Your questions answered

Paul Charlton: Welcome to the Improving Healthcare Through Clinical Research Question and Answer Session. My name is Paul, Paul Charlton. I am a patient research champion. For some 10 years now, I’ve been involved in health research from the perspective of a patient who has experienced illness, and also from the perspective of a carer. I’m a patient mentor on the course. I’m delighted to welcome Professor Allan Gaw, the lead educator for this course. We both hope that you’ve enjoyed making your way through the content. And we’re looking forward to answering your questions. Allan.

Allan Gaw: It’s a great pleasure to join you today, Paul.

Paul: Welcome. Well, throughout this course, the learners, you have developed questions you wanted to ask about health research. You may have asked these in the comments section on a particular step. You may also have asked questions of the educators, mentors, and other learners at the end of each week. So, we’ve reviewed and selected some of the more commonly asked questions, those of particular of interest or those that have provoked a lot of discussion and debate. And Allan, thank you Allan, will be answering those questions in more detail today. But perhaps a question about you first, Allan, so, what has been your journey into clinical research?

Allan: I suppose, like everybody, as a child I asked lots of questions about the world. Most people I think managed to grow out of that. I didn’t. And it was a bit later on I discovered you could actually earn a living asking questions. I studied medicine because I thought the questions there were the most important ones to answer, and I studied science to try and help me answer those questions effectively. That’s really how I ended up where I am today.

Paul: And what was your first steps? What was the first kind of stimulus that you came across?

Allan: I think just looking at the world, like everybody. Every child asks questions about why the sky is blue, why do trees grow, why do rabbits do that, why do dogs do that. And, of course, it’s just a natural extension of that kind of thinking to realise that, well, there are deeper questions to answer, questions about healthcare, which, obviously, are so fundamental to us. And those are the ones that should be answered well.

Paul: OK, well, that takes us nicely to the first question. This learner’s concerned about the impact of clinical research on the economy. They ask “I agree investing in research is important for the improvement of a nation’s health. However, it is very difficult to convey the economic benefits of health research to individual research participants. How can we make this more visible?”

Allan: I think when we come to think about the economic benefits of anything, it’s often really quite difficult to convey that information, because a lot of those benefits are often quite long term. They’re almost societal benefits rather than benefits for the individual. I think probably the most important thing is to, first of all, recognise that healthcare and healthcare research brings with it very significant benefits in terms of the economy. I think when we look at how people respond to some of that information that we deliver in the MOOC over the years, one of the things I think people have said is most surprising is just how big an impact on the economy healthcare can have and healthcare research can have.

I think that’s really the starting point for all, making sure people are aware that healthcare research does have this huge impact.

Paul: Well, it has to be done well, which, of course, is what our course is concerned about. So, these questions, we are going to consider, are about the design of modern clinical trials.

This first question says: “Will our accumulated research knowledge someday allow us to define treatment for a new illness without relying on the randomised control trial, the gold standard? Perhaps data modelling could replace the randomised control trial?”

Allan: I think that in many people’s mind, that is this kind of dream that one day we will know so much about everything that all we’ll do is, say we develop a new drug or a new treatment, we’ll just plug it into some sort of computer and it will give us the answer, whether that is going to be a safe, effective treatment. That will involve some form of modelling. I think we have this notion that modelling is all about certainty. Well, I’ve done a lot of modelling in my research career, and I think it’s important to understand that it’s not like that at all, that really what you’re dealing with is educated guesswork.

The guesses that you make, the better they are, the better the data you have to inform them, the better the guesses are. But they ultimately are just guesses. Also, your better understanding of the system that you’re dealing with, the better the guesses will be. When it comes to healthcare, we’re thinking the system is actually the human body. Despite millennia of trying to understand how the human body works, I have to tell you, we are still nowhere close to understanding how humans work in every specific detail.

