A portrait of Chris Butler by Tanya Poole from the Panoramic Principle exhibition. See below for a full explanation
General Practitioner, clinical trialist, and listener, interpreter and teller of stories.
A GP by background, Chris Butler is Professor of Primary Care, Director of the University of Oxford Primary Care Clinical Trials Unit, and Senior Research Fellow at Trinity College, University of Oxford.
His training and experience span the University of Cape Town, Cecilia Makiwane Hospital (Mdantsane), McMaster University, the University of Wales College of Medicine, and the University of Toronto—bringing a global, clinical practice-embedded perspective to the design and delivery of clinical trials.
He has led the design and delivery of more than 30 randomised trials, including the 10-country PRUDENCE point-of-care diagnostics trial and the 8-country ECRAID-Prime adaptive platform trial—providing practical insights into designing, governing, and delivering studies across diverse health systems.
Chris has helped pioneer pragmatic, “democratised” trial methods, exemplified by the UK National Urgent Public Health trials PRINCIPLE and PANORAMIC. Together, these trials randomised over 40,000 participants and evaluated nine treatments for COVID-19, generating transferable lessons on adaptive design, rapid recruitment, research equity, and evidence generation at scale.
He is currently co-leading the EU-funded ECRAID-Prime adaptive platform trial in acute respiratory infections across eight European countries.
Use this hyperlink to access the University of Oxford webpage for Chris Butler
Chris Salisbury is Emeritus Professor of Primary Health Care at the University of Bristol. He describes himself as having had three overlapping careers: as a full time GP for more than 10 years, then as an academic doing research and teaching alongside general practice, and finally as a leader and manager. His academic work has focused on how to ‘do family practice better’
Hello, I’m Chris Salisbury and today I’m talking to Chris Butler who is Professor of Primary Care at the University of Oxford, where he also leads the Infections and Acute Care research group. And he’s Clinical Director of the University of Oxford Primary Care Clinical Trials Unit. Chris, thanks for joining us. You look like you’re somewhere very sunny ….
Chris Butler: I’m actually in Cape Town, just below Table Mountain. In the reflection in the glass door behind me, you might see a bit of the mountain which is a great place to be talking to you from because the influence of the city and that mountain is, in a way, my spiritual medical home …
Chris’s tudent card from his 6th year at University of Cape Town.
and where I sort of started off studying medicine just around the corner of the mountain from where I am now in Tamboerskloof.
CS: That’s a lovely introduction to the first question I was going to ask you- tell us a bit about your background, because you grew up in South Africa…
CB: I grew up in a small town in Eastern Cape of South Africa, now known as Makhanda, formerly Grahamstown, and my dad was a professor of English literature at Rhodes University. I kind of went with the currents and ended up studying English literature myself at Rhodes, which was fantastic. If anybody says that time emersed in literature was a waste for a medical career, I’ll object in the strongest possible terms. Understanding stories is so fundamentally important. Being able to listen, interpret, and tell stories is so fundamentally important to clinical medicine, and also to research.
In those days there was a military draft in South Africa, and, at the end of my BA, I had three choices: I could go to the military, I could go to jail for six years, or I could leave the country. Actually, there were four choices at that time, in that I could carry on studying. So I looked around for quite a long degree, and while I had ended up by default studying a BA, as enjoyable and valuable as it was, I actually had a passion for something more scientific and, clinically important. Luckily, and I don’t know how it happened, they accepted me into medical school in Cape Town where I got the most fantastic clinical training and ended up doing a bit of pediatrics, and working in the trauma unit. Then the military really came down on me and said, if I wasn’t in a particular military camp on the 2nd of January, I would be arrested. Curiously, that military camp goes by the name of Bethlehem. So if I wasn’t in Bethlehem on the stroke of new year more or less, I’d be in trouble.
I then ended up leaving the country, going to Saskatchewan, where I was a solo doctor for a short while. And then I came back to South Africa and worked as a medical registrar In the Cecilia Makiwane Hospital ln the Ciskei, a so called ‘Independent Homeland’, where I was immune from the draft. In a nutshell, that led me to again face choices that were quite stark. I ended up meeting my partner there and we went to Britain for six months to start off with and one thing led to another. We went to Canada for a while, came back, went to Canada for another while, came back to Britain, and that’s where our resting place is now.
