Trial design


Adaptive trials can innovate by adjusting methods mid-study, improving accuracy – and patient outcomes.


Although the initial drugs didn’t work, the approach is still valid, he adds. Had the treatments been effective, this one study could have produced evidence in support of three different biomarkers. Not only can this approach save time, but it may help form a more robust understanding of the disease and biomarkers being studied. “It gives us more information, because you’re putting things in context with other things,” says Siu.


And if you’re just investigating the one biomarker, you can test different therapies to learn which it may be suited to. Siu gives an example: tumour mutational burden (TMB) is a measure of the total amount of mutations in the DNA of cancer cells. Tumours with a higher number of mutations may be more likely to respond to drugs that help the immune system attack cancer cells (immunotherapy). Here, you could run an adaptive trial that assesses different combinations of immunotherapy on people with high TMB.


Benefiting patients


The percentage of eligible adult cancer patients estimated to participate in clinical research.


3–5% NCBI 28


When there are multiple treatment arms, an adaptive design allows you to randomise more patients into those which are showing a better effect. This is especially impactful with cancers where the standard treatment received by those on the control arm is known to be ineffective. If a trial has a single experimental arm and one control, a patient’s chance of receiving the standard treatment is 50%. But if there are three experimental arms, those odds drop to 25%. As the trial continues and data is analysed, patients are then more likely to be randomised into groups with treatments that are showing a better effect – so their chances of getting the control dip even further. This is done statistically and is known as Bayesian adaptive randomisation. “The algorithms learn, so that the arm that is more efficacious has a higher probability that a patient will be randomised into that arm,” says Wen. “It’s in the hope that you would benefit more patients and you get more data into the arm that you think is most likely to go forward,” says Siu. Patients


have a greater chance of receiving the best treatment available to them at that time, “instead of having to choose one of several studies to enter on [their] own,” she adds. And if patients know they’ve got higher odds of getting the better treatment, they may be more likely to enrol in the trial. It’s estimated that currently, just 3–5% of eligible adult cancer patients participate in clinical research. Having a 50% chance of receiving a standard treatment you’re confident won’t help you is a big disincentive, says Wen. “Reducing that to at least 25% or potentially less helps a little bit.” For this reason, people with cancers that have limited or no treatments available may be particularly amenable to adaptive trials. Per a whitepaper by the Cholangiocarcinoma Foundation, these groups can see clinical trials as their best option – so receiving an ineffective therapy or placebo would be out of the question.


Looking ahead


While adaptive trials can be more efficient and appealing to patients, it’s important to remember that they aren’t the answer to every question in oncology, cautions Siu. It depends on “the agents you have and all the circumstances operationally”. For instance, if you were measuring an outcome that takes a long time to observe, there may not be a point in using an adaptive framework. Plus, some fields in oncology may not have enough drug candidates to put into adaptive trials in the first place. There are relatively few glioblastoma treatments that are suitable for trials, notes Wen. Yet the promise of adaptive trial design is immense: we could get answers quicker while benefitting more patients. And the potential time and cost savings may convince more companies to ramp up their oncology R&D, Wen says. “Companies that may have thought, ‘I don’t want to do glioblastoma trials,’ now might think, ‘Well, it’s not so big a trial and it’s not so expensive’. “That’s part of the reason we did all these trials, to have more companies become interested in helping our patients.” ●


Clinical Trials Insight / www.worldpharmaceuticals.net


elenabsl/Shutterstock.com


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