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Clinical Trials

What are clinical trials and why do we need them?

Clinical trials are research studies involving people. They test whether particular treatments are safe and how well they work. (‘Trial’ in this sense means testing something, and has nothing to do with legal trials or court cases).
 
We need to know: 
  • Does a treatment work?
  • Does it work better than other treatments?
  • Does it have any side effects?
Clinical trials are designed to answer these questions and improve health and quality of life for patients. Until well-designed trials have been carried out, we simply do not have enough evidence to know if a treatment is both effective and safe. Without trials, there is a risk that people will be given treatments which do not work and which may even be harmful.
 
Experimenting and testing have long been a part of medicine, and there are many different kinds of trial. (See below for an explanation of Phase 1, Phase 2, Phase 3 and randomised controlled trials). It is only quite recently that randomised clinical trials (RCTs) have been generally recognised as the best way to compare different approaches to preventing and treating illness. They can be used to compare drugs, but also to compare other types of treatment, across a range of conditions. (See also ‘Different types of trial’).
 

Sir Richard Doll, a pioneer of clinical trials, explains an early attempt to run a randomised...

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Age at interview: 92
Sex: Male
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In the first year of the war I tried to do a prophylactic trial of the value of the relatively newly introduced sulphonamides* and the question was, which we didn’t know an answer to at that time' Do you wait until a wound has become infected before you give the treatment, or do you give treatment prophylactically when a person is wounded? And I thought well, in normal civilian life the wounds would be through a car accident or something, but when I went into the army I was a regimental medical officer in 1939 and I thought well now, it would be good to do a trial on wounded soldiers that, and I could, I would not of course I would only treat them very superficially before sending them back to an ambulance or a hospital but I could test whether or not it was good to give sulphonamide prophylactically and I would give half of them sulphonamides and the other half alternately not sulphonamides and then keep a record; and we’d see later which ones, if there was any difference in the infection rate. So [laughs] I went to the senior medical person in our division, what we call the Assistant Director of Medical Services, and asked if I could have a supply, or rather I wrote to him, asked if I could have a supply of sulphonamide for this purpose. Well he sent for me and he said, “What’s this you’re suggesting? If sulphonamides are good and prevent infection then you should give all the soldiers that. If they’re no good then you mustn’t waste his Majesty’s money and it’s ridiculous.” So I said, “Yes sir, well but can you tell me which it is, are they good or not?” He said, “Oh I don’t know, that’s your job.”
 
* Footnote' Sulphonamides are an anti-bacterial treatment
It may come as a surprise to many people that sometimes doctors don’t ‘know’ which treatment is the best. When doctors make decisions about how to treat a particular illness or condition, they use their medical knowledge, based on the textbooks they have read, the results they have observed in previous patients, similar observations by their colleagues, what they have heard at conferences and what they have read in medical journals. RCTs provide a different kind of knowledge, based on statistics; this type of knowledge sometimes shows that what doctors had ‘known’ in the everyday sense was wrong.
 

Amanda has worked on reviews of evidence about medical treatments, and is still shocked sometimes...

