Can we make clinical trials more ethical?

Medical research presents an inevitable ethical dilemma. On one hand, you gain knowledge that will help future patients. On the other, you subject current patients to an unknown treatment that may not benefit them and may even cause harm. The more participants in a trial, the more certain you can be of your results. But balancing the need for certainty while minimising the number of participants can be tricky. 

Dr Hannah Johns, a statistician at the Florey Institute of Neuroscience and Mental Health, has spent years tackling this problem.

“Randomised clinical trials are the gold standard for testing new treatments,” she explains. “They compare two treatments: the experimental treatment and a control. Each patient is randomly assigned to one of these.” An example is A Very Early Rehabilitation Trial After Stroke (AVERT), for which Dr Johns has analysed data. In this trial, stroke patients were randomly assigned to either standard care (the control) or earlier and more intensive rehabilitation (the experimental treatment).

Dr Johns says that randomised clinical trials are necessary for testing new medical treatments. But while they help remove bias, they also have a downside. “By their very nature, they give some patients a treatment which is worse for them. If an experimental treatment is better for you than the control treatment, we’re denying the control group the better treatment. If the control treatment is better for you than the experimental treatment, we’re causing harm to the treatment group.”

But Dr Johns believes we can do better. She is part of a team at the Florey developing an “ethical trial design” for stroke research known as a Response Adaptive Clinical Trial.

“In a Response Adaptive Clinical Trial, we use a different set of rules to assign patients so that the treatment which appears to be better for patients is received by more people,” she says. “Whenever a good outcome is observed in the trial, the chance of being assigned to that treatment increases. Whenever a poorer outcome is observed, the chance of being assigned to that arm decreases. This means that as the trial progresses, the chance of being assigned to each arm will change rather than remain fixed.”

This method maximises the number of patients receiving the better treatment option. So why isn't it widespread?

“First, response adaptive trials need more patients,” Dr Johns explains. “In extreme cases, this can backfire and cause more patients to receive a less beneficial treatment.”

And it's a complicated process. “In conventional trials, we use relatively simple formulas to determine how many patients we need, a process called Power Analysis. For Response Adaptive trials, no such formulas exist. We have to build a computer simulation instead. Building and using this computer simulation is time-consuming and requires advanced programming skills.”

Luckily, Dr Johns has these skills. She is implementing response adaptation in a new trial called AVERT DOSE that wants to reduce disability after stroke. The trial looks at how much and how often patients should be moving in the early days after their stroke.

AVERT DOSE will look at whether getting people moving shortly after their stroke is beneficial.

Professor Julie Bernhardt, who is leading the trial, is excited about the potential of response adaptation in the trial. “The results of AVERT, the precursor to AVERT DOSE, showed that too much training too soon after stroke can be harmful,” she said. “This has led to greater caution with higher dose training, particularly with certain patient subgroups, but has not provided the evidence needed to help guide treatment protocols. That is the aim of AVERT DOSE.”

“Testing multiple, promising treatment regimens using the adaptive trial approach, we will determine the safest and most effective early treatment approach,” she says. “This will be developed into clear, practical treatment guides for clinicians everywhere.”

With 2,700 stroke patients involved, researchers want to give as many participants as possible the best treatment. Assigning more patients to the more promising treatment as time goes on is Dr Johns’ domain.

Response adaptation is not the only way AVERT DOSE will be more ethical and efficient than its predecessors. Because we don’t know how much mobilisation is best for stroke patients, or how often they should mobilise, the trial will test many frequencies and doses. But having so many subgroups could increase the number of participants required.

This is why the trial is also ‘multi-arm multi-stage’. The first stage will test multiple frequencies and doses. Based on the results, only the most effective treatment will be tested in the second stage. This allows the involvement of fewer patients, while still testing lots of different treatments.

Dr Johns hopes these measures mean more patients receive the best possible treatment – while maintaining the quality of the trial. This way, there is more benefit not only for future stroke patients, but for current patients too.

Dr Hannah Johns is an early-career researcher in the AVERT Early Rehabilitation Research Group. Her work focuses on the development and application of new statistical and visualisation methods to understand complex clinical trial data.