So could you just start by giving your name and your title affiliation, etc.?
Oh, yes. My name's Peter Horby. I'm professor of Emerging Infectious Diseases in the Department of Tropical Medicine at the University of Oxford.
Thanks very much. So could you just start by telling me a little bit about yourself?
So we probably don't have time for your entire life story, but just in general,
if you could go from how you first got interested in medical science and up to up to where you are now.
Right. Well, that is a long story, isn't it? Well, you know, I trained trained in medicine in London.
And what and what made you choose that as a subject for your first, which was I always found, you know, biology to be my favourite subject.
I found it quite fascinating biology and evolution and the complexity of human systems and biological systems.
So it was really the most appealing area of further education and I thought doing medicine would be the,
the most valuable way of following that interest.
So. So I trained in London. And I think quite early on got an interest in infectious diseases.
I actually did an intercalated Bachelor of Science degree in History of Medicine and was particularly
interested in at that time in the history of epidemics and expand the history of infectious diseases.
So I think really quite early on I was interested in infections for lots of reasons, both because.
You've got multiple facets. You've got the the biology of of the human disease, which you have for all all of medicine.
But you also, in addition, have the potency of the virus,
and you have this sort of the evolutionary competition between the viruses and individuals at the individual level and the population level.
And also, you know, there's a lot of.
Social behaviour and political elements as well.
You know, if you've got heart disease and I'm sitting next to you, it doesn't affect my risk of having a heart disease.
But if you've got Ebola, it does, you know, so there's a whole sort of social and societal construct to it, too.
So it's a really fascinating area. And so that's why I went into infectious diseases.
And where did you go after your first after you qualified?
Well, I actually my my very first job was on an HIV ward in the very early days of the HIV epidemic at the Middlesex,
where the patients were incredibly sick. This is before any effective antivirals were available.
And that really, I think, sealed the deal. And my interest in doing infectious diseases,
seeing these young people with these devastating infections and also cancers which were arising because of a lack of, you know, immune tolerance.
You know, so those very early days were very formative.
And very soon my interest in infectious diseases, I then went on, you know, to various medical specialities but with particular interest.
Infectious diseases worked to the hospital for Tropical Diseases in London,
then took decision to specialise actually in public health of infectious diseases rather than clinical infectious diseases.
And so did higher training then was public health laboratory service and has now gone through various metamorphoses in different agencies.
And, you know, actually, when I first qualified a consultant,
my very first job was head of the variant CJD unit, the mad cow disease infection in humans.
So right early on, it was really working on sort of epidemic prone infectious diseases.
I then went to Vietnam for the SA's outbreak, silenced one outbreak in 2003.
I originally went for six months and ended up staying eight years there.
So had the the Oxford University unit in Vietnam already opened by that time or did it?
Was it set up as a result of that epidemic?
There was an Oxford University clinical research unit in in the South in Ho Chi Minh City that was working on infectious diseases.
And I actually went to Vietnam, to Hanoi in the north, working for the World Health Organisation.
I worked for that for three years. And then I was asked by Jeremy Farrell, who is director of the City Unit, if I would open assist to you in Hanoi,
which I did, which opened the the the National Hospital for Tropical Diseases in Hanoi.
And that was that was that was great. That was my first foray into academia.
So I guess, I guess for a lot of people based in the UK,
the idea of the the threat of global pandemics until the last couple of years had been relatively theoretical.
But for you, it you were, you were seeing it firsthand in a developing country.
What were the main threats that that were faced in Vietnam?
Well, you know, we saw the sales outbreak, which was a real warning shot of what's possible.
And, you know, I went in there for the for the outbreak and was involved in in the response to the outbreak.
I then stayed on with W.H.O. And, you know, I remember I got a call from the director of the paediatric hospital, Penicillium,
who said he had some children who were very sick and he was worried that it was solved.
So I immediately stopped what I was doing, which was actually teaching some people about infectious disease epidemiology,
travelled back to Hanoi and went to that hospital and with Professor Williams saw the children and was suspicious that it wasn't SaaS,
SaaS company to not call severe disease in children and these were some very sick children.
So we arranged to take some biological samples, some swabs and blood from these children and send them off to a laboratory in Hong Kong,
because we suspected that they might have a severe influenza. And it turned out they did.
So these were the first cases detected of the resurgence of bird flu, H5N1 bird flu in Vietnam.
So and that was just at the end. It was just around Christmas, 22,003, 24.
So all of these things happened around Christmas for some reason.
So then we saw that, you know, these severe zoonotic influenza influenzas from animals, really quite scary, 50, 60% fatality in hospitalised cases.
So, you know, yeah, I was very much aware from my direct your hands on experience of patients and populations,
missiles and bird flu that these things are really serious, you know, present real threat.
I was I brought under control in a relatively short space of time and didn't become a global global pandemics.
Well, Charles Wang did. It did travel to many, many countries and caused quite a lot of deaths and disruption in Singapore, Hong Kong, Canada.
But actually it was. There were two elements of the reason of that was control.
One is it's not as infectious as COVID 19.
And secondly, the peak infectiousness is much later in disease.
So people were less infectious in the community, but were more infectious by the time they got to hospital.
And so what you mostly saw was transmission within hospitals, which is different with Sars-Cov-1 virus to COVID 19,
where actually your, you know, your peak infectiousness is early in disease when in the community.
So that makes it harder to to to detect and control and then bird flu.
But actually, these viruses, there is very limited capability for person to person transmission.
But so far they've been well adapted mostly to birds and they transmit very efficiently between wild birds and domestic poultry,
etc., but don't efficiently transmit between humans.
So for that reason, they've only ever caused you to mostly survive slight cases or small clusters.
But clearly, you know, influenza has the capability to become very transmissible between people.
And the real worry is that you get at a highly pathogenic, you know, a virus that causes a lot of deaths from birds,
but then it adapts in humans and becomes readily transmissible and causes a pandemic.
So, you know, when people say that we were in one sense lucky with COVID 19, because the case fatality rate is is a lot less than 1%.
They're right.