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Age at interview: 54
Sex: Female
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I actually think, what I’ve done - when I say I was a doctor, a public health doctor, actually for the last ten or twelve years, what I’ve done is learned how to look at research evidence and find out what it is we actually do know and put it together in a form people understand. So for example I put together systematic reviews of the evidence for NICE [National Institute for Health and Clinical Excellence]. For example we did some new drugs in rheumatoid arthritis, which were called anti-TNFs [tumour necrosis factor], things like etanercept. And to do that we needed to get the evidence for all the old drugs, and I was very shocked, having had rheumatoid arthritis for years and tried most of these drugs, to actually find that the evidence base for all of them was extremely poor. There was only one with really... good evidence, which was methotrexate, and it was the one drug that I’d actually refused to have, because the first patient I’d seen was a girl of 26 dying from side effects, and I’m thinking- and it just, the individual patient shocks you. So I had never wanted it, but actually it’s a very good drug, and having done the review for NICE, I actually switched my medication to methotrexate, and I’ve been a lot better than I’ve ever been before. So the evidence is important, and it’s that it influences me. No, so I think it’s quite shocking how the medical - people, the members of the public would be shocked at how many treatments we do that are not, have not been shown to be effective or indeed have been shown to be ineffective or, where we just don’t know. I mean, one that shocked me the other day was and in fact something I would like someone to do something about, what’s the first thing you do when someone’s had a heart attack and the ambulance turns up? Well, you give them oxygen, don’t you? Well, has a trial been done on it? Well, yes it has, and what does it show? Well, it wasn’t big enough to get a definitive result, but nearly three times as many people died in the oxygen group as in the other group, and yet we’ve never done the definitive trial because that could, almost, well it could be a chance finding. There are so few numbers of people dying it could so easily have occurred by chance. But with that evidence, if that’s the only evidence there is, why are we still doing it and why aren’t we doing the definitive trial?
Phase 1 and Phase 2 trials
Many clinical trials (especially for new drugs) are carried out in a number of stages, or phases. When a new treatment is first developed, such as a new cancer drug, it will be tried first in a few people to get an idea how safe it is. They may be healthy volunteers, who are given a compensation payment for taking part, or they may be people who are ill, perhaps people who have already tried all the usual treatments. This is called a Phase 1 trial. At this stage, the treatment is usually given to all those taking part, and it is not being compared against some other treatment (see below).
 

Anthea describes what a Phase 1 trial is. No-one knows what the side effects will be and whether...

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Age at interview: 58
Sex: Female
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Phase 1 trial is they don’t know what the results are going to be. They don’t know what side effects you’re going to have. They don’t know how well it’s going to work, whether it’s going to work. It’s got to be started somewhere, and [sighs] if, if the phase 1 trial does work on some, they might be able to adjust it to do a different, using the same drugs used in a different way. I actually found out this morning that the dacarbazine could actually be given in tablet form as well, which I didn’t know. But it’s very, very expensive in tablet form, so obviously money does, money obviously comes into it, so that’s why it’s done as a intravenous one. But [sighs] you know, we’ve got to start somewhere and you can only do so much on animals. You don’t ever know what’s, what the human body’s going to do. You know, I look back, when I knew it was a phase 1, and thought of the four chaps that almost died, which was a phase 1 trial*, and thought, “No, you know, it’s closely monitored, very closely.” Because the first two treatments they were taking blood tests every fifteen minutes. It was lots of blood tests so that’s why you were in all day, but very, very closely monitored. And you know, I have been closely monitored. Each time I come there’s ECGs, blood pressure, temperature, urine samples, blood tests.
 
*FOOTNOTE' Anthea is referring to a Phase 1 trial at a commercial research unit based at Northwick Park Hospital in 2006 when several healthy volunteers became extremely ill. Early phase studies are carried out precisely because we need to find out about possible risks and side effects before giving the treatment more widely.
By the time a drug reaches Phase 2, researchers will know more about it. In Phase 2 the aim is to test the new drug in a larger group of people to better measure safety and side effects and see if there are signs of positive effects in patients. Phase 2 trials may or may not involve comparison with another treatment (see below).
 

Tom was invited to join a non-randomised Phase 2 trial of chemotherapy for inoperable lung cancer...

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Age at interview: 63
Sex: Male
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So this young lady asked me if I would like to take part in a clinical drug trial, and she explained the situation. She says, “It might not help you. There’s no guarantee.” She says, “It might help other people further down the line.” And again she said, “You’re a perfect patient for a drug trial, for a clinical trial.” She says, “You’re young, you’re fit and you’re healthy” [laughs]. You know, even I had to laugh – I was young, fit and healthy, the only problem I’ve got is I’m dying from lung cancer, you know.
 
So anyway, that was okay, so she says, “Right, I’ll phone the trials unit and see what I can do.” So she phoned up, got an appointment there for the following week. Went along and, you know, a medical, a check-up to see that I was okay to take part in a trial, so I was accepted into the trial, which I believe was a phase 2 trial. It wasn’t randomised and as I said, I think I just quite followed, not quite followed the mice, but their tails were just disappearing round the corner.
 
