Clinical Trials

How treatment trials are conducted, the challenges MS poses, and trial phases

Conducting Treatment Trials

When conducting treatment trials (known as "clinical trials"), half of the participants often receive a placebo. A placebo is medication with no active ingredients or physical value of any kind. Those receiving the placebo are said to be in the "control group" and are also referred to as "controls."

The control group shows researchers what the treated group would experience, under the same exact conditions, without the drug. By comparing the control group to the treated group, the drug's effectiveness may be accurately evaluated.

When conducting clinical trials, great efforts are made to have members of the treated group be as close to identical as possible to those in the control group. The trials are usually "randomized," which means that the participants are allocated to the treatment or control group through random numbers.

In "single-blinded" trials, the participants or the evaluating doctors do not know who is being given the real drug and who is being given the placebo. In "double-blinded" trials, neither the participants nor the medical staff administering or evaluating the new treatment are told who is receiving the drug and who is receiving the placebo. Results are reported to members of a
separate medical staff, who are aware of what each patient is receiving. Studies that are double-blinded are considered more "rigorous" (scientific, or likely to be correct).

Studies that have the treatment and control groups exchange treatments after a predetermined period of time are called "crossover trials." These are not as common in MS trials because disease response to treatments is often slow and may not begin or end immediately.

Typically with MS, some of the placebo group will improve without active treatment. Treatments are considered successful only when the rates of stabilization or improvement exceed those of the controls.

Challenges with MS Trials

Trials for new agents in the treatment of MS pose particular challenges to researchers. Their goals are to first establish safety and dose and then the effectiveness of a drug or therapy. They also must determine if the positive effects outweigh any side effects that occur.

Perhaps the greatest obstacle faced is the behavior of the disease, which naturally relapses and remits at the onset for 80 percent of the people who have MS. When a new agent is administered, clinicians have difficulty determining if an improvement or worsening was caused by the particular treatment, if it occurred independent of the treatment, or if the treatment enhanced or lessened the positive or negative outcome.
For this reason, matched controls are needed in an effort to determine what the outcome would have been without treatment. Controls must be carefully selected, with particular attention given to demographic characteristics (such as age, gender, and duration as well as severity of MS) prior to enrollment.

Trials for MS are also difficult to design and evaluate since the cause of this disorder is still unknown and the mechanisms involved with its development are extremely complex. Additionally, MS trials are often small (fewer than 150 patients), short in duration (less than three years), and outcome measures (such as exacerbation rate and severity, change in disability, and disease progression) are difficult to consistently measure.

Compounding these challenges is the fact that most people with MS have already received treatment, making them less desirable candidates in trials. And with a disease like MS, where so many fluctuations can occur, the trials also tend to have a high dropout rate. This can bias the trial toward those who had positive changes, while not counting the ones who dropped out from either group because their symptoms worsened.

Now that treatments are available to reduce exacerbations and slow progression, large placebo-controlled studies may no longer be ethical. New trials may compare those receiving the new treatments to controls who are taking one of the presently approved drugs for MS (including Avonex®, Betaseron®, Rebif®, Copaxone®, and Novantrone®). These would be "open" trials, where both the treating physicians and the participants know what drug is being administered. Those who read the MRIs and the evaluating doctors could still be "blinded."

Trial Phases and Analysis

When referring to a trial, the particular phase is always mentioned. Each phase corresponds to a level the study has reached, and trials must complete each required phase before moving on to the next one.

Drug therapies always begin in the preclinical phase, where animal studies are performed. Using animal models of the disease, researchers look at safety, side effects, and how the disease may be affected.

Phase I trials test the treatment on humans and are considered preliminary. These studies are for establishing the optimal dose as well as safety and include only a small number of participants. They are also unblinded and open-label, so everyone is aware of what is being administered.

Once the trials enter phase II, efficacy comes into the picture. These studies are also small, but now include a control group and are double-blinded. In addition to looking at the effects of the treatment on the disease, safety and side effects are still a big part of the study.

Phase III is the final testing phase for a drug. These studies are large and are conducted at more than one center, referred to as "multicenter." They are randomized, double-blinded, and placebo-controlled.

Phase IV trials are done after a drug has been approved. Participants are enrolled to further monitor safety and side effects, while evaluating continued efficacy.

All five phases (beginning with "preclinical") are necessary to be considered for FDA approval. If a drug has already been through safety studies for another indication, early phases may not need to be repeated. After phase III, a data analysis is done to determine the overall effectiveness and safety of the drug or therapy.

If the results are positive, an application for approval of the drug is submitted to the FDA, whose panel reviews the results and recommends approval if they find the treatment to be beneficial and safe. Once approved, the drug company that conducted the research may then market its drug in the US for the specific indication (or illness) for which it was approved. Physicians have the option to prescribe an approved medication for other indications if appropriate.

A prospective trial is one that specified the specific treatments (in terms of drug, dose, route of administration, frequency, etc.), as well as techniques for evaluation (such as MRI, lab studies, EDSS, etc.) in advance, so the possible outcomes were considered during the planning stages. This type of trial is the most scientific and results in the most reliable findings of any trial.

When researchers look back at a trial already conducted to evaluate effectiveness, they are doing a retrospective trial. A
meta-analysis looks at all the trials conducted on a particular treatment and reviews the findings to make an overall evaluation of a treatment's performance and safety.