Understanding Placebo-Controlled Trials

The idea of trying an experimental therapy is often regarded positively, despite knowing that risks may be present. However, some people have misgivings when they learn that some participants in a trial may receive a placebo rather than the drug being tested. Every ALS researcher has been asked the very reasonable question, why use placebos in a trial for a disease as serious as ALS?

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A placebo is an inactive substance that looks and tastes like the drug being tested but has no effect on the disease that the new drug is intended to treat. A placebo is sometimes called a sugar pill, or dummy. The active treatment is the drug or other form of treatment that researchers are testing to see if it will help people living with ALS.

A placebo-controlled trial is a trial in which there are two (or more) groups. One group is given the active treatment, while the other group is given the placebo. Otherwise, everything else is in the trial is structured the same between the two groups. Thus, any difference in a participant’s outcome can be attributed to the active treatment.

In a double-blind trial, neither the researchers nor the research participants know who is being given active treatment and who is getting placebo. A monitoring group independent from the study randomly assigns participants to one group or the other, keeping track of the group assignments throughout the study. At the end of the trial, the “blind is broken,” and the researchers and participants find out who received active treatment and who received placebo.

In contrast, in an open-label trial, both researchers and patients know the patient is receiving an active treatment. The placebo effect refers to the tendency humans have to feel better or a possible improvement when we think we are receiving a treatment that will help us. The placebo effect can occur whether a treatment is actually helping, when it is doing nothing, or when it is in fact causing harm.


The double-blind, placebo-controlled trial is considered the “gold standard” for clinical trials, because it has the best chance of determining whether an active treatment is effective. This is true for several important reasons:

  • Because no one knows if they are receiving active treatment, the chances are reduced that any benefit seen will be due to the placebo effect.
  • People with ALS are a diverse group. One important way in which they differ is in the speed of progression of their illness: some people progress slowly, while others, unfortunately, progress more quickly. By randomly assigning subjects to active treatment and placebo groups, that diversity is spread equally between the groups. This increases the chances that any benefit seen will be due to differences in treatment, rather than differences in the patients in each group.

The fastest way to develop new treatments for all people with ALS is to test new drugs in studies designed to give the answer quickly and without doubt. Currently, this is only possible by comparing the active treatment (new therapy) with a placebo.

Two recent ALS clinical trials show how important double-blind, placebo-controlled trials are in weeding out ineffective treatments:

  • An open-label trial of lithium in a small number of patients suggested this drug helped slow the disease. But a larger, placebo-controlled, double-blind trial found no effect. Without that trial, many ALS patients may have gone on to take a useless medication.
  • Animal studies and open-label human trials suggested the antibiotic minocycline was beneficial. But a larger, placebo-controlled trial showed it was not, and may even have been harmful. Without that larger trial, patients may have continued taking minocycline, causing harmful effects without helping their disease.

Only with placebo-controlled trials could these two treatments be ruled out as ineffective in ALS, saving patients from taking medicines that offer no benefit and that could even be dangerous. An important point to remember is that experimental drugs are indeed experimental. That means that the drug can have a positive effect, no effect at all, or be detrimental. It is sometimes difficult to keep in mind that a patient on a placebo may actually be getting better treatment than someone on the active medication. A trial with a negative result is very disappointing to both participants and study organizers. But every trial teaches us something valuable and makes subsequent trials more likely to succeed. The disappointment of negative trial results such as these only strengthens our commitment to finding truly beneficial treatments for ALS. That work can only succeed if patients enroll in clinical trials.

Yes, if the treatment does provide benefit. We work with the drug companies that supply the treatment for the trial to make sure that if the treatment does prove to be useful, anyone in the trial can continue to receive it after the trial. We feel this is critical to offer treatment to those who have contributed so much to the research by joining the trial.

A common complaint in ALS trials is that they take too long. We share that concern, and are working to make sure that all trials are completed in the shortest time possible.

  • Biomarkers We are looking for new measures of disease progression that are more sensitive to treatment effects, and less susceptible to the daily fluctuations in function that every ALS patient is familiar with. These new measures, called biomarkers, may shorten future trials.
  • Larger Trials One major factor in determining the length of a trial is the number of patients enrolled in it. When more patients are enrolled, beneficial effects are seen sooner. This is because different patients naturally progress in their disease at different rates. Those natural differences may temporarily mask any differences in the rate of progression due to a treatment. But with large numbers of patients in each group, those natural differences cancel out sooner, so that even small differences due to treatment emerge quickly.