Trial Phases for Investigating Drugs and Treatments

Every approved treatment for MS has undergone extensive study prior to receiving approval by the United States Food and Drug Administration (FDA). The process of testing a new drug therapy for MS is time-consuming, and all drugs must undergo several phases of investigation in order to be deemed both safe and effective.

Before a pharmaceutical company can initiate testing in humans, it must conduct extensive preclinical or laboratory research. This research typically involves years of experiments in animal and human cells, to develop compounds that have the desired biological effect. Once such a drug is developed, it is often tested on animals before human studies can even begin. The clinical testing of experimental drugs is normally done in three phases, with each successive phase involving a larger number of people. Sometimes fourth-phase trials are conducted after approval for additional data on effectiveness and adverse events over a longer period of time.

MS poses a specific set of challenges for clinical research. It is a highly-variable condition that affects everyone differently. Choosing the correct population of MS patients to study poses formidable challenges to clinical research, and is a major reason why accurately comparing the results of different MS drug trials (in order to answer the question “which drug is better?”) is impossible.

In addition, MS varies over time, even within the same person. He or she may experience “good days” and “bad days,” as well as actual MS relapses that last for days to weeks and even months. Symptoms may persist from previous relapses, and other effects, such as fatigue, stiffness, and pain, are difficult to study.

Choosing what outcome to study is another challenge to MS research design. Some of the most commonly studied include: number of relapses; time to next relapse; number of new lesions seen on MRI; and cumulative disability (as measured by the EDSS). “EDSS” refers to the Kurtzke Expanded Disability Status Scale, which uses numbers from one to 10 to measure degree of disability, largely in terms of mobility.

All of these variables take time to assess. In general, several years of research are needed for an MS drug to even begin Phase III testing. Once begun, Phase III trials require several months to enroll, often two years to conduct, and another year for the results to be fully analyzed and published. Obtaining FDA approval after studies are complete usually takes the better part of a year as well. The standards for proving that a drug is safe for patients and proven effective against MS are incredibly high, and many years of work are necessary to meet these standards.

PHASE I: Phase I studies are primarily concerned with assessing the drug’s safety. This initial phase of testing in humans is done in a small number of healthy volunteers, and is designed to determine what happens to the drug in the human body – how it is absorbed, metabolized, and excreted.

Phase I trials are referred to as “open label” and “unblinded,” because everyone – the patient, medical staff, and investigators – knows the drug and dose that each participant is receiving. A Phase I study will investigate side effects that occur as dosage levels are increased. Phase I trials can take several months to one year to complete.

PHASE II: Once a drug has been shown to be safe, it must be tested for efficacy. This second phase of testing may last from several months to two years, and involve up to several hundred patients. Phase II studies are often “double-blinded,” meaning that the participants, medical staff, and investigators are not told who is receiving the drug and who is receiving the placebo.

These studies are also “randomized,” so that participants are assigned to treatment groups (or “treatment arms”) based on chance. One group of patients receives the experimental drug, while a second “control” group will receive a standard treatment or placebo. In this manner, the study can provide information to the pharmaceutical company and the FDA about the relative safety of the new drug, and its effectiveness.

In multiple sclerosis (MS), Phase II trials frequently use disease-activity measurements determined through MRI scans (such as new lesions or gadolinium-enhancing lesions) as the primary outcomes. MRI scans are used because this sort of data can be obtained more quickly and with fewer patients versus determining clinical outcomes, such as relapse rates or permanent disability. Only about one-third of experimental drugs successfully complete both Phase I and Phase II studies.

PHASE III: In a Phase III study, a drug is usually tested in several hundred to several thousand patients, usually in multiple medical facilities around the world. Phase III studies typically last two or more years. This large-scale testing provides the pharmaceutical company and the FDA with a more thorough understanding of the drug’s effectiveness, benefits, and the range of possible adverse reactions.

Most Phase III studies are randomized and blinded trials. Only after a Phase III study is successfully completed can a pharmaceutical company request FDA approval for marketing the drug.

PHASE IV: Phase IV clinical trials are conducted after a drug has been approved. Participants are enrolled to further monitor safety and side effects, while evaluating long-term efficacy.