Germany: IQWIG Report to government on ME/CFS - report out now May 2023

Solstice said:
Do you have to be a member to be able to use that button?
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Yes, it's available via my Mastodon instance (Fediscience.org) when reading posts from any other instance, but I don't know how widespread that functionality is. It's very useful of course, but otherwise it would have been a manual collated copy-paste into Google translate or similar.
 
SNT Gatchaman said:
"In the context of appropriate studies, the potential benefits and harms of activating therapies such as GET should be further investigated."
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Playing Devil’s Advocate, there is much that would be helpful to know about the relationship between activity management and PEM and about the duration of PEM, particularly what aspects might be transient and what involve long term negative consequences.

Here are some pacing ideas commonly used or pacing advice often proffered by specialist services:
  • Break any activity into smaller time limited components, that is for example rather than doing an hour long activity break it into six ten minute components. However we have no idea what the impact of this is on total activity levels comfortably achievable: how long should the gaps between these shorter components be; should these gaps involve rest or contrasting activity, eg switching from physical activity to mental activity; what form should any rest take, eg lying horizontal in a silent darker room versus sitting in a chair listening to music; etc.?
  • Keep activity levels below the PEM trigger point. However we do not know what is more significant, the intensity of any exertion or the period of exertion, is lifting ten stone once better or worse than lifting one stone ten times; what sort of time units should we be looking at for potential adverse events, for example if a twenty four hour period can be got through without negative consequences can we look on the risk of PEM in the next twenty four hour period returning to baseline or do we need to taking into account cumulative activity over longer time periods, that is in assessing what we can do today do we need to take into account what we did yesterday or the day before or even a week ago?
  • Do one thing at a time. Is PEM triggered by a single aspect of an activity, such as duration or intensity of exertion or is it compounded by orthostatic intolerance, degree of associated sensory stimulation and any associated emotional aspects, can more be done lying down in a silent darkened room than outside on a sunny day next to a busy road? More practically do such as dark glasses, noise cancelling headphones and compression garments increase how much activity can be undertaken without triggering PEM?
  • Keep overall activity below the level of triggering PEM. What sort of percentage of activity bellow the trigger level is safe or achievable, should it be 99% of the trigger level or 75% or 50%? Is this to allow for unexpected complications, such as an aerial display team deciding to practice over your house or the washing machine flooding the kitchen or is the safety margin part of
  • Use preemptive rest and post activity recovery rest. How much pre and post activity is needed to avoid longer term negative effects and does increasing the amount of rest increase the total amount of activity possible, for example if staying in bed the day before and after a wedding works could two days in bed before and after allow you to go to the rehearsal dinner too, or would three days rest allow attendance of the stag/hen do as well?
  • Avoid PEM and you can do more overall. If PEM is avoided in a time period does this allow a higher level overall of activity in that time period?
  • Pacing up. The current model of rehabilitation general in use is that doing an activity within your current limits over time results in increasing those limits, though this is generally unarticulated it is an underlying assumption for many health professionals, and are also seeing it being formalised as graded activity management as a recommended treatment in some UK specialist services now NICE rejects GET. However we have no idea whether or not avoiding PEM has any impact on potential future activity levels beyond an activity ceiling.
  • Use of biofeedback, such as heart rate monitors, etc
[Added - Any meaningful research will be complex, given the complication that patients continue to exist and function in the real world in between treatment sessions, and ethical considerations need to put avoiding potential long term harm to the fore. This is particularly important in that we need to look at implications over months and years, not short term intervention periods.]

However any recommendation for activity/exercise based treatments or research is profoundly premature when we have not yet established practical activity monitoring protocols or agreed clinical definitions of PEM. GET/CBT for ME (and now for anything else BPS advocates can think of) has always been putting the cart before the horse, and what we are seeing here and to a lesser extent even in the current NICE guidelines is an attempt to remedy the situation by grooming the horse and painting the cart, not actually addressing the real problems.
 
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SNT Gatchaman said:
@iqwig Your press release leaves me quite perplexed.

You write "In the context of appropriate studies, the potential benefits and harms of activating therapies such as GET should be further investigated."

Against the background of the many case reports of patients who have suffered massive damage in connection with GET and the fact that experts strongly advise against it: What would a good study design look like that is ethically justifiable, i.e. minimizes the risk of serious harm to patients? Shouldn't there rather be a risk-benefit assessment of whether such studies should be carried out at all and whether other options should be explored instead? This clearly comes up short in your comments. Simply demanding more data seems very technocratic at this point and does not exactly win the trust of patients.

