Research updates
Phase III clinical trials   page 5
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4. Blinding and placebos Link to the Medical Research Council web site
Trials are blinded if the patients do not know which treatment they are receiving. A single-blind trial means that the patients do not know what trial treatment they have been assigned to take, but their physicians do know. In a double-blind trial, neither patients nor physicians (nor those conducting the study) know which treatment an individual patient is taking. This is done to avoid bias in the decisions they make about their condition or apparent side effects of the treatment or any other therapy they receive.
Here are some examples of this type of bias. A patient who is aware that they are receiving what they believe to be an effective treatment may report that they feel better. Similarly a doctor may expect a patient to make progress on a particular treatment and judge their condition accordingly. The reporting of adverse events may also be biased without blinding. Consider a patient who suffers a headache. If she knows she is not taking a new drug she may not report it, but if she is aware that she is receiving the new drug, she may decide that the headache was caused by the drug and therefore report it as an unwanted effect. In both case, the headache may have been caused by something else - for example, too much red wine!

Double blind clinical trials minimise the risk of such biases and ensure that the outcome of a trial is assessed as fairly as possible in terms of both efficacy and toxicity. Even those analysing the trial data may not know which treatment a patient is receiving since the treatments may be coded as A and B etc. When the trial reaches a predefined point the code is broken and the trial is 'unblinded'.

In some trials blinding may not be feasible. For example trials of radiotherapy or drug trials where the treatment on one arm is given orally (by mouth) and on the other arm is given intravenously. In these instances, the trial must be designed rigorously to minimise any biases from this inability to blind due to practical or ethical reasons.

The preparation of a placebo, or dummy treatment, is one of the techniques used in blinding trials. Sometimes the fact of receiving a treatment - even if it is only a sugar pill - seems to help some people; this is known as the placebo effect. Placebos ideally should be similar in every way - appearance, taste, smell, etc. - to the actual experimental treatment.

A trial in which one group receives the investigational treatment and the control group receives a placebo is known as a classic placebo-controlled trial. The World Medical Association holds the view that:

‘in general it is ethically unacceptable to conduct placebo-controlled trials if a proven therapy is available for the condition under investigation’.

Exceptions may be made in some situations, for example a very short term treatment or a minor ailment, but this generally means that the control group is given a placebo only when no other approved treatment is available. It would be unethical to give a trial volunteer a placebo if they could have an effective standard treatment for a serious disease.

The Cannabis in Multiple Sclerosis (CAMS) trial is an example of a placebo-controlled trial which is ethically acceptable because no approved truly effective treatment exists.

The CAMS trial
The CAMS trial is an RCT of the effects of cannabis on the symptoms of Multiple Sclerosis (MS).

Cannabis has been used medicinally for over 2000 years including for the relief of pain, cramps, nausea, and fits. Famously, Queen Victoria was prescribed cannabis for menstrual cramps by her personal physician, Sir Russell Reynolds. In 1971, the drug was reclassified as a Schedule One drug, meaning that it is regarded as having no medical value and a high potential for abuse. More recently, many sufferers from multiple sclerosis have reported that using cannabis (illegally) has helped their symptoms and in 1998 the House of Lords called for further research.

The CAMS trial investigates whether cannabis, as either whole plant extract or one of its active components, can help the muscle stiffness and spasms. The trial closed in October 2002 having met its recruitment target with 667 patients.

All trial treatments are given orally (i.e. no patients will be asked to smoke cannabis): Treatment A (given to 1/3 patients) is cannabis oil and Treatment B (given to 1/3 patients) is tetrahydrocannabinol, which is believed to be the active ingredient in cannabis; the remaining patients receive a placebo.

This is a double-blind, placebo-controlled trial. Because of difficulties in making the active treatments look alike, there are two treatment arms and two placebo arms (see figure 5). Patients may know that they are on an A arm, but not whether they are on treatment A or placebo A (and similarly with B).

Randomisation flow diagram
Figure 5. CAMS trial - an example of a double blind trial.

The primary outcome measure is muscle spasm (also known as spasticity) using a clinical assessment scale known as the Ashworth scale. The secondary outcome measures are mobility, quality of life, disability and side-effects. Results should be available in Summer 2003.

The trial is sponsored by the MRC. It is led from Plymouth by Dr John Zajicek and coordinated by Dr Jane Vickery. Support is being provided by the MRC Clinical Trials Unit. Over 20 UK sites are taking part.

Special issues
There are some special issues around the availability of approved treatments in developing countries. Even though effective treatments exist they may not be standard or even available where the trial is conducted. In these cases it is argued by some that the ‘no treatment/placebo’ arm is ethically acceptable. The problem is that non-availability of drugs might be used as a justification for conducting trials in poor countries of the world, a situation which could easily lead to exploitation.

Placebos may be used to blind trials even where there is a standard treatment if the two treatments cannot be made to look the same. By making placebos to match each treatment (standard and experimental) the two treatments can be masked. In such studies, each group receives two trial treatments, one of which is an authentic drug and the other a placebo (i.e. participants take either Treatment A plus Placebo B, or Placebo A plus Treatment B)—the so-called “double-dummy” approach.

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Question 4
A new drug, X, is to be tested in a disease area.

a) Why would you use a placebo if there is no current standard treatment?

b) i. How might you use a placebo if the current standard treatment is drug Y? Draw a diagram similar to Figure 4 to explain.

ii. Why would you use a placebo?