Moloch is stifling UK clinical research

And crushing us under a mountain of small things

Der Götze Moloch

Britain should be the best place in the world to do medical research. We have four of the top ten universities. Two of the ten biggest pharmaceutical companies. Two of the ten largest funding bodies. We have a rich history of scientific breakthroughs. We are second only to the US in Nobel laureates. We have a universal, state-funded healthcare system, in which each individual patient has a unique personal identifying number. We are leading the world in open-science projects like the UK Biobank.

The Covid-19 pandemic demonstrated our potential. We invented one of the first vaccines. We were the first country to approve and administer a vaccine outside clinical trials. We conducted the largest trial of potential treatments, RECOVERY, which was set-up within six weeks, had over 185 sites, enrolled 40,000 patients, and demonstrated the efficacy of dexamethasone. We conducted the largest at-home trial, PRINCIPLE which dispelled ivermectin.

Despite the above - despite all of the above - medical research in the UK is broken. The pharmaceutical industry complain that our processes are slow, complex and unreliable. They describe a ‘culture of nit-picking’. Trial set-up is more difficult than other countries. There is no accountability for under-delivery. Researchers bemoan clinicians having no interest in research, while clinicians bemoan the barriers preventing them doing research.

How did we get here? Masud Husain, a neurology professor at Oxford and editor of the journal Brain, last month published a polemic, Why we need a revolution in clinical research. Masud has previously railed against bureaucracy (he calls this the mountain of small things) but this one focuses specifically on the dysfunctional relationship between our two behemoths, the NHS and the Universities. I think it’s an example of how short-term incentives can misalign to the detriment of all, a phenomenon which has been called Moloch.

Moloch

Moloch is an ancient God associated with child sacrifices, often represented as a bull-headed idol. More recently, it has been used as a personification of the competitive forces that cause individuals to act in a way that makes everyone worse off. An idea introduced in Scott Alexander’s essay Meditations on Moloch.

As an example, think of the incentive structure of science. An inordinate amount of time is spent writing grant applications or papers for publication. These are the metrics by which scientists are judged and will influence job prospects. The time spent doing ‘science’ (conducting studies, running experiments, thinking about problems) is less than you may expect.

Most scientists would prefer to do fewer grant applications (most of which will be unsuccessful) and minimise the growing body of trivial publications. Society, I’m sure, would prefer scientists to actually get on and make discoveries that will benefit us all. The status quo has resulted in a vast increase in publications but a stagnation in genuine breakthroughs.

If all scientists agreed to spend a smaller proportion of their time on these tasks and a larger proportion on actually doing science, they would all be happier, scientific innovation would increase, society would benefit, and there would still be the same finite sum of grant funding to be shared round. However, for any one scientist acting in their self-interest, spending less time grant-writing or manuscript-writing has an adverse effect. By doing less than their peers, they will be less likely to get that promotion or to even have a scientific career.

Scientists are trapped. Everyone is compelled to do more meaningless work, less they fall behind. Meanwhile, all scientists are worse off, and wider society suffers as a result. Clinical academics (clinicians who also do research) will experience this trap, but their situation is even worse because they serve two masters, the University and the NHS, each with different goals.

Doing clinical research

The processes and structures of clinical research are largely opaque to those outside the field. Generally, a group of researchers write a grant application, proposing a clinical study. This is submitted to a funding body (governmental or charity) who arranges peer-review of the applications (done by anonymous experts in that area). With the reviews as guidance, funding is awarded to the best applications, in a highly competitive process.

After the award of a grant, the problems start. The research team have to jump through a seemingly never-ending series of administrative hoops to get the study off the ground, usually taking much more time and effort than the original grant application. Each time you think you’re near the end of this process and close to actually starting the study, more administrative tasks pop up. Masud describes previously getting an ethics application approved in 2-3 weeks; now a simple small observational study would take at least 10 times as long.

Clinical studies need to be sponsored by an institution, meaning they take legal responsibility. To gain sponsorship, the researcher has to submit all documents related to the study to the University, including the protocol, consent forms, questionnaires, information leaflets, recruitment adverts, etc. The University has to approve the ethics application itself. All these need to be checked, amended and eventually signed-off by the University. For a straightforward study, this back-and-forth would typically last many months and countless redrafts. More complicated studies, like those involving a new drug, take considerably longer. It is a full-time job to liaise with the sponsorship department; responding to queries and making the required changes.

When the study has been given sponsorship, it then needs ethical approval. The study documents will be reviewed by a Research Ethics Committee. A researcher will attend the meeting to answer queries. A formal written response to the committee will be sent and further amendments made.

Even when the study has ethical approval, the administrative burden isn’t over. Contracts need to be signed with any partnering institutions. Data protection risk assessments have to be drafted. Security assessments of third parties need to be made. The costs of doing the study within the NHS needs to be calculated, using the Schedule of Events Cost Attribution Template, ensuring every tiny use of NHS resources (like using an interview room in a hospital) is costed.

