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N-of-1 Randomized Controlled Trials: Gordon Guyatt, MD, discusses n-of-1 randomized controlled trials.
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N-of-1 Randomized Controlled Trials: Gordon Guyatt, MD, discusses n-of-1 randomized controlled trials.
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>> I'm Joan Stephenson, Editor of JAMA's Medical News and Perspectives section. Today, I have the pleasure of speaking with Dr. Gordon Guyatt about the intriguing topic of N of 1 randomized controlled trials, a topic that he covers in Chapter 9 of Users' Guides to the Medical Literature. This chapter, co-authored by Dr. Guyatt, discusses what an N of 1 randomized controlled trial is, when to consider conducting one, and what the study design should include. Dr. Guyatt, why don't you introduce yourself to our listeners?
>> Gordon Guyatt. I'm a Professor of Medicine at McMaster University. >> Dr. Guyatt, what is an N of 1 randomized controlled trial? And why would a clinician consider conducting this type of trial? >> Well, N is the symbol that we usually use in randomized trials for the sample size. So, a conventional randomized trial has an N of dozens or, more often, hundreds and sometimes thousands.
And N of 1 randomized trial is just that, the N is 1. In other words, it's a single-patient trial. The times when a clinician might consider doing such a trial is when a patient is taking a medication and you are uncertain whether that medication is effective or is not effective or when a patient is having side effects or apparent side effects from a medication and you are uncertain whether those side effects are, in fact, due to the medication.
Or if you are starting a patient on a medication in which you are uncertain whether a patient benefits or doesn't and you want to be sure when you start the medication that there is or is not benefit. >> What is the basic design of an N of 1 randomized controlled trial? >> There are alternative designs one could use, but the design that we found most useful is as follows You have pairs of treatment periods.
During one period, the patient is taking the active treatment, and during the second period or in the alternative period of each pair, placebo. The order of the two periods, active and placebo, are randomized, and the pairs are repeated as often as is necessary until the patient and clinician are persuaded one way or the other about the effect of the treatment.
Pretty difficult to go beyond three pairs, but in our N of 1 randomized trials, often we did go to three pairs. The patient and clinician are both blinded so it requires the help of a pharmacist to prepare identical active and placebo medication. The patient completes a diary where the patient describes the key symptoms, typically an individualized diary targeted to the individual patient's symptoms.
So, pairs placebo and active, the order randomized, clinician and patient blind, patient completing a diary describing the patient's symptoms. And at the end after one, two, or three pairs, seldom sometimes more but seldom, the clinician and patient review the results and determine the impact of the patient's medication, whatever one is being tested, on those patient's symptoms, either beneficial or detrimental.
>> What questions should clinicians ask when determining if N of 1 trials are appropriate for their patients? >> Well, first of all, one wants there to be uncertainty about the effect of the treatment. That is often not too difficult because many of the symptomatic treatments that we use are effective in some people and ineffective in others or not everybody gets the side effects, some do and some do not.
So, the first issue is uncertainty about typically the benefit but sometimes the adverse effects. Second, it needs to be an intervention that works relatively quickly and stops acting relatively quickly. Because, for instance, if the intervention takes a week to become fully active and a week to stop being effective, one might make two-week treatment periods and only look at the second week of each period.
If one did that and did three pairs, the whole exercise would take about three months. So, even with relatively quickly acting treatments that stop acting relatively quickly, if you're going to do three pairs, it's quite a relatively prolonged exercise. So, you need an intervention, typically a drug, that acts quickly and stops acting quickly. And, thirdly, the patient has to be eager to participate in the trial.
This is a collaborative venture between a patient and a clinician and everybody needs to be enthusiastic about conducting the trial to determine typically the effectiveness of the intervention. >> What ethical issues should clinicians consider when using an N of 1 trial? >> The ethical history of N of 1 randomized trials is interesting. When we started them, the initial ethics committee we went to was a research ethics committee who said, this isn't research, this is clinical care, and go to the clinical ethics committee who gave us a carte blanche to do as many N of 1 trials as we wish.
Subsequently, they changed their mind, they took us back to a research ethics committee, and we had more structured constraints. When N of 1 trials have been done with other institutions, ethics committees have taken variable approaches but often been relatively strict about it. To me, this is tremendously ironic because consider the fact of a casual approach, you give the patient a treatment, and perhaps you assume that it's going to work even though, as I say, for most of our symptomatic treatments their effect is variable, they work in some patients and not others, and even in the patients in whom they work there are sometimes substantial effects and sometimes very trivial effects.
