Preclinical Studies

Before pharmaceutical companies start clinical trials on a drug, they conduct extensive preclinical studies, which involve in vitro (i.e., test tube or laboratory) studies and trials on animal populations (in vivo). Wide-ranging dosages of the study drug are given to the animal subjects or to an in-vitro substrate in order to obtain preliminary efficacy, toxicity and pharmacokinetic information (basically what a drug does to a body) and to assist in deciding whether it is worthwhile to go ahead with further testing.

Phase 0 (a very small number of human subjects: 10–15)

Phase 0 is a recent designation for exploratory, first-in-human trials conducted in accordance with new FDA guidelines. Phase 0 trials also are known as human microdosing studies and are designed to speed up the development of promising drugs by establishing very early on whether the drug behaves in human subjects as was anticipated from preclinical studies. They enable go/no go decisions to be based on relevant human models instead of relying on animal data, which can be unpredictive and can vary between species.
Phase I (a small group of human subjects: 20–80) Phase I trials are the first “official” stage of testing in human subjects. Normally, a small group of healthy volunteers will be selected. This phase includes trials designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of a drug. These trials often are conducted in an inpatient clinic, where the subject can be observed. The goal is to determine what the drug’s most frequent side effects are and, often, how the drug is metabolized and excreted.

Phase II (the number of subjects ranges from a few dozen to about 300)

Phase II studies begin if Phase I studies don’t reveal unacceptable toxicity. While the emphasis in Phase I is on safety, the emphasis in Phase II is on effectiveness. This phase aims to obtain preliminary data on whether the drug works in people who have a certain disease or condition. For controlled trials, patients receiving the drug are compared with similar patients receiving a different treatment—usually a placebo or a different drug. Safety continues to be evaluated, and short-term side effects are studied. Typically, at the end of Phase II the FDA and sponsors try to come to an agreement on how the large-scale studies in Phase III should be done.

Phase III (The number of subjects usually ranges from several hundred to about 3,000 people)

Phase III studies begin if evidence of effectiveness is shown in Phase II. These studies gather more information about safety and effectiveness, studying different populations and different dosages and using the drug in combination with other drugs. While not required in all cases, it is typically expected that there will be at least two successful Phase III trials, in order to obtain approval from the FDA.

Phase IV

A Phase IV trial also is known as a Post-Marketing Surveillance Trial. Phase IV trials involve the safety surveillance and ongoing technical support of a drug after it receives permission to be sold. The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being no longer sold or restricted to certain uses; a recent example is the drug Vioxx (rofecoxib).

For more information on Alzheimer’s drug development, visit www.alzforum.org, which provides a thorough, more technical explanation of drug discovery, and www.clinicaltrials.gov, which provides information on becoming involved in clinical trials.