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• The ME community support NICE and reject the misguided attack in ‘Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis
  Denise Spreag, Janet Sylvester and Malcolm Bailey
  Published on: 22 September 2023
• Shortcomings in the commentary by White et al.
  Dom Salisbury, Robert H Saunders and Jonathan CW Edwards
  Published on: 27 July 2023

• Published on: 22 September 2023

  The ME community support NICE and reject the misguided attack in ‘Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis

  • Denise Spreag, Retired, Trustee of MEAction UK
  • Other Contributors:
    • Janet Sylvester, Retired
    • Malcolm Bailey, Technical Director

  The authors revised this Rapid Response at BMJ's request in line with BMJ's Terms and Conditions for Rapid Responses.

  Dear Editor,
  In the article ‘Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis’ published in the Journal of Neurology, Neurosurgery & Psychiatry on 10th July 2023, the authors claim NICE invented a new definition of ME. These claims are unfounded as NICE used the Institute of Medicine (IOM) criteria which is now 8 years old and was created using a more robust process than many other definitions as it drew on samples from different countries and compared the most widely used definitions of ME.
  One area where NICE felt there was a gap in the IOM criteria was the lack of an empirical process alongside other methods. Leonard Jason's four-item empiric criteria were the only criteria that used adequate empiric methods, and this aligned very closely with the IOM criteria. As a result, NICE operationalised the IOM criteria for use in the NHS, with the four-item criteria helping to substantiate their approach.
  NICE does not measure a trial’s success based on the researchers’ own terms but by analysing the raw data and applying the committee's agreed protocol. This allows NICE to measure whether a treatment had an effect or not. This is striking when looking at the assertion that research showed that the favoured treatment...

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  The authors revised this Rapid Response at BMJ's request in line with BMJ's Terms and Conditions for Rapid Responses.

  Dear Editor,
  In the article ‘Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis’ published in the Journal of Neurology, Neurosurgery & Psychiatry on 10th July 2023, the authors claim NICE invented a new definition of ME. These claims are unfounded as NICE used the Institute of Medicine (IOM) criteria which is now 8 years old and was created using a more robust process than many other definitions as it drew on samples from different countries and compared the most widely used definitions of ME.
  One area where NICE felt there was a gap in the IOM criteria was the lack of an empirical process alongside other methods. Leonard Jason's four-item empiric criteria were the only criteria that used adequate empiric methods, and this aligned very closely with the IOM criteria. As a result, NICE operationalised the IOM criteria for use in the NHS, with the four-item criteria helping to substantiate their approach.
  NICE does not measure a trial’s success based on the researchers’ own terms but by analysing the raw data and applying the committee's agreed protocol. This allows NICE to measure whether a treatment had an effect or not. This is striking when looking at the assertion that research showed that the favoured treatments of CBT and GET were safe, when, in reality, safety data either was not collected or was incomplete or uninterpretable. These treatments have led to many complaints from people with ME that they were harmful and led to deterioration. This was illustrated in the MEAction UK 2019 report, ME services in the UK Not Fit For Purpose.
  The authors of this critique also claim that NICE didn't aggregate data properly, but there are hundreds of pages of meta-analysis proving they were meticulous and gave detailed consideration to every trial they looked at. The real complaint here seems to be that NICE didn't aggregate data in the way the authors of this paper wish they had. For example, the Cochrane review of exercise in ME, which many of these authors favour, pools results from multiple different interventions with very different protocols, and this has been argued to provide an evidence base for GET by extension. But that would be like pooling the evidence for CBT, DBT, ABA, psychoanalysis and counselling, and then claiming this proves ABA alone is effective. NICE sensibly grouped "like with like", so that trials with similar protocols were grouped together, improving the accuracy and specificity of their analysis.
  The criticism that NICE gave too much weight to survey evidence, and the lived experience of people with ME, was factored into the committee's decisions alongside other evidence. ‘NICE considers all types of evidence in its evaluations. This includes evidence from published and unpublished data, data from non-UK sources, databases of ongoing clinical trials, end-to-end studies, conference proceedings, and data from registries, real-world evidence and other observational sources.’
  The complaint that energy management isn't evidenced is bizarre. Energy management isn't offered as a therapy and it isn't curative. It is essentially the same as the activity management of the last guideline - which many of the same authors were happy to accept when they contributed to that guideline. Energy management is essentially a continuation of those same principles of care but it is not offered or presented as a treatment. The Forward ME group of charities has also endorsed this approach.
  With regard to GET and whether fixed increments in activity were required, NICE had to look at the evidence from the trials. Numerous trials refer to increments that are fixed and shouldn't be changed except with the approval of the clinician. The PACE manual for therapists explains that GET is based on the deconditioning model and discourages reductions in exercise when in a crash, ‘A central concept of GET is to MAINTAIN exercise as much as possible during a CFS/ME setback. This is to reduce the many negative consequences of rest, and to allow the body to habituate to the increase in activity. If activity and exercise is reduced at this time, the boom/bust cycle continues, and the body is not able to desensitise to the increase in activity: which is, of course, an essential component of a graded increase in exercise and activity.’ If the treatment was delivered in a different way in practice it would indicate that the GET as researched wasn’t effective in clinical settings.
  Similarly, it cannot be merely assumed that because one approach is helpful elsewhere, that it is helpful here. There is no treatment that is suitable for all diseases. Chronic primary pain isn't ME and asthma isn't diabetes and it should be self-evident that different illnesses need different treatments.
  We are also concerned that news coverage about this paper (and previous news coverage quoting the same authors) continues to paint people with ME as unreliable witnesses to their own illness and lives. This is a long-standing form of bias against disabled people.
  In conclusion, this article reads as an attack on the 2021 NICE guideline for ME/CFS by a group of researchers who have focussed on treating ME with Graded Exercise Therapy and CBT. By contrast, the patient community welcomes the NICE guideline and the robust review of the evidence that NICE carried out. The guideline is a real improvement on the previous version and the removal of Graded Exercise Therapy as a recommended treatment was greeted with relief. It is now time for researchers and medical staff to work with people living with ME to implement the NICE guideline throughout the NHS. Further delay and obstruction will cause more harm and increase the suffering of a very vulnerable group of people.

