Big clinical trials are broken – together we can fix the system

Large-scale trials are the solution to some of the world’s biggest health problems. So, why are they happening less, not more? Jen Dumbleton explores an industry in crisis and how through novel and collaborative approaches we can turn things around, for the benefit of millions worldwide.

Common diseases are some of the biggest causes of death worldwide – and they are rising at pace.

Ischaemic heart disease, the biggest killer, is responsible for 13% of the world’s total deaths – 9.1 million in 2021. According to the World Health Organization (WHO), that’s an increase of 2.7 million since 2000.

The same upward trend can be seen in many other common diseases, including lung cancer, Alzheimer’s disease, diabetes and kidney disease. The impact? Declining health for millions of people worldwide and enormous pressure on the health systems that support them.

As anyone reading this journal will know, clinical trials are at the heart of medical advancement. We also know that randomised controlled trials (RCTs) are the gold standard of evidence generation. In times of crisis, when impactful solutions are urgently needed, they should be a focal point.

We only need look at exemplar trials like the RECOVERY trial into treatments for COVID-19, which had its first results within three months of set-up and is believed to have saved hundreds of thousands of lives, for the proof of what RCTs achieve when we desperately need it. And we should make no bones about the fact the global common disease burden is indeed a desperate situation.

Given the scale of their impact for so many people worldwide, common diseases should surely be top of the trial agenda. But the opposite appears to be true. Instead, there has been a shift towards clinical trials for rare diseases.

That’s not to say that important trials for rare diseases should be shelved – quite the contrary. But neither should it be one or the other. Relatively speaking, finding new treatments for common diseases will have an impact for far more people.

We have to find a way of rebalancing the scales. So, what’s stopping that from happening?

What’s often driving this shift is the fact that large clinical trials have become expensive – excessively so. They’ve also spiralled in terms of complexity, bureaucracy and misplaced resource, while they often do not yield the results needed to reliably inform clinical decision making.

For instance, in registered trials for COVID-19 only ~5% of 2,895 trial arms could be considered randomised and adequately powered, and only a quarter of enrolled patients contributed to adequately powered and well-controlled trials. This meant that, despite the incredible efforts undertaken during the pandemic, the majority of these trials weren’t able to have the desired impact.

RCTs, when not designed properly, can also end up becoming very complex. To avoid the scenario I’ve just outlined, they do need to be designed extremely well. In my experience, this is what’s often putting off many researchers – to the detriment of global health.

But simpler, more efficient and, therefore, cheaper RCTs are achievable. Principally, we should look to explore which approaches and technologies are out there to help us. However, it’s also about taking a step back and assessing what are we doing because it should be done vs because we’ve always done it that way.

No single organisation can do it alone. Together, as clinical triallists, we have a collective responsibility to design and deliver good clinical trials. Fortunately, in my experience, whether through altruism or just good commercial sense, we are a community that does strive to do better. So, what are the priority areas to focus on?

All good clinical trials start with the design. Simplicity is one of our best ways of eliminating error, reducing bureaucracy and, as a result, increasing quality. But how do we make things simple, and do so in the protocol and right across a trial’s lifetime?

Despite inevitable commonalities between trials, each trial should begin with its own blank sheet of paper. The purpose is to establish: what are the questions that each trial is specifically looking to answer, within which context, and what do we need within this trial to find the answers we need – and only those answers.

Often, we collect information that we don’t really need, and we do this multiple times. This creates pointless burden for participants and clinical staff alike. A proliferation of data to manage also increases the risk of error.

Instead, we should be distilling things right down to the essentials – and adopting the mindset that anything else is going to be detrimental to the trial’s ultimate success.

It takes a brave person to say, “We can manage without this.” But that’s exactly what good trial design needs. Often a culture of overcautiousness, which then bleeds into trial design, is down to the over-interpretation of regulatory requirements.

This is understandable given what we’re doing – giving medicines and treatments that haven’t been approved yet to patients. Another narrative that could be flipped is that the regulation is there to catch us out. It isn’t. It’s there to help and guide us. By considering each trial as its own unique entity, and taking a proportionate, risk-based approach to regulation, again, we’re going to simplify things.

As I mentioned previously, this isn’t a one-person – or one-company – job. As well as the regulation, there’s plenty of resource within our ecosystem that we can draw upon to help hone our approach. One such example is the Good Clinical Trials Collaborative. That its five principles for good clinical trials were recently adopted by the WHO into its “Guidance for best practices for clinical trials” is a huge victory for well-designed RCTs.

Once we have the protocol, how then to operationalise it in an efficient way? As clinical trial managers and clinicians well know, one of the greatest bugbears in delivering clinical trials is the inadequate IT systems underpinning most of them, particularly for large trials. The user experience on the front end is often a struggle, let alone the difficulty of preserving data integrity while wrangling with multiple different systems.

It’s important that we share useful technological solutions that streamline the process, because they do exist! Our Cantata platform is a great example. And this sense of streamlining can be applied whether you’re dealing with a digital system or in the material and visits that we’re expecting participants and clinicians to absorb and manage.

With each element we have to ask questions like: is this information/process/request being conveyed in the simplest language? Is it devoid of duplication? Is it reasonable? If the answer is no to any of these, we need to rethink what we’re asking of people.

Patient and public involvement and engagement (PPIE) is, therefore, vital if we are to improve how RCTs are designed and delivered. After all, clinical trials can’t happen without the public taking part.

Far from being a nice to have, as it once might have been seen, PPIE is increasingly a regulatory requirement – and rightly so. Ideally this would be from the outset, at the protocol design stage, but even if activities are only conducted once a trial is underway, for example to get input on the drafting of participant-facing study materials, all feedback is useful.

Ultimately, we want participants to have a good experience, to complete the full trial, and to share that positive experience with their communities, so that others might also consider taking part in a trial. When 30% of participants drop out before trial completion, and 85% of trials fail to recruit or retain a sufficient sample size, anything that helps to alleviate these statistics is a good thing.

I’ve alluded to collaboration and I want to end by coming back to this. As clinical researchers, we are problem solvers by trade. Through my own career as a clinical trial manager, I’ve seen first-hand the incredible wealth of knowledge that my peer group has about what it takes to deliver successful trials – and what doesn’t work.

We must come together as an industry to share knowledge and problem solve together. For example, the UK Trial Managers Network is an excellent community for UK-based academic researchers. How do we scale up these sorts of initiatives so they are industry – and world – wide?

Improving the healthcare of millions is a long game, and it’s dependent on the successfulness and longevity of many and varied organisations in the field of clinical research. Through collectively recognising the problem, facing it, and working towards the solution together, there are huge benefits to be had. Cheaper trials, reduced bureaucracy, motivated staff focused on areas where they can really add value… And above all a better future for the millions of patients worldwide who, ultimately, we are doing this for.

A version of this article was first published in International Clinical Trials, a specialist print journal by Samedan pharmaceutical publishers.