ME/CFS Skeptic
Senior Member (Voting Rights)
Many of the arguments are the same as in the Lancet commentary. Here's a brief overview of my comments based on the arguments in the press release.
1. The 2021 guideline proposed a new definition of CFS/ME which required the presence of four symptoms. One of these was ‘post-exertional symptom exacerbation’ (post-exertional malaise), which had not been mandatory in previous Applying this new definition retrospectively, the NICE committee downgraded the large majority of trials of CBT and GET that had not specifically and explicitly required post-exertional symptom exacerbation to be present.
It was not the NICE committee that came up with a new definition. In the past 20 years, multiple case definitions have been published that require PEM as a core feature of ME/CFS such as the Canadian Consensus Criteria (CCC), International Consensus Criteria (ICC), and the National Academy of Medicine criteria. The NICE definition is based on the latter. These criteria are the ones used in research and clinical practice. It is logical that NICE evaluates the evidence for this patient group, for how ME/CFS is defined today, and not for an older case definition published 30 years ago. Other reviews such as the one by the German IQWIG have used a similar approach. Also: the previous NICE guidance from 2007 already highlighted PEM as a core feature of ME/CFS and studies that used this 2007 description were not downgraded.
2. The NICE committee considered outcomes for each trial at a time furthest away from when participants were allocated to their groups and received their treatments. This meant that some treatment outcomes were simply ignored. In other trials, participants in the comparison (control) groups had received another therapy by this longest follow up, making it impossible to accurately assess differences between groups, which is methodologically imperative in the context of a clinical trial.
I agree that NICE could have used the primary outcomes of the trials as well so that patients were still randomized to their treatment group. In the long-term follow-up, they might have received additional treatments.
Past reviews, however, have often overlooked the negative results of these long-term follow-ups, so I think it is good that NICE highlighted these. It would be strange to recommend treatments if the long-term follow-up showed no benefit at all.
In both GETSET and PACE, a sensitivity analysis showed that it was unlikely that additional treatment after randomization explained the null results. The authors of GETSET for example, reported that “there is no evidence that the improvements observed in the SMC group [the control group] were due to them having received more exposure to therapy than the GES group [the intervention group] after trial completion.” Similarly, in the PACE trial the control group caught up on the intervention group and “there was some evidence from an exploratory analysis that improvement after the 1 year trial final outcome was not associated with receipt of additional treatment with CBT or GET.” In other words, at long-term follow-up patients who received GET or CBT seem to do just as poorly as those who did not.
3. The assessment of harm from treatment in the NICE 2021 review prioritised evidence from qualitative studies and patient organised surveys. On this basis NICE concluded GET was unsafe. However, rigorously conducted systematic reviews, which included gold standard randomised controlled trials, found no evidence that GET caused harm.
This is not entirely true. The Cochrane review looked at the randomized trials and stated: “We are uncertain about the risk of serious adverse reactions because the certainty of the evidence is very low.” There was simply not enough data in the RCTs to make a conclusion.
On the other hand, there are lots of surveys that indicate GET has a negative impact on some ME/CFS patients so it is not unusual for NICE to express a concern about this treatment. In medicine, potential harms are evaluated differently (taken more seriously) than potential benefits – primum non nocere etc.
4. In their assessment NICE downgraded all outcomes related to fatigue, considering it to be too subjective to measure. But how else than asking patients how they are can one assess whether a treatment has worked?
I think this is probably the weakest point. NICE did not say this at all. Blinded trials that used fatigue as an outcome were not downgraded.
NICE downgraded quality of evidence when subjective outcomes (not just fatigue, but also pain, sleep, quality of life etc.) were used in non-blinded trials because this creates a high risk of bias. This is standard practice.
In the case of graded exercise and CBT, the treatments aimed to change how patients interpret and report their symptoms. Therapist were instructed to encourage optimism while patients were told to focus less on their fatigue. Symptoms were said to be the result of anxiety, stress, or deconditioning which could be overcome by graded exercise or CBT. This creates a high risk of bias where patients are stimulated to report their symptoms as less severe, even if these did actually not improve.
‘How else than asking patients how they are can one assess whether a treatment has worked?’ By using objective data such as activity levels, employment levels, disability payments, fitness data, etc. These showed available but showed no improvements.
5. Normal NICE guideline development involves the synthesis of research evidence by experts but for this guideline there was remarkably little aggregation and meta-analysis, making it hard to conclude what treatments worked. The analysis fell short of international standards.
They seem to suggest that the evidence review was not prepared by methodological experts as usual. As far as I can tell, however, this was the case: hundreds of pages with meta-analyses were prepared by the National Clinical Guideline Centre (NCGC) which is hosted by the Royal College of Physicians (RCP).
White et al. seem disappointed that NICE didn’t perform the data synthesis as they would like it, namely by combining as many GET and CBT trials as possible so that a strong conclusion can be made.
