The study design that provides the most compelling evidence of a causal relationship between the treatment and the effect, is the randomized controlled trial. Studies in epidemiology such as the cohort study and the case-control study are clinical studies in that they involve human participants, but provide less compelling evidence than the randomized controlled trial. The major difference between clinical trials and epidemiological studies is that, in clinical trials, the investigators manipulate the administration of a new intervention and measure the effect of that manipulation, whereas epidemiological studies only observe associations (correlations) between the treatments experienced by participants and their health status or diseases. Currently some Phase II and most Phase III 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. It has become a common practice to conduct "active comparator" trials (also known as "active control" trials) - in other words, when a treatment exists that is clearly better than doing nothing (i.e. the placebo) for the subject, the alternate treatment would be a standard-of-care therapy. While the term clinical trials is most commonly associated with large randomized studies, many clinical trials are small. They may be "sponsored" by single physicians or a small group of physicians, and are designed to test simple questions. Other clinical trials require large numbers of participants followed over long periods of time, and the trial sponsor is more likely to be a commercial company or a government, or other academic, research body. It is sometimes necessary to organize multicenter trials. Often the centres taking part in such trials are in different countries (in which case they may be termed international clinical trials). The number of patients enrolled in the study also has a large bearing on the ability of the trial to reliably detect an effect of a treatment. This is described as the "power" of the trial. It is usually expressed as the probability that, if the treatments differ in their effect on the outcome of interest, the statistical analysis of the trial data will detect that difference. The larger the sample size or number of participants, the greater the statistical power. However, in designing a clinical trial, this consideration must be balanced with the greater costs associated with larger studies. The power of a trial is not a single, unique value; it estimates the ability of a trial to detect a difference of a particular size (or larger) between the treated and control groups.

Phases

Pharmaceutical 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 pharmaceutical companies start clinical trials on drugs, extensive pre-clinical studies are conducted.

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.

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.

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 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 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.