The draft updated NICE guidance for ME/CFS highlights the unreliability of subjective outcome measures in non-blinded trials

Abstract

The National Institute for Health and Care Excellence (NICE) recently published its draft updated guideline on the diagnosis and management of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). NICE concluded that ME/CFS is a complex multisystem chronic medical condition for which graded exercise therapy should not be used and cognitive behavioural therapy is only a supportive therapy and not a treatment or cure. The draft guidance also highlighted the unreliability of subjective outcome measures in non-blinded trials. High quality randomised controlled ME/CFS trials are now needed to find pharmacological treatments that lead to substantial objective improvement and restore the ability to work.

Keywords

CFS cognitive behaviour therapy graded exercise therapy ME/CFS women’s health

The National Institute for Health and Care Excellence (NICE) published its draft updated guideline on the diagnosis and management of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in November 2020 (NICE, 2020). NICE concluded that ME/CFS is a complex multisystem chronic medical condition and that it is important that people remain in their energy envelope when undertaking activity of any kind.

Additionally, any program based on fixed incremental increases in physical activity or exercise, for example graded exercise therapy (GET), should not be offered for the treatment of ME/CFS. NICE emphasized that cognitive behavioural therapy (CBT) is not a treatment or cure but that it might be offered as a supportive therapy. These conclusions are in line with the conclusion from the prestigious American Institute of Medicine (IOM, now the National Academy of Medicine) (2015) and the Dutch Health Council (2018).

In a recent editorial in the British Medical Journal (BMJ), Turner-Stokes and Wade (2020), professors of (neurological) rehabilitation, expressed their surprise that according to NICE there is “a lack of evidence for the effectiveness of these interventions” [CBT and GET] despite “the overall positive results of randomized evidence published since 2007.” They also argued for doing studies into the efficacy of individualised multidisciplinary rehabilitation treatment (MRT) and using subjective outcomes in non-blinded studies because ME/CFS is a complex disease. At the same time, they also noted that “goals for intervention may be to manage and prevent deterioration as well as supporting adjustment.” This is in line with the conclusion by NICE that CBT for ME/CFS is only a supportive therapy.

Moreover, the Dutch FatiGo study already looked into the efficacy of MRT (Vos-Vromans et al., 2016). A reanalysis showed that MRT does not lead to objective improvement either (Vink and Vink-Niese, 2018).

Serious questions about research methodology in the PACE trial and other studies of CBT and graded exercise therapy for ME/CFS were raised by an editorial by Geraghty (2016) and by the Journal of Health Psychology’s special issue on the PACE trial (Marks, 2017). Professor Edwards (2017) concluded in one of the articles in that special issue, that the researchers of the PACE trial failed “to address the key design flaw of an unblinded study with subjective outcome measures, apparently demonstrating a lack of understanding of basic trial design requirements. The failure of the academic community to recognise the weakness of trials of this type suggests that a major overhaul of quality control is needed.”

Additionally, as concluded by the BRANDO project (Bias in Randomised and Observational studies), which amongst others included Stanford professor Ioannidis, “as far as possible, clinical and policy decisions should not be based on trials in which blinding is not feasible and outcome measures are subjectively assessed” because lack of blinding is “associated with an average 13% exaggeration of intervention effects [. . .] Therefore, trials in which blinding is not feasible should focus as far as possible on objectively measured outcomes” (Savovic et al., 2012).

As found by the reanalysis of the amended Cochrane exercise review (Vink and Vink-Niese, 2020), analysis of objective outcomes from three CBT and GET trials for ME/CFS confirmed the unreliability of subjective outcomes in non-blinded studies, as shown by the following examples:

In Jason et al. (2007) there was a substantial difference in subjective physical functioning scores at baseline between the exercise and control group, yet objectively there wasn’t (6-minute walk test or 6MWT);

In Moss-Morris et al. (2005), after GET, physical functioning subjectively improved by 30%, yet objectively deteriorated by 15% (CPET);

In the PACE trial by White et al. (2011), the released individual participant data showed that 20% of par-ticipants whose physical functioning improved subjectively had deteriorated objectively (6MWT) (FOIA request to QMUL, 2016; Vink and Vink-Niese, 2020)

Turner-Stokes and Wade (2020) also state that “many patients do recover from chronic fatigue symptoms.” Yet according to an influential systematic review by Cairns and Hotopf (2005), only 5% recover from ME/CFS. Moreover, according to the IoM (2015), between 35% and 69% of ME/CFS patients are too ill to work. Therefore for society, employers and most of all patients, it’s not very relevant if patients in clinical trials improve subjectively by a few points on a fatigue scale if it’s not accompanied by a substantial objective improvement and restoration of the ability to work. Analysis of clinical studies that used objective outcomes and/or reported on work status before and after treatment, showed that CBT and GET do not lead to (substantial) objective improvement or restore the ability to work (Vink and Vink-Niese, 2019a, 2019b, 2020). Additionally, three studies that reported on work outcome after treatment in the Netherlands (Koolhaas et al., 2008) and the official CFS centres in Belgium and the UK (Collin and Crawley, 2017; Stordeur et al., 2008), found that the percentage of patients who were on disability benefits increased from 54% to 57% in the Belgium CFS clinics. They also found that the percentage of patients who were able to work declined:

from 30% to 18% (UK)

from 41% to 31% (Netherlands)

from 18% to 14% (Belgium).

Turner-Stokes and Wade (2020), also expressed their surprise that “the new draft emphasizes the potential harms of exercise” because according to them this is only “based on qualitative evidence provided by a small number of service users.” However, Collin and Crawley (2017) who analysed the treatment outcomes in a large cohort of patients (n = 952), found that treatment in CFS clinic in the UK was detrimental in 10% to 20% of cases. Koolhaas et al. (2008) found that 38% of patients were harmed by CBT in the Netherlands. Moreover, research by the Oxford Brookes University (2019) in a substantial number of patients (n = 2274), carried out for the NICE review process, reported worsening of symptoms in 58.3% (CBT, which for ME/CFS contains an element of GET) and 81.1% (GET).

NICE (2020) recommends that post-exertional malaise, the characteristic feature of ME/CFS is renamed post-exertional symptom exacerbation (PESE). It’s then not surprising that patient’s health is negatively affected, in a disease characterised by PESE, by treatments, that is, CBT and GET, that instruct them to ignore and push through their symptoms and through symptom exacerbation. As noted by Saunders (2020), “anyone whose condition is not made worse by exertion, which the NICE ME/CFS draft Guideline refers to as exceeding one’s “energy envelope,” does not have ME/CFS by definition.”

Conclusion

The conclusions by NICE, that CBT is neither a treatment nor a cure for CFS, and graded exercise therapy is harmful and should not be used, signals a paradigmatic shift which was started by the Institute of Medicine in 2015. Such a shift might be difficult to accept for some, but the fact that neither treatment leads to (substantial) objective improvement nor restores the ability to work, means that it’s now time to find pharmacological treatments that do get patients back to work. Additionally, many young people are developing an ME/CFS like illness after a mild to moderate infection with Covid-19. At the moment we do not have any effective treatments we can offer them either. We should now use well-designed randomised controlled trials that use objective primary outcome measures as much as possible, to assess if a treatment is effective or not. This to prevent that history repeats itself and that patients are again treated with ineffective treatments which are sold as effective based on badly designed studies that used subjective outcome measures.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Mark Vink

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