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@smu Thank you for your comment!

We can't shake a study design off the cuff here, but at least we can record it:

(1) According to the descriptions of numerous affected persons and experts, activating therapies are currently carried out in rehabilitation facilities in Germany. This widespread practice could be accompanied by studies without the need to treat even one additional person with ME/CFS with GET.

(2) There are other variants of cautious activation that could be compared to GET in such trials, as well as pacing. Thus, the number of affected individuals treated with GET might actually decrease - because many would end up in the comparison arms.

(3) If methodologically adequate, meaningful studies show clear disadvantages of activating therapies such as GET, this may help to rapidly change treatment practice.

(4) In surveys like the one by Kindlon 2011, a part of the affected persons report deteriorations of their condition after a GET, but a part also reports improvements (see p. 175 of our report). At the moment, it is unclear to what these extremely heterogeneous results are due. It would be important to find out, within the framework of appropriate studies, on which parameters this depends. In this way, in the future, those for whom the chances of improvement are high could be given a cautious activation offer without at the same time causing harm to the other persons concerned.

(5) No one can be forced to participate in a study. Consent is always preceded by an explanation of the aims of the study and of the therapies that will be used in it.

This would presumably also be an improvement compared to the current situation, in which, according to the descriptions of many patients, there is often no open information about the chances and risks (!) of an activation therapy.

Many greetings from the IQWiG - AK
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They're really not trying hard, uh? As in, not at all.

How can they talk about GET being commonly used without evidence and find nothing wrong with that? In 3) they explicitly state that they need evidence against to stop using something that has no evidence for. This is insane.

In 4) they mention reports of harms, but emphasize few reports of benefits. Harms matter more, this is what the hypocratic thing is all about.

And in 5) the issue of consent is not about studies, it's about patients being told they HAVE to try this treatment, or be dropped, then get dropped anyway because it's all a belief system, which is confirmed by the fact that 1) it has no evidence for, and 2) they require evidence against in order not to support it, which is the very definition of ideology.

Complete amateur hour. Actually, far far worse than what most amateurs have done. Literally within months groups of amateurs managed to formally put out a roadmap that understands all those issues. This is dereliction of duty.
 
Peter Trewhitt said:
Playing Devil’s Advocate, there is much that would be helpful to know about the relationship between activity management and PEM and about the duration of PEM, particularly what aspects might be transient and what involve long term negative consequences.

Here are some pacing ideas commonly used or pacing advice often proffered by specialist services:
  • Break any activity into smaller time limited components, that is for example rather than doing an hour long activity break it into six ten minute components. However we have no idea what the impact of this is on total activity levels comfortably achievable: how long should the gaps between these shorter components be; should these gaps involve rest or contrasting activity, eg switching from physical activity to mental activity; what form should any rest take, eg lying horizontal in a silent darker room versus sitting in a chair listening to music; etc.?
  • Keep activity levels below the PEM trigger point. However we do not know what is more significant, the intensity of any exertion or the period of exertion, is lifting ten stone once better or worse than lifting one stone ten times; what sort of time units should we be looking at for potential adverse events, for example if a twenty four hour period can be got through without negative consequences can we look on the risk of PEM in the next twenty four hour period returning to baseline or do we need to taking into account cumulative activity over longer time periods, that is in assessing what we can do today do we need to take into account what we did yesterday or the day before or even a week ago?
  • Do one thing at a time. Is PEM triggered by a single aspect of an activity, such as duration or intensity of exertion or is it compounded by orthostatic intolerance, degree of associated sensory stimulation and any associated emotional aspects, can more be done lying down in a silent darkened room than outside on a sunny day next to a busy road? More practically do such as dark glasses, noise cancelling headphones and compression garments increase how much activity can be undertaken without triggering PEM?
  • Keep overall activity below the level of triggering PEM. What sort of percentage of activity bellow the trigger level is safe or achievable, should it be 99% of the trigger level or 75% or 50%? Is this to allow for unexpected complications, such as an aerial display team deciding to practice over your house or the washing machine flooding the kitchen or is the safety margin part of
  • Use preemptive rest and post activity recovery rest. How much pre and post activity is needed to avoid longer term negative effects and does increasing the amount of rest increase the total amount of activity possible, for example if staying in bed the day before and after a wedding works could two days in bed before and after allow you to go to the rehearsal dinner too, or would three days rest allow attendance of the stag/hen do as well?
  • Avoid PEM and you can do more overall. If PEM is avoided in a time period does this allow a higher level overall of activity in that time period?
  • Pacing up. The current model of rehabilitation general in use is that doing an activity within your current limits over time results in increasing those limits, though this is generally unarticulated it is an underlying assumption for many health professionals, and are also seeing it being formalised as graded activity management as a recommended treatment in some UK specialist services now NICE rejects GET. However we have no idea whether or not avoiding PEM has any impact on potential future activity levels beyond an activity ceiling.
  • Use of biofeedback, such as heart rate monitors, etc
[Added - Any meaningful research will be complex, given the complication that patients continue to exist and function in the real world in between treatment sessions, and ethical considerations need to put avoiding potential long term harm to the fore. This is particularly important in that we need to look at implications over months and years, not short term intervention periods.]

