So in managing large clinical trials, a trial of any size or any complexity is is hard work and requires one thing in abundance.
And that's efficient trial management.
It also requires dedication and a lot of passion because a lot of it can be very paperwork orientated unless you've got a passion for the subject.
It can grind you down. But managing international trials requires all of that and a bit more.
So what makes a successful trial? Well, I'm sure I'm talking to the converted.
You all know these things, especially if you're working on evidence based medicine courses,
but also because we all need a burning question, a burning scientific question,
where you've got enough people,
where you've got equipoise and enough uncertainty around the country or around the world to make this something that they want to know the answer to.
Relevant outcome measures, which is a topic of great debate and outcome measures that are acceptable to the participants.
I mean, most of us setting up a trial in mass and the clinicians were very keen on relapsing remitting time to remission, time to relapse.
But when we talk to the most patient groups, all they wanted to know was when we don't have to be in a wheelchair.
And so these outcomes that are relevant to clinicians and outcomes that are relevant to participants,
and hopefully you get something that's relevant to both and the sample size that is feasible.
We do large trials and the PTO motto is The bigger, the better, but it's got to be feasible.
I mean, the incidence of the disease, you can't do a big trial and something that's very rare.
So a feasible sample size and quite often trials fail because the original sample size is just unrealistic, a realistic timeline.
I mean, these days we have got into this sort of 70 days of first patient into a trial, which I think has been plucked out there,
don't see any rationale for it, but it's all to do with realistic timelines, enthusiastic teams.
As I said before, you've got to have a passion for some of this and enough resources.
And you all know we all suffer from a resource dirge and a trial manager.
And I have to say this because I am one and, you know, trial managers can actually make or break a trial.
And the importance of a trial manager was recognised quite a long time ago by the MLC and latterly by the HCA because
they actually did some work around whether a trial was managed by a trial manager or by a team of our clinician.
And the successful trials had somebody that had an overview of the trial and actually knew what was going on in all aspects,
didn't have the answers and couldn't actually provide the answers in the clinical areas or the quality controllers,
but had an overview of what was going on. And as I say there,
a good trial is involved in all aspects of it and it avoids sort of unworkable systems and things that you have to go back and review all the time.
And there are generic job descriptions provided by the NIH and the UK trauma network which really said I'm involved in,
and these are some of the responsibilities that you would expect a trial manager, a good trauma to undertake.
Now, there's also a road, of course, he or she just run around for somebody.
Everyone knows a trial manager, and it's not of my six, so they don't do it on their own.
There's obviously a team, but as I say, it's that overview, it's the big picture and project planning, which is crucial.
I mean, no business whether you were remodelling your house with your open shop school or whatever.
No, nobody would go into it without having a plan.
And, you know, project management plans, the print series, etc., all have these features a clear, objective aim to bring about change.
That's what we do with the trial. We have a clear objective. We aim to bring about change, requiring a team of people to do it.
We require a team of people. We hire statisticians, our clinicians, our health, economics people, etc. to set time scale,
to find resources and tasks that which needs to be completed to a pre-specified standard.
Our SOPs guidelines, our approval systems.
So this is what project management is. It's nothing different from running a trial.
In fact, it's essential to running a trial.
The five basic processes in project management of initiation, planning, executing, monitoring and controlling analysis, reporting and closure.
This is what we do. These are our five processes.
So we initiate our sites. We plan in detail the way forward.
We then have the plateau phase where we're executing this, where there's recruitment and the trial sort of goes into a plateau phase.
Monitoring and controlling. So we had our monitoring site visits and the way we control drug dispensation, etc.
Analysis, reporting and closure. All of these should be very familiar with.
But what I don't think a lot of trials people realise, especially people that run them like me, is that it is part of a well known process.
It's just not us being trial managers, it's all part of a project management plan and they are project managers over the world.
So the whole team efforts that you need to actually put this project plan in place is one of collaboration.
And we talk about collaboration all the time in clinical trials and it tends to
sort of err on the side of it's the collaboration with the investigators at sites,
but actually is collaboration between internal or external in your within your team with your statistician,
everybody needs to own it because if everybody owns it, then it becomes real and it will it will deliver.
The trial is more likely to be successful if everybody enjoys it.
If members of the team feel that they're part of it and they're all valued and quite often that is not the case.
There's a very much a hierarchy and people get sort of left behind.
And when it's a team and it's a multidisciplinary team and they own it, it's more likely to succeed.
And this is everything through from when you first had the first idea and the CEO comes and says what you think to this,
and you sit down around the table and you start developing the question right the way through to,
you know, dissemination and the archiving of the data. And everyone needs to know where it is and for how long it's going to be there, etc.