I suspect NCGC did not do this because it results in high heterogeneity. This signals that the trial design or interventions differed too much to be added to the same analysis. In case of high heterogeneity in meta-analyses, it is usually recommended to split up comparisons into studies and interventions that are more alike. This is what NICE did. A 2015 review on ME/CFS by a National Institutes of Health Working Group in the US used a similar approach.
6. In the 2021 guideline NICE described GET as incorporating fixed increments of exercise that are pursued irrespective of how the patient feels. However, this does not reflect the therapy reported in the research. Clinical trials, and the previous NICE guideline are clear that activity in GET is determined collaboratively with the patient and only increased as the patient feels able. NICE banned a treatment that no one provides.
Here they might have a point that the wording ‘fixed increments’ is not on point. But that is merely a language issue because the underlying argument remains the same.
Graded exercise therapy is not ‘symptom-contingent’ because symptoms are viewed as an unreliable signal that keeps patients in a vicious cycle of inactivity and disability. The goal of the therapist is therefore to break this cycle by encouraging patients to gradually increase their activity levels even if they do not feel up to it. Here’s how Peter White himself described the rationale behind GET: “Patients can be released from their self-perpetuating cycle of inactivity if the impairments that occur due to inactivity and their physiological deconditioning can be reversed. This can occur if they are willing to gradually exceed their perceived energy limits.” If a patient develops symptoms as a response to increased activity, they were told to keep exercising at that level, based on the assumption that the body would adapt. PEM is not taken into account.
7. In NICE guidelines on other relevant health conditions such as chronic unexplained pain, GET and CBT are still recommended. Since such pain is common in CFS/ME, how can a clinician choose which guideline to follow?
Since ME/CFS is a more specific diagnosis than pain, it is likely that a clinician will folow the ME/CFS guideline. This seems like another weak argument. It is not uncommon for patients to have multiple conditions where treatment advice conflicts. A patient with kidney or liver disease, for example, will have to take this into account when he/she takes drugs for other health conditions. Clinicians always need to balance the benefits and possible side effects of treatments based on their patient's individual case.
8. Having downgraded the evidence for trials of CBT and GET, NICE recommended the use of “energy management,” in which patients are encouraged to stay within the energy limits imposed by their illness, also known as pacing. But there is little or no evidence to support such an approach. The only substantial trial of pacing for CFS/ME published to date showed that such an approach was no more effective than specialist medical care alone and less effective than either CBT or GET.
The version of pacing used in the PACE trial does not correspond to how patients use and interpret it. It is not seen as a treatment or intervention, but a way of managing symptoms more efficiently much like MS patients would use a wheelchair for difficulty walking.
1. The 2021 guideline proposed a new definition of CFS/ME which required the presence of four symptoms. One of these was ‘post-exertional symptom exacerbation’ (post-exertional malaise), which had not been mandatory in previous Applying this new definition retrospectively, the NICE committee downgraded the large majority of trials of CBT and GET that had not specifically and explicitly required post-exertional symptom exacerbation to be present.
It was not the NICE committee that came up with a new definition. In the past 20 years, multiple case definitions have been published that require PEM as a core feature of ME/CFS such as the Canadian Consensus Criteria (CCC), International Consensus Criteria (ICC), and the National Academy of Medicine criteria. The NICE definition is based on the latter. These criteria are the ones used in research and clinical practice. It is logical that NICE evaluates the evidence for this patient group, for how ME/CFS is defined today, and not for an older case definition published 30 years ago. Other reviews such as the one by the German IQWIG have used a similar approach. Also: the previous NICE guidance from 2007 already highlighted PEM as a core feature of ME/CFS and studies that used this 2007 description were not downgraded.
2. The NICE committee considered outcomes for each trial at a time furthest away from when participants were allocated to their groups and received their treatments. This meant that some treatment outcomes were simply ignored. In other trials, participants in the comparison (control) groups had received another therapy by this longest follow up, making it impossible to accurately assess differences between groups, which is methodologically imperative in the context of a clinical trial.
I agree that NICE could have used the primary outcomes of the trials as well so that patients were still randomized to their treatment group. In the long-term follow-up, they might have received additional treatments.
Past reviews, however, have often overlooked the negative results of these long-term follow-ups, so I think it is good that NICE highlighted these. It would be strange to recommend treatments if the long-term follow-up showed no benefit at all.
In both GETSET and PACE, a sensitivity analysis showed that it was unlikely that additional treatment after randomization explained the null results. The authors of GETSET for example, reported that “there is no evidence that the improvements observed in the SMC group [the control group] were due to them having received more exposure to therapy than the GES group [the intervention group] after trial completion.” Similarly, in the PACE trial the control group caught up on the intervention group and “there was some evidence from an exploratory analysis that improvement after the 1 year trial final outcome was not associated with receipt of additional treatment with CBT or GET.” In other words, at long-term follow-up patients who received GET or CBT seem to do just as poorly as those who did not.