And when the treatment is ineffective or trivial effective, the patient may be exposed to the cost, inconvenience, and potential adverse effects of a treatment over long periods of time for little or no benefit. So, you could just give the treatment to the patient and leave it at that. Or you could give the treatment to the patient and have them come back and just say, how's it going? Does it feel good? And the patient says, oh, yeah, I think I'm feeling better and then you continue the medication.
Well, under those circumstances, the treatment may work but there are other reasons why the patient may say they're better. It might have been the natural history. Symptoms of chronic conditions tend to fluctuate, they're sometimes worse and sometimes better and perhaps the patient would have improved without the treatment. Or the patient may have experienced placebo effects, which we know can be powerful and their feeling better has nothing to do with the biologic effect of the medication.
Or the patient may be pleased and grateful for the clinician's great attention to their care and the nice way they've been treated and feel like the least they can do to reward the physician is to say that they're feeling better when the physician has offered them a particular treatment. So, there are a variety of reasons that conventional clinical practice can give what one might call a false positive and the patient then is taking a potentially expensive and inconvenient medication and at risk of the side effects for little or no benefit.
The N of 1 trial ensures that the patient at the end of the trial you know whether the treatment is working or is not working. These casual clinical approaches, subject to error, no one ever raised any ethical concerns about. On the other hand, you give what I consider optimal care ensuring that the patient, if they take a medication one knows whether it is effective or not, then you have to be subject to ethical constraints and get informed consent and various other things.
So, to me, the ethical standards applied to N of 1 trials often have gone very wrong because, to me, it is just the optimal way to deliver clinical care when one is uncertain about the benefits or adverse effects of an intervention. >> Well, I can see why you would find that ironic. >> Yes. It is quite striking to me. >> What types of medical conditions are good candidates for N of 1 randomized controlled trials?
>> As a general rule, it is conditions where the patient has symptomatic. So, it's not good for conditions in which one is preventing some event that is going to happen down the line. So, the patient has to be symptomatic and the symptoms have to be chronic and ongoing, typically experienced by the patient on a daily basis. So, all sorts of pain syndromes. So, headaches, back pain, muscle pain, joint pain would be a very appropriate candidate.
Conditions in which the patient has symptoms other than pain on a chronic basis. So, chronic airflow obstruction or asthma. Typically, chronic airflow obstruction would be the best. Other conditions where the problems occur on a daily basis, psychiatric conditions, typically anxiety. Depression could be a potential candidate, although most or all antidepressants take too long to work to be appropriate for an N of 1 trial as I've mentioned earlier.
So, pain, anxiety, insomnia, fatigue. So, the general theme of all these conditions are they are symptomatic, they are chronic, and the patient experiences the problems or symptoms on a daily or near-daily basis. >> What are the limitations or risks of using an N of 1 trial in clinical practice? >> Well, the limitations are two. One, I listed the situations in which an N of 1 is appropriate.
There are many situations in which it is inappropriate. So, if there's a treatment that is potentially curative it is not appropriate. If you are trying to prevent an event that happens down the line, it's not going to work, if the condition is one where the only available treatments take a long time to act and a long time to wear off, or if the patient is not the sort of patient who is interested in keeping a daily diary of their symptoms it's not going to be appropriate.
The other limitation is if one does the most rigorous N of 1 design, one requires the help of a pharmacist and the preparation of placebos and that may be difficult to secure. One could do N of 1s that are unblinded where you give the treatments on and off in this paired design that I talked about and have the patient monitor their symptoms, but clearly, the rigor is decreased under those circumstances. So, it's appropriate for not all clinical conditions, probably a minority, and not all patients, probably a minority, and there are logistical challenges to carrying it out.
>> Is there anything else you would like to tell our listeners about N of 1 trials? >> Well, yes perhaps. The N of 1 trials is still one of the sad stories of my career. When we started with the concept over 20 years ago now and published it in The New England Journal of Medicine, we had the idea that it had such potential it could be transformative in terms of clinical medicine and we set up an N of 1 service in our community where we helped physicians do N of 1 trials and did about 100 of them here.
But even in our community, the interest gradually died out. For many clinicians, it was just too much time and effort. And around the world, there have been many people who have actually got very interested in the idea and started N of 1 services or did start doing N of 1 trials themselves, but never has the idea caught to the extent that it has seen the widespread use that we were hoping.
But I would still -- I continue to think that it's a good idea, certainly when we've published ourselves the results of, I think over 100 such trials and other groups have published a large series and they do, when used, seem to be potentially enormously useful and I just encourage people to if they have any interest to give it a try. >> Thank you, Dr. Guyatt, for this overview of the use of N of 1 trials in clinical practice.
