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

I would be happy to have this kind of health info on an official website instead of the one that we have here, it would be an improvement indeed.

 

Does anyone know to which study they are referring here on page 7 of the PDF, in the introduction:

"Eine erste Studie zur Verbesserung der Versorgung mit einem speziell auf ME/CFS angepassten Rehabilitionskonzept ist in Deutschland bereits gestartet."

 

https://innovationsfonds.g-ba.de/pr...drom-myalgischer-enzephalomyelitis-cfs-me.427

Not sure what to think about this:

"An overall concept of diverse treatment approaches is being developed and launched. This concept includes behavioral and symptom-oriented therapies as well as drug and physical therapies.

"This approach will be tested on 120 CFS patients and compared with 120 patients of a control group who are treated on an outpatient basis (according to the current standard of care). "

Edit: Link to trial protocol: https://drks.de/search/en/trial/DRKS00028115

Haven't read the trial protocol but am afraid that the comments on a forum thread on a similar endeavor to investigate the efficacy of rehab for another disease will apply here, too -- no adequate control group?


edit / clarity

 

https://www.iqwig.de/presse/pressemitteilungen/pressemitteilungen-detailseite_93184.html

 

It says 'the full report is now available' in this but I'm struggling to actually find it - I don't know whether it is the first link at the bottom because it doesn't translate for me

 

From https://www.iqwig.de/projekte/n21-01.html

Final report [PDF, 3 MB]

 

Link to trial protocol: https://drks.de/search/en/trial/DRKS00028115

see post above:

Edit:

From the trial protocol:

Primary outcome:
health-related quality of life (SF-36) at 12 months

Secondary outcome:

ability to work (able to work yes/no, sick days); health status (Bell scale, SF-36); symptoms (Chalder Fatigue Scale, CCC criteria, COMPASS, IPAQ, EQ5D, PHQ9, ESS); physical or apparatus functional parameters (hand strength, number of steps, activity, orthostasis, vascular function)

 

Adding to the above:

Seems not to be an actual trial protocol, just an entry in the trial registry -- e.g. description of control group is missing -- but see the other link & quote above.

And from the entry in the trial registry: Allocation is non-randomized.

edit: cross-posted with Hutan

 

I think it's good IQWiG acknowledged how small the effect sizes are in the press release. I think that's something obvious but it's also very overlooked - the effect sizes are very small, it's not clear they have any clinical importance.

I haven't read through much of the report because it's very long, but it doesn't seem like they've actually changed much in the report besides changing the conclusion for GET in way that seems a bit inexplicable, and the prevalence. It doesn't seem like they incorporated any of my or (any significant amount of) others' criticisms into the actual report.

 

There's another website with some additional info about the study referred to in the report (see Hutan's posts above).

Google translate link here.

See my quote above:

"An overall concept of diverse treatment approaches is being developed and launched. This concept includes behavioral and symptom-oriented therapies as well as drug and physical therapies.

"This approach will be tested on 120 CFS patients and compared with 120 patients of a control group who are treated on an outpatient basis (according to the current standard of care). "

That still doesn't seem an adequate control to me.

AlsO

"In particular, the physical performance of those affected should be increased and thus their possibilities for professional participation should be preserved."

Not sure whether they actually think people with ME could increase their physical performance long-term in a way that they could preserve their working ability?

 

A snippet of how IQWiG interpreted and dismissed some comments on the issues about subjective endpoints in unblinded trials, discrepancy between subjective and objective endpoints, what patient-reevant and validated endpoints are etc.

IQWiG Report, p.254-255 / deepl translate:

"In the hearing, both the use of subjective endpoints and the non-inclusion of objective endpoints of the PACE study in the present report were criticized:

"In principle, the benefit and harm assessment of an intervention is based on results from scientific studies on the influence of patient-relevant outcomes. According to the General Methods [88], IQWiG understands this to mean how a patient feels, how he or she can perform his or her functions and activities, or whether he or she survives.

"Consequently, the endpoints 'number of days lost from work' and 'payment of social benefits', which are specifically mentioned in a statement and described as objective, are classified as not relevant to patients and rather represent an economic measure.

"Patient-reported outcomes can also be used to assess the benefits and harms of an intervention. The commenter agrees that such subjective outcomes are of limited validity in unblinded trials due to their nature. Accordingly, in the results of such endpoints were assessed with a high potential for bias in the present report.

"In principle, such instruments are required for benefit assessments that are suitable for use in clinical trials and for the corresponding population. The instruments criticized in a large number of comments, such as the Chalder Fatigue Questionnaire or the Short Form-36 Physical Function, are proven, frequently used and also recommended instruments for patients with ME/CFS. At this point, reference is made, for example, to the explanations of various instruments in the criteria catalogs of the IoM (IoM 2015), the CCC (Jason 2010), and the CDC (Reeves 2003).

"With regard to the argument put forward in many comments that no effects are shown in objective endpoints, it should be noted that this cannot, conversely, be evidence that a therapy has no effect at all."

