Newsletter 118

By Professor Peter White, responding to “It is not only drugs and devices that can harm” (HealthWatch Newsletter issue 114, Summer 2021)

Until I retired, a physician colleague and I jointly ran a clinic for people suffering from chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME). We looked after many patients who benefitted from cognitive behaviour therapy (CBT) and graded exercise therapy (GET).

So, it was more than disappointing to us when the National Institute of Health and Clinical Excellence (NICE) recently recommended that GET should no longer be offered (having wrongly said that it involved fixed increases in exercise) and qualified the use of CBT (only to be used to relieve distress, not fatigue itself).(1) It also perturbed four Royal Colleges of Medicine who responded: “Graded Exercise Therapy as defined in the guidance is not reflective of the personalised paced exercise programmes that are currently used in the NHS and termed GET. These have provided benefit to many patients and should not be discontinued.” And “CBT remains a valuable treatment for alleviating symptoms in ME/CFS and services should ensure patients have access to this… .”(2) The new NICE guideline was also not approved by three CFS/ME clinicians who were members of the guideline committee; they resigned before publication.(3) A Lancet commentary was more critical: “In our view, this guideline denies patients treatments that could help them, undermines NICE as an international authority in guideline development, and jeopardises fundamental scientific principles by allowing some processes driven by ideology.”(4)

Some of the reasons why NICE recommended that GET should no longer be offered were outlined by Caroline Struthers in her article in HealthWatch Newsletter 114, summer 2021, entitled “It is not only drugs and devices that can harm” .(5) Few would disagree with her point that we have not paid sufficient attention to the safety of psychosocial and behavioural interventions.(6)

But rather than refer to the potential harms of psychotherapies when used by people with mental illnesses, Caroline Struthers wrote about the safety of these treatments in people who don’t have a mental illness – people with CFS/ME. As evidence, she criticised the largest trial of such treatments for CFS/ME – the PACE trial (which I helped to lead).(7) The trial found that CBT and GET were moderately effective and safe treatments, when added to specialist medical care, in comparison to two other treatments: specialist medical care by itself, and with additional adaptive pacing therapy (staying within the energy limits imposed by the illness).

A show trial?

Caroline Struthers asked whether PACE was a “show trial” – implying a verdict that was fixed before hearing the evidence. As evidence she noted that participants were told beforehand that CBT and GET were evidence-based, i.e., previous (smaller) trials had suggested that they worked. But research ethic committees rightly demand that researchers explain to patients the potential benefits and risks of any trial treatment. Having said that, we thought it important to see whether expectations influenced how well the treatments worked, and so built this into the trial design.(8)  

"fewer participants were confident that CBT would help them, yet it worked as well as GET and better than pacing"

We found that similar numbers of participants who were about to start either pacing therapy or GET were confident that it would help them, whereas the results showed that GET worked better than pacing therapy. In contrast, fewer participants were confident that CBT would help them, yet it worked as well as GET and better than pacing.(7) So, patients’ expectations did not seem to determine how well the treatments worked – the verdict was not fixed beforehand. Caroline Struthers mentioned funding by the Department for Welfare and Pensions (DWP), which contributed £90,000 out of a total budget of nearly £5 million for the PACE trial, the major funders being the Medical Research Council (MRC) and Department of Health. But the DWP were not involved in any aspect of planning, delivery, analysis, or interpretation of the trial. And we reported that the numbers of patients receiving welfare benefits increased during the trial, with similar proportions between treatments.(9)

“Subjective” outcomes

A second concern of Caroline Struthers was that the trial was biased by using patient reported outcome measures (PROMs) as the primary outcomes, which might be influenced by participants knowing which treatment they had received, instead of using more objective outcomes, such as getting back to work.

We decided the best way of testing effectiveness was to ask patients to rate their own symptoms and how well they were functioning, something supported by others.(4) Who better to know whether these treatments work than patients themselves? As to whether using PROMs biased the results, we found that patients’ expectations were unimportant (see above).(7) Additionally, a recent Cochrane systematic review suggested that using PROMs probably doesn’t cause much bias.(10) We did report several objective measures, such as employment and benefits;(9) these treatments made no significant difference to the numbers working six months later, but there may have been alternative explanations for this, such as not having a job to return to.(9) The one objective measure to improve more after GET than comparison treatments was the distance walked in six minutes.(7)

Assessing recovery

Caroline Struthers pointed out that we changed the PACE trial criteria for determining who had fully recovered during the trial (because we thought they better reflected recovery), but it was not the case that “a participant could get worse on that measure during the trial, and still be classed as recovered at the end”.(5) To be considered recovered participants had to meet not one but five separate measures of recovery, including rating their overall health as “much better” or “very much better”.(11) The recovery rates were not the main findings of the trial;  these were that the two primary outcomes of fatigue and physical function were both clearly better after both CBT and GET, when compared to either pacing therapy or medical care alone.(7)

Who should do research?