However any recommendation for activity/exercise based treatments or research is profoundly premature when we have not yet established practical activity monitoring protocols or agreed clinical definitions of PEM. GET/CBT for ME (and now for anything else BPS advocates can think of) has always been putting the cart before the horse, and what we are seeing here and to a lesser extent even in the current NICE guidelines is an attempt to remedy the situation by grooming the horse and painting the cart, not actually addressing the real problems.
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Some really important questions here I often don’t see raised and often assume it’s because others definitely think bite size chunks vs do it all then rest (whereas it’s been more complicated than that with me albeit so many caveats)

I’d love to see an individual thread on some of these questions at some point
 
ME/CFS Skeptic said:
Looking back at the report the main thing that stands out is that they only looked at studies that required 80% of patients to have PEM. This meant that they disregarded about 90% of all RCTs. That is a much more extreme position than the NICE committee which only downgraded the quality of evidence of those studies because of indirectness.

Because of this decision, IQWiG only had 3 trials on GET and CBT to work with: The PACE trial, the GETSET trial and a 2018 Dutch trial on CBT by the research team of Hans Knoop. IQWiG correctly notes that all 3 studies were at high risk of bias because of lack of blinding and the reliance on subjective outcomes. They even write (on page 124) that: "Since the risk of bias of all 3 studies included was already classified as high across outcomes, there was no outcome-specific assessment of the risk of bias." So no need to look closer, these trials were already high risk. But then they conclude that there is evidence for CBT, without taking the high risk of bias into consideration. So once again we see the problem of a 'bias ceiling': where the highest risk of bias taking into consideration is still good enough to make treatment recommendations. There is no option for a junk trial: one that is so high risk of bias that nothing useful can be concluded from it.

Even if one would to disregard the bias, the trials still do not show a convincing effect. Most of the outcomes were not statistically or clinically relevant and none were maintained at the long-term follow-up. The clearest estimate was arguably for CBT after 24 weeks or 6 months. The meta-analysis of 2 studies found an effect size of 2.95 points on the Chalder Fatigue Scale, corresponding to a SMD of -0.39 [-0.57, -0.21]. The confidence interval is 0.01 point above the insignificance threshold of 0.2 and some studies have suggested 3 points to be the minimally important difference on the Chalder Fatigue Scale. So this isn't a clear effect at all. The same story for 'social participation' using the Work and Social Adjustment Scale (WSAS).

For both outcomes, there was no longer a statistically significant effect at long-term follow-up. And for sleep quality, pain, activity levels, physical performance, physical function, cognitive function, and mental status there was no indication of an effect of CBT at any time point. So even if they speak of a 'hint' of an effect it still seems like an overstatement of the actual evidence.
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For those that don't know it, here are the questions for the Work and Social Adjustment Scale. According to the press release, CBT was shown to improve return to work/school but this subjective measure looks at a variety of issues:

Work and Social Adjustment Scale

Rate each of the following questions on a 0 to 8 scale: 0 indicates no impairment at all and 8 indicates very severe impairment.

Because of my [disorder], my ability to work is impaired. 0 means not at all impaired and 8 means very severely impaired to the point I can't work.

Because of my [disorder], my home management (cleaning, tidying, shopping, cooking, looking after home or children, paying bills) is impaired. 0 means not at all impaired and 8 means very severely impaired.

Because of my [disorder], my social leisure activities (with other people, such as parties, bars, clubs, outings, visits, dating, home entertainment) are impaired. 0 means not at all impaired and 8 means very severely impaired.

Because of my [disorder], my private leisure activities (done alone, such as reading, gardening, collecting, sewing, walking alone) are impaired. 0 means not at all impaired and 8 means very severely impaired.

Because of my [disorder], my ability to form and maintain close relationships with others, including those I live with, is impaired. 0 means not at all impaired and 8 means very severely impaired.

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