So, while maybe one day far in the future we may be able to do something like this, I think for the foreseeable future, we are still going to have to rely on some form of testing in real-life situations with people. Whether that’s in the form of randomised control trials or other kinds of studies will depend on what we’re trying to test. But ultimately, we’re going to have to see, does it actually work in real life?

Paul: You mentioned guesswork and how little we know about the body, about the mind. This next question takes us to that quite nicely, and it talks about bias, and the bias that we bring to our work, including in research.

This learner asks: “What is bias in research, and how does it undermine good research practice? How do institutions, such as the NHS and universities, guard against publication bias that show study results which only demonstrates significant benefit over usual care, and not publishing studies that do not demonstrate a significant benefit?”

Allan: Well, we’re all subject to bias because we’re all human, and that goes for researchers, just like everybody else. In the course, we’ve tried to outline some of the key ways that we try when we design our studies and carry them out, the way we try to acknowledge that problem and how we try to minimise it through things like randomisation and having proper controls in our trials.

But the particular form of bias that you highlighted there in your question relating to publication bias is an important one that we also have to be aware of and think about how we can fix that, too, because there, the notion is that only studies that perhaps are showing positive outcomes are going to end up in the public domain, and therefore are going to inform policy. There are two main reasons I think why that might happen. Partly it’s because of the publication model

that we follow: the idea, perhaps a belief, but maybe just a perception that studies that are positive and show some sort of positive outcome are more likely to be accepted for publication by the various scientific journals. Also, there’s the issue of the opinions of the researchers, who may feel that only if they have a positive story to tell, is actually one that their peers are going to want to hear. They’re only going to share that information.

Of course, the reality that we must teach all researchers and everybody involved in research is that all well-conducted studies, irrespective of the outcome, whether it’s a broadly positive or negative outcome, if the study has been well done, then that answer is valid and important. And we need to know about it. It needs to be shared. So, it needs to be published, it needs to be talked about, it needs to help inform the next set of research that comes along. So it’s a recognition of it again. I think so many problems that exist within research are partly solved by, first of all, being aware of them.

That’s really part of the reason why we have this MOOC, because we’re trying to raise awareness of research

and the research process across the board: people who work in healthcare, people who don’t, people who work in research, people who don’t, people who regard themselves as patients or individuals, or just anybody interested in the process. Raising awareness about what research is and what it isn’t.

Paul: OK, well, here’s one of more curious parts of research, which is the use of placebos.

This question says: “It’s interesting to learn about the use of placebos. I wonder how much effect they can actually have. Is it long lasting?”

Allan: The placebo effect, I think, fascinates many people and, obviously, we’ve known about it for quite a long time, certainly hundreds of years at least. It’s probably still fair to say, it’s still relatively poorly understood. It’s a complex process. It also varies a lot from person to person, and it also varies within a person depending on the circumstances and the settings. So, there’s very few universal things we can say about it, other than the fact that it exists. And again, an awareness of it allows us to design our studies and conduct them with that in mind so that we actually get the right answers at the end of it.

If we didn’t account for the placebo effect and the potential strength of that placebo effect, we’d actually probably get the wrong answer quite a lot of the time. That’s why we have placebo-control studies. That’s why we have properly controlled studies so that we know whether the treatment that is under test is actually having the kind of benefit that we think it is.

Paul: Well, developing that consideration about placebos,

this question says: “I found myself asking, is it ethical to have a placebo in surgery?” The question says, “in certain cases, it may have been shown to have benefits to the patient. But am I alone in thinking it’s just not right? A surgery always, always carries a risk, including when it’s a placebo surgery design.”

Allan: I was quite keen when we designed the MOOC to actually include some mention of placebos within a surgical context, because I think when people mostly think of placebos, they often think of medications, tablets. The whole idea of control within a clinical trial context applies not just to drug studies, but to any kind of study. It’s definitely more acceptable in most people’s minds to take an ineffective, an inactive tablet as part of a study than it would be to undergo an inactive or ineffective procedure, surgical procedure.