You know, their advice is out there with with case fatality rates above 10%, which would be an absolute catastrophe if they were to spread.
So back to your personal story. You ended up staying in Vietnam for within nine years.
Eight years? Yes. So I was three years with W.H.O.
Then I set up the research unit in Hanoi, which is still running and very successful, and I'm very pleased with that.
I then went to Singapore for three years where I was still doing work in Vietnam,
but I was also running an infectious disease programme in Singapore and then I returned.
Well, in return, actually, I've never actually lived in Oxford.
I came to Oxford in 2014 where I set up the Epidemic Disease Research Group in Oxford because it just a small group of us.
And that very year, the West Africa Ebola outbreak happened.
And so we just come to Oxford, just set up quite a small group and immediately thrown into the West Africa Ebola outbreak,
which we you know, I think we did quite a lot of work in that area.
And what what what sort of answers did you come to with Ebola?
Oh, well. In the 2009 influenza pandemic.
And it showed us that we had a real problem with clinical research in epidemic infections.
We did a bit in sales one, we did a bit in bird flu, but then we had a pandemic 2009 influenza pandemic.
And what was striking was actually the poor quality of clinical research we did at that
time did not have any licenced antiviral drugs or treatments for severe influenza.
There were treatments for mild influenza in the community, but they were not licenced to the hospitalised cases.
And following the 2009 pandemic, which we kind of knew was coming, everyone's been doing pandemic flu preparedness, so it wasn't a surprise.
We still didn't have any licenced antivirals for severe influenza because nobody was able to do the trials that were needed.
And now, more than ten years later, we still don't have any licenced antivirals for severe influenza.
And so it was a real. No real message, really, that, you know, if you're wanting to improve care for epidemic infections,
you need to treat people with those infections, which you can only do during the epidemic.
So you need to have systems that can operate in epidemics and pandemics.
Otherwise, you're never going to improve care. And the 2009 the influenza pandemic is a map to the exemplar of that,
where because everyone was too busy and they didn't really hadn't really thought through how we were going to do a clinical trial in the pandemic.
We didn't manage to get any new answers, and so we didn't improve Cam and we haven't been able to sense that.
You know, you have to take the opportunity when there's an outbreak, when there's an epidemic, you have to act.
You have that one window of opportunity to get the data you need.
And so you've just got to get on to it and to do the best you can and do it as quickly as you can.
So we're going to get onto COVID very soon. But first of all,
I just wanted to get you to tell me a little bit about the international Severe Acute Respiratory and and Emerging Infections Consortium is Eric,
if that's how you normally pronounce it? I don't know. It's a bit of a terribly long acronym, need to be thinking about changing it.
But it's it's kind of got a bit of a brand name.
Yes. And it does what it says on the tin, doesn't it. So yeah,
you so it was was was actually set up after the 2009 pandemic specifically to to try and bring
together clinical research networks to try and improve the response to epidemic infections.
So to do day to day research that has day to day utility for patients that people are seeing every day.
But it also has the capacity to respond quickly to epidemics.
And so that's what we've been working on since 2009 is to do that.
And I think we've made steady progress. You know, we did manage to start trials,
clinical trials in Ebola and actually then the next big outbreak after the West Africa outbreak which occurred,
the second outbreak was in eastern Democratic Republic of Congo and a clinical trial
was done and it was completed and said there were new treatments now for Ebola,
seven now approved treatments without it because of that. And then, you know, that was the position we were in as COVID 19 emerged.
And actually, we'd been working for, you know,
a decade really in sort of preparing to be able to do clinical research in this kind of context and how does that network work?
But from what I've looked at, it's extremely multidisciplinary, it's extremely international and involves people at all levels coordinating.
That must be quite, quite a challenge. WORK Did you have a model to follow or did you have to make it up from scratch?
Well, I'm. You know,
having worked for the World Health Organisation and and for National Public Health Agency and
in research it's clear that all of those different systems have their different strengths.
They're all equally important and they all got something to offer.
But you know, peer to peer research networks have a real advantage in that they're not politicised generally.
You know, they're much hard to politicise and you have the ability to sort of build up a longer term trusted relationship.
And so for me, that was the essential ingredient to things really is getting together people who have a common interest,
which is basically improving the care of patients who've got, you know,
severe infections from epidemics, and secondly, building that trust over a decade.
So you're in a situation that you can just find someone up and they know you and they trust you and that
they're happy to talk to you about potentially sensitive issues and to collaborate with you and with others,
with your sense I.T. about whether their research ideas will be stolen or whether they'll get the recognition they need, etc., etc.
And so really that that's the two forms of currency, really common interest and trust.
It's not heavily financed. It's not heavily regulated.
It's it's it's a you know, it's a special interest group of people who want to make a difference.
Hmm. It's really interesting. Um. So.
Yeah. I think we finally got to it. Can you remember how you first became aware that COVID was a thing and that it might become a serious pandemic?
Yeah, well, you know, there was the there was obviously the The Pyramid Report, which is a sort of online disease,
sort of, I guess almost like it might have been a precursor to a sort of social network.
It's basically an interest group where, you know, people can tell the primate group of about suspicious outbreaks or clusters of
diseases and the primate group kind of screen newspapers and news streams.
And then they put out, you know, very regular emails to to people who are on what's called a list survey in the old days.
And they said a primate report came out 30th of December about this cluster of infections in China.
And obviously, there's this you know, you've been around the block a bit, you know, could see some red flags in that,
you know, cluster severe acute respiratory pneumonia potentially linked to a wild animal market.
You know, many of these viruses come via in animal sources originally.
In fact, the majority of emerging infections from animal sources originally.
So that was the first signal. And at the same time, you know, the chatter started amongst, you know, the sort of special interest group,
you know, amongst the snake and between people like Jeremy Fowler and other colleagues about, well, what's this?
And so, you know, right from, you know, first to January,
we we were having discussions by SMS and an email telephone about, you know, what's going on in China.
But I mean, I've been saying to everybody else, how did you decide to pivot your research to this new thing?
But in fact, it didn't take much pivoting really for you because you're already right in the middle of that in that.