For additional information about this topic, JAMAevidence subscribers can consult Section 5 of Chapter 9 in Users' Guides to the Medical Literature. This has been Joan Stephenson of JAMA talking with Dr. Gordon Guyatt for JAMAevidence.
Segment:0 .
>> I'm Joan Stephenson, Editor of JAMA's Medical News and Perspectives section. Today, I have the pleasure of speaking with Dr. Gordon Guyatt about the intriguing topic of N of 1 randomized controlled trials, a topic that he covers in Chapter 9 of Users' Guides to the Medical Literature. This chapter, co-authored by Dr. Guyatt, discusses what an N of 1 randomized controlled trial is, when to consider conducting one, and what the study design should include. Dr. Guyatt, why don't you introduce yourself to our listeners?
>> Gordon Guyatt. I'm a Professor of Medicine at McMaster University. >> Dr. Guyatt, what is an N of 1 randomized controlled trial? And why would a clinician consider conducting this type of trial? >> Well, N is the symbol that we usually use in randomized trials for the sample size. So, a conventional randomized trial has an N of dozens or, more often, hundreds and sometimes thousands.
And N of 1 randomized trial is just that, the N is 1. In other words, it's a single-patient trial. The times when a clinician might consider doing such a trial is when a patient is taking a medication and you are uncertain whether that medication is effective or is not effective or when a patient is having side effects or apparent side effects from a medication and you are uncertain whether those side effects are, in fact, due to the medication.
Or if you are starting a patient on a medication in which you are uncertain whether a patient benefits or doesn't and you want to be sure when you start the medication that there is or is not benefit. >> What is the basic design of an N of 1 randomized controlled trial? >> There are alternative designs one could use, but the design that we found most useful is as follows You have pairs of treatment periods.
During one period, the patient is taking the active treatment, and during the second period or in the alternative period of each pair, placebo. The order of the two periods, active and placebo, are randomized, and the pairs are repeated as often as is necessary until the patient and clinician are persuaded one way or the other about the effect of the treatment.
Pretty difficult to go beyond three pairs, but in our N of 1 randomized trials, often we did go to three pairs. The patient and clinician are both blinded so it requires the help of a pharmacist to prepare identical active and placebo medication. The patient completes a diary where the patient describes the key symptoms, typically an individualized diary targeted to the individual patient's symptoms.
So, pairs placebo and active, the order randomized, clinician and patient blind, patient completing a diary describing the patient's symptoms. And at the end after one, two, or three pairs, seldom sometimes more but seldom, the clinician and patient review the results and determine the impact of the patient's medication, whatever one is being tested, on those patient's symptoms, either beneficial or detrimental.
>> What questions should clinicians ask when determining if N of 1 trials are appropriate for their patients? >> Well, first of all, one wants there to be uncertainty about the effect of the treatment. That is often not too difficult because many of the symptomatic treatments that we use are effective in some people and ineffective in others or not everybody gets the side effects, some do and some do not.
So, the first issue is uncertainty about typically the benefit but sometimes the adverse effects. Second, it needs to be an intervention that works relatively quickly and stops acting relatively quickly. Because, for instance, if the intervention takes a week to become fully active and a week to stop being effective, one might make two-week treatment periods and only look at the second week of each period.
If one did that and did three pairs, the whole exercise would take about three months. So, even with relatively quickly acting treatments that stop acting relatively quickly, if you're going to do three pairs, it's quite a relatively prolonged exercise. So, you need an intervention, typically a drug, that acts quickly and stops acting quickly. And, thirdly, the patient has to be eager to participate in the trial.
This is a collaborative venture between a patient and a clinician and everybody needs to be enthusiastic about conducting the trial to determine typically the effectiveness of the intervention. >> What ethical issues should clinicians consider when using an N of 1 trial? >> The ethical history of N of 1 randomized trials is interesting. When we started them, the initial ethics committee we went to was a research ethics committee who said, this isn't research, this is clinical care, and go to the clinical ethics committee who gave us a carte blanche to do as many N of 1 trials as we wish.
Subsequently, they changed their mind, they took us back to a research ethics committee, and we had more structured constraints. When N of 1 trials have been done with other institutions, ethics committees have taken variable approaches but often been relatively strict about it. To me, this is tremendously ironic because consider the fact of a casual approach, you give the patient a treatment, and perhaps you assume that it's going to work even though, as I say, for most of our symptomatic treatments their effect is variable, they work in some patients and not others, and even in the patients in whom they work there are sometimes substantial effects and sometimes very trivial effects.
And when the treatment is ineffective or trivial effective, the patient may be exposed to the cost, inconvenience, and potential adverse effects of a treatment over long periods of time for little or no benefit. So, you could just give the treatment to the patient and leave it at that. Or you could give the treatment to the patient and have them come back and just say, how's it going? Does it feel good? And the patient says, oh, yeah, I think I'm feeling better and then you continue the medication.