  Denise Spreag
  Janet Sylvester
  Malcolm Bailey

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  Conflict of Interest:
  All authors are trustees of #MEAction UK

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• Published on: 27 July 2023

  Shortcomings in the commentary by White et al.

  • Dom Salisbury, Independent Patient Researcher None
  • Other Contributors:
    • Robert H Saunders, None
    • Jonathan CW Edwards, Emeritus Professor of Medicine

  There are several shortcomings in the commentary by White et al. For brevity, this response focuses on four main points.

  1. New case definition
  In the past 20 years, multiple case definitions have been published that require post-exertional malaise (PEM) as a core feature of ME/CFS, such as the Canadian Consensus Criteria (CCC), International Consensus Criteria (ICC), and the Institute of Medicine (IOM) criteria. NICE’s definition is based on the latter.

  These case definitions are the ones used in research and clinical practice today. White et al. refer to the 1994 criteria developed by the Centers for Disease Control and Prevention (CDC) but the CDC no longer seems to use this case definition. Instead, they advise healthcare providers to diagnose ME/CFS using the IOM criteria where PEM is a required symptom.

  NICE evaluated scientific evidence for ME/CFS as it is currently defined and not for a case definition that was published nearly 30 years ago. Other reviews on ME/CFS, such as the recent one by IQWIG in Germany, have used a similar approach. (1)

  It is incorrect to state that NICE “downgraded nearly thirty years of research.” The previous NICE guidance from 2007 on ME/CFS already highlighted PEM as a core feature of ME/CFS, and studies that used this description were not downgraded in the evidence review. Neither were studies that used the CCC, ICC, or IOM criteria mentioned above.

  2. Blinding and subjective outcomes
  White...

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  There are several shortcomings in the commentary by White et al. For brevity, this response focuses on four main points.

  1. New case definition
  In the past 20 years, multiple case definitions have been published that require post-exertional malaise (PEM) as a core feature of ME/CFS, such as the Canadian Consensus Criteria (CCC), International Consensus Criteria (ICC), and the Institute of Medicine (IOM) criteria. NICE’s definition is based on the latter.

  These case definitions are the ones used in research and clinical practice today. White et al. refer to the 1994 criteria developed by the Centers for Disease Control and Prevention (CDC) but the CDC no longer seems to use this case definition. Instead, they advise healthcare providers to diagnose ME/CFS using the IOM criteria where PEM is a required symptom.

