose (MTD)).
Multiple Ascending Dose studies are conducted to better understand the pharmacokinetics & pharmacodynamics of multiple doses of the drug. In these studies, a group of patients receives multiple low doses of the drug, whilst samples (of blood, and other fluids) are collected at various time points and analyzed to understand how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level.
3. Food effect
A short trial designed to investigate any differences in absorption caused by eating pre-dose, and its effect on the pharmacokinetic profile. These studies are usually run as a crossover study, with volunteers given two identical doses of the drug on different occasions; one while fasted, and one after being fed.
Once the initial safety of the therapy has been confirmed in Phase I trials, Phase II trials are performed on larger groups (20-300) and are designed to assess the activity of the therapy, as well as to continue Phase I safety 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 activity or toxic effects. Phase II studies are sometimes divided into Phase IIA and Phase IIB. Phase IIA is specifically designed to assess dosing requirements, whereas Phase IIB is specifically designed to study efficacy. Some trials combine Phase I and Phase II into a single trial, monitoring both efficacy and toxicity. Some phase II trials are designed as case series, demonstrating safety and activity in a selected group of patients. Other phase II trials are designed as randomized clinical trials, complete with a treatment arm and a comparison arm. Randomized phase II trials have far fewer patients than randomized phase III trials.
Phase III studies are randomized controlled trials on large patient groups (300-3,000 or more depending upon the condition) and are aimed at being the definitive assessment of the efficacy of the new therapy, in comparison with current 'Gold Standard' treatment. 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 for marketing approval. It is also common practice with many drugs whose approval is pending, that certain phase III trials will continue. This typically serves to provide lifesaving products after involvement in a clinical trial until the marketed product can be obtained. Other reasons for performing trials at this stage include attempts at "label expansion" to prove additional efficacy for uses beyond the original use for which the drug was designed, to obtain additional safety data, or to support marketing claims. Studies in this phase are by some companies categorized as "Phase IIIB studies."
While not required in all studies, it is typically expected that there be at least two successful phase III trials, proving a drug's safety and efficacy, for approval from the standard regulatory agencies (FDA, TGA, EMEA, etc.). Though the current trend in recent months seems to be a move toward adaptive (live, changing) studies to expedite the process, there are no formal regulations for these trials in the pharmaceutical industry as of yet.
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 (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials). 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.