It was six months of chemo. I was quite fortunate I wasn’t too bad with the side effects. It ended up there was a kind of group of us of four or five. There was about eight people I think getting the drug, but there was about four or five of us always seemed to be at the same point where we were, of getting the course of the drug but we’re at different stages of actual lung cancer. So during the course of that, you know, one was dying, a couple of weeks later another one would die, so it was a case of thinking, “Well, you know, who’s next? When’s it going to be your turn?” so to speak.
(See also ‘Non-randomised trial designs and other studies’ for more detail).
In Phase 2 trials we can start to get some idea of whether a treatment works for some people, and what kind of side effects they experience. But at this stage the numbers of people included are still too small to give us firm evidence about its effects and that any observed change is not just happening by chance. This is why Phase 3 trials are needed.
 
Phase 3, randomised clinical trials
Phase 3 trials are usually large, and may include hundreds or even thousands of patients. They often compare the effects of newer drugs or treatments with standard treatments if there are any. They provide a better test of whether new treatments work better than existing treatments, and firmer evidence about how common and serious any side effects are.
 
Almost all Phase 3 trials are randomised clinical trials (RCTs). In an RCT, one group of people, the experimental group, is given the new treatment. The other group, called the control group, is given the standard treatment. If no standard treatment exists, the control group may not be given any specific treatment or may be given a placebo. Some trials may compare more than two groups.
 
A placebo is a treatment, with no active ingredient, which is designed to appear very like the treatment being tested. By comparing people’s responses to the placebo and to the treatment being tested, researchers can tell whether the treatment is having any real benefit, rather than patients simply feeling better because ‘something is being done’.
 
There are several ways in which the results of trials can be made as reliable and accurate as possible. One of these is to make the trial a ‘blind trial’. In a blind trial the participants are not told which group they are in. This is because if they knew which treatment they were getting it might influence how they felt or reported their symptoms. Some trials are double-blind, which means that neither participants nor the doctors and others treating them know which people are getting which treatments. This also avoids the doctors’ hopes and expectations influencing the results of the trial
 
Here Wendy describes a typical RCT design comparing standard treatment for bowel cancer with an extra chemotherapy drug.
 

Wendy was asked to take part in a year-long trial of chemotherapy for bowel cancer. She thought...

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Age at interview: 51
Sex: Female
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Just before Christmas I went to a major hospital away from where we lived, and I had an appointment there to see one of the oncology team. I also saw a professor, who was leading a trial. They explained about the facts up until - you know, went over all the surgery I’d had, reiterated all the things the surgeon had told me, but added into that the news that out of the fourteen lymph nodes two had cancerous activity. I didn’t know at that stage whether that was good, bad or indifferent, but I wasn’t, you know, I wasn’t very happy about that. Based on that, that’s why I was offered the chemotherapy, because there is a strong possibility if it’s reached the lymph nodes it’s on its way elsewhere. So I was then told the, the plan was to have six months of chemotherapy. Alongside that I was offered the chance, if I wanted to, to go into this clinical trial. And whilst I’d been waiting in the waiting room I’d read up about clinical trials, so I knew exactly what they were talking about. I asked a few pointed questions. It was all taped, by the way, so we could take the tape away, listen to all the questions, listen to all the things the professor had mentioned. We also had it all in writing as well, so we could read it. Which was really, really helpful, because I asked a friend who’s a doctor of our, a doctor friend of ours to read through it.
 
She did some research. We researched it and we had about, I think, two weeks. We went back to see him, at which point he wanted an answer as to whether we were going to go through with it or not. We were explained to us that it’s a six-month chemo anyway, but the trial would be a twelve-month trial. So for the first six months I’d be on both, for the latter six months just the clinical trial. They explained all the side effects and everything. And after much discussion in the family, thinking about the impact on the children, and if all these side effects did materialise what impact that would have on us as a family with no extended family to call upon, I thought it was too selfish of me to ask for that. But my children said, “Look, Mum, we’d put our lives on hold for a year if it means that you’re going to be better at the end, if you’ve got a better chance of survival.” So I ended up deciding to go into that.
 