Each of these steps is manageable, but in total they accumulate to be a substantial body of work, a mountain of small things that consumes time that could have been spent elsewhere. Many of the assessments require input of a single specialist person at the University. The barriers are so high that some studies have years of delay or never get started at all. Inevitably, the studies with highest risk (and consequently those most likely to result in new treatments for patients) are the most difficult to launch.

When the study finally has approval, further hurdles await. In order to recruit participants, researchers rely on NHS clinicians (often doctors and nurses) to approach patients. Ethical approval usually stipulates that researchers can’t ‘cold call’ patients, they need to be introduced by one of the clinical team. Naturally, clinicians are busy people and mentioning research studies is not a high priority. Researchers have to ingratiate themselves with clinical teams, sitting through largely irrelevant team meetings, explaining their study to harangued clinicians.

Incentives matter

Before losing hope, let’s take a moment for the parts of the current system that work well. Firstly, approval is given jointly by the NHS Health Research Authority and Research Ethics Committee, meaning that these reviews do not need to be done sequentially. The process of finding a Research Ethics Committee is much easier than before. Since the pandemic, these are done online, meaning that a slot with any committee across the country can be arranged. Finally, many but not all of the forms are standardised across the country meaning that, in theory, the whole system could be streamlined centrally.

Overall though, it can feel like the current system is designed to frustrate researchers. That senior clinical academics write editorials bemoaning the state of research and are met with nods of recognition tells a story: it is not just junior researchers who are frustrated by the cumbersome, lumbering bureaucracy.

Clinical researchers and their funders desperately want studies to be done. In contrast, universities receive the benefits of funding awards whether or not the study is completed. Their big incentive is in mitigating institutional risk, in terms of financial and reputational damage. This is why so many risk assessments and layers of approval are needed. While long-term, universities could benefit from the prestige associated with transformational clinical research, in the short-term their incentives favour safer, lower-risk studies.

The NHS would benefit long-term from new treatment discoveries but in the short-term, they have little incentive to support new research. Most NHS trusts are treading water; facing increasing demand, increasing costs, and increasing waiting lists. Their biggest motivation is to treat and discharge patients from caseloads. Busy clinicians have little to gain from supporting clinical studies.

In reality, universities and the NHS have little incentive to prioritise research. So studies are delayed, fail to launch, or struggle to recruit. This is not the fault of any individual or even of the institutions themselves, it is a natural consequence of misaligned incentives.

There are second-order consequences too. Upcoming clinical-academics (people like me) are disincentivised from real clinical-research by the sheer volume of red-tape. No-one wants to spend their PhD filling out endless forms for a study that might not even get started and certainly won’t finish on time. Far more appealing are studies which are ‘oven ready’. Meta-analyses, secondary datasets (UK Biobank), electronic health records. These types of studies are safer. Less likely to fail. More likely to produce publications. But they are not going to transform clinical care.

What’s more, the NHS is full of clinicians with ideas for small research projects to answer clinical problems they encounter every day. Clinical discovery is often by such maverick doctors, rather than ivory-towered academics. Think of Barry Marshall drinking a vial of Helicobacter pylori to prove it caused peptic ulcers! In today’s system these people are priced out of the research market. They might have the time to run small research study but they do not have the resources to get through the institutional gatekeepers.

Make British science great again

I constantly hear people lamenting the UK. Many criticisms are valid but there is so much untapped potential. Our achievements during the pandemic are a concrete reminder. We are situated within overlapping Venn diagrams: world class universities, big pharmaceutical companies and a universal single-payer healthcare system. For real economic growth, we need to recognise this comparative advantage: life science, and specifically clinical research, is our edge.

How do we turn it around? It must be a top-down priority. Single individuals or even single institutions are powerless against the forces of Moloch. Universities and NHS trusts have no incentive to make these changes, it has to be an initiative from central government. As the pandemic showed, many of the approval processes in research can be simplified, run in parallel, or cut-back. Research can be less risk averse without being risky.

Make Britain the best place in the world to conduct medical research.

If not, we will remain buried under the mountain of small things. I’ll leave the final poetic description of this dystopia to Masud.

I live under its shadow. I suspect most of you do too. It is the great mountain of small things. Every year, it grows a little taller, a little more imposing, a little more daunting. The higher it gets, the bigger the shadow it casts: a malignant darkness that pervades our lives, one that becomes ever more difficult to breach. So much so that it has become the norm for many of us to live entirely in the gloom. We no longer ask why it has come to this, even though we barely glimpse the light that warmed us in the past. Here, we stand trembling, our energy for innovation sapped, our motivation to focus on research drained. Tell me, have you had a great thought lately? I rest my case. The mountain of small things makes transformative research far less likely to happen. Its shadow smothers our aspirations.