The issue of its ethics, it does raise the issue, well, if we think it’s unethical to properly control and test a surgical procedure, we would have to at the same time think it was ethical to allow people to undergo procedures that had been not tested and that we actually didn’t know whether they worked or not. Just as it would be unethical ever to evaluate a drug without testing it against any kind of inactive treatment, it is probably really unethical to actually perform surgical procedures that we don’t know if they work.

Having said that, the nature of surgery is going to potentially pose a great deal many more problems to people thinking about it, just as your questioner has said, than perhaps taking a tablet. But if we think about it quite fundamentally, there isn’t a great deal of difference between the two.

Paul: Here’s an interesting question: “Do you think that we’ve become too attuned to searching for cures as opposed to seeking to maintain a healthy mind-body state, using preventative approaches as opposed to curative approaches?”

Allan: I don’t think so. I mean, I think a lot of treatments that are being evaluated, they traditionally tend to make the headlines. Those are the ones we see in the newspapers about the new wonder drug, the new wonder treatment. We don’t tend to see the big headlines about preventive treatments for the most part. But they do go on and huge amounts of effort are put into them. Part of the challenge with them is that they often are much longer course studies. It often takes many years to evaluate whether, say, a lifestyle change is going to actually result in the prevention of the onset of a condition some years into the future.

So, they’re often a much greater investment for people. But I don’t think that we are underestimating the importance of preventive measures. I mean, take, for example, the recent pandemic. There, huge amounts of effort and money went into trying to find preventive treatments for that, looking at vaccines and the development of them. Yes, we also studied treatments for people who were, unfortunately, having to be admitted to hospital with COVID. But most of the effort went into trying to create a preventive measure, a vaccine. So no, I don’t think we have the balance quite wrong. I do think you hear more about the treatments. But a lot of the preventive measures are being evaluated in the background.

Paul: The next section is about ethics and respect and broader societal concerns about health research. You have already referred to the pandemic across the world and the crisis that we see in front of us still every day.

And this learner asks: “Do we all have a duty to participate in health-care research and drug and vaccination clinical trials?”

Allan: I think the short answer is no, we don’t. I think all consent, for it to be valid, it has to be voluntary. It’s important that people are not coerced into taking part in research against their will. That can take many forms. I think it can also take the form of trying to convince people that they have a duty or a responsibility to take part in research. If they don’t want to, they shouldn’t have to. I think what we do have a responsibility, if you like, a duty to do is to be aware of research and to be aware of its importance, to be aware of its importance to healthcare.

It’s ultimately a personal choice whether we choose to take part in research or not. It doesn’t matter really what other people are doing here. Often, healthcare professionals are asked by potential participants in research, what would you do, doctor? Or what would you do, nurse? And the short answer is, it actually doesn’t matter what they would do because it’s about that individual. It’s about them. They have to make a choice that matters and is meaningful for themselves. That’s what true informed and voluntary consent is.

Paul: Well, this questioner asks a little bit more

deeply about that: “How does the researcher check if consent is actually really informed? Might the person just sign papers given to them without really understanding what’s on them? There are issues here around people who don’t have English as their first language or the first language of the country in which they live in and those who have limited reading ability as well as children, those who have communication difficulty. The consent information must be made accessible to all, surely?”

Allan: We use the term a lot in clinical research of “informed consent”. And we say it as if it’s something easy. And it is if you say it quickly. But the reality of it for people in a clinical research setting who are responsible for taking and recording informed consent is that it actually can be a very difficult thing. As the questioner points out, how do if that consent is truly informed? We give people information often in a variety of formats. Many people taking part in research will be given written information. They may also have the opportunity to speak to one of the research team. They may watch videos.

That information is given hopefully in accessible, easy ways, and ways that they will understand. As you point out, it may have to be given in an appropriate language or in an appropriate format, maybe not in words at all but in pictures when we’re thinking about younger participants. But ultimately, the person taking the consent has a responsibility to make sure that consent is valid. So, they have to ensure that the consent is given freely and voluntarily. They have to make sure that it is given by somebody who is competent to do so, and that usually means having the mental capacity to give consent on their own behalf, and ultimately also given by somebody who is informed about the process.