“… the curiosity, and the quality improvement aspect of research, was a bug that bit me early on. I just knew that this was the field for me, trying to get under the skin of these problems that we were facing each day.”
As a GP, seeing one of the fist patients with COVID in the Cardiff Road Medical Centre in Mountain Ash
CS: You went to Wales, to Cardiff didn’t you, as a research fellow, lecturer, and senior lecturer. Why Wales?
CB: In those days, there were very few opportunities for people to develop their careers in academic primary care. Nigel Stott, who was a great mentor of mine and one of the giants of our discipline, claims that the University of Wales College of Medicine was the first academic primary care department in the country, but I think colleagues from Edinburgh might disagree. And that debate probably still runs. Nigel advertised for a clinical fellow position in general practice, which was half time academic, half time clinical. And so I became a half time partner in Llanedeyrn Health Center, where, again, I got fantastic clinical experience and was able to do teaching and start research. It was one of very few openings that were available. Luckily for me, I was successful in applying, and that brought me to Cardiff where I went up through the ranks becoming Head of Department of Primary Care and Public health. But I always kept my clinical work going which has been key to my career, I think, all along.
CS: You always thought you wanted to be an academic from when you were at medical school?
CB: I think, in a way, a full time clinical job in general practice might have been a bit too tough for me. I’ve stopped in clinical work now. But, when I was still doing clinical work a couple of years back, I saw my colleagues getting there at seven in the morning, leaving at seven at night, having seen heaven knows how many patients and made so many critically important decisions. And then they have a little bite to eat, open up the computer and deal with the results and referrals. I don’t think I was strong enough to sustain that, decades in decades out. But also the curiosity, and the quality improvement aspect of research, was a bug that bit me early on. I just knew that this was the field for me, trying to get under the skin of these problems that we were facing each day. I like to think it was all clinically-led, in that I might scratch my head sometimes when with a patient, and think, “I wonder what would be the best way of doing this or that?” That kind of fed into the formulation of questions and broad applications and so on.
CS: I found the second half of your answer about wanting to answer questions very convincing. But, not so much the first half that it was all terribly hard work because, as people will find in a minute, you’re not exactly afraid of hard work. You do a lot of a lot of different things. And, weren’t you also Dean for a while in Cardiff.
CB: I was Dean of Research in the medical school, not of the whole outfit.
CS: And how did you find that?
CB: I enjoyed it but it was quite tricky because, as a humble GP, you’re dealing with a lot of very clever people with white coats, and rats and labs, and petri dishes, and so on.
In general medical practice, we generally don’t have the ‘machine that goes ping!,’ we don’t have the labs and all that stuff. What we do is that we deal with people, we manage uncertainty, and I think there was still a little bit of a residual prejudice, amongst the gene jockeys and immunologists. There was still a bit of that attitude of where they would turn up and say to us- “I need a sample, young man. I need a sample. Get me a sample.” Then I would say, “What’s the hypothesis?” The attitude occasionally was- don’t worry your pretty little head about that, my friend. Just give me the sample and you stay in your box. There was a lot of that still going on, but I think things have changed and there is much more mutual respect.
Swimming in the Grwyne Fawr river in the Brecon Beacons National Park, near Chris’s cottage in South Wales
CS: And then in 2013, you went to your current role in Oxford, and you were doing your big trials. But when I looked at your CV, something I hadn’t realized is that some of your early research included qualitative studies, which is quite a different fit and particularly working with Stephen Rollnick and others looking at motivational interviewing. You’re still involved in that, but that’s a very different paradigm from big complex randomized controlled trials. So, why the change? And are those quite different interests or do they kind of complement each other?
