The what's and why's of clinical trials.

A clinical trial is a scientific experiment testing the efficacy or usefulness and the safety of a new drug or device for a disease in people who have that disease. Clinical trials involve people not test tubes, and so they must be designed with important safeguards. In MS, clinical trials can be particularly difficult. First, MS is highly variable and unpredictable. Natural spontaneous changes in the disease can be confused with treatment benefits. It must be possible to distinguish a true treatment effect from this natural variability.

Second, different agents may have different effects on various types of MS. Thus, trials must be designed to answer questions about effects on a specific disease type and extreme care must be taken to accept only volunteers who have that type of MS.

Third, people with MS are generally highly motivated to search out a treatment. This motivation can actually interfere with objective assessment, because of a phenomenon called the "placebo effect".

Placebo effects - which are improvements that occur simply because of participation in the trial, even if no active treatment is given - are largely psychological in nature. But they have some basis in physiology, related to production of hormones that can affect one's sense of well-being in times of great hope and positive anticipation. Placebo effects must be carefully separated from true treatment effects. For a new agent to be considered useful, it must have an effect that is greater than the placebo effect.

Over the years, clinical investigators have developed strategies for conducting MS clinical trials that avoid these three potential pitfalls.

Generally, clinical trials are done in several phases. First, data must be collected that suggest that a new treatment may be useful in MS - this is the "scientific rationale" for a clinical trial. Such data often come from laboratory studies, often with laboratory mice or rats that have EAE (experimental allergic encephalomyelitis), which is very similar to MS. But sometimes the rationale emerges from experience with human diseases that seem to be related to MS - for instance, rheumatoid arthritis.

Once there is a strong reason for thinking that a treatment may work, the first human studies can begin. These are called toxicity . studies. They are designed to see if the new agent can actually be used safely in people. Traditionally, these studies are called, "Phase I" trials. Only a few, usually seriously ill, people participate, since the potential risk of an untested treatment may be acceptable for them, given the grave nature of their illness. In these, and in all clinical trials, investigators must clearly inform everyone who asks to participate about potential benefits and risks. Each person must formally consent to participate.

If these first studies demonstrate an acceptable risk, researchers may move to larger studies to get a sense of the possible usefulness. Such studies - traditionally called Phase II or Phase Ill studies - document the ability of a new treatment to affect the disease process while they continue the process of assessing safety. These studies must be "controlled", which means the new agent is tested against a "control" substance - which is either an approved and accepted therapy or an inactive sham substance or placebo.

Volunteers are enrolled according to strict criteria - relating to their age, the type and duration of disease, and other factors. Then they are randomly assigned to "treatment" and "control" groups. This process is done without permitting patients or examining, physicians to know who is in which group. This "double-blinding" is essential to reduce bias and ensure objectivity.

For clinical trials at this stage, statistically relevant numbers of participants are essential, so they are often conducted at a number of different sites. You'll see the phrase "multicenter". Multicenter trials also help ensure that the agent can be used equivalently in many different environments.

At the end of double-blind clinical trials, when the treatment codes are broken, the status and performance of treated people are compared with that of people who received the placebo, and the true efficacy and safety of the new agent can be determined. Only if the agent seems to be both effective and relatively safe, can a sponsor (usually a pharmaceutical company) approach the Food and Drug Administration (FDA) for approval to market the agent for MS in the United States.

The FDA will scrutinize the study design, the collected data, and all the toxicity information. This examination is time-consuming but important: the health and safety of thousands of people may be at stake.

Once the FDA formally approves, the new agent may be sold by prescription. The labeling will indicate the type of MS for which it has been found useful and provide full disclosure of side effects and adverse reactions. Even after FDA approval, data continue to be gathered about safety - the post-market analysis - and additional clinical studies may be undertaken to see if the agent is useful for other types of MS, or for other related disorders.

Should you volunteer for a clinical trial?

The key element in any clinical trial is the volunteer - the person with MS who consents to the risk and pledges the time. No new drug can be developed without the selfless involvement of volunteers.

Benefits

* You are participating in a significant clinical experiment that may benefit many thousands of people with MS.

* You are on the cutting edge of medical care for people with MS, with access to new treatments that have not yet been proven beneficial.

* You receive close medical scrutiny - most of it at no cost - during the course of the study.

* If the agent proves to be safe and useful, you may receive medication from a sponsoring pharmaceutical company for a period equal to the clinical trial, or certainly during the time between the end of the trial and the FDA approval.

Risks

* You may receive agents which have the potential for short-or long-term side effects.

* You may be randomized into the placebo group, and thus not receive the active experimental agent

* You will have to refrain from participating in any other experimental studies until this one is complete.

* You will need to make regular - sometimes quarterly or even monthly - doctor visits, and undergo frequent tests such as MRI, blood drawing, or neurologic exams.

* You might volunteer and be rejected.

Why willing volunteers are

sometimes turned down

* Geography: Trials are usually limited to people who are geographically close to centers where the study is being done. Having to travel long distances for regular appointments may mean missed appointments - which could damage a clinical study.

* Type of MS: Trial are generally restricted to one type of MS - such as relapsing-remitting or chronic-progressive - or to people with an identified symptom. Studies are often additionally restricted to those of a certain age, with a certain duration of MS, or with certain levels of disability. People who do not have that profile have to be turned down.

* Present treatment: Prior or current use of some other drug may also prevent participation, as there may be dangerous or confusing effects of the drug in combination with the experimental agent.

Stephen Reingold is vice president of Research & Medical Programs at the National MS Society.