Oh, yeah. You know, we've kind of been I guess I'm in a sort of slightly luxurious position of epidemic.
Clinical research response is my raison d'etre, you know, so it's core business for us.
So there was no question about not responding because.
If we didn't what we here for with the you know around the epidemic diseases research group.
So and there's an epidemic within research and you had colleagues in China that you were already in touch with, presumably?
Well, yeah. So, you know, having worked in Southeast Asia for a long time and worked on Sars-Cov-1 and avian influenza,
both of which have been issues in China and worked on influenza in general with colleagues in China.
Obviously, I had had very close links with, you know, quite a few Chinese colleagues who I've known for a very long time, for ten years or more.
So we were able to reach out very quickly and and have a discussion about what was happening there and what might be possible in terms of
clinical research to improve our understanding of this virus to disease causes and how we might prevent spread and treat patients better.
I would I mean, one important thing to say is. I've taken a very deliberate decision to focus on patients points because you
can focus on virology or you could focus on epidemiology and public health.
But I've taken a very conscious decision to focus on patients with these infections for a number of reasons.
One is they tend to have been neglected, and it's a bit more challenging really than sometimes to say, virology,
because you have all the issues of consent and privacy and all these other, you know, very important issues that you need to consider.
But also, you know, actually studying patients is central to all of that activity.
You know, where do you get the viruses from? You get them from patients who are infected and taking swabs from them.
How do you understand about the immune response that you need to develop vaccines or vaccines if possible?
Again, you get it from looking at antibody responses in patients.
How do you understand what kind of infection control or public health measures are necessary to do that?
You need to understand, you know, when people are infectious and how long they're infectious for and whether it's,
you know, which body tissues are infectious, etc., again, you get that from patients.
So when you're studying patients helps you understand the clinical presentation and improve the care.
But it also really informs basic policy and public health responses.
So. Were you able to actually in a hands on way approach patients in the early days?
Or presumably travel was a bit of an issue?
Not myself, no. But 390. Yes, we did.
We co-wrote with George GAO, the senior person in China, with the very first sort of commentary on what was going on.
Our colleagues in China that I knew very well wrote the very first clinical description,
and we were able to support our Chinese colleagues to set up two clinical trials in the mine.
And that was a great example of how it worked, because we had colleagues in China who were wishing to do clinical therapeutic trials.
We also had colleagues in in the Middle East who had been doing clinical trials in type since with Middle East respiratory corona virus.
This is known as coronavirus, which comes out of camels causes.
It can cause severe disease in humans. It has been around for a while, but it hasn't really caused it hasn't haven't spread internationally very much.
But he was running trials of Qualidade Yassine Arabe was doing clinical trials in those patients.
And so we were able to, you know,
call up and get a call together with myself and Yazdi and colleagues in China and adapt the protocols that were being used for Murres for SARS-CoV-2.
So it really was showing you how the network. Can function really well.
You know, we knew each other well enough. We were prepared enough to get on the phone chat protocols and get trials up and running very quickly.
And what were you trialling at that stage? So early on,
we started with a drug called Lopinavir Ritonavir because there was some preliminary data in other coronaviruses in
Sars-Cov-1 and emerged which suggested it might have an antiviral effect against the new cells going about to virus.
And it's a readily available drug. It's it's been used HIV for a long time.
And we knew the safety profile. It's available in pharmacies.
So it was something we could start very quickly. So we we started initially with the Lopinavir Ritonavir and we were able to start
that really quickly thanks to the fantastic work of our colleagues within 20 days.
Know by late January we had the first patients enrolled in that trial and so that was the very first randomised controlled trial ever done in,
in COVID 19. It wasn't placebo controlled, I, you know it was just the drug first is standard of care and people knew what they'd been allocated to.
But meanwhile we were setting that up. We were also working hard to try and get Remdesivir into the country,
working very hard with the drug company Regeneron to try and get their normal channel.
And so I get to try and get the the drug into the country.
And we managed to do that. So we managed to get the drug and placebo in the country.
And so by February, we were able to start the very first placebo controlled trial in COVID 19.
And what what what had remdesivir been useful previously of Remdesivir was it was again,
it was an antiviral drug that wasn't licenced for any indication, but it had a sort of fairly broad spectrum antiviral activity in the laboratory.
And so there were suggestions that it would be effective against coronavirus, too.
So that was a more attractive drug.
So whilst we were starting to have a ton of it, we managed to secure the the remdesivir and placebo and get that started in China.
So by what month are we in by now, by the time you arrive in February, yes.
You know, by fairly early in February, we had two trials running.
And by that time, the spread around the world was beginning to look quite significant.
Yeah, that's right. So what happened in China is we got the trial started pretty quickly.
And I remember giving a presentation at the time, around that time about what we what our response was.
It was at the Royal Society of Tropical Medicine and Hygiene that the response,
the clinical research response to COVID 19 and same with Chinese colleagues,
we managed to get the first patient into this trial within 20 days of of the outbreak being recognised or reported,
which really, you know, was a record I thought I could never beat.
And I gave examples of how long it takes normally, takes years to get trials started and then how we did in in Ebola,
where we managed to get things started in a couple of months.
And then so to get the pilot up and running and the patient first patient involved in three weeks, I thought was a record we never beat.
But unfortunately, unfortunately, fortunately, what happened was the the Chinese authorities, you know,
recognise the risk put in place very stringent public health measures in Wuhan and very big city, complete lockdown.
And so they managed to control transmission very effectively in Wuhan.
So what happened was the trials, even though they opened very quickly and recruited,
they eventually finished with insufficient patients for a clear answer.
So both trials had roughly 200 patients in them each, which really wasn't enough to give a clear answer.
So we, we started the clinical research activities on one, you know, treatments for COVID 19.
But because the outbreak had been controlled, we weren't able to answer that question at that time.
So it's a bit of an irony that in order to get these clear answers, you actually need more people to get ill.
Yes, I know. It's a it's a strange dilemma. That's actually if you want clear answers, you need more patients.