How you actually check they’re informed varies from study to study. But many people in research will say things like “could you tell me what you think this study is about in your own words?” In other words, they will probe and check to find out to their own satisfaction if the person in front of them has actually understood what’s going on, that they haven’t just skimmed over things and they aren’t just going to sign a piece of paper without thinking about it, because it’s very important that the consent is truly valid. And it’s only going to be valid if it is informed.

Paul: Well, what about this question: “How is research in recently deceased people conducted? How is informed consent gained in these circumstances?”

Allan: When it comes to consent in many different settings in clinical research, there are often legal requirements and there are also, I think, moral requirements, and they don’t always align. Just because something is legal doesn’t necessarily mean it’s moral and vice versa. When you’re dealing with really the very sensitive issue of dealing with people who have recently died, there are, obviously, legal requirements there but there are also moral imperatives, I would say, as well. And ultimately, researchers have to be extremely sensitive, which often means going beyond the basic legal requirements. It also depends a lot on where you’re working, because the laws around consent vary from country to country quite dramatically.

So, you cannot assume as a researcher that the way you do something, say, in England is going to be the way you do it in another part of the world. Similarly, even within the United Kingdom, there are stark differences between consent within healthcare between, say, Scotland and England, or Northern Ireland and England. So again, if you’re doing a study across the UK, you’re going to have to be aware of differences there. In a legal perspective, within the UK, people who are dead have no data protection rights. Their data is freely available for anybody without consent. Now, that doesn’t mean for a moment that a researcher is going to go in and simply take that data. But that’s the legal position.

And that’s where I think there’s that clash between what is morally right and what is legally appropriate. Also, if it’s just data that you’re looking for, you’re going to have a different set of rules applying to you than, say, if you wish to examine the dead body or take samples from the dead body. Again, there would be different requirements there that you have to follow. So, the bottom line is that it’s complicated. Anybody who’s working in this field needs to know very well what the up-to-date rules are that they have to follow. I say up to date because, regrettably also, they’re always changing.

They are developing as we’re trying to improve these rules and regulations, not just in this country, but everywhere. But sensitivity I think is all important. And fundamentally, it comes back to that word

that I use all the time: it’s about respect.

Paul: A concern now about the results of research this person

asks: “What happens if a study fails to prove a hypothesis? So, you’re trying to show that, say, drug A is better than the usual drug B, and it turns out that it isn’t”.

Allan: I think the first thing to realise is that there is no such thing as proof in medicine. When you have a hypothesis, which is a suggested solution to the… suggested answer to the question you’re trying to get, like this drug is better than all the others, you can do a study which will give you evidence to support that, but it will never prove it. You similarly could also gather evidence that will find that it doesn’t support it. If you gather evidence that doesn’t support your hypothesis, you haven’t proven that it doesn’t work or, indeed, proven that it does work. You’ve just found a balance of information about it. It may mean that you have to adjust your hypothesis.

You may have to adjust your thoughts about it. It might be that this drug is not better for everybody. Maybe it’s only better for some people. Or maybe it’s only better at a particular dose or it’s only better at a particular stage of a disease. You may have to refine and develop it. That’s what the research process is very much about. It’s about collecting information, adjusting your ideas in accordance with that information, listening to the data that we get and listening to what it’s going to tell us and try and improve and push it forward that bit more.

Paul: Sometimes we’re in a hurry. Like now, we need with COVID-19 to have accelerated discovery for treatments, discovery in vaccines. This question says “I agree that it all takes time to evaluate the results for safety reasons. When results are achieved and if time is a constraint, like right now, who has the final say for that so-called drug to have a widespread distribution?”

