Can placebo groups be reduced in MND clinical trials?

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Clinical trials are vital in the hunt for effective treatments of motor neurone disease. They provide the evidence needed to determine whether a drug is safe and effective. In trials, participants are randomly assigned to receive either the treatment or a dummy drug, also known as a placebo. While this group is crucially important in helping to determine if a treatment is beneficial or not, there is much discussion in the community around the ethics of placebo groups. New research from the University Medical Centre Utrecht has hinted at the possibility of reducing the number of people assigned to the placebo by supplementing trials with additional data from outside a clinical trial.

What are clinical trials?

Clinical trials are scientific experiments which test new potential treatments in people. They help to show whether a treatment has a beneficial effect in people living with a disease, as well as showing if the treatment is safe.

There are four stages to clinical trials, click on the tabs below to learn more about each stage.

Examines the safety of the potential new treatment, often in just a few (5 – 20) people. In many cases, this phase involves healthy volunteers rather than people with the disease. Participants are monitored for adverse reactions or side effects; if any appear that are judged too dangerous, the drug will not advance to further clinical trials phases. Phase 1 trials can also look at the optimal dose size, timing of doses and drug delivery route (e.g., by mouth, or injection).

Determines the optimal dose size, timing of doses and drug delivery route (e.g., by mouth, or injection) for the next phase of testing. Although Phase 2 may provide some indication of the drug’s ability to treat the disease, the numbers of patients involved in this phase is too small for such findings to be relied upon.

Aims to show whether the drug has a beneficial effect on patients. This stage of testing will usually involve hundreds of patients, which is enough to allow a reliable assessment of the drug’s efficacy. Phase 3 results will usually determine whether a drug is approved as a treatment for a disease.

Occurs after the drug has been approved for use. With the drug in general use, further data can be gathered on its effects in an extremely large number of people over an extended period of time. This can provide information on the long-term safety and benefit of taking the drug.

What is a placebo and why is it used?

A placebo is a medicine which is designed to have no benefit but looks and tastes the same as the potential treatment being tested in a trial. The placebo is sometimes known as a ‘dummy drug’.

For phase 2 and 3 clinical trials, participants will be randomly chosen to be given the placebo or the treatment. The placebo acts as a control, allowing researchers to ensure that any beneficial effects observed in the trial are entirely down to the treatment itself. In these trials, neither the participants nor the researchers will know who is receiving the treatment or the placebo. This is important as it prevents any unintended bias when participants report how they feel or when researchers are making assessments or looking at data from the trial.

Placebo groups are vital in the fight against MND as they help to determine if a treatment is beneficial. However, there are many discussions around the ethics of placebo groups.

This has led to a shift in clinical trial design over recent years. For example, it used to be the norm that participants would have a 50/50 chance of receiving the treatment. Nowadays, in many trials participants now have a greater chance of being assigned the treatment than the placebo. Many trials also now provide those who are assigned the placebo an opportunity to take the treatment as part of an extension to the trial. These are called open label extensions and allow everyone on the trial an option to take the treatment after a certain period of time.

Can reducing the size of the placebo group have an impact on the results of the trial?

While the design of clinical trials has led to less people being recruited to the placebo group, this can sometimes affect the ‘power’ of a clinical trial. This is a statistical calculation which describes how likely it is that the results from the trial are valid. In clinical trials a higher statistical power means the results are more likely to be valid. While a low statistical power means the results are probably questionable. Although using, for example a 2:1 ratio of treatment group to placebo group reduces the number of participants on placebo, in order to have a high statistical power more participants will need to be recruited to the trial overall.

In a recent paper Ruben van Eijk and his team discuss a potential new approach. They theorise that a hybrid clinical trial design, where real-world data is used alongside placebo groups, could result in the reduction of participants assigned to the placebo without negatively impacting the statistical power of the trial.

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What is real-world data?

Real-world data is data that has been collected outside of a clinical trial. For MND there are several registries which look to collect information on people living with MND. This includes information about disease onset and progression. These registries can contain:

Historical population data –from the last several decades or more.
Concurrent population data – from people who are living with MND while the trial is running.

As real-world data has come from outside of the clinical trial, it can also be called an external control arm.

Using hybrid clinical trial design in MND

To test the theory of using a hybrid clinical trial design, the researchers used data from an already completed clinical trial alongside real-world data from people living with MND while the trial was running. Click the tabs below to find out how the test was designed.

The clinical trial

To test this theory, the researchers used an already completed trial. This trial investigated whether lithium carbonate was beneficial for people living with MND compared to those receiving placebo. Unfortunately, this trial did not find lithium carbonate to be beneficial. As a side point, since the trial, researchers have re-analysed the data and found that there was potentially a beneficial effect for a small subgroup of participants on the trial. You can read more about this in another blog post here. .

The external arm

The researchers used a population-based register to find people who were living with MND while the trial was running.

Matching the external arm with the placebo arm

Introducing an external arm into a clinical trial design can increase the risk of bias, as the trial population might be different to the external population. Bias can make the results from a trial less reliable, as there is chance that other factors could influence any effects observed from the treatment. To overcome this, the team carefully matched the two populations. This wasn’t as simple as just applying the inclusion and exclusion criteria of the clinical trial. They used a variety of measures to create a scoring system to help them match the two populations, this included factors such as age, duration of symptoms, rate of change of ALSFRS-R and site of symptom onset.

Number of people used in the external arm

The team matched 133 people from outside of the trial to the participants who were randomised to the placebo in the trial. No statistically significant difference in baseline characteristics between the two populations was found after matching. This means that the two arms were very closely matched based on the factors that the team were using.

When the researchers compared the original trial with the hybrid design, they were able to confirm that the treatment had no effect, but with more precision. This suggests that the hybrid design could have benefitted the trial in the following ways:

1. Improved the confidence that the results from the trial were correct

When clinical trials read out results, they will include statistics to show how likely the results are to be correct. Supplementing the placebo group found that the trial had the same outcome, but this could be reported with greater confidence.

2. Reduced the time to show if the trial was beneficial

During clinical trials there is often regular monitoring in place to assess whether to continue testing the drug. This means that testing of a drug which is not showing signs of benefit can be stopped earlier. Throughout the trial there are time points where the data is analysed, and a decision is made to continue testing. Using the external arm alongside the placebo arm, these time points were reached sooner. This allows for more frequent monitoring of any effects. Using this approach highlighted that the lack of benefit from lithium carbonate could have been shown 7.5 months earlier than in the original trial.

3. Lowered the overall number of participants needed to take part

Using the external arm meant that the same outcome from the trial could have been reached using 13% less participants. Reducing the total number of participants in a trial will also reduce the number of people assigned to the placebo group. Recruiting less participants in a trial could help speed up the trial process and get an outcome faster.

An image of a Stethoscope, a pill bottle, some pills and a syringe

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Moving forward

The results from this study show the potential of using hybrid clinical trial designs in MND. However, further work is now needed to check this approach across a variety of different clinical trial scenarios.

We are grateful for everyone who takes part in research, whether that is by providing information to be held on registers, or by taking part in a clinical trial. Each new piece of research is helping us take a step closer to a world free of MND.