And that means you do, but you have a bigger outbreak.
So, you know, we do try and get the best evidence we can with the patients we have.
Yeah. And so, you know, by that time it was starting to spread internationally and actually I'd,
I'd applied for a grant to extend this research programme with colleagues in China
because up until that point the research had not required any external funding.
It was being funded by just, you know, volunteer time or from the Chinese government.
So I applied for a grant to expand that research programme, that clinical trial research programme in China on therapeutics for COVID 19.
But by the time the the panel had sat and made a decision and decided to award us the grant,
there was not much COVID 19 in in China anymore, and there was quite a lot in northern Italy and other parts of the world.
So I actually got a phone call from the grant agency saying, we're going to give you the grant, but you're going to have to do it in in UK or Europe.
Because that's where we think the cases will be. It's a witch hunt funding body was this.
And this was the Medical Research Council. Oh, it was. So we got the money, but we had to move from China where we meant to do it to the UK.
And is that what became the recovery trial? And that's right. That's what became the recovery trial.
Yes. So tell me a little bit about how that was set up. So the recovery trial.
Yeah, which has been phenomenal experience, really.
So we were in a situation where we started two trials in China that had not reached sufficient patients to give us a clear answer we had.
So we had a summit and we had secured funding to expand the programme and we need to set up the trial now in the UK.
And at that time it was becoming clear that.
It's a very transmissible virus and things would take off pretty quickly in the UK as we were seeing what was happening in Italy at the time.
So we had to get this up and running really very quickly in the UK.
And so I was thinking about how this is going to happen because I'm in the tropical medicine department and I work on sort of high,
high threat pathogens, mostly in tropical countries, and never had a clinical trial in the in the U.K.,
which is a very different context from where I've generally done my work.
And at that time, Jeremy Farrar, who, you know, obviously was a is a close colleague and friend, said, oh, you should talk to Martin Landry.
And Martin obviously has a lot of experience of Olympic trials in high income settings because he
works in the group that runs many beat cardiovascular trials and other sorts of clinical trials.
And so Martin and I got on the phone, and I think it was a sort of marriage made in heaven, really, because, you know,
I had the infectious disease threat pathogens, epidemic experience,
and he had the experience of setting up mega trials, basically, and very streamlined trials.
And so we came together and that became the recovery trial.
And how did you recruit patients into the trial? Well, that just just take me through the kind of nuts and bolts of how you set up a trial like that.
Yeah. I mean, it was a it was a a fraught time, I think, because on the one hand, we were we were, you know,
being you know, I had been working with W.H.O. on the clinical research response to COVID 19 since the early days.
And I personally was frustrated at the pace of change and progress and felt that it was too slow.
And so there came a point when we had to decide, were we going to wait to W.H.O. and do this with W.H.O., or were we going to just go it alone?
And, you know, after a busy deliberation, a few conversations, we decided that really, you know.
We couldn't wait. Much as I'm supportive of W.H.O. and the work they do,
I really felt that we were the right decision was to go it alone and set up the recovery trials, which we did.
So, you know, I think Martin and I had and also we interviewed, you know, he dug out an old protocol of a very simple trial,
the very earliest chances of clot busting drugs back in the eighties,
and took that together with the information we had about the trial designs that we were already using for COVID 19,
and sketched out a highly simplified protocol that focussed on the important things around patient safety and
welfare and getting clear answers but streamlined wherever we could streamline because we knew a lot of things.
We knew the trial had to be big.
You know, because there's not going to be a miracle cure.
And a lot of people are designing their trials based on the idea that there's some miracle cure out there.
It's going to reduce mortality for 50% and that ain't going to happen.
So you're looking for modest benefits. And in a pandemic, a modest benefit is a huge value.
And so. If you wanted to have a 20% reduction of a 20% case fatality rate, which is kind of what the estimates were in hospitalised patients,
you need about 2000 patients per RCD, 2000 patients on the active treatment and 2000 not on the active treatment for comparison.
So you need 4000 patients per drug and since so need to be big.
And it needs to be quick because, you know, we were going to see we knew we were going to see a very rapid uptake and it needed
to be practical in the situation where hospitals were going to be overwhelmed,
which, you know, we'd seen had.
And we saw in northern Italy that hospitals and health care staff were under extreme pressure, you know, and so if you need to try,
this can be big and it has to be quick and it has to function in a very, very stretched health care system.
And it's got to be simple. That's the only way it's going to work. Is it simple?
You know? So it was stripped back to the bare necessities.
And so. We had a very simple sort of what we call case liquid form, which is the baseline information about the patient.
We had a very simple consent form and we had a very simple follow up form.
And the beauty of the system currently in the NHS is that we could use data linkage and again Martin has a lot of experience
in his team and that's area where instead of asking doctors and nurses and others to fill in forms on all patient outcomes,
we could collect a lot of it from electronic sources like death registration and intensive care unit registries and things like that.
So a huge amount of effort starting to date, data linkage and it's been a real triumph, a fantastic team led by Marion,
not simply to put together all the data linkage, which means that we've managed to really decrease the burden on the frontline health care staff.
And so we had a very simple protocol. We had a data linkage that would be set in place.
So we knew we could use that to supplement the simple data collection.
And in the in the UK, we had the National Institute of Health Research, which is this national health research infrastructure that parallels the NHS,
which meant that there was an existing infrastructure across across the NHS to doing research.
And in 2009 the from the pandemic, the principle had been set of priority public health research.
So in the event of a health emergency, the NIH are we have a process to prioritising what research done so that they prioritise the important stuff.
And that also was pretty unique in the UK.
Not many countries were able to do that to have a system where you actually set across the whole health service.
These are the priorities you need to stop doing this other stuff or we're not going to stop doing this other stuff.
And so that was essential as well. So given those things, you know, I had a meeting with with Chris Whitty and Jonathan Van-Tam,
the Chief Medical Officer and the Deputy Chief Medical Officer in in March where I was going there
to present the the principles of what we wanted to do because we needed to get CMOs by them.
I think it was a 10th of March that I met them and said, Yeah, in a very quick meeting, 15 minutes in the Department of Health.