Well, under those circumstances, the treatment may work but there are other reasons why the patient may say they're better. It might have been the natural history. Symptoms of chronic conditions tend to fluctuate, they're sometimes worse and sometimes better and perhaps the patient would have improved without the treatment. Or the patient may have experienced placebo effects, which we know can be powerful and their feeling better has nothing to do with the biologic effect of the medication.
Or the patient may be pleased and grateful for the clinician's great attention to their care and the nice way they've been treated and feel like the least they can do to reward the physician is to say that they're feeling better when the physician has offered them a particular treatment. So, there are a variety of reasons that conventional clinical practice can give what one might call a false positive and the patient then is taking a potentially expensive and inconvenient medication and at risk of the side effects for little or no benefit.
The N of 1 trial ensures that the patient at the end of the trial you know whether the treatment is working or is not working. These casual clinical approaches, subject to error, no one ever raised any ethical concerns about. On the other hand, you give what I consider optimal care ensuring that the patient, if they take a medication one knows whether it is effective or not, then you have to be subject to ethical constraints and get informed consent and various other things.
So, to me, the ethical standards applied to N of 1 trials often have gone very wrong because, to me, it is just the optimal way to deliver clinical care when one is uncertain about the benefits or adverse effects of an intervention. >> Well, I can see why you would find that ironic. >> Yes. It is quite striking to me. >> What types of medical conditions are good candidates for N of 1 randomized controlled trials?
>> As a general rule, it is conditions where the patient has symptomatic. So, it's not good for conditions in which one is preventing some event that is going to happen down the line. So, the patient has to be symptomatic and the symptoms have to be chronic and ongoing, typically experienced by the patient on a daily basis. So, all sorts of pain syndromes. So, headaches, back pain, muscle pain, joint pain would be a very appropriate candidate.
Conditions in which the patient has symptoms other than pain on a chronic basis. So, chronic airflow obstruction or asthma. Typically, chronic airflow obstruction would be the best. Other conditions where the problems occur on a daily basis, psychiatric conditions, typically anxiety. Depression could be a potential candidate, although most or all antidepressants take too long to work to be appropriate for an N of 1 trial as I've mentioned earlier.
So, pain, anxiety, insomnia, fatigue. So, the general theme of all these conditions are they are symptomatic, they are chronic, and the patient experiences the problems or symptoms on a daily or near-daily basis. >> What are the limitations or risks of using an N of 1 trial in clinical practice? >> Well, the limitations are two. One, I listed the situations in which an N of 1 is appropriate.
There are many situations in which it is inappropriate. So, if there's a treatment that is potentially curative it is not appropriate. If you are trying to prevent an event that happens down the line, it's not going to work, if the condition is one where the only available treatments take a long time to act and a long time to wear off, or if the patient is not the sort of patient who is interested in keeping a daily diary of their symptoms it's not going to be appropriate.
The other limitation is if one does the most rigorous N of 1 design, one requires the help of a pharmacist and the preparation of placebos and that may be difficult to secure. One could do N of 1s that are unblinded where you give the treatments on and off in this paired design that I talked about and have the patient monitor their symptoms, but clearly, the rigor is decreased under those circumstances. So, it's appropriate for not all clinical conditions, probably a minority, and not all patients, probably a minority, and there are logistical challenges to carrying it out.
>> Is there anything else you would like to tell our listeners about N of 1 trials? >> Well, yes perhaps. The N of 1 trials is still one of the sad stories of my career. When we started with the concept over 20 years ago now and published it in The New England Journal of Medicine, we had the idea that it had such potential it could be transformative in terms of clinical medicine and we set up an N of 1 service in our community where we helped physicians do N of 1 trials and did about 100 of them here.
But even in our community, the interest gradually died out. For many clinicians, it was just too much time and effort. And around the world, there have been many people who have actually got very interested in the idea and started N of 1 services or did start doing N of 1 trials themselves, but never has the idea caught to the extent that it has seen the widespread use that we were hoping.
But I would still -- I continue to think that it's a good idea, certainly when we've published ourselves the results of, I think over 100 such trials and other groups have published a large series and they do, when used, seem to be potentially enormously useful and I just encourage people to if they have any interest to give it a try. >> Thank you, Dr. Guyatt, for this overview of the use of N of 1 trials in clinical practice.
For additional information about this topic, JAMAevidence subscribers can consult Section 5 of Chapter 9 in Users' Guides to the Medical Literature. This has been Joan Stephenson of JAMA talking with Dr. Gordon Guyatt for JAMAevidence.
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