And integrating all the procedures is another thing that I think is so crucial to clinical trials.
Clinical trials shouldn't be something that's put upon people. It should be integrated into their routines.
If it's integrated into their routines, then it will become part and parcel of what they do day by day.
And other than specific forms they might have to sign or complete,
it won't be a chore to them, because if it is a chore, then your recruitment will be less.
And if the data collection follows the clinical progress and the chances are they will also fill in your form.
Because I'm not doing anything different to what they would do normally in their day to day task.
For looking after that patient, we try to minimise extra visits or tests for participants,
purely so they don't have to keep going back to host hospitals or clinics and the costs attached to that.
But if you've got a bunch of clinicians who are very busy or a bunch of nurses very busy,
you don't want them to actually feel that they've got to do extra work.
And usually in our field for nothing and with international trials I run, the resources are even less.
And so therefore we do try to keep everything to a minimum, but enough data to answer our question.
And efficient systems are again, very crucial to the whole running of the trial.
I mean, I started off running trials with index card system and a daisy will typewriter.
It wasn't efficient, but that was what we had then.
And but now we have the, you know, the benefits of systems, I.T. systems that can be robust,
that produce reports and newsletters and letters to patients, etc., as the click of a button.
And so a good trial has a good, robust, transparent system and something that, you know, will, if you like, service the trial.
You're not there to service the computer, the computer and the system, service the trial.
And this the trials, international trial.
They should take account of all the different different practices and work environments and obviously governance.
But what we found is most important is that all our systems work well for all different
browsers because in the international arena you don't have the latest windows,
whatever. You have something that's still work working on Windows three or whatever,
and they have to be able to use them because otherwise it costs you, you and your funder a fortune to keep updating everything.
And having said that, in this study I've recently been running, they didn't want to buy Microsoft because it was expensive.
And the thought of spending £40 on a disk where they could get it for £2 in the market,
when we pointed out to them that £2 in the market actually is not a microsoft system, it's a black one and it's full of viruses.
It's just that that initial thought of spending £40 is probably a whole.
A month's wages for somebody is completely foreign to them.
So making sure that they can work on their what they've got. Without too much fuss.
And efficient recruitment militaries. A trial succeeds or fails and whether it manages to recruit the pre-specified number of participants.
And as I said earlier, sometimes it's not realistic the the sample size.
So making sure that it's right up front and that you've you've got the centres that have the patients is,
is really crucial and work done in developing those sort of things is time well spent.
But there's very little evidence about, you know, what recruitment strategies we should go for.
I mean, it's we need to recruit 770,000 or whatever patients and off you go.
There's lots of information out there about, you know, good clinical practice and the stats and equipoise and consort,
but we've got no guidance for what recruitment strategies we should use.
And there has been, you know, recently some in the last ten years, some work done on it, but nothing that actually points you to something specific.
So I will start here. This is where we need to start and this is the process we need to take.
And you know, experienced trials managers just have learnt by socket.
And so see really it's like, you know, okay, we'll start off with give them a target and we see how it goes.
And this is where I just get very frustrated that we've got lots of guidelines and sort of Damocles consults, whatever, on how to report a trial.
We've got lots of things when it comes to GCP on how we should set up a trial and get our approvals and permissions.
But there's the bit in the middle that we've got no real model of management and maintaining recruitment over a long period of time,
you know, requires real stamina from everyone. So your trial's got to be interesting.
It's got to have a passion and it's got to have that ownership which will enable them to feel that they can carry on.
And this is what a Cochrane review of clinical conditions participating cities found when they looked at 11 relevant observational studies.
And they looked and they asked the clinician, So what would prevent you recruiting into the trial or what would help you to recruit in the trial?
What would maintain your interest? And the first one was your interest in evidence based practice.
So they want a question that's going to actually hopefully change practice.
And if it doesn't change you for, you know, something different, it sometimes just stops it.
I was involved in a trial once where they were doing an AC ICI bypass and actually they stopped the surgeons
doing it because the result of the trial was they were doing harm and there's quite a few trials like that.
They get more and more getting published nowadays and participation in an academic group.
So lots of clinicians would be more inclined to be involved in a trial if they were working with an academic group rather than industry,
if they had extra staff to help them recruit, if they thought the patients were interested.
And that's where I go back to the MF study, where the patients weren't interested in how long it was going to take for them to relapse.
They were more interested in how long before they were in a wheelchair and
actually at their home and they felt comfortable explained in trials to patients.