  NICE evaluated scientific evidence for ME/CFS as it is currently defined and not for a case definition that was published nearly 30 years ago. Other reviews on ME/CFS, such as the recent one by IQWIG in Germany, have used a similar approach. (1)

  It is incorrect to state that NICE “downgraded nearly thirty years of research.” The previous NICE guidance from 2007 on ME/CFS already highlighted PEM as a core feature of ME/CFS, and studies that used this description were not downgraded in the evidence review. Neither were studies that used the CCC, ICC, or IOM criteria mentioned above.

  2. Blinding and subjective outcomes
  White et al. write: “The NICE committee decided to downgrade all fatigue outcomes based on the premise that it is a subjective measure.” This is incorrect. Fatigue outcomes in studies with a low risk of bias such as the double-blind Rituximab trial were not downgraded.

  NICE did downgrade quality of evidence when subjective outcomes (not just fatigue, but also pain, sleep, quality of life, etc.) were used in trials where participants and therapists were not blinded as this combination creates a high risk of bias. This grading is in accordance with the Cochrane Handbook which states that “the potential for bias cannot be ignored even if the outcome assessor cannot be blinded." (2) In the case of patient-reported outcome measures such as fatigue, the Cochrane Handbook considers patients to be the outcome assessor.

  Moreover, trials of GET and CBT also included objective measurements such as fitness tests, actigraphy, and employment data and these indicated no clinically relevant improvements. (3)

  3. Long-term follow-up
  The largest studies on GET and CBT — the PACE (4) and GETSET (5) trials — failed to find significant benefits of these interventions at their longest follow-up. This suggests that initial improvements might be due to response bias or a placebo effect. It is questionable to recommend treatments if the long-term follow-up shows no benefit.

  In both GETSET and PACE, a sensitivity analysis indicated that additional treatment received after randomization was unlikely to explain the null results. The authors of GETSET reported that “there is no evidence that the improvements observed in the SMC group were due to them having received more exposure to therapy than the GES group after trial completion.” (5) 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.” (4)

  4. Harms
  The Cochrane review on GET included only randomized trials but concluded: “We are uncertain about the risk of serious adverse reactions because the certainty of the evidence is very low.” (6) There was too little data on adverse effects to form a conclusion.

  Surveys and qualitative studies, on the other hand, have consistently found a negative impact of GET on some ME/CFS patients. This has been reported for several decades, in multiple countries, and with little indication that harms are due to improper implementation of GET. (7) Considering the adage ‘primum non nocere’, it is sensible to use a lower threshold for evaluating evidence on the potential harms of a medical intervention compared with its potential benefits.

  At the NICE Roundtable Discussion prior to Guideline release (8), health profession stakeholders had ample opportunity to raise concerns. Following clear, succinct responses from a representative of the committee, consistent with our comments above, no further objections were raised.

  References
  1. Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG). Current scientific knowledge on myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). [N21-01]. 2023. Available from: https://www.iqwig.de/download/n21-01_me-cfs-aktueller-kenntnisstand_absc...

  2. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane Handbook for Systematic Reviews of Interventions. 2nd Edition. Chichester (UK): John Wiley & Sons; 2019.

  3. Vink M, Vink-Niese A. Graded exercise therapy for myalgic encephalomyelitis/chronic fatigue syndrome is not effective and unsafe. Re-analysis of a Cochrane review. Health Psychol Open. 2018 Dec;5(2):2055102918805187.

  4. Sharpe M, Goldsmith KA, Johnson AL, Chalder T, Walker J, White PD. Rehabilitative treatments for chronic fatigue syndrome: long-term follow-up from the PACE trial. Lancet Psychiatry. 2015 Dec 1;2(12):1067–74.

  5. Clark LV, McCrone P, Pesola F, Vergara-Williamson M, White PD. Guided graded exercise self-help for chronic fatigue syndrome: Long term follow up and cost-effectiveness following the GETSET trial. J Psychosom Res. 2021 Jul 1;146:110484.

  6. Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2019 02;10:CD003200.

  7. Geraghty K, Hann M, Kurtev S. Myalgic encephalomyelitis/chronic fatigue syndrome patients’ reports of symptom changes following cognitive behavioural therapy, graded exercise therapy and pacing treatments: Analysis of a primary survey compared with secondary surveys. J Health Psychol. 2019 Sep;24(10):1318–33.

  8. https://www.nice.org.uk/guidance/ng206/documents/minutes-31

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  Conflict of Interest:
  None declared.

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