Randomized controlled trials are the gold standard of scientific testing for new medical interventions. They have become the standard that must be met by pharmaceutical companies in the process of working out what level of efficacy and safety can be achieved by an experimental drug.
The three words for this method of clinical testing - randomized controlled trial (RCT) - represent important elements of the scientific design:
- Randomized - the decision about whether a patient in the trial receives the new treatment or the control treatment (or placebo) is made randomly
- Controlled - the trial uses a control group for comparison or reference. In the control group, the patients do not receive the new treatment being tested, but a reference treatment or placebo instead
- Trial - the drug is on trial during an RCT; it will be approved for wider use only if the results of the testing program prove that there is a worthwhile level of efficacy, which must be balanced against an acceptable level of side-effects (safety).
Why are clinical trials 'randomized'?
Randomization is important because, if the decision about who receives the new treatment in a clinical trial is not decided by random, the patients and the scientists can influence the results.
The selection of patients into one arm of a clinical trial or the other (into the treatment arm or the control group) is left to the play of chance.
Thanks to randomization, the selection of patients into one arm of a clinical trial or the other (into the treatment arm or the control group) is left to the play of chance. This way the results are free from any bias that might otherwise be introduced by the people involved.
For example, if patients are chosen to receive a treatment that the doctors really hope will work, the doctors may be tempted to offer that treatment - subconsciously, even - to those who have less severe disease, or some other factor that may improve the drug's chances of success.
You can imagine the risk of this bias being higher if the treatment allocation is decided by doctors who are in the pay of a pharmaceutical company, which will have a clear (and usually very large) financial interest in achieving positive results.
Knowing which patients are getting the experimental drug can result in sound motivations as well as questionable ones. Doctors could have a well-intentioned influence over the results.
If the active treatment seems to be producing bad side-effects, for example, doctors may protect certain types of patient from the drug. Treating subjects in the trial differently in this way reduces the integrity of like-for-like comparisons and gives false results.
In summary, randomization in a clinical trial helps to remove bias and to ensure that the two groups being compared are truly similar, and that - as far as possible - the only difference that could influence the outcome in their disease is whether or not they are receiving the new drug.
Fast facts on randomized controlled trials
Here are some key points about RCTs. More detail and supporting information is in the body of this article.
- Randomized controlled trials are the gold standard of clinical testing applied to new medical interventions.
- RCTs are usually required in pharmaceutical testing programs before regulators will allow new drugs to be sold.
- Randomization means pure chance is used to decide who gets the new treatment and who goes into the comparison group of the trial.
- Randomization is done so that 'selection bias' is removed when treatment is allocated, making the results of the comparison more reliable.
- RCTs are 'controlled' so that investigators can tell for sure if any health effects are the result of the drug treatment, by observing effects in the reference group not given the new drug.
- Placebos may be used for the control group - dummy treatments that look the same as the experimental treatment but contain nothing.
- It is not always ethical to give a placebo, such as when this would mean denying treatment to people who have a life-threatening or serious illness.
- A standard treatment that is already established against the disease can be used in the control group for comparison.
Why are clinical trials 'controlled'?
The importance of employing the control in a randomized controlled trial is to help prove that any benefits (and risks) identified during the process can be attributed to the drug itself.
The trial could use a placebo control - a dummy pill that looks exactly like the treatment, but lacks the active ingredient.
If there is no control - no reference or comparison group - an improvement in health may be recorded that has nothing to do with the drug.
There may be others factors about being in the clinical trial that could explain the results, and without comparing what happens in similar patients taking part under similar conditions - but not getting the new drug - there is no proper measurement of any health changes that may be observed.
This value of employing a control group is produced only if the trial is sufficiently large. It must have enough people taking part to ensure that chance differences and unusual cases do not have a large effect on the results.
The control group may be receiving a placebo - a dummy treatment that looks exactly the same as the drug being tested, but that does not actually contain the active agent.
The quality of the control group is important, in terms of how well its participants match those of the active group. For example, randomization (explained above) helps to ensure that there is no bias influencing the selection of people into the control group.
Comparison with standard treatment
Many drug trials give the control group a treatment that has already become established against the disease. The purpose of this type of control is to find out if there is any comparative benefit from the new drug versus the standard treatment. Even if the new drug does give positive results in itself, the other established treatment may work better still.
Comparative drug trials are important beyond the pharmaceutical development process, helping to guide decisions about healthcare resources.
For example, healthcare policymakers around the world are particularly interested in how a new drug fares against existing treatment options, taking into account cost-effectiveness, effects on quality of life, and other factors that add to the picture of overall benefit and cost to society, as well as to individuals.
Impractical or unethical use of dummy treatments in RCTs
Rigorously scientific trial design is not always practical. It can be difficult to achieve a true placebo, to disguise the dummy completely. And in some cases, it is unethical to give a dummy treatment.
Desire for a randomized controlled trial may be defeated by the following examples of practical limitation:
- Treatments that are more invasive - involving devices or surgery, for example - may be impossible to mock-up realistically in the comparison group
- There may be too few people with a certain disease available for investigation in both treatment and non-treatment groups
- The recruitment of patients to a particular trial may be too difficult.
A placebo-controlled trial is often simply an unfair prospect for participants. For example, a placebo is not allowed to be given for comparison in serious or life-limiting disease if it would mean denying usual care.
Here, the comparison group would instead be given a treatment that is already available, so that the patients would not be sacrificing their standard care for the sake of a dummy treatment.
If no existing treatment is available, another trial design may be used. Decisions about whether trial designs are fair on the participants are made by independent ethical review boards. A clinical trial cannot go ahead without this ethical approval.
Written by Markus MacGill