 

My hope is that someday in the nearer future S4ME could invite German charities to co-work or at least discuss on establishing some standards for

a) what's good clinical trial methodology (including endpoints) for different trial designs (blinded drug trials vs unblindable therapist-delivered interventions studies)

b) what could be helpful instruments for clinical services to diagnose and monitor pwME, including disability assessment.


Edit: And then approach the IQWiG again with our suggestions.

 

Yes, I read that and wasn't impressed with that. Diagnostic criteria referring to instruments doesn't mean they're "proven", nor does being commonly used. And, they also used scales which were both not validated in any way at all and not commonly used at all. They didn't address that (besides justifying one with "face validity")

 

Skimmed through the report. It seems that they toned down their statements on GET and CBT and changed their prevalence estimates but that not much else has changed.

They previously only relied on the 0.1% prevalence estimate of the Nacul et al. 2011 study because that is the only one that clearly used a case definition where PEM is required. But various submissions pointed out that this is likely an underestimation because it was based on ME/CFS diagnoses that doctors already made. Patient organizations pointed to other studies that had sufficient data on PEM that could be used, namely the Jason et al. 1999 estimate for adults and the Crawley et al. 2011 and Jason et al. 2022 studies for children and adolescents.

This resulted in a 0.1% - 0.32% estimate of ME/CFS in adults which in Germany would mean 70,000 to 220 000 patients. For young people/adolescents they used a 0.75%-0.98% estimate which would mean around 70,000 and 90,000 ME/CFS patients in that age range (6-17 years). In total, there would be 140,000 to around 310,000 ME/CFS patients in Germany but they note a lot of issues with extrapolation of the studies so this is only a rough estimate.

For the evidence review of GET and CBT I did not note any differences at first glance. It seems that they mostly toned down their conclusions based on reports of negative experiences with these treatments. It wasn’t so much the published patient surveys that influenced their decision (they still argue that many of these reports show that a large group also reports benefit of GET or CBT) but the reaction of patients and expert physicians to the draft. They wrote on page 197 (Google translation):

“Surveys of those affected about the advantages and disadvantages of activating therapies such as GET do not give a clearly negative or positive picture either: larger subgroups report deterioration, others report improvements. In contrast to this, patient reports submitted as comments during the hearing on the preliminary report stated, for example, activating therapies experienced during rehabilitation as the reason for serious deterioration in health. This potential for damage is also seen by specialist societies and experts in the field (see documentation of the hearing). It therefore remains incomprehensible why these reports from patients have not yet led to a systematic investigation of the potential for harm of the treatments practiced in Germany with the aim of activation.”​

 

Why would the forum need to be involved? Obviously we have a platform where discussions can take place but I don't understand why we would need to extend an invitation.

 

Here's a comparison of the summary section on treatment in the draft versus the final report. The bolding is mine because it seems that this is an important sentence that was removed.

Before:

ME/CFS may have different causes in different people. In addition, the severity and type of symptoms vary greatly. It is therefore not surprising that patients have different experiences as to which recommendations help them and which do not.

Ways to deal with the disease include:

• Energy management: You should learn to dose stress in such a way that the symptoms do not get worse if possible. Activities are adjusted to keep the effort required within certain limits (so-called "pacing", English for "adjusting speed").

• Activation: Here the emphasis is on taking medical and physiotherapeutic care to gradually and slowly increase physical stress. It is important to adjust the stress so that the symptoms do not worsen.

• Cognitive Behavioral Therapy (CBT: This therapy aims to help with the cope better with the psychological stress caused by the disease. In this way, strategies are to be learned that help in dealing with the symptoms and with consequences such as depressive thoughts and fears. This can also include better assessing the disease and learning to dose activities correctly.

Good studies have not shown a clear advantage for any of these three options. However, individual studies indicate that cognitive behavioral therapy and physical activation can help some people with mild to moderate ME/CFS to at least temporarily reduce certain symptoms. Treatments for people with severe ME/CFS are poorly understood.

There are also other supportive treatments, such as mindfulness training, physiotherapy or occupational therapy. However, there are hardly any studies on the effect of these treatments in ME/CFS.​

After:

Studies have examined various ways of adapting to the restrictions as best as possible. However, these studies leave many questions unanswered, making it difficult to assess the advantages and disadvantages of the various approaches. Especially in people with severe ME/CFS, they are poorly understood:

• The so-called energy management (pacing; English for "speed adapt") is intended to help dose stress in such a way that the symptoms do not worsen if possible. Activities are deliberately adjusted and distributed throughout the day so that the effort is kept within certain limits.

• Depending on your personal situation, it may be possible to gradually and to increase slowly. It is important to adjust the stress levels so that the symptoms do not worsen and trigger PEM. Activation should therefore take place under medical and physiotherapeutic care. However, there are many unanswered questions about the limits of activating programs such as Graded Exercise Therapy (GET).

• Cognitive behavioral therapy (CBT): This therapy should help to better deal with the mental stress caused by the disease. In this way, strategies are to be learned that help in dealing with the symptoms and with consequences such as depressive thoughts and fears. This can also include better assessing the disease and learning to dose activities correctly.

There are also other supportive treatments, such as mindfulness training, physiotherapy or occupational therapy. However, there are hardly any studies on the effect of these treatments in ME/CFS.​