Allan: Obviously, every country has significant checks and balances in place to try and prevent the public being exposed to untested, untried, unsafe treatments. And a new drug, for example, has to undergo testing. But that body, that portfolio of evidence that is gathered by the researchers will ultimately be reviewed by a body that has the right to give a license to the drug so that it can be sold and used or to deny that. In our country in the UK, that body is part of the Department of Health. It’s called the MHRA. It’s called the Medicines and Healthcare Product Regulatory Agency.

If you have a new treatment that you want to market, say a drug company develops a new drug, say a drug company develops a new vaccine, they have to go along with all of that evidence to this body, who are an independent group. They review it all in great detail and then they will make the decision, is this good enough, is it safe enough to put out there? Only if you do that can you actually get out there. That’s exactly what’s happened recently with any drug. It’s also what’s happened with any new vaccine that’s been developed.

People, I think, sometimes recently have seen the MHRA being talked about on the news, perhaps for the very first time realising that there’s that level of regulation in the background to protect us all.

Paul: The COVID-19 pandemic, I think perhaps we should finish with our question and answers and discuss this a little bit more. It’s timely to reflect now on the fact that medical research has brought us so far and provided vaccines or treatments for so many previously life-changing or life-threatening conditions. The COVID pandemic has demonstrated the vital need for clinical research. Treatments for COVID-19 have been developed as research. Developing a vaccine in such a short time has been an amazing feat of research. In light of all that has happened, how do you think clinical research has evolved because of the coronavirus respiratory infection as a global health crisis? And how will it continue to evolve in the coming years?

Allan: I think with any crisis like this, we always look for the silver linings. I think there are two big silver linings here when it comes to research. I think the first one relates to researchers themselves. I think the necessity to push things quickly but still safely and effectively have forced us to look at some of the ways that we traditionally did things. They’ve given us an opportunity to revise the way we do things, and perhaps revise the way that studies are approved, the speed with which they are looked at, the way that we can get things up and running faster, the way we can mobilise clinical research to actually find answers.

I think a lot of people are now looking at thinking if we could apply that same vigour, that same ability to mobilise things to other areas, for example, our fight to try and find new treatments for cancers, heart disease, and so on, maybe we could amplify the effect in other areas in research. And I think we’re going to see a lot of new ideas being put into practice in a way the pandemic has given us the confidence to try new things, to not just be stuck in the ways that we’ve done things for decades, but to actually force both researchers and regulators to try new things, to make things better.

The other silver lining, I think, comes from the hugely greater awareness people have had of research. Never in my lifetime has there been so much talk about clinical research on the news, in the newspapers, and so on. Everyone at the moment is interested in how new treatments are being developed. I mentioned that people were talking about the MHRA, people who had never heard of it before, but now realising that there was this regulatory body that had to license things for their approval. We watch how it’s happening in other countries as well, how perhaps one country approves a treatment, but another country doesn’t. We start to see that. We’ve learned about ethical approaches to research.

There’s been a lot of debate about different kinds of studies that have been going on. So there is a buzz and a chat about research as never before. I think this has to be capitalised on. Part of the reason we have the MOOC that we have is an attempt to raise awareness about research amongst a wider population. I think what’s happened as a result of the pandemic is that quite a lot of our work has been done for us there. Hopefully people have an interest in it. They can go to other resources, like our MOOC, and actually find a bit more about research.

So, I’m hoping that we end up with a much more research-aware, a more research-savvy population by the end of it.

Paul: Well, thank you, Allan. That’s all the time we have for our learners’ questions. Thank you to everyone who submitted a question. And thank you to you, Allan, for joining us today. We hope that you have found this Q&A session interesting and informative. You can let us know what you thought about this session in the Comments section below. I hope this made the course a bit more personal, and maybe a live Q&A next time, Allan?

Allan: Yes, thanks very much, Paul, for the questions. And thank you for everyone who submitted them. It’s always a pleasure to try and expand on some of the things that we’ve been able to do in the MOOC. I hope people are enjoying the MOOC and continue to do so.