CB: I think they very much complement each other and that stream has always been flowing in parallel. There are a couple of points to make. The first is that no information is useful, unless it is used. And if you’re coming up with a new way of doing things, a new intervention, and you’ve shown that this works, you need to take both clinicians, and the patients who need to act on that information, with you. Complex behaviour change must happen, and there are different ways of doing that, which needs to be supported by evidence. How do you achieve that? There are very few ‘simple interventions’ in our world, they’re all ‘complex interventions’ and therefore they all need heavy social science multidisciplinary input If they’re going to reap the dividend that they deserve. It goes back to what I said about stories and my love of English literature. In understanding your findings, it’s a narrative. In the quantitative stuff, there are stories behind it that really get you under the skin of the problem, to the deeper meaning of the quantitative research.
“… no information is useful unless it is used. And if you’re coming up with a new way of doing things, a new intervention, and you’ve shown that this works, you need to take the both clinicians and the patients who need to act on that information with you.”
Just recently, for example, we published the results from a trial called the PRUDENCE Trial– Point of Care testing to guide antibiotic use for respiratory tract infections. Its an amazing trial in my view, covering ten countries and we recruited to the required sample size for a very well worked out intervention, and overall we showed no benefit from testing compared to not testing people who were consulting in primary care with acute respiratory tract infection. That’s a massive finding, because a lot of people say you should not give an antibiotic before you’ve tested. And yet, here we showed that this major tool, promoted far and wide for antimicrobial stewardship, actually wasn’t having the effect that people had assumed. It emphasised the need for evidence-based medicine (as opposed to proceeding on the basis of ‘assumption-based medicine’). So, how do we understand that finding? Well, luckily from the outset, we had planned a process evaluation with Sarah Tonkin-Crine Maarta Wanat, and Sibyl Anthierens and many other ‘blackbelt’ social scientists, using qualitative interviews, spoke to the clinicians who used the tests, spoke to the patients, and then we got a nuanced understanding of ‘how’: it’s not actually ‘yes’ or ‘no’. There are sub-groups within the average finding of no difference where you might find benefit. If you do something differently, then you’re going to make progress. So, the behaviour change aspect and the social science aspect is fundamental to everything that I’ve ever done.
CS: And, after doing that early research in Cardiff you went on to do a number of randomized controlled trials, and that experience really seemed to me to come into its own during the COVID-19 pandemic, when you led two enormous adaptive platform trials and you got them off the ground in a matter of weeks, recruited thousands of people, and produced results within months ( https://www.youtube.com/watch?v=Kt0hflNW1Uc&t=11s).
Not everyone will know what an adaptive platform trial is, can you just briefly explain what that is?
CB: Perhaps I’ll just rewind a little bit to a study that I was involved in before that as part of an EU funded consortium called PREPARE. From the swine flu pandemic we realized that trials started too late to be of any use within the pandemic, so that consortium built up the expertise to try and get trials research going from the get go. And we did a trial in primary care called the ALIC4E trial of an antiviral for ‘flu. One person said to me, “Look, that drug could be out of date in a year or two. Why don’t you design a trial that is flexible, that could take in new interventions as the trial is going on?” And that’s called an adaptive trial where you can add to the protocol, without losing quality as the trial goes on. And we did that trial within budget, within time, and we finished just before the pandemic. We couldn’t keep the trial open because it had closed but, if it was still open, we could have made amendments and would have carried on, as the REMAP-CAP trial was able to do because, they started later than us and were just getting going when the pandemic broke. So with that interest, we then developed the adaptive trial and a platform trial that could take a number of interventions at the same time.
And, as I say, you could add in additional interventions for evaluation in the trial under its master protocol as you go along. The first trial was called PRINCIPLE. We were contracted to evaluated hydroxychloroquine as the first agent into the trial. People were scurrying around in the dark, clutching at straws, and I think over 200 trials clutched at that particular straw. Very few, less than a handful, gave useful information. Nevertheless, we designed this trial, we used Bayesian statistics, and a lot of modelling went into it the design. I think I got the message that we’d been funded in mid March 2020, and we had our first patient in on the 2nd of April 2020. We didn’t cut corners. We were able to have dialogues with the regulators and with the ethics committees beforehand, and they didn’t cut corners either. It was all done very rigorously, but with that helpful initial dialogue to get us going. That first trial was focusing on repurposed medicines and we produced evidence for seven repurposed medicines. One of the first outputs showed that doxycycline (https://pubmed.ncbi.nlm.nih.gov/34329624/), and then azithromycin (https://www.thelancet.com/article/S0140-6736(21)00461-X/fulltext), were not useful treatments in the community for Covid 19. And that changed practice around the world. These so-called ‘negative findings’ struck a homerun for antimicrobial stewardship, patient safety, and refocusing the research agenda.