This is what we going to do is that's going to work. Response was, yeah, do it.
Go ahead. Green light. And we enrolled the first patient in the John Radcliffe Oxford nine days later.
So we beat our 20 days. We have halved it just nine days after that meeting, at which point we didn't even have a protocol in time in the first place.
It was nine days. It's not an absolutely fantastic team effort from the clinical research team and the programmers
and the clinical trials management team and research services and everyone in Oxford,
plus the Ethics Committee that we used in Cambridge and the medicines, health regulators, our team are all the same, you know, and.
Did a fantastic job in in reviewing the proposal made short time and signing off set to get the protocol written
together with all the stuff set up by the the IT infrastructure and the RANDOMISATION procedures and materials,
the consent forms, the website and to get approval,
ethics approval and regulatory approval and it was the first patient in nine days was quite, quite phenomenal.
I remember going over to the John Ratcliffe with them, Richard Haynes, who's the person that makes the whole thing, Ron Tindall, the first patient.
And it was just it was an amazing to you know, we started so quickly with the mode of transportation.
Mm hmm. So just to clarify for future listeners that the recovery programme is.
Is. The recovery trial is for patients who are sick enough to have been admitted to hospital.
Yes. So it's a clinical trial of treatments for hospitalised patients with with COVID 19.
Yep. And then and so what, what was the first because you've trialled a number of different treatments.
Run me through those quickly. Oh, well, I guess that's actually a long list.
So we'll pick out the key ones because haven't drugs so far.
All right. Okay. Well, we have results for nine of them.
Hmm. It was a yeah it was interesting the in the very first patient enrolled I think was randomised to dexamethasone the low cost
stellar drug and I believe you know something which you know since then there might be a contract that he was a little acid,
he was allergic to medicine which nobody never is allergic to.
Steroids really is very strange. And so you give people if they have allergies, that's what you do.
If someone has an attractive response, you give them steroids.
It it's very strange. So then you have to find the find the patient's GP and say, oh, what's this?
You know, is that true? And the GP said, No, it's a mistake.
He's not allergic to steroids. So and the patient was kept out of it could be randomised to dexamethasone or not.
So the very first patient we had to sort of pick up the first patient become randomised.
So we initially started with what we call repurposed drugs,
which is drugs that were already available and licenced for other indications
like dexamethasone as a standard use for lots of inflammatory conditions like,
you know, skin diseases or asthma, etc. So that's licenced.
There was also hydroxychloroquine, which is exactly an anti-malarial drug,
but it's been used for many decades and was available and lopinavir ritonavir again,
the one we didn't get an answer for in there in Milan was included.
So we started with the repurposed drugs,
knowing that later on we could bring in more experimental drugs that became available, which we have subsequently done now.
Yeah. And so, yeah, 1111 drugs so far as we speak.
Trial still ongoing. And we have we have nine answers, six negatives and three positives, which is great.
Three new drugs that save lives in COVID 19.
Yeah. So that's the next step. Obviously, what you've done has an immediate impact on policy and practise in the treatment of of patients.
So how big a difference have those positive results made to the the the death rate in in hospitalised patients.
Well I mean first I would say that, you know, three AB nine is a pretty good hit, right?
Yeah, absolutely. A lot of drugs fail and we were starting with a brand new virus,
which we didn't know anything about and we didn't have any specific drugs developed for it.
And we were just using repurposed drugs to begin with. So three out of nine is pretty good.
It's also important to know that, you know, showing things don't work is important.
You know, lots of people were taking hydroxychloroquine. It's myosin.
And, you know, we were talking about things and actually many, many national treatment guidelines were recommending these drugs based on their data.
They were saying, you know, there is no doubt about it, we recommend you try it anyway.
So a lot of people getting these drugs recommended, not treatment guidelines.
You know, we were able to pretty conclusively well, very conclusively showed they were not effective.
They were not effective and they were not to be used for treatment.
And that's a good thing, because that means that you can stop giving drugs unnecessarily to patients.
You can stop wasting the time of the prescribers and the pharmacist to prescribe this stuff,
and you can focus on then evaluating drugs that are much more promising.
So our very first result was I don't see chloroquine just doesn't work in hospitalised patients drew a lot of anger
because a lot of people had been convinced by very poor quality observational data that it was very effective.
When you say people, do you mean clinical, clinically qualified people?
Yes. Surprisingly, some of members in non clinically qualified members of the public life is not quite the right word.
But were convinced and many politicians were convinced that, you know, examples of Bolsonaro and Trump saying, we think this stuff works.
Stepping outside their area of expertise, I might add. And a lot of people believe the hype around these drugs,
which has been shown very clearly to be just that, just to be hype, and that they're not effective.
But because I think we were the first trial to to say that Dr. Kevorkian was not affecting hospitalised patients,
we were the very first to draw from a lot of the fire around that.
You know, we used a high dose of hydroxychloroquine based on very careful modelling of what concentrations you need to have
an antiviral activity and very careful modelling of the safety profile and then what doses it might be harmful.
But that didn't stop people saying that the trial didn't work because we were poisoning people,
etc., etc. But subsequently one of the other big randomised trials have been negative as well.
In fact every result we've had this been looked at in other big trials, adequately powered trials have been confirmed.
So we're very confident that our results are very reliable because we're the biggest trial.
So that was our first result. Hydroxychloroquine doesn't work. I spent a lot of time dealing with hostility for that result.
Second result was that dexamethasone does work, which is fantastic.
If you were to use any of the drugs to work, you would win that one because it's extremely well understood.
It's pretty safe. You know, you get some complications in a poor diabetic control and some secondary infections and things.
But we really know how to use this drug and it costs virtually nothing, you know, and it's available everywhere in the world.
You know, you can get steroids over the counter in many pharmacies around the world.
And so we had a drug that costs very little and was available everywhere and in some patients had a good effect.
So it didn't have a benefit in everyone, but in patients who were more severe,
so who required oxygen or high levels of respiratory support and there was a very clear mortality benefit.