Caroline Struthers wrote that those who developed treatments should not undertake trials of them, suggesting that we would be conflicted and would want to show that they worked. But all three leaders of the PACE trial (and all six centre leaders) had personally led CFS/ME clinics and were motivated not by money or reputation, but by wanting to know which treatments work. Why would doctors want to give their own patients treatments that didn’t work? And the trial design allowed for treatments not to work; the analysis was done by a statistician who did not know which treatment was which (she was blind to treatment allocation). Social and other media are full of people promising cures for all manner of illnesses in return for money. In contrast, PACE trial treatment manuals are freely available for anyone to download (12).

Are these treatments harmful?

Some patient self-help group surveys have found that many patients complain that both CBT and GET are harmful, particularly GET.(13) But there are problems with this evidence; we do not know whether survey respondents had CFS/ME,(14) and we don’t know whether these patients received CBT and GET as they should be given.(15) Because of the concern about possible harm, we systematically measured six harmful outcomes in PACE and another more recent trial, such as reporting feeling worse, having side effects, or withdrawing from treatment.(7, 16, 17) We found that CBT and GET were just as safe as pacing or simply seeing a doctor.

"NICE was right to warn against undertaking exercise 'such as telling them [patients] to go to the gym or exercise more' (1); in other words, don’t do an exercise programme that is neither graded nor therapeutic"

Last year, following NICE’s expressed concern about the harm of GET, we undertook a meta-analysis (analysis of all trial data combined) of three safety outcomes from the published trials of GET – feeling worse, withdrawing from treatment, and dropping out of trial follow-up.(18) We found no statistically significant differences in the numbers reporting feeling worse or stopping treatment prematurely, although we did find more patients dropped out of trial follow-up after GET (11%) than the control treatment (7%). We don’t know why these patients dropped out, but this seemed to occur mainly in trials with high initial intensity of exercise.(18) It seems that GET is not harmful so long as it is delivered properly. NICE tried to move things forward by describing what they thought was a safer exercise programme,(1) but instead described something closer to pacing, which may not work.(7) But NICE was right to warn against undertaking exercise “such as telling them [patients] to go to the gym or exercise more”;(1) in other words, don’t do an exercise programme that is neither graded nor therapeutic.(12)

No long-term follow up?

Caroline Struthers complained about the lack of proper post-marketing surveillance for CBT and GET. But this is not the case. The PACE trial followed up patients until 2.5 years after they started their treatments and 18 months after the end of their participation in the trial – and found the effects of CBT and GET were maintained, with no evidence of harm related to receiving these treatments.(19) UK CFS/ME clinics have undertaken such surveillance several times, and these have suggested that these treatments do help some people, with no evidence of harm.(20-22) As is often the case, the limitation of these studies is that they were unable to follow up everybody, with outcome data available from between 51% and 78% in these studies; we have no certain way of knowing what happened to those who were missing.

PACE trial criticisms

The PACE trial has been criticised a lot over the years.(5, 23) These criticisms would be justified if the trial was either poor science or poorly conducted. Against these criticisms one might consider the following points: The trial was funded largely by the prestigious Medical Research Council, following peer reviews;  a national ME patient charity helped to design and manage the trial; two independent oversight committees approved and monitored the trial; the trial results published in mainstream peer-reviewed journals, such as The Lancet;(7) and not one of the trial’s twenty odd papers has been retracted following multiple complaints to journal editors. More detailed responses to these criticisms can be found on the trial website.(12) Regarding trial conduct, following a complaint to the Health Select committee, the independent Health Research Agency, which oversees all NHS research, concluded: “Our review suggests that the PACE trial exceeded expectations in its transparency when judged against contemporary expectations. … We have reviewed the concerns about conflicts of interest that were raised with me at the Committee and have found that the declarations were consistent with the contemporary standards. … We have therefore concluded that there are no regulatory concerns about the conduct of the investigators in relation to these issues.”(24) Although no research trial can be perfect in every way, journal editors, funders, and independent oversight authorities continue to support PACE.

What is going on?

