Phases of a Clinical Trial

Clinical trials are broadly divided into four phases, each of which has a specific purpose in the stepwise study of investigational drugs (See Box 1 below). Phase I studies, sometimes referred to as “First-in-Human” trials, are those designed to study the way the body handles an investigational drug and then eliminates it from the blood stream. Various doses are usually administered to subjects based on data obtained from prior studies in animals. Thus, the primary goal of a Phase I trial is not to test how well or how poorly a new compound works, but rather to determine how it is handled by the human body and to be alerted to any signs of toxicity. Accordingly, the vast majority of Phase I trials are conducted in healthy subjects who volunteer (usually for money) to undergo Phase I testing. Sometimes, however, Phase I trials can only be conducted in patients who represent the target population for which the new therapy is intended. Examples of this include the relatively new fields of gene or stem cell therapy or trials involving new anti-cancer agents, administration of which would be unethical in healthy individuals, often because giving these drugs to healthy volunteers would be too risky.

 Phases of a Clinical Trial

  • Phase I: Drug metabolism and dose-ranging studies in healthy volunteers
  • Phase II: Blinded or open-label studies in the target population for safety and efficacy
  • Phase III: Randomized double-blind placebo-controlled study in target population for safety and efficacy
  • Phase IV: Post-marketing study in target population at large

Funding sources: government, industry, private foundations, philanthropy

 

Phase II studies are usually conducted in the target population (for example, a new blood pressure-lowering medication in patients with hypertension) to gain further knowledge about the safety of a drug and how it is handled by the body at doses that might be prescribed once the drug is approved. Some insight can also be gained about the potential biological effectiveness of the drug (as in lowering blood pressure). However, as with a Phase I study, efficacy is not a major endpoint of a Phase II trial because most subjects receive the drug in an “open-label” or “unblinded” fashion. This means that both the investigator administering the drug and the patient know exactly when the drug is administered and at what dose level. Alternatively, Phase II studies may employ a single-blind design in which the investigator compares the test drug against a placebo, which is a substance made to look, smell and taste like the drug but which has no biological activity. In a single-blind trial, patients do not know whether they are receiving the placebo or active drug.

Once sufficient information about how safe the drug is and how the body handles it is obtained through Phase I and II trials, the next step is to rigorously investigate both safety and efficacy in the target population by conducting one or more Phase III trials. The common features of these trials include the following:

  • Randomization: patients are divided into groups by a process somewhat like the flip of a coin to receive either active drug or placebo;
  • Double-blind: neither the patient nor the treating physician knows whether the subjects are receiving drug or placebo;
  • Placebo-controlled: the active drug is almost always compared to an inert placebo, although sometimes the test agent is compared against an already approved drug for the same indication.

For common diseases, such as elevated blood pressure or cholesterol, thousands of patients may be recruited into a Phase III trial. For rare diseases, which are defined by the 1983 Orphan Drug Act as having a frequency of less than 200,000 individuals in the U.S., Phase III clinical trials may be conducted with less than 100 subjects.

If one or more Phase III trials of an investigational therapy are positive, in other words, if the results show that the investigational drug appears to be both safe and efficacious, the sponsor may submit a New Drug Application (NDA) to the FDA that summarizes the results of all the pre-clinical and Phase I-III clinical trials and petition the FDA for approval of the drug for general use in the target population.

Finally, if the drug is approved, it enters post-marketing, or Phase IV, evaluation, which can extend for as long as the drug is prescribed. The purpose of Phase IV studies is to continuously assess the long-term safety of the medication, as determined largely by feedback from physicians and patients in the community. Thus, drugs undergo indefinite surveillance for untoward side effects (and potential new therapeutic indications) that either were not identified or were not considered to be significant during Phase I-III testing.

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