And the whole issue of explaining randomisation, I've had people say,
if we just flip a coin and then you get whatever treatment, that's probably not the best way forward.
So these were what the pointers that the clinicians gave us in trying to work through recruitment strategies.
And then again they go back to the ownership thing and making sure everyone is credited for
the trial right the way through to from the beginning to authorship and dissemination.
It's very easy for people to get missed off.
Very important people sometimes.
I mean, you've got your clinicians, your investigators, but then you've got the nurses on the ward that get the notes all the time,
or you've got the pharmacists who make sure that the drugs are accounted for and accountable.
And sometimes all those people get missed, missed or for publication, and they don't get that sort of credit.
So developing ownership throughout and making sure you keep track of it is so important, is really so important.
That's how you build up networks that will go on to the next trial and go on to the next trial because
they feel comfortable and they feel valued in the trauma and just guide that we've we've over the years,
we've got three C's for trial management.
And it's obviously collaboration, it's communication, it's creativity and common sense.
Now, the creativity, we can't do so much of it these days because we're a bit tied with regulations,
but we can be a bit creative and the common sense is the one that I think.
Glaze lays over everything because the whole thing about trial management is cool.
Since you don't actually do a trial of a rare disease and expect to do 10,000 patients in two years in two centres.
It's the common sense that goes through everything and the communication.
The second see is again making people feel valued but making sure that you talk to them all the time.
So if they're not recruiting, you don't just go off and say to all the good centres, go, well done.
Thank you very much for doing brilliantly. You say the same to the centre that not recruiting.
I have a conversation to find out why they're not recruiting. Sometimes it's something very, very simple,
something they've misunderstood or something they've been on honest comment somewhere and you've not known it,
so you just sort of just synthesise the hopeless, but actually they're not.
So, you know, how do we get to the point where we can run big trials, which may have many challenges?
And according to the EU directive, we're all should be educated, trained and experienced in the task we will perform in a trial.
Well, for trial managers, that's a bit difficult because there's no specific trial training.
But to be a trial manager and we can't evidence it anywhere we are other than years of experience.
And so I find this very difficult and I'm quite passionate that there should be ways that trial managers
can become qualified and recognised from the top down so that we're not always struggling to sort of,
if you like, justify ourselves. There are no messes around over the last ten years and Mrs. popped up and a lot of
the the stuff in there in the EMRs is about the practical side of running a trial.
But at the moment, much of the collective wisdom of of people like me and there are many more of me
sort of suck it and see trials and we pass it on by word of mouth and just say,
Well, I did this, why don't you try that?
And that is really probably at the detriment to a lot of trials that we don't have a qualified staff who can manage trials to a particular standard,
to a particular model.
And the survey was done just last year by the UK chairmen and of the 460 trial managers, 60% of them did not want a higher degree.
What they wanted was they were seeking, you know, specific training to do their job.
But what they did, what was the recognition for that? And they wanted to be accredited somehow and that's what we were working towards,
some sort of accreditation system where people who don't want to go to a higher degree have some accreditation that can take
forward almost like your sort of your years of experience that you can put in when you you go for a higher education post.
And the other thing is, although intuitively trained managers actually use project management principles and practices,
I think we need to have more evidence that it works in a trial situation and more research on research.
I mean, I've been trying to persuade trauma just to do research on their research for years and in the way they do it.
What works, what doesn't work?
Bits and pieces coming out in the literature from time to time, but not a lot because not a lot of journals are interested.
In fact, it's only trials that I think takes everything that way.
Most of the other journals, we're not interested in that sort of research.
So if it's large or it's international or if it's small and it's local,
trials fail because tried and tested systems have not been documented or evaluated or published so that the next one's coming along behind us.
The next generation can read up in the literature how to do it, what worked, what didn't work, etc. And we've been reinventing the wheel all the time.
And still today somebody said to me, What would you do if?
And I said, Well, I did that in the US at that trial and they did that in that trial and it was who would find out about that.
And if you read the trial publication, there's very little on how we did it.
The methods section will have a lot about maybe the randomisation and the minimisation,
but very little about what challenges we're faced with with recruitment and retention, how it was overcome.
It's not it's just not acceptable by the journals.
And so that's what we carry on doing.
So to improve the successful delivery of trials, we do need management guidelines and we do need robust methods of evaluating what we do.
But international trials do bring added challenges. And, you know, they can be overcome with some good systems,
but some of the obvious differences between a national or local trial, international trial or languages time difference.
Is local regulations and in-country problems.
And they can be many, many. But if you've got a good project plan,
you should have space within your planning to allow you to take take the emergencies as they arrive and deal with them.