So it was a really fantastic result. I can remember looking at those results with Martin just thinking, Wow, yeah, this is great.
But there was also a lot of resistance to putting dexamethasone into the trial.
There were many clinicians who thought it was dangerous to give a steroid, to suppress your immune system in somebody who's got an infection.
Kind of goes against the grain and you might end up making the infection worse and that the box will replicate.
So we had quite a lot of people telling us that it was not ethical to put steroids into the trial because we would definitely make people worse.
So there was a bit of nervousness about putting that in because, you know,
we did get letters and those letters were copied to people in government saying it was unethical to put steroids into the trial.
So it was remarkable to see that it was so effective.
And that went into policy overnight. And the day we announced the results, we did a, you know, a press conference.
And then, you know, I went to number ten when we announced it and that evening that the chief medical officers of the UK sent out a an alert
to all clinicians to start using it in patients who are more severely ill and subsequently been adopted worldwide.
Which is which is amazing. Hmm.
So what were the other two worked? So you actually did what was a drug called an interleukin six inhibitor.
So this particular one was tocilizumab. So this is a much more targeted anti-inflammatory.
So you might think of steroids like dexamethasone is a bit of a blunderbuss sort of approach.
It really dampens down the whole immune system in many in many different ways.
Whereas Tocilizumab is a very highly targeted targets, just one specific part of the inflammatory pathway and that also had a mortality benefit,
which is great again in a subset of patients and patients who have signs, inflammation and the need for oxygen therapy, then tocilizumab helps.
And what's important is it helps on top of steroids.
So. Steroids became standard practise.
And so we were testing Tocilizumab on top of steroids being used as standard of care.
When we show, we saw an additional incremental benefit with the use of Tocilizumab and again that entered into into practise in the UK and elsewhere.
And I think it was a we'll be approved we believe fairly shortly by some of the regulators.
So that would be two drugs, dexamethasone,
tocilizumab where it's come right through from first in inpatient in these patients right through to full approval from regulators and changing of see
of the product in setting the boxes to say you can now use this for kind of patient and recovery trials that's that's really fantastic to see that.
Hmm. And if the drug was a monoclonal antibody preparation, which is an artificial antibody preparation.
The particular one we tested was called one, two, three.
And what we showed was that in patients who did not have their own antibodies in giving them artificial antibodies improved their survival.
So again, in a subset of patients, this drug is effective.
The difficulty with the monoclonal antibodies, though, is that the.
Okay. Targets the virus. You can get resistance to the monoclonal antibodies.
And with the American variant, there's just a reason we have seen that,
that it looks like there will be some problems of resistance against some of these
monoclonal antibodies so that we don't have the full results as we speak at the moment.
But the monoclonal antibodies are great because you can design them for new viruses quite quickly.
But there is a challenge that resistance can develop.
Okay. So I've noted various other things that you are involved with as well as the recovery trial,
and you were also interested in predicting how well patients were going to do from the.
Yeah. So yeah, it's been a busy couple of years.
So there was the there was trials in China, there was the recovery trial.
And then through esoteric, um, we set up a clinical characterisation database again so that we could work ten years.
So talk me through how, what, what is that and what does it do.
So what it is, is, it's a form basically that, that, that gathers information about patients with a disease, about their character.
It does this in an anonymous way. So we can't identify anyone.
But what's their age bands, their gender, how they got diabetes,
they overweight how long since symptom onset and then follows them through through their treatment and their outcomes.
And it really helps you understand who's at risk of severe disease because this is a database of patients who've made it to hospital.
So who's at risk of severe disease? And that helps you targets preventive measures.
All right. Or early treatments. What's the clinical presentation?
What do people present with? What sort of symptoms do they present with?
And then what's their clinical progression?
What factors lead you to end up needing higher levels of care, going to intensive care, being ventilated or even dying?
And so we set up that database. Very early on again in January.
And at the moment it's got about three quarters of a million patients.
So I'd say it's a really big database and it's been really useful. So in the UK that data was used and looked at by the Sage Committee every week.
They were looking at that technical data and we've now produced a lot of bigger reports,
global reports, and we've got a lot of papers and insights published and a lot more planned as well.
And we can look at many different things like the risks of needing support for kidney function,
the risks in pregnant women, as you said, risk scores, who's predicting, who's likely to do badly.
And so you can give some more intensive treatment earlier on and so many, many things.
So that's been really another great success.
And I think. Um, is another example of where preparation helps because we've been working on those forms and the procedures for many years.
So by January we had to step it up and we had to network the network where
people trusted us that we weren't going to just steal the data and publish it.
So they felt confident to contribute. Now more than half the data is from low and middle income countries,
and we set up a very clear process of making sure that people are putting data
and get the recognition that they deserve and are involved in the analysis.
So again, it's the preparation in terms of the the technical side and the methodology,
but also the preparation in terms of building up a network where people trust each other.
This explains why some of your papers have an awful lot of authors on them.
They do have a lot of balance. So, I mean, you've talked several times about things becoming policy and going to Downing Street.
I mean, was that something you were already I mean, you must have been to a certain extent familiar with that from your previous work.
But what observations would you like to make on the relationship between research and
clinical medicine and how that interacts with policymaking at the government level?
Yeah, I mean, I have experience because I have been on one of the Department of Health's
committees called the New and Emerging Respiratory Viruses Threats Advisory Group,
which was nervtag. Yes, yes, yes. And another terrible I still do.
But it was, you know, looking at severe influenzas, most corona virus, avian influenza, etc.
And I was a member of that and actually became the chair of that committee just before the pandemic started.
So it was spaced out to two meetings a year at most.
And, you know, it's a voluntary thing.
It's it's independent experts who are volunteering their time so you can get paid anything to meetings a year and, you know, X number of hours a year.
And I think we up to more than our 65th meeting last two years.
So Nervtag is at the peaks was meeting every week.
So that was keeping me busy as well because we were having to sort of prepare the papers for that and
chair that and then do reports back to government about some the science and what it means and how.
How does Nervtag relate to Sage? So is only set up during emergencies.
