The role of placebo control in clinical trials for neurodegenerative diseases

A screenshot of the header of the publication in the scientific journal

Oct 2023: The MND-SMART trial team, and the people living with MND who are co-producing the trial, have considered the pros and cons of including a placebo group in a trial like MND-SMART.

Including a placebo group, which is also called a control group, means that some people will be randomly assigned to receive a dummy pill, and as such will not be taking the drugs being tested. Our team wanted to formally assess whether this is the best approach.

Advantages of a multi-arm trial

Because MND-SMART is a multi-arm trial, several drugs are being tested at once against a single placebo arm. Compared with a traditional two-arm design, a practical advantage for participants of this trial format is that it increases the chance that they will be randomly assigned to take one of the drugs being tested, instead of placebo.

However is it possible to reduce or even remove the placebo group altogether? And what implications would this have for the trial results? The key question is: Would a different approach help accelerate the identification of medicines that improve outcomes for people living with MND?

Implications of reducing or removing the placebo group

In the context of MND-SMART, the research team and patient representatives have considered several options. These are:

  • Deliberately skewing the numbers so that the placebo group has fewer people than the drug groups
  • Using placebo data from previous trials to supplement or replace the placebo group
  • Replacing placebo group data with real-world data from disease registers, or predicting the data by computer modelling
  • Not using any placebo data

These approaches may accelerate a specific trial, in that if more participants were assigned to active drug, it would be quicker to gather enough data to draw conclusions about its effectiveness. However — crucially — this comes at the price of introducing uncertainty into the trial results. Using any of the above approaches might introduce bias, as it is then not guaranteed that the placebo group is comparable to the drug group.

This is likely to lead to disagreement over the reliability of results, with consequent difficulties in obtaining regulatory approval and widespread use. Indeed, it might mean that a further trial has to take place, this time including a placebo arm, to confirm the results.

It’s also vitally important to acknowledge that participants receiving placebo are receiving the current standard of clinical care and are not at risk of adverse side effects from trial drugs. Some drugs being tested in clinical trials might be unpredictably harmful, as well as ineffective.

Head-to-head comparison

In conclusion, we believe that it is important to continue to research how to minimise the number of trial participants taking a placebo without compromising the result. But at the present time it’s in the best interest of all parties – and of participants in particular – that MND-SMART and similar trials continue to include a randomised placebo group.

The data we gather from participants taking placebo is equally important as that obtained from those taking a drug, and a head-to-head comparison at the same time is the quickest and most effective way to reach a definitive conclusion.

We would like to thank to all our participants for their valuable role in this research.

Related links

Read the scientific article: Mehta AR, Carpenter JR, Nicholas JM, Chataway J, Virgo B, Parmar MKB, Chandran S, Pal S.  Nat Med. 2023 Sep 14. doi: 10.1038/d41591-023-00080-0. (article not freely available; unformatted version available via Edinburgh Research Explorer)

Find out more about the MND-SMART trial design: About MND-SMART

Read the other scientific publications about MND-SMART: Scientific publications

This article was published on: Thursday, 5 October, 2023