Randomized controlled trials are the most reliable method available for testing new treatments.

They have become the standard that pharmaceutical companies must meet for calculating and proving the level of efficacy and safety of an experimental drug.

In this article, we look at the setup and advantages of a randomized controlled trial (RCT), as well as some ethical considerations of placebo treatment.

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Randomized controlled trials are the "gold standard" for testing the safety and efficacy of drugs and treatments on the market.

Researchers set up a trial to test the effects of a drug on a specific group of people while measuring another for reference.

The scientific design of a randomized controlled trial is as follows:

  • Randomized: The researchers decide randomly as to which participants in the trial receive the new treatment and which receive a placebo, or fake treatment.
  • Controlled: The trial uses a control group for comparison or reference. In the control group, the participants do not receive the new treatment but instead receive a placebo or reference treatment.

The United States Food and Drug Administration (FDA) will generally only approve a new treatment as safe and effective for wider use if results indicate that the effects of the drug are in line with its claims, and if these benefits occur without causing unsafe adverse effects.

However, between 1999 and 2014, 76 applications received approval without undergoing an RCT. Discussion continues as to whether a product is definitely safe without passing an RCT.

Randomization prevents the skewing or deliberate manipulation of results. Both participants and research scientists can influence results unless the researchers assign participants to groups at random.

Scientists refer to this skewing of results as selection bias. An RCT gets rid of selection bias by removing the element of choice.

For example, without randomization, scientists may consciously or subconsciously assign patients to the group receiving the active treatment if they look more likely to benefit from the experimental treatment. This could make a treatment appear more beneficial than it actually is.

On the other hand, if scientists are looking to demonstrate the ineffectiveness or potential danger of a certain treatment, they may assign participants who have a higher risk of complications or a lower chance of success to the group receiving the treatment.

The risk of selection bias may also be high in trials by researchers who have received either direct or indirect funding from a pharmaceutical company looking to prove the efficacy and safety of a new drug.

For this reason, researchers must disclose any potential conflict of interest when conducting a clinical trial, as pharmaceutical manufacturers have a clear financial interest in achieving positive results.

Knowing which participants 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. Even selection bias with good intentions, such as researchers having concerns about the safety of a drug, is scientifically unsound.

If the active treatment seems to be producing severe side effects, for example, doctors may try to protect certain types of participant from the drug. Treating different subjects in different ways during the trial reduces the integrity of like-for-like comparisons, giving false results.

Randomization removes bias and truly allows for a direct comparison between two groups in a trial, providing a real representation of how the drug will react with the wider population after distribution.

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An RCT will have a control group to which the researchers will randomly assign people.

The purpose of a control group in a randomized controlled trial is to help reduce the likelihood that any benefits or risks that the researchers identify during the trial occur due to factors outside of the experimental treatment.

The absence of a control group would mean that the researchers could not attribute any improvement or decline in health to the drug or treatment.

Others factors about the clinical trial could explain the results. Without comparing what happens in similar participants facing similar conditions without getting the new drug, accurate measurement of any observed health changes would not be possible.

A control group is a key part of large trials. Enough people must be taking part to ensure that chance differences and unusual circumstances do not have a decisive effect on the results.

Researchers normally match people in a control group for age, sex, and ethnicity, along with any other factors that may influence the effect of a drug or treatment, such as body weight, smoking status, or comorbidities.

The control group may receive a placebo. This is a dummy treatment that closely resembles the experimental treatment but does not contain the active ingredient that causes the treatment's supposed benefits. Alternatively, they may receive standard treatment without the additional elements under investigation.

In some cases, typically those investigating the benefits of an intervention to healthy individuals, such as a supplement, the control group may receive no treatment and simply consist of individuals similar to those receiving a supplement or therapy.

The quality of the control group is important in terms of the similarity of its participants to those of the active group. Randomization helps to ensure that no bias affects the selection of people for the control group.

High-quality clinical trials will publish baseline measurements for both the treatment and control arms of the trial, allowing for direct comparison.

Comparison with standard treatment

Researchers design some trials investigating new drugs or treatments for a disease so that the control group receives an established or standard treatment for that condition, rather than a placebo or dummy treatment.

This type of control seeks to identify any comparative benefit from the new drug over the treatment options that are currently available. Even if the new drug does appear to have a beneficial impact, the established treatment may still be safer and more effective.

Comparative trials are important beyond the development of new drugs and treatment. They can help guide decisions about the allocation of healthcare resources.

Healthcare policymakers around the world often have a particular interest in how a new drug fares against existing treatment options, taking into account cost-effectiveness, the possible effects on quality of life, and other factors that paint a picture of overall benefit and the cost of the drug to society and individuals.

Policymakers also have to account for the lack of diversity in clinical trials when making decisions about healthcare guidelines and funding.

Historically, clinical trials have typically been carried out using white male patients, resulting in the approval of a range of drugs and interventions that have subsequently appeared to be less effective or riskier in people of different sex or ethnicity.

RCTs help to get around this bias.

Research in non-human animals or a limited section of the population is, in most cases, insufficient for recommending the widespread use of a drug or treatment within the general population.

The approval of some drugs based on animal research has led to significant harm in humans, as non-human animals are generally a poor model for predicting the human response to a drug or treatment.

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Giving a placebo can sometimes be unethical. However, when they are ethical to provide, they help the reliabiliity of RCTs.

Rigorously designing a scientific trial is not always practical.

A true placebo can be difficult to achieve and disguise. In some cases, giving a placebo is unethical.

The following practical limitations can disrupt the designs for an RCT:

  • Treatments that are more invasive, involving devices or surgery, may be impossible to mock-up realistically in the comparison group.
  • Too few people might have a certain disease and also be available for investigation in both treatment and non-treatment groups.
  • The recruitment of participants to a particular trial may be too difficult.

A trial using a placebo might not be fair on participants. For example, a placebo is not ethical for use during a trial for treating a serious or life-limiting disease if it would mean denying the participant's normal course of treatment.

In these circumstances, the researchers would give an already-available treatment to a comparison group. The participants would not be sacrificing their standard care for the sake of a dummy treatment.

Researchers may use a different trial design if no existing treatment is available. Independent ethical review boards make decisions about whether trial designs are fair on the participants.

A clinical trial cannot proceed without this ethical approval.

RCTs are the gold standard for clinically testing treatments and drugs.

The researcher assigns participants to experimental and placebo groups randomly, removing any selection bias from the sample. Selection bias can skew results in a way that benefits a researcher or the body funding the study at the expense of scientific integrity.

A placebo is a treatment that resembles the experimental drug. When a placebo is not ethical to use, for example in instances of trials for the treatment of a life-threatening disease for which the participant cannot stop their course of treatment, the researchers will use a treatment that is standardly available to test the differences.

A drug or treatment generally have to pass an RCT before the FDA approves it as safe and effective for wider distribution.

Q:

I’m not a research scientist. What impact do RCTs have in my life if I’m not part of one?

A:

Many of the medications you take on a day to day basis will have been tested on human participants, often in a RCT format, to demonstrate safety and efficacy.

RCTs offer the best chance to show that a medication is not only effective at what it claims to do, but also well tolerated, safe for dosing, and important your overall health.

Daniel Murrell, MD Answers represent the opinions of our medical experts. All content is strictly informational and should not be considered medical advice.