At that point we were told it’s 50% of the people that are picked go on the trial, 50% don’t. It wasn’t a placebo, nothing like that. You’re either on it, or you’re on the trial but you’re not having the drug. They wanted to compare the two. It was a drug that has been used very, very successfully in advanced bowel cancer patients and they now want to trial it to see what the implications are of it on other bowel cancer patients.
 
FOOTNOTE' Randomised trials are done when we don’t know which treatment is best, in other words when the relative merits and disadvantages of different treatments are uncertain. Of course trials are done because there is a possibility that a new treatment will be better than the standard or control treatment, and it may have already been shown to work for other conditions or groups of patients. However, trials are just as likely to find that new treatments are no better, or indeed worse.
(Sometimes you may hear the experimental group called the ‘trial group’ or ‘intervention group’. This can be confusing, as all the groups, including the control group, are part of the trial, and people in the control group may also be given an intervention, in the form of the standard treatment).

To make sure that each group contains a similar mix of people, many trials are ‘randomised’. This means that people are allocated at random to one of the groups in the trial, often by using a computer programme. When people are randomised they have an equal chance of being in either of the trial groups. Random allocation helps ensure we are comparing two very similar groups of patients, so if one group does better than another, it is very likely to be because the treatments being compared have different effects, and not because of differences between the people in the groups. (See also ‘Feelings about being allocated (randomised) to a treatment group’ and ‘Feelings about being in a placebo-controlled trial’).
 

In a randomised trial we do not know which treatment is best, so we don’t know if it’s better to...

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Age at interview: 54
Sex: Female
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Well, it sounds terrible that, you know, you’re just going to be chosen by lot whether you’re going to get the treatment or not. Well, I think the, the key thing is to explain to people, “We don’t know which treatment’s better, so that whatever happens, we don’t know whether you’re going to be advantaged or disadvantaged by it.” I mean, there’s been a recent pro-biotic yoghurt trial in pancreatitis, and they had to actually stop it early because it appeared to be killing people. Now people probably wanted to get the pro-biotic yoghurt, but we didn’t know. And it’s, and it’s quite a shock to people that “Actually, hang on a sec, these things could do more harm than good.” There’s some idea that if something’s natural that it can’t be harmful, but it’s just not true.
 
So I think people have to understand about that we don’t know. People have got to understand just how often we’ve been misled, and we’ve done things that really looked good and actually have turned out to do masses of harm, and that our only way is that as a collaborative venture, to go in these things together. I – how do I explain? When I’m teaching the public about trials, I don’t teach them about randomisation I, I say to them, you know, “Here, let’s do, let’s do this experiment, you design it” and then they design it in one way, and I say “Can you think of why you might get a result which isn’t true due to the design, that is not an effect of the drug but for some other reason?” and they come up before, by the time we get to the end of the workshop, they’ve come up with randomisation as a method, they’ve come up with blinding, they’ve come up with all these things.
 
And because they’ve designed it themselves, because they see that unless you have two groups that are truly comparable, you can’t know whether if one group does better than the other group whether it was due to the intervention or due to some pre-existing difference. And then, you know, we play games with chocolate in envelopes and things and they note - to show that randomisation actually is strangely enough the best way of getting two groups that are comparable. It’s better than, it’s better than matching the groups. It’s strange but true. And if you play those games and then you realise that this is the best way to get two groups that are comparable, and if they’re not comparable, the whole trial you can’t believe the results, then people have no problem with it.
 
I think, you know, how much can you do, consent people? I think there needs to be a more generalised educational process really.
 

Iain explains why he thinks randomised trials are the only ethical way to make progress when we...

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Age at interview: 62
Sex: Male
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Someone who's properly informed about PSA screening [for prostate cancer] should know what the treatment options are before they go in for it. I think that's part of the information they need.
 
And the side effects of the treatment presumably?
 