And so nervtag was the standing committee. I see.
Yes, actually, NERVTAG met before Sage was convened, so we had a couple of meetings about COVID 19 before Sage even started.
Once Sage was stood up. Then really, Nervtag becomes a sort of committee sage.
And in one way it's owned by the Department of Health and reports to the Department of Health.
But in another way, it also has a sort of reporting functions for Sage.
And then I was, you know, a member of the Sage Committee stopping on the Sage Committee for COVID 19 since the subsequent experience.
Now, science and policy, you know,
I think it's critically important that the independent scientists can give independent scientific advice to government.
And I think the real trick is making sure that as scientists, we give scientific advice, but we don't tell the government policies to follow.
You know what we tell them? Is it this is what we know. If you do this, this is what might happen if you do that, this is what might happen.
It's up to them to decide if they do this or that. Not us.
But we tell them what we think, the implications, what's the evidence base then for this or that,
and what might happen if they do this or that and they take the decision?
So there's doubt, I think, standing up now a pandemic sciences centre here in Oxford.
Is that right? Tell me how that came about. Well.
Very early on. Again, data was escaping very early on.
I went to see which is the head of department here.
He's head of the Nothing Department Medicine Oxford. So he's my my boss, in a sense.
I went to see him and said it's early days.
But I remember during the Ebola outbreak, the West Africa Ebola outbreak,
the London School of Hygiene Tropical Medicine said it set up a school wide Ebola taskforce
and they basically turned everything around to Ebola across all all of the departments.
And it was extremely effective. And as a result, they did some really good work.
And I think we should do this for COVID 19.
We should set up almost like a taskforce across the department to bring everyone together, because there were so many people doing things.
You had people doing wonderful structural biology, people working on the diagnostics, people at the G.A. working on vaccines.
We were working on clinical characterisation of therapeutics.
We need to sort of all be on the same page and collaborate and have a programme.
And so Richard agreed and he convened a meeting of all of the key scientists in the medical sciences division,
and that proved to be really successful.
And I think that's one of the reasons that the university was so productive was because of the leadership of people like Richard,
who saw that there was huge capability within the university, but it could be even greater if we put everyone together and supported them.
So Richard was really central in making sure that we'll work together and when we needed support and,
you know, if we needed financial backstopping or we needed to turn over some lab space urgently, he did that.
And so, you know, he's he needs to take some credit for the successes of of of what's been done.
And the same is true of other departments as well enough the department population elsewhere will be comments and yeah,
it's turned over the whole machinery of clinical trials to the recovery trial.
And so that kind of leadership has been really important.
And so having seen what's possible in terms of coordination of scientific power across the university
and seeing what's possible in terms of accelerating going from science through to actual impact,
both in terms of the therapeutics but also the vaccine.
I'm sure you'll talk to Sarah and others about the AstraZeneca Oxford vaccine and also diagnostics.
You know, the university runs them, you know, the diagnostic platforms for some of the national studies in the UK.
Having seen what's possible, what we can do if we really put our shoulders to the wheel and do things differently,
we so we need to sort of formalise that.
And that's the idea behind the Pandemic Sciences Centre,
which is to bring together the expertise working on emerging infections, epidemic prone infections, pandemic infections,
and get us all working together on a day to day basis, not just during a crisis,
and try to ensure that we can work at the same pace on other diseases, not just on COVID 19.
So that'll be a virtual centre, will it, rather than a physical space? It will be a physical space.
We have a lot. So we're hoping that we will be able to raise enough funds to build that.
So there will be a building. I probably take, you know, I think 3 to 5 years to finish the building.
So it will be virtual for a couple of years and then it will start to consolidate and eventually we will have a new building.
You're you're the director? Yes. I've been asked to be the director.
So that's also something that's, you know, an active part of my work, my wife's finances, etc.
Yeah. Yeah.
So so that's is that that's actively operating at the moment as a virtual centre, but with a focus presumably on Corona for the time being.
Corona virus is operating in the sense that we've even started looking beyond COVID 19 actually.
But a lot of the activities at the moment of setting up the scientific, you know, so it is working, but we're still,
you know, formulating the full scientific strategy and and also the sort of the operational governance strategy as well.
So presumably this is something that you would have even before COVID 19, you would have thought this was something that was a good idea.
But it took I suppose it took COVID 19 to bring home the necessity and the possibility of doing something like that.
Absolutely. You know, I had in the past written funding applications, you know,
to set up a sort of multi-disciplinary research centre, an academic sciences at Oxford, which had not been successful.
I think because people didn't potentially see the value or the risks from pandemics.
I think that's changed a bit now. So hopefully we'll be able to get the right investment we need.
So I'm just going I've just got a few questions that are more about how you sort of personally affected by by the pandemic.
So did did the lockdown and other provisions that were mitigating regulations that were brought in have an impact on on what you were able to do,
change the way you worked? Well, like everyone I mean, I'm not I'm not a laboratory person, you know,
so we so we work with clinicians and nurses and pharmacists working in hospitals.
So you need access to that to our own laboratories.
So subsequently we did do some about to work on some of the drugs we evaluating, but.
It meant that a lot of it could be done from home and so from, you know,
meetings virtually simply so very quickly I to make time pretty much home working.
And because you know, our building, which is the port two cabins were closed down pretty,
pretty early and pretty extensively and actually have only just reopened after being shut for almost 18 months.
I think that that had to do it all from home working.
So I've spent a very many long hours in this office, I mean, at the start of the pandemic in 2020.
But I was having in telephone calls with colleagues every night at midnight.
For many, many weeks. It's been I'm pretty sick of this, to be honest.
And to what extent did you feel personally threatened by the infection, if at all?
No, not really. I mean, I think having dealt face to face with patients with sores and bacteria and Ebola and Lassa fever,
I felt less threatened by this because I knew that it was an individual level.
You know, the risk of fatalities is not that high.
The problem is, is that, you know, because it's so transmissible with so many, you know,
hundreds of millions of infections that you do end up with a lot of sick people.
But the individual person, individual risk of any one person ending up in hospital dying is relatively low,
although I am only getting towards the old age spectrum where we may start to shoot up.
