Phases of Clinical Trials

There are several phases of studies used to bring a medication to market.

Preclinical Studies

This phase consists of the laboratory studies of a medication. The medicine must be produced and the production process standardized so that a reliable product can be created. Also, the medication must be tested in animals for safety and dose. This is usually tested in at least 3 species of animals for safety (commonly mice, rats and rabbits). The safety of the medication in pregnant animals is also usually tested. The safety testing ranges from low doses to very high doses. It is also important to determine the dose. This is usually done in an animal model of multiple sclerosis called experimental allergic encephalomyelitis (EAE). EAE is not an animal model of multiple sclerosis, but it does represent a good system to study the effects of a treatment in an immune disorder of the nervous system. At the end of the preclinical studies, a medication must show some benefit in EAE, at achievable doses with acceptable safety.

Phase I Trials

Phase I trials are the first time that a medication has been given to humans. The phase I study has 2 purposes: safety and dose finding. Oftentimes, the medication is started at a low dose. After several patients have successfully received the low dose, the dose is increased. The dose continues to be increased until a target is reached. This target can be a target level that worked in the animal studies, or it can be based on some marker of the medication’s activity such as a blood level of the drug. This allows the dose to be determined. There are many tests for safety including blood tests, ECGs and other measurements. MRIs are usually done to assure that the medication dose not worsen the multiple sclerosis. For multiple sclerosis studies, 10-80 patients are usually included in phase I studies.

Phase II Trials

Phase II trials include larger numbers of patients and the introduction of a comparison group (usually a placebo). The primary purpose of the phase II study is to obtain additional safety data. This again includes blood tests, ECGs and other measures of safety. If there were any areas of concern identified in the phase I study, then additional testing in this area will be included. The other purpose of the phase II study is to collect information needed to design the phase III study. This means that various measures to determine effectiveness must be included. In multiple sclerosis, this commonly includes measures of MRI as well as measures of multiple sclerosis attacks and physical function. The phase II study is not large enough to prove that a medication is successful, but the data from this study can be used to calculate the size of the phase III study that will be required. For multiple sclerosis studies 80-200 patients are usually included in phase II studies.

Phase III Trials

Phase III trials are the final study used to prove that a medication is successful. If these studies are positive then the medication can be released to the market by the FDA. The phase III study must have one primary outcome measure that is the primary endpoint, and this endpoint must be clinically important (for multiple sclerosis usually attacks or disability). Many secondary endpoints may be included such as various MRI measures. The secondary endpoints help confirm the findings of the study, but the primary endpoint is the one that will determine whether the study is a success. MRI cannot be used as a primary endpoint because it is not clear whether a change on the MRI will be relevant to the person’s day-to-day life. Phase III studies also collect safety data. In multiple sclerosis, phase III studies have 250 to over a thousand patients. The FDA also usually requires that at least 2 phase III studies be conducted for a medication to come to market.

Phase IV  Trials

Phase IV trials occur after a medication is on the market. These are also called post-marketing studies. These are required to look for additional safety data as larger numbers of patients are treated with the medication. In addition, studies may be done to expand the types of patients treated with the medicine, or the diseases it is used for. The safety studies in phase IV involve tens of thousands of patients.