Many hands make light work – the evolution of clinical trials

Today is International Clinical Trials Day, which aims to raise awareness of clinical trials – and their importance in modern medicine.

It falls on 20^th May because that’s the date of the first recorded clinical trial, conducted in 1747 by a Scottish naval surgeon called James Lind. He showed that giving scurvy-ridden sailors two oranges and a lemon every day cured their disease, providing the first evidence that including citrus fruits in people’s diets can prevent scurvy.

More than two centuries later, trials are now a vital part of medicine. They prove, in a carefully controlled, scientific way whether or not new treatments (or, more accurately, ‘interventions’) are effective and safe for human use. And by comparing different interventions across groups of similar people, their findings let doctors make an informed, evidence-based decision on how to best treat their patients.

Trials vary in their objectives – some test how safe a drug is, or what dose works best. Others look at how effective an intervention is at treating a disease, and several aim to find new therapies that are just as good as the current ones, but cause fewer side effects and are cheaper to use.

And although things have evolved since Lind’s 18^th century clinical trial, they remain the gold standard by which a treatment’s effectiveness is measured.

But how have things changed? In this post, we look at how cancer clinical trials are evolving to become more flexible and adaptive, with the ultimate aim of bringing new treatments to cancer patients sooner.

The original template

James Lind (1716-1794) carried out the first recorded clinical trial

When someone says the words ‘clinical trial’, you probably think of the way classic trials were designed, like Lind’s scurvy trial.

This is where patients are divided into two groups (or ‘arms’, to use the more jargon-y term), and given different treatments. The two treatments are pitted against each other to see which works best.

One arm typically receives the standard treatment (or sometimes no treatment, or a placebo). This acts as a reference, or ‘control’, against which the treatment arm is compared to determine if the new intervention is better than the control.

In the case of cancer clinical trials, this could be comparing a standard chemotherapy drug with a new treatment. Or it could test if combing radiotherapy and chemotherapy is better than having either treatment on its own.

In conventional trials, patients are allocated into groups at random – or ‘randomised’. This improves the trials reliability and avoids introducing any other factors or bias which might affect the trial results. And in some trials, neither patients nor their doctor know who receives what treatment. To drop into trial jargon again, these types of trials are said to be ‘double-blinded’.

Such trials are known as ‘double-blind, randomised, controlled’ trials. These are often viewed as the ‘gold-standard’ for gathering evidence on whether a new intervention will truly benefit patients.

New kid on the block

But things are changing.

More and more in the fight against cancer we’re seeing scientists and doctors use what are known as multi-arm clinical trials.

By the very nature of their design, these allow researchers and doctors to test several different treatments at the same time.

Watch this animation to find out how a randomised trial works

Just like conventional trials, they’re randomised and usually double-blinded. And, multi-arm trials also have a control arm, against which each of the other arms can be compared.

Let’s look at an example. STAMPEDE is a multi-arm trial that Cancer Research UK is funding, looking at new treatments for men with advanced prostate cancer. The control arm is a group of men who receive today’s standard treatment: hormone therapy. Then there are no fewer than eight treatment arms, in which the men receive hormone therapy in combination with other treatments, such as chemotherapy.

Early results, presented at a conference last week, show that hormone therapy combined with the chemotherapy drug docetaxel, given from the beginning of treatment, improves survival in men with advanced prostate cancer by almost two years.

So why are things changing?

The main reason is our rapidly increasing understanding of cancer. For example, thanks to our METABRIC study, we now know breast cancer is not a single disease but in fact 10 different subtypes. And the ongoing research of our experts like Dr Sergio Quezada and Professor Peter Johnson is demonstrating the importance of the immune system in the development of cancer, and how it can be manipulated to fight the disease.

This increased basic knowledge of cancer is leading to the development of scores of new experimental treatments – either brand new drugs, or new combinations of older drugs.

And compared to standard trials, multi-arm clinical trials have a number of advantages that have the potential to help bring these new treatments to cancer patients sooner.

One is that they are cheaper to run. Instead of carrying out several separate two-armed trials, each with its own control group and associated running costs, scientists and doctors can carry out one multi-arm trial which only needs one control arm and would have lower overall running costs.

And according to Professor Allan Hackshaw, who works in the Cancer Research UK Cancer Trials Centre at University College London, “there is less bureaucracy with multi-arm trials because instead of setting up five separate trials you’re setting up one. This will also help reduce costs”.

Another advantage is that they’re more likely to produce a positive result compared to two-armed clinical trials, because there are more new therapies being tested.

If we look back down the history of trials, it turns out that not all clinical trials show a new intervention is better than the standard treatment. In fact, only four in 10 two-arm cancer trials produce a positive result. On the other hand, in a multi-arm trial, the probability of at least one arm producing a positive result increases to nearly nine in 10 (87 per cent).

They can also boost participation, since multi-arm trials generally involve more people than standard trials. And as Hackshaw highlights, “having multiple treatment arms means more patients have a chance of being recruited to a potentially more effective treatment arm”.

The final, and perhaps biggest, benefit is that multi-arm trials are much more flexible, and are designed so doctors can modify them if they see fit. As advantages go, this is a big one. Arms can be taken away if they’re not showing a benefit to patients, or new arms can be added to accommodate new treatments that become available during the trial (as has happened during STAMPEDE). The latter means that instead of having to set up a separate trial to test a new drug, doctors may be able to add it to an existing trial which will save time and money.

The other new kid on the block

Multi-arm trials aren’t the only new type of trial on the block. ‘Basket trials’, like our Lung Matrix trial are a form of multi-arm study which are becoming increasingly common. “These aren’t randomised trials. Instead, patients’ cancers express some kind of genetic marker or mutation, and based on this, they’re put into one of several different arms where each treatment is targeted to a specific marker,” Hackshaw explains.

“These trials probably won’t change practice on their own, but rather would be used to see if a targeted treatment(s) works as expected. These treatments could then be tested in a controlled trial, for example in a multi-arm trial.”

End of an era?

Given the advantages of multi-arm trials over two-arm trials, you’d be forgiven for thinking standard trials are on the way out.

But Hackshaw is quick to point out that this isn’t the case: “There will always be a need for two-armed clinical trials. They are simple to run and for uncommon cancers it’s unlikely that there would be enough patients to do trials with five or more arms.”

“And in some situations, for some cancers, we haven’t got three or four more treatments to test – we might only have one. This means that for some cancers a multi-arm trial probably wouldn’t be possible.”

That’s why as well as funding multi-arm trials like STAMPEDE and FOCUS4, Cancer Research UK is continuing to fund scores of conventional trials – for example, in our work on rare cancers as part of the International Rare Cancers Initiative.

We’re not finished yet

Clinical trials are a vital part of cancer research. As the National Cancer Institute says, “well-designed, well-run clinical trials are the only way to determine the true effectiveness of a promising new agent or intervention being investigated.”

That’s why we’re proud of the fact that, over the last five years, more than 160,000 patients have been recruited to Cancer Research UK-funded clinical trials – trials that have been at the heart of progress in the fight against cancer.

And they’ve helped thousands of people survive their disease too.

But we’re not done. We will continue to raise awareness of clinical trials through our recent clinical trials campaign and fund life-saving clinical trials across the UK. And, in collaboration with international partners, these trials will help bring forward the day when all cancers are cured.

Áine

Images

• Hands by Victor Gutierrez, under CC BY 2.0 via Wikimedia Commons
• James Lind by Sir George Chalmers, c 1720-1791 – Public domain, via Wikimedia Commons