And that's what I found with the internationals over the year.
I've got to have a plan almost day by day, week by week, so that when something comes on your desk on a monday morning,
you can move it to Friday because you know that that's within the emergency.
You just left yourself enough time to do what you going to do on Monday to move it for days so you can deal with something else.
But knowing your audience in an international trial is really crucial.
And knowing the countries, the people, traditions and the culture are all so very important.
If you're going to actually get the recruitment in knowing that the participants understand what they're entering into.
So spending time talking to the local investigators, the nurses and the participants is valuable time spent in the development time that you,
you know, save time as the trial progresses when you're not having to unpick misunderstandings, etc.
And also, flexibility is key. So I'm not saying that we give away from our sop's or whatever,
but being able to think about how flexible you can be in an international trial, again, is important upfront because things will happen.
You know, we in the trial I've just been running have had all sorts of things like, you know, civil war, floods, earthquakes.
But you can be flexible in some things. You can allow consent to be taken with a thumbprint.
You can allow consent by a spouse providing that you know, this upfront and when it goes to their local ethics committee, that's what's agreed.
But that's where the time in the development is really important.
And again, encouraging the local ownerships, because the results must be applicable within that country.
You know, if they never do a laparoscopy, what is the point in proving laparoscopy works for whatever procedure works in whatever procedure,
if they haven't got a lack of scope and we've had that sort of it's happened.
So I just want to run you through this trial, which I'm just bringing to an end and clear out the back.
There will probably be saying if she did she so describe this is a caesarean section is one of the most common operations carried out in the world.
I think some of you might be surprised to know that, you know, in developing countries, as many as 25% of births are by caesarean section.
And in places like Sudan, it's 59%. And then likewise in Brazil.
So it's an operation that's carried out daily, which you think is very safe,
but it's done in all sorts of different ways and a variety of surgical techniques,
none of which have ever been proven to be one better than other are used.
So it was a distinct lack of good quality of evidence when we started to look at this issue.
So but we did realise that not only was it a huge population we had to look at, we also realised that, you know,
if you had a tiny difference it would make a lot of difference to a lot of women and a lot of babies.
So the trial design was a two by two by two by two by two factorial fractional factorial design trial, which is very difficult.
It's two pairs to five intervention pairs and it's called non-regular because
we only randomised them to three of the five and that's why it's fractional.
And it was done like this because these are the five main techniques used to enter a woman's womb and retrieve a baby.
So these five techniques were the main ones and we only randomised to three four for compliance reasons to give the clinicians some clinical freedom.
So for instance, if a woman, if a site rather only ever done a single layer closure because that was their protocol,
we didn't want them to differ from their protocol. We will carry on doing what they usually do because that was their protocol.
If they could do the others then they could be randomised to the other three.
We had 90 sites in seven countries and eight regional trial offices.
I have to say the five by two not making fractional factorial design has never been used in medicine before.
It's only ever been used in agriculture. So this is the very first trial ever to be done like this.
It was published in The Lancet last May, May 13.
We had eight regional trial offices, which was also a first for me,
because what we did was we wanted to set up trial offices in every country so that they could do their own data cleaning.
They could we could teach them how to run a good local trial.
So in fact, we got eight local trials and it's that capacity building for the next.
Generation in those countries, which was very important to me.
So we ended up with 54 tribal members in the truly regional offices that we worked with daily.
So we recruited between May oh seven and December ten, and we recruited 50,935 women.
And it was a bit it was on target.
We extended for about three months purely because we had a few difficulties at the beginning and some of our countries had to start late.
President Bhutto went and got assassinated on the day we were flying to Pakistan to start off the Pakistan sites.
So we couldn't go. So, unfortunately, Pakistan starting six months late.
So therefore, we had to switch the recruitment back to the end.
And this is where they were. So Asia, Africa and South America.
And the primary outcome was death or composite of maternal infection.
And you'll see that the components of the return infection and blood transfusion of more than one unit and there's a story to that,
too, is the transfusion for postpartum haemorrhage.
And it's more than one unit, because we after the first interim analysis,
there was a big spike and the GMC asked us to look at blood transfusions and we realised that 75% of our blood transfusions
were coming from one country because they all take one with them when they go in for operation and we have to use it.
It is not ethical to take it home. So in Pakistan, every woman is given one unit of blood after her caesarian section,
which is probably no bad thing because a lot of them are anaemic, but they take that blood in in donated by a relative and they don't take it home.
So we then changed. We had an amendment to our protocol and we changed it to more than one unit so that we didn't have this big scare.