3. The assessment of harm from treatment in the NICE 2021 review prioritised evidence from qualitative studies and patient organised surveys. On this basis NICE concluded GET was unsafe. However, rigorously conducted systematic reviews, which included gold standard randomised controlled trials, found no evidence that GET caused harm.
This is not entirely true. The Cochrane review looked at the randomized trials and stated: “We are uncertain about the risk of serious adverse reactions because the certainty of the evidence is very low.” There was simply not enough data in the RCTs to make a conclusion.
On the other hand, there are lots of surveys that indicate GET has a negative impact on some ME/CFS patients so it is not unusual for NICE to express a concern about this treatment. In medicine, potential harms are evaluated differently (taken more seriously) than potential benefits – primum non nocere etc.
4. In their assessment NICE downgraded all outcomes related to fatigue, considering it to be too subjective to measure. But how else than asking patients how they are can one assess whether a treatment has worked?
I think this is probably the weakest point. NICE did not say this at all. Blinded trials that used fatigue as an outcome were not downgraded.
NICE downgraded quality of evidence when subjective outcomes (not just fatigue, but also pain, sleep, quality of life etc.) were used in non-blinded trials because this creates a high risk of bias. This is standard practice.
In the case of graded exercise and CBT, the treatments aimed to change how patients interpret and report their symptoms. Therapist were instructed to encourage optimism while patients were told to focus less on their fatigue. Symptoms were said to be the result of anxiety, stress, or deconditioning which could be overcome by graded exercise or CBT. This creates a high risk of bias where patients are stimulated to report their symptoms as less severe, even if these did actually not improve.
‘How else than asking patients how they are can one assess whether a treatment has worked?’ By using objective data such as activity levels, employment levels, disability payments, fitness data, etc. These showed available but showed no improvements.
5. Normal NICE guideline development involves the synthesis of research evidence by experts but for this guideline there was remarkably little aggregation and meta-analysis, making it hard to conclude what treatments worked. The analysis fell short of international standards.
They seem to suggest that the evidence review was not prepared by methodological experts as usual. As far as I can tell, however, this was the case: hundreds of pages with meta-analyses were prepared by the National Clinical Guideline Centre (NCGC) which is hosted by the Royal College of Physicians (RCP).
White et al. seem disappointed that NICE didn’t perform the data synthesis as they would like it, namely by combining as many GET and CBT trials as possible so that a strong conclusion can be made.
I suspect NCGC did not do this because it results in high heterogeneity. This signals that the trial design or interventions differed too much to be added to the same analysis. In case of high heterogeneity in meta-analyses, it is usually recommended to split up comparisons into studies and interventions that are more alike. This is what NICE did. A 2015 review on ME/CFS by a National Institutes of Health Working Group in the US used a similar approach.
6. In the 2021 guideline NICE described GET as incorporating fixed increments of exercise that are pursued irrespective of how the patient feels. However, this does not reflect the therapy reported in the research. Clinical trials, and the previous NICE guideline are clear that activity in GET is determined collaboratively with the patient and only increased as the patient feels able. NICE banned a treatment that no one provides.
Here they might have a point that the wording ‘fixed increments’ is not on point. But that is merely a language issue because the underlying argument remains the same.
Graded exercise therapy is not ‘symptom-contingent’ because symptoms are viewed as an unreliable signal that keeps patients in a vicious cycle of inactivity and disability. The goal of the therapist is therefore to break this cycle by encouraging patients to gradually increase their activity levels even if they do not feel up to it. Here’s how Peter White himself described the rationale behind GET: “Patients can be released from their self-perpetuating cycle of inactivity if the impairments that occur due to inactivity and their physiological deconditioning can be reversed. This can occur if they are willing to gradually exceed their perceived energy limits.” If a patient develops symptoms as a response to increased activity, they were told to keep exercising at that level, based on the assumption that the body would adapt. PEM is not taken into account.
7. In NICE guidelines on other relevant health conditions such as chronic unexplained pain, GET and CBT are still recommended. Since such pain is common in CFS/ME, how can a clinician choose which guideline to follow?
Since ME/CFS is a more specific diagnosis than pain, it is likely that a clinician will folow the ME/CFS guideline. This seems like another weak argument. It is not uncommon for patients to have multiple conditions where treatment advice conflicts. A patient with kidney or liver disease, for example, will have to take this into account when he/she takes drugs for other health conditions. Clinicians always need to balance the benefits and possible side effects of treatments based on their patient's individual case.
8. Having downgraded the evidence for trials of CBT and GET, NICE recommended the use of “energy management,” in which patients are encouraged to stay within the energy limits imposed by their illness, also known as pacing. But there is little or no evidence to support such an approach. The only substantial trial of pacing for CFS/ME published to date showed that such an approach was no more effective than specialist medical care alone and less effective than either CBT or GET.
The version of pacing used in the PACE trial does not correspond to how patients use and interpret it. It is not seen as a treatment or intervention, but a way of managing symptoms more efficiently much like MS patients would use a wheelchair for difficulty walking.
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