Absolutely, yes. Doctors who are paid on a piece work basis are paid for every radical prostatectomy that they do. You can imagine that some doctors are very keen on maintaining their income by doing lots of radical prostatectomies. Now if there was really good evidence that these operations actually did have an impact both on the duration of life and on the quality of life - to the extent that individual men would consider important - then we would be in a better situation than we are. As it is, we don't know. We do know that the operation can sometimes cause incontinence and impotence. I imagine that incontinence is going to be a distressing complication for most men; impotence some will be bothered about it, others won't. But those things have to be set against whatever advantages the operation has to offer and I think they're far less clear than some people are led to assume by those promoting these operations.
 
In the current state of knowledge I think it's unethical to offer treatment outside the context of randomised trial. Why should it be ethical to give a treatment the benefit of the doubt because doctors think it's useful, but also because they're actually going to get paid on a piecework basis for the treatment that they're offering? Why should that be ethical when there's no strong evidence to support the treatment and yet treating people within the context of a controlled trial not being ethical? The whole thing is completely upside down.
 
So if you were a urologist and a man came to you with an enlarged prostate at the moment, what would you recommend that he did?
 
If systematic reviews of controlled trials had shown that, in the circumstances in which that particular patient found themselves, there were useful treatments, useful in the sense that at least they had been shown to have some beneficial effects, even if there might be side effects too, the first thing to do would be to share that evidence with the patient. If on the other hand their condition was such that there were no clear answers, then the patient should know that. And if there was a randomised trial as an option for offering treatment, then I would want to suggest to that person that they might like to participate. Faced with uncertainty, the most appropriate way forward is to deal with the uncertainty by contributing to efforts to reduce the uncertainty, and that's certainly what I'd want for myself. I carry around a card with me saying 'invite me to participate in any randomised controlled trial for which I am likely to be eligible'. I don’t do that out of any altruism; it's purely selfish.  
 

Hazel feels passionately that the public needs better information about trials. The need to...

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Age at interview: 74
Sex: Female
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I have a passion to see that people have a working knowledge of what a trial is before they’re asked to participate in one. I don’t really know how I sort of knew. I perhaps I didn’t know very well, but I think with my previous work I had quickly had to get to grips with things. It was how I functioned. But if you know what the purpose of research is, if you know what a, testing treatments is about - that it has to be by comparison, that it has to be done in the very best way possible - if you understand why it’s necessary to group people - commonly called randomisation, which is not an awfully good word, because it’s sounds so haphazard.
 
It’s haphazard in one sense but in another sense it’s very particular. If people were brought up to understand this - and it’s been found that young children, I was having a conversation with my granddaughter who’s six and a half, I can’t remember what we were talking about, but she inherently had this realisation that you’ve got to compare things before you can decide which is best. Work on the children. Make it clearer that this is the only way to reduce any sort of uncertainty about anything, and to do it with those people who are very expert at doing it. But it needs a lot of disciplines to do a good trial, all sorts of disciplines, a team effort, including the patients and the public [laughs].
Many people have heard of clinical trials of new drug treatments, especially in the field of cancer. But clinical trials can also be used to test and compare all sorts of different types of treatments across a range of conditions, including surgery, physiotherapy and rehabilitation programmes, screening, prevention (such as vaccines), complementary therapies, radiotherapy and chemotherapy. They can evaluate talking therapies such as cognitive behavioural therapy for mental health problems and behaviour change programmes, and they can be used to assess the value of particular tests for screening or diagnosis. Trials can also compare different ways of giving people health information. (See ‘Different types of trial’ for examples).
 
Clinical trials are designed by doctors, scientists and others, and increasingly together with patients. The first step is to decide which questions need answering, and then to look carefully at the results of any trials that have already been done and any other research evidence (a systematic review). Then doctors, nurses, patients and researchers work together with statisticians and trial managers to design the trial. This is written down in the trial protocol. All trial protocols in the UK have to be approved by a research ethics committee which checks that the trial is ethical. In particular they should check that the questions being addressed in the trial have not already been answered, and that people are asked to take part in an appropriate way, with clear information to help them decide whether to take part.
 
Lester, whose son Ellis died of Creutzfeldt-Jakob Disease (CJD), was asked to help chair the committee for a trial of treatments for CJD. Here he explains the process of designing and approving the trial, and the important role lay representatives can play.
 

Lester describes the process of designing and approving a trial, from steering group and...