I remember a meeting a colleague from Belize who said, “I walk around the wards and the clinics in Belize with a copy of that doxycycline paper, and telling them to stop using it for COVID-19”. And the guidelines in India, the WHO, and so forth changed. And we had clinical alerts where the Chief Medical Officer said to every prescriber in the UK, “Do not to use these drugs for that indication.”
CS: That was an incredibly important trial and necessary at that time. I know how hard it is to get trials off the ground but to start recruiting patients within two weeks, there must have been an enormous amount of setting up beforehand, or perhaps you were building on previous work where you already had many of the methods worked out, and the recruiting sites already engaged through the trials unit.
CB: That EU funded trial (of oseltamivir for influenza, ALIC4E) helped us with the design and statistics and so forth. But, the NHS and the National Institute of Health Research in the UK was of fundamental importance to get us going, and the Urgent Public Health prioritisation approach where they said that instead of everybody who felt like it doing a trial of hydroxychloroquine, let’s do one national trial. The NIHR, its Research Delivery Network, and the Urgent Public Health platform swung behind three key platform trials in the UK. There were fewer trials in the UK, but these were of international importance: The REMAP-CAP, RECOVERY and PRINCIPLE and later, PANORAMIC. So, in taking a systems wide approach, we made sure that we weren’t engaging in massive research wastage. But to go back to your point about work, I’ve still got a little bit of PTSD from those times, and I don’t use that term lightly, because while I was talking earlier about how hard GP’s work, those trials entailed working from 6.30am to 10 p.m. just about every day of the year including Christmas day sometimes, for a couple of years. There was obviously a massive team behind us, amazing people who were all working like that, so that within a couple of weeks, we opened up 800 general practices as sites with contracts, etc.
“…the ‘inverse research participation law’- those who have got the most to contribute to research, and the most to gain from the findings, often marginalized people, people living in high social deprivation, these are the very people who have the least chance to participate in research.”
The most recent paper from the PANORAMIC trial has just been published
Butler CC, Pinto AD, Harris V, et al. Oral nirmatrelvir–ritonavir for Covid-19 in higher-risk outpatients. N Engl J Med 2026;394:1583-94.
This publication represents a landmark in international trials collaboration. It includes data from a trial in Canada because the protocol was franchised to the Canadians and to symbolise a better way of doing trials in pandemics that involved international collaborations.
CS: Some of the stuff you’ve done more recently like PANORAMIC (for the paper on molnupiravir see: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02597-1/fulltext) and (for the paper on nirmatrelvir-ritonavir see: https://www.nejm.org/ ), and we were talking earlier about rats and labs and people in white coats, it’s quite hard science, cutting edge, new drugs. And yet something in particular interests me about you, because I remember hearing you do a keynote lecture at a conference probably 15 years ago in Cardiff and, what really struck me then is that while you’re doing these cutting edge complex trials, you really do have the heart of a real GP. You understood what real general practice is about, and cared about it, and you worked in a very poor part of the Welsh valleys. Do you think that your experience as a GP has informed your work a lot?
CB: We all stand on the shoulders of giants. I go back to one of our founding fathers, Julian Tudor-Hart, who formulated the’ Inverse Care Law’ in the early 1970’s- that those in most in need of health care are the least likely to get it. In February 2020, I was working in the Cynon Valley, Mountain Ash, and I think I saw the first patient in the valley, or certainly in that practice, who had Covid, and I was terrified. I didn’t really know what to do. Nobody knew what to do. But, I checked his oxygen level and did the best I could. But what struck me was not only that I had no treatment, but I had no study to offer this person to, to help us figure out what we should be doing. That led us to elaborate what is known as the ‘inverse research participation law’, that those who have the most to contribute to research, and the most to gain from the findings, often marginalized people, people living with high social deprivation, these are the very people who have the least chance to participate in research ( https://pmc.ncbi.nlm.nih.gov/articles/PMC10773679/).
