Phase 0 represents pre-clinical testing in animals to obtain pharmacokinetic information.

Phase I trials investigate the effects of various dose levels on humans, The studies are usually done in a small number of volunteers (sometimes persons without the disease of interest or patients with few remaining treatment options) who are closely monitored in a clinical setting. The purpose is to determine a safe dosage range and to identify any common side effects or readily apparent safety concerns. Data may be collected to provide a description of the pharmacokinetics and pharmacodynamics of the compound, estimate the maximum tolerated dose (MTD), or evaluate the effects of multiple dose levels. Many trials in the early stage of therapy development either investigate treatment mechanism (TM) or incorporate dose-finding (DF) strategies.

To a pharmacologist, a TM trial is a pharmacokinetics study in which an attempt is made to investigate the bioavailability of the drug at various sites in the human system. To a surgeon, a TM study investigates the operative procedure. A DF trial usually tries to determine the maximum tolerated dose, or the minimum effective dose, etc. Thus, phase I (drug) trials can be considered TM and DF trials.

A Phase II trial typically investigates preliminary evidence of efficacy and continues to monitor safety. A Phase II trial may be the first time that the agent is administered to patients with the disease of interest to answer questions such as: What is the correct dosage for efficacy and safety in patients of this type? What is the probability a patient treated with the compound will benefit from the therapy or experience an adverse effect? Most trials in the middle stage of therapy development investigate safety and efficacy (SE). The experimental drug or treatment is administered to as many as several hundred patients in Phase II trials.

At the end of Phase II, a decision will be made as to whether or not the drug is promising and development should continue. In the U.S. there will be an ‘End of Phase II’ meeting between the pharmaceutical company and the FDA to discuss safety and plans for Phase III studies. Ineffective or unsafe compounds should not proceed into Phase III trials.

A Phase III trial is a rigorous clinical trial with randomization, one or more control groups, and definitive clinical endpoints. Phase III trials are often multi-center, accumulating the experience of thousands of patients. Phase III trials address questions of comparative treatment efficacy (CTE). A CTE trial involves a placebo and/or active control group so that precise and valid estimates of differences in clinical outcomes attributable to the investigational therapy can be assessed.

If things go well during Phase III, the company with the license for the compound will submit an application for approval.to market the drug. U.S. FDA approval hinges on ‘adequate and well-controlled’ pivotal Phase III studies that are convincing of safety and efficacy.

A phase IV trial or expanded safety trial occurs after the regulatory approval of the new therapy. As the usage of the new drug becomes widespread, there is an opportunity to learn about rare side effects and interactions with other therapies. An expanded safety (ES) study can provide important information that was not apparent during drug development. For example, a few thousand patients might be involved in all of the SE and CTE trials for a particular therapy. An ES study, however, could involve >10,000 patients. Such large sample sizes can detect more subtle safety problems for the therapy if such problems exist. Some Phase IV studies will have a marketing objective for the company as well as collect safety data.

The terminology of phase I, II, III, and IV trials do not work well for non-pharmacologic treatments and does not account for translational trials

Most trials in the early stage of therapy development either investigate treatment mechanism (TM) or incorporate dose-finding (DF) strategies.

Some studies performed prior to large scale clinical trials are characterized as translational studies. Translational studies have as their primary outcome a biological measurement or target that has been derived from an accepted model of the disease process. The results of the translational study may provide evidence of a mechanism of action for a compound. Target validation can be an objective of such a study. Large effects on the target are sought. For example, a large change in the level of a protein, or the activity of an enzyme might support the therapeutic activity of a compound. There is an understanding that translational work may cycle from preclinical lab to a clinical setting and back again. Although the translational studies have a written protocol, the treatment may be modified during the study. The protocol should clearly define what would be considered ‘lack of effect’ and the next experimental step for any possible outcome of the trial.