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Age at interview: 59
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But anyway, the trial was decided. It would be run in England and, or in the UK, and they set up what they call a trial steering committee. I didn’t know what that was, but it’s just like the overview group, the group that sits above, if you like, the researchers, the chemists, the scientists, and has a range of people on it who can actually give advice and say, “Well, this doesn’t feel right. This is...” - not in respect of the data. Not in terms of the scientific stuff that’s coming out, but more, “Does this feel right? Does it feel right for people?” Anyway the, I was asked if I’d sit on that committee and I said, “Absolutely.” Ellis by then was, had died, so it was just an interest of mine. And they asked a man called Iain to head up the trial steering group. And he’s, you’d call him an academic, I guess, but an interesting man, and he agreed to do this job, but only on two conditions. One, he wanted what’s called a systematic review done of all other therapies, so that we could see if quinacrine had been trialled before and what the results were. And he also insisted that he’d only do it is if a layperson co-chaired it with him, on the basis, “What does he know about the disease?” Well, the Medical Research Council suggested he might like to meet me. We met, we got on. And so for the trial steering group there were two chairs, myself and Iain.
 
And what did we do? As the trial was set up, what happens is that the researchers design a protocol, a sort of a set of rules of what they’re going to trial, and also importantly what they’re going to look at as important indicators if something’s working or not. And it’s a very, very complicated document. It starts with what is going to be done to people on the trial and it ends up with what they will look at to see if there is any benefit. So you could say I suppose in its very simplest form with something like CJD, where people always die, “Do people stop dying?” You could use that as a marker. “Do they live longer?” So all of that sort of thing was brought in. It then has to go through to an ethics committee, a group of people, a broad range of people who sit two or three steps away from all of us, and look at it and say, “Look, does this feel right?” Because I guess people who are going into a trial, participate in a trial, need to be reassured that there’s no self-interest at stake here, that the researchers, it’s not just one of their pet themes, a little idea, “Let’s give it a go.” So therefore the structure around setting up a trial, before it even gets going, before even the first person gets into it, is very pure.
 
I guess sometimes it could be too pure. There could be times where an ethics committee would look at something and say, “Wow, that’s just too risky. We don’t think that’s fair.” Whereas the people who were going to take part in it would say, “Actually, it is fair. There’s nothing else going on for us. We want it.” And again, CJD would have been a good case in point, because if you are caring for somebody you love and they are definitely going to die, you may well feel it’s better to take a bit of a chance than no chance at all. So when we went to the ethics committee, I went as an observer and sat at the back, not commenting. But had the ethics committee said, “Well, we’re not sure about this”, I would have been happy to stand up and represent the families, if you like, and the patients, and say, “Well, look, actually just think about it. Let’s take a balance on it.” So ethics committee sets up, everything gets going and the trial starts.
 

Lay people can help make trial information leaflets more responsive to patients. There are...

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Age at interview: 59
Sex: Male
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Within the trial steering committee there are people from a broad range of disciplines and say several laypeople. And one of the things the laypeople would look at, and have quite a lot of control over, is things like, “Well, from, what would be acceptable to a person with no other agenda other than to get better or to learn? And how can you present that information?” So things like patient information leaflets, patient briefings, all of that would really have a big stamp of the layperson on it, so that they could look at it and say, “Yeah, this fits the bill.” Because again, you can imagine if you’re seeing somebody like a doctor or a surgeon who you hold in high esteem - because we do hold them as a profession in high esteem - it’s not a meeting of equals. They are in a position of power. I’m not saying they abuse it, but they are. They’ve got the knowledge or some of the knowledge, they’ve got the strength, they’ve got the reputation. There are you, or either as the individual or as a representative of an individual, sort of feeling vulnerable because you’ve got an illness, lonely because you’ve got the illness and here’s somebody who wants to talk to you about it, and also ignorant of a lot of what’s going on. So that meeting is a meeting of un-equals. And the trial steering group, I think, just try and make sure that all the information that a patient or a carer has is good enough to be able to get over that, that element really.
For further information, see our Resources section.

Last reviewed September 2018.
Last updated June 2013

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