And so, addressing that, based on my clinical experience with a patient in front of me wondering what the heck do I do now, we’ve got to have the machinery standing there, ready to efficiently give us the answers. I think that illustrates why or how the clinical interface has always fed my passion for the deep understanding of these questions. Building on ALIC4E, PRINCIPLE and PANORAMIC, we now have another EU-wide Europe wide adaptative platform trial of therapeutics for acute viral respiratory infections open and recruiting in 8 countries, recruiting and adapting, and which is generating key findings on low cost, safe and widely applicable interventions for primary care and possibly self-care, it is key for our pandemic preparedness (https://www.ecraid.eu/ecraid-prime).
Nominated for an honorary degree by Prof. Samuel Coenen of the Faculty of Medicine and Health Sciences at the University of Antwerp, March 2024.
CS: Over the last 20 years your contribution has been recognized in lots of ways https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00583-3/abstract. You are an NIHR Senior Investigator, a Fellow at the Academy of Medical Sciences, and only a handful of GP’s can say that, and then there are honorary professorships in Stellenbosch and Cape Town in South Africa, and McMaster in Canada, and then you were awarded a Doctorate Honoris Causa in Medicine and Health Sciences by the University of Antwerp in 2024 which is, I gather, the one of the most prestigious awards that any university can offer for exceptional lifetime achievements (https://www.youtube.com/watch?v=1hapjQxS93k Start at 13.49 minutes).
And these are all richly deserved for the important number of things you’ve done. But, what do you think you’ve learned from all that experience? What tips would you pass on to new early career academics who want to achieve half of what you’ve done?
CB: That’s a big question. If I had to say one thing, it is to connect yourself as closely as possible with the realm of care or the problems that you’re trying to solve. To go back to the work that I’ve done, it’s always been clinically rooted. You need to be familiar with the real world context of where people are living and working.
I’ll tell a quick story against myself… I did a trial, the PACE trial, using a C-reactive protein point of care test to guide antibiotic prescribing decisions for people with exacerbations of chronic obstructive airways disease.( https://www.journalslibrary.nihr.ac.uk/hta/HTA24150) I designed the study and also recruited a few patients into it in Mountain Ash in the Cynon Valley in South Wales where there are massive problems with COPD that I was concerned by. I’m telling all these GP’s to please recruit patients, and here I am, I’ve got a patient that I begin to recruit. I’ve got this form and that form, and the next form. And, I thought to myself, “Which idiot designed this damn trial?” And then I realise, oh, hold on, it was me. So, that’s just about research process. Make it easy. Make it realistic to do the research, make it easy for the patients to contribute. And, that’s just about the research process. But then it goes back to that clinical link. How does this evidence relate? Have you got a “solution looking for a problem?” And that is often the case with research that I see around me today. Start instead with a problem. Identify, from bottom up, what do the people out there need? What’s the evidence they need? And that’s why PPI (patient and public involvement), public contributors, are so important. That’s why starting with the clinicians is so important. Point of care testing is an interest of mine and so many people come and say- I’ve got this magic machine that can do A, B, and C, and I say, but why do we need A, B and C? Ask the guys sitting at the clinical coalface if that is going to help them, or is it just going to add hassle?
It’s these connections with reality that I say – don’t ever lose and always develop them.
CS: Any other pressing tips?
CB: Be confident. Microbiologists, for example, have often said to me, unless a swab is taken by a healthcare professional, it’s not much good. But in the PANORAMIC trial, for example, we’ve done some studies where people have taken their own swabs and they’ve even taken their own blood tests, sent them back to the lab, and we found perfectly good, usable, rigorous data from that (https://www.nature.com/articles/s41467-024-45641-0) You might have a white coat in a lab, but I know the world that I inhabit, and I’m confident that these findings are useful. In many ways, we in primary health care lead when it comes to study design methods and clinical epidemiology. I think the days are gone when GP researchers need to be a little bit insecure in relation to the fields and the worlds that we inhabit.