So I didn't feel particularly affected at all really.
And given the fact that we were having all the social measures in place, it really I don't think is a concern for me personally.
Mm hmm. I mean, you mentioned that you're pretty sick of people at that space.
And I think that was one of the major issues for most people in lockdown,
was that the limited social contact and the fact that they were stuck in the same place.
Did the fact that you were working on something that was clearly going to be helpful towards resolving the the the pandemic,
do you think that helped your your own wellbeing? Oh, I'm sure.
Yeah. You know, I think we're in a luxurious position of being able to do something.
I mean, it must be terrible if, you know,
you're you're seeing all this unfolding without the sort of the expert content knowledge that we have and
without being able to sort of see your friends or work colleagues and not being able to do anything about it.
You see an American that could be quite, quite distressing, really.
You know, we were in the position where we understood the virus, kind of knew what the lab looks like,
and we were doing something that was useful and it was working.
And it could be frustrating if you were trying to do something and and it and it wasn't being effective for whatever reason that would that would,
I'm sure not be a good place to be in.
But it was also it was working when we saw that the for example, you know, the trials could get up and running and they they were doing that quickly.
In that case, numbers were coming out from them and seeing a lot of patient information being uploaded on the databases.
We could see that what we're doing is working. So, you know, that gave us a lot of succour.
And do you think that amongst the people that you that you worked with your colleagues
and was there any need to sort of be aware that you might need to put in place extra
support for them for their mental and emotional well-being as a result of things like
family members being sick or just very long hours or isolation or anything like that.
Yeah, well, to be honest, I probably neglected that. We were so busy during the response that I actually worried that actually some of our
team members who it and who were less involved probably had a more difficult time.
And because of those issues. I've done that.
I've done that. Okay. I think. I think we're moving towards a conclusion, though, actually.
So this sort of sounds like a silly question. I read it, but has the work raised new questions that you're interested in exploring in the future?
Well, it's really showing the power of these sort of these mega trials,
which are platform trials where you can add in new treatments and just keep the platform going.
It's really showing the power of that. And I think, you know,
many people have said that the recovery trial is a transformation in the way that it's really simplified
to become an extremely complex trials network and showing that you can you can make a real difference.
And regulators have accepted the results of these trials and we've changed practise.
So why can't we do this every day? So I'm really hoping that it will have a long term legacy from the trials in the way things are done,
and simplifying trials and making sure that we get big numbers of patients in simple
trials to give clear answers on a more sort of technical level that the the benefits of.
Immuno modulation. So the anti-inflammatory drugs in COVID 19 have been a bit of an eye opener to see that steroids work and that the other drugs,
tocilizumab and some other anti-inflammatories are beneficial.
So I think it really has opened the door for looking at the more closely at the role of anti inflammatory approaches in infectious diseases.
You know, there are some well, we know that anti-inflammatories can work like TB, meningitis, etc., but.
Then I just kept optimising that and there may be scope for using immunomodulators in in other infectious diseases.
So one of the things we'd like to look at is the use of steroids in severe influenza to patients
hospitalised with influenza because again there is evidence of a severe inflammatory line that's going on.
So I think that's, you know, an area of scientific endeavour, which is quite exciting.
Mm hmm. And in terms of global health, generally,
what lessons do you think there have been and what would you like to see change in the way global health research and practise is implemented?
But that's another talk, isn't it?
Uh, well, I think. Seeing, you know, serious investment in research and development for health threats is the key is is the key lesson.
And we said this after the Sars-Cov-1 outbreak, and really there wasn't much investment and it was very short lived amendments and very short.
And now we've seen, you know, the massive impact that is possible from these viruses.
And this is with the virus is not even that severe. Can you imagine, as I said, you know, five or 10% mortality or even sort of, you know,
mortality that isn't concentrated in the older age groups but is concentrated in younger age groups.
You know, the fear, the disruption, the cost is astronomical.
And, you know, others have said it, but I'll say it as well.
You know, we spend billions and billions on defence spending for weapons,
weaponry that really does not have quite this sort of global health value of research and development on pandemic infections.
You know, this is our insurance policy. We need to take it seriously.
We need to invest properly, heavily in it, in a sustained way in research and development for infectious diseases.
And that can be focussed day to day on day to day infections.
You know, we still have plenty of infectious diseases we need to tackle, like dengue.
TB You know, still the HIV is not not curable.
There's plenty of work to be done, dates down infections and we can invest heavily in that.
And it will also be an insurance policy against pandemic infections.
I think also there's a need to look at the ecology of emerging infections.
Most of these viruses do come from animal sources. We need to think about how we are managing the ecology of these animals and how we're
interacting with them and what risks we are generating and how we can mitigate them.
Is that, do you think is a better way of organising internationally?
I mean, you mentioned that W.H.O. was a bit slow early on and is Eric was able to be quite fleet footed because it was a peer to peer network.
Is is does something need to be done about essentially the human resources and infrastructure globally to to improve things?
I'm absolutely sure that there's a lot that could be done in that there's there's this whole areas that we haven't touched on like,
you know, uh, you know, political decision making and interaction between governments financing an equitable access to vaccines and drugs,
which, you know, really she was inequitable access to vaccines.
Many of the drugs, for example, the monoclonal antibodies that we tested are very expensive.
You know, that needs to change. There's some way of making them available, affordable prices to the whole world, not just selected parts of the world.
And in terms of the research response, yeah, I think, you know, we have to look at what's worked and what hasn't worked.
I think what has worked is. Having invested in infrastructure and people over a long time periods to work on infectious diseases,
but also empowering them to be able to respond quickly to in 19 threats.
I think that's the way forward and I think international agencies like W.H.O.
have a really important role in sort of normative saying normative standards.
How should we be doing this? How do we ensure equity of access and costing and pricing?
How do we prioritise what we do? And then secondly,
the implementation really needs to build up grassroots capabilities because this research needs to be done by people who are on the ground,
know the patients and know the health care system and the public health system they're working in.
Great. Thank you.