Okay. So some of the challenges we faced, randomisation was done by web and telephone.
And as you can see, the web and telephone lines, the connectivity was was amazing.
They had hanging out windows anywhere they could get a line in to get Web Internet connection.
But they managed 24 seven randomisation during the day time.
It was done over the web, in the trials offices in the night time.
It went through to our office here in Oxford.
It was a voice recognition system in three languages.
It was in Spanish, English and Indian English because our Asian site said, Well, we can we can sort of understand the English,
but can I investigate investigator come into his English because then we'll understand it better.
So he came, did a tape for us. So we had Indian English as well.
And apparently the people in Pakistan understood that the CIA was English and of course very different to the UK.
This is Ghana 16 bed ward and probably about four to a bed, as you can see, under the beds as well.
But they're very jolly and they're also happy and it makes you feel quite humble to go there and work there and then
come back and see what we've got whinge about because they're all very happy with all these lovely babies and you know,
the nurses are all jolly and so we go there and we come back and they can't get GP appointment for next Friday.
So this was our recruitment and as I say, we, we started in May oh seven and we official start was September.
So because we had a running period where we expected to get up, as you say, we went from 12 to 25 to 50 to 75%.
So we we hope to reach our 400 a month, which was our target by September, which we did.
We had some dips and a lot of our dips with the religious holidays, Ramadan and things like that.
And we got to it again, you see, that's knowing your culture. It's not going into a panic when suddenly in August, the first year,
recruitment drops off because, you know, the Sudan and Pakistan, etc., the Ramadan.
So they're not going to recruit. And these were the five intervention pairs.
And one of my jobs and one of the questions I was at interview was, okay, Barbara,
if you got five intervention pairs and they start to deviate, what would you do change them?
So I said would probably change the intervention.
See that could change them through another side and about May, May nine as up to one and five started to deviate out.
As you can see, I sit there and started to deviate out.
So because we knew our sites and because we knew that the level of recruitment and because we had asked the questions early,
early on, what would you be prepared to do? We could change two of our sites to a different intervention.
So they stopped what they were doing and they started to do the other two or three intervention pairs, which as you could say brought it back.
So at the end they were. I sleep together and we had about over 9000 in each pair, which was what we were aiming for.
But that was a challenge, monitoring this every week.
And, you know, down here thinking, oh, crikey, they're getting a bit wide, they're getting a bit wide.
And these were uncontrollable events. We couldn't actually build this into our project plan at all.
So. Assassination of Bhutto. Civil war in Sudan, which split the country in half.
Tribal conflicts in Kenya.
Which meant that a lot of our women would come from the areas around Nairobi and they'd all been taken off of the Rift Valley into camps.
Terrorism and flooding in Pakistan. Heatwaves in India.
In fact, we were there setting up the site when that road was melting in Delhi.
It was the hottest it ever been, an earthquake in Chile and all these things,
you know, you have to sort of take in your stride because what can you do?
I mean, we're not going to stop.
What we did worry about, we worry very much about we did worry about the tribal conflicts and the civil war in Sudan and the flooding in Pakistan,
which moved women away. And we were very worried because we were doing at least three year follow up.
So we did worry about attrition when it comes to the fallout because we thought a lot of our women would be so far away.
But having said that, technology has taken over in these countries big time and mobile phones.
Everybody everybody from the four year old onwards got a mobile phone.
So providing you collect enough mobile phone numbers, the chances are you will actually be able to find your woman in the end.
So follow up. We still found out 13,226, which is 84%, which we thought wasn't bad given what had gone on before.
And we're at the moment writing this paper, hopefully published in The Lancet this year.
But some other statistics, this is where we travelled, so you might find this a bit interesting.
The equivalent of 17 times around the world and 28 miles per woman.
And we survived.
But we only survive with around about 800 anti-malaria tablets between the three of us, 20 different hotels, eight passports, all this sort of stats.
This decision is not it's not interested in that. We were and our paper is about 103 Cronus team members because this is because the Eiffel Tower
and we're trying to find somewhere to accommodate all this is what we've been doing for 35 years.
I find it very challenging. I find it very, very interesting.
It's a job I'll always go but for. And as I say, it's been humbling, but also it's been exciting and it's been fun.
And this is, I think, something that is getting lost in clinical trials.
And I think it needs to come back because every job you work in everywhere has to have a bit of fun.
And if you can enjoy it with your experiences with your investigators and the variety of people that you work with on clinical trials,
if you can enjoy it and have fun, then there'll be a good trial and it'll be one worth doing.
Thank you.