“I always go back to doing research in the intended use populations, in pandemic preparedness and in many other areas, we need to be doing research amongst those people who are most likely to benefit.”
CS: Finally, what do you do outside work?
CB: I was going to say I’m a runner but that’s a bit grandiose. I’m a jogger. And, we have a little cottage in the Welsh mountains, in the Black Mountains. It was a ruin that we got in 2011, and it’s completely off grid. There’s no signal, there’s no mains, or anything. We go there as much as possible, get on with some work, but also hiking in the Black Mountains. I can think of very little else that brings me so much pleasure. Also, being in South Africa, working with colleagues, developing new research ideas.
You asked me about things not related to work, but I suppose that’s so much part of my life that it’s everything, all encompassing, so I don’t know.
And, the most important thing, obviously, is that my wife is an amazing person to be with and I get so much from my relationship with her. The kids keep me lively and growing. And I’ve got a 15 and a half year old Labrador that I love to bits.
Bridal Veil waterfall in the Hoggsback- a mountain retreat in the Amathole Mountains in Eastern Cape, South Africa
CS: Do you spend time in South Africa?
CB: Not as much I would have liked, but I’m here for a couple a couple of months now and I think as time goes by, I’m hoping to spend more time here.
I always go back to the importance of doing research in the ‘intended use populations’, in pandemic preparedness and in many other areas, we need to be doing research amongst those people who are most likely to benefit. Just around the corner from me here, in Table Mountain, is Crossroads and Khayelitsha, where there are massive informal settlements. And the people living there are the ones who are most affected by many communicable and non-communicable diseases. And getting evidence that applies to them has to be done with them. And so, expanding from the European context to LMICs in future research is something that I really want to do. And, that’s one of the reasons why I’m here now.
CS: Chris, thank you so much for your time. It’s pleasure to talk to you.
CB: Thanks so much, Chris. And, we certainly go back a long way, because I think you kindly gave us a keynote address at an All Wales GP conference in the 90s, and that was a great inspiration. And, of course, I’ve followed your amazing work over the years. Thank you for your contribution as well.
The Panoramic Principle Exhibition
While war artists and war rhetoric was used in the battle against Covid, its very unusual for a clinical trial to have an artist in residence. Chris commissioned Tanya Poole to do mount an exhibition to celebrate the diversity of participants, clinicians trial professionals and others who made the PRINCIPLE and PANORAMIC trials possible. These images are from the catalogue. This is a remarkable collaboration between the humanities and clinical trial science promoting research inclusivity, celebrating the many different people who make these things happen, and furthering multidisciplinary work in the public understanding of medical research. The exhibition is on display in the Radcliff Primary Care building in Oxford
Addendum (CB)
There was a point that I really wanted to make in the interview, and would like to add in now. Penicillin was first given to humans in 1941, and it didn’t take long before we started assuming that if it worked for pneumonia, it must work for coughs, sore throats, and snotty noses too. That kind of “assumption-based medicine” led to massive overuse of antibiotics. It wasn’t really until the 1970s, when people like Stott, Howie and Verheij began doing proper trials in these everyday conditions, that we started to build a genuine evidence base.
Those early studies—and later large-scale trials led by Paul Little and others—helped us understand much more precisely who actually benefits from antibiotics for common infections, and who can be safely managed without them.
We’re now at a similar moment with antivirals. As viruses evolve and new drugs come on stream, the stakes are just as high. I don’t think it’s an overstatement to say that our long-term ability to live with these infections depends on getting this right. We need to do large, rigorous trials—like PRINCIPLE and PANORAMIC—beforewidespread use of antiviral drugs, to work out which subgroups genuinely benefit and which don’t.
Because, just as surely as night follows day, the overuse of antibiotics drove antibiotic resistance—if we use antivirals unthinkingly, we’ll drive antiviral resistance and cause catastrophic mutations too.