So, why has the PACE trial been so frequently criticised? It could be because it was the largest trial ever undertaken of these treatments, clearly showed the superiority of CBT and GET, and so is the most definitive trial published. Some people think that accepting that CBT and GET work implies that CFS/ME is either psychological (so explaining why therapy works) or due to being inactive (so exercise should help). But this is a misunderstanding; CBT and GET are also effective in reducing fatigue and improving function in many medical conditions, such as cancer, multiple sclerosis, arthritis, and lung diseases, where no one would suggest that these conditions are psychological. And we know that GET doesn’t work by improving fitness. It seems to work by gradually removing the fear of engaging with usual everyday activities – gradually getting used to being active again.(25) And even if the PACE trial had never happened, the evidence from many other trials of these treatments still suggests that CBT and GET are the best available treatments.(26)

"Some people think that accepting that CBT and GET work implies that CFS/ME is either psychological or due to being inactive. But this is a misunderstanding; they also reduce fatigue and improve function in cancer, multiple sclerosis, arthritis, and lung diseases, where no one would suggest that these conditions are psychological"

In conclusion, Caroline Struthers is right to underline the importance of assessing the safety of psychotherapies and rehabilitation therapies in general. But my concern is that  treatments that are safe and help some people suffering from a life-changing chronic illness, for which there are no other effective treatments, should be available and recommended. In the end it is up to patients to decide whether they want to try a recommended treatment. But they won’t be able to try it if it can’t be offered.(4)

And what does this controversy tell us about the future, with many patients now suffering from chronic post-Covid fatigue and other symptoms? We need to properly diagnose these patients, researching into the different illnesses that make up “long Covid”, and then test treatments that might help in the different groups of patients. For those with unexplained chronic fatigue, these treatments trials should include rehabilitation therapies, such as CBT and GET; then we will know whether these can help or not. And like in the PACE trial, outcomes should include: (subjective) ones that matter to patients (such as fatigue), ones that help us understand how a treatment works, and ones that measure harm.

Peter White, Emeritus Professor of Psychological Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK

Disclosure

Professor White was one of the principal investigators of the PACE trial, is an independent member of the Independent Medical Experts Group, which advises the Ministry of Defence about its Armed Forces Compensation Scheme, and provides consultancy to the re-insurance company, Swiss Re.

References

  1. Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management. NICE 2021, NG206. https://www.nice.org.uk/guidance/ng206 (accessed 7 Feb 2022).
  2. Royal College of Physicians, 2021. Medical leaders sign joint statement in response to NICE guidance on ME/CFS. https://www.rcplondon.ac.uk/news/medical-leaders-sign-joint-statement-response-nice-guidance-mecfs (accessed 7 Feb 2022).
  3. Torjesen I. Exclusive: Four members of NICE’s guideline committee on ME/CFS stand down. BMJ 2021; 374: n1937. doi: https://doi.org/10.1136/bmj.n1937
  4. Flottorp SA, Brurberg KG, Fink P, Knoop H, Wyller VBB. New NICE guideline on chronic fatigue syndrome: more ideology than science? Lancet 2022; 399: 611-613, https://doi.org/10.1016/S0140-6736(22)00183-0
  5. Struthers C. It is not only drugs and devices that can harm. HealthWatch Newsletter 2021; 114. https://www.healthsense-uk.org/publications/newsletter/newsletter-114/221-114-cbt-get.html?s=09
  6. Nutt DJ, Sharpe M. Uncritical positive regard? Issues in the efficacy and safety of psychotherapy. Journal of Psychopharmacology. 2008 Jan;22(1):3-6. https://journals.sagepub.com/doi/pdf/10.1177/0269881107086283
  7. White PD, Goldsmith KA, Johnson AL, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011;377:823–36. https://doi.org/10.1016/S0140-6736(11)60096-2
  8. White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R ; PACE trial group (2007). Protocol for the PACE trial : a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BioMed Central Neurology 2007, 7, 6. https://doi.org/10.1186/1471-2377-7-6
  9. McCrone P, Sharpe M, Chalder T, et al. Adaptive Pacing, Cognitive Behaviour Therapy, Graded Exercise, and Specialist Medical Care for Chronic Fatigue Syndrome: A Cost-Effectiveness Analysis. PLoS ONE 2012 7(7): e40808. https://doi.org/10.1371/journal.pone.0040808
  10. Moustgaard H, Clayton GL, Jones HE, et al. Impact of blinding on estimated treatment effects in randomised clinical trials: meta-epidemiological study. BMJ. 2020;368:l6802. https://doi.org/10.1136/bmj.l6802
  11. White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological medicine. 2013 Oct;43(10):2227-35. https://dx.doi.org/10.1017%2FS0033291713000020
  12. PACE Trial website. https://www.qmul.ac.uk/wiph/centres/centre-for-psychiatry-and-mental-health/research/pace-trial/ (Accessed 11th Feb 2022)
  13. Kindlon T. Do graded activity therapies cause harm in chronic fatigue syndrome? Journal of Health Psychology 2017; 22: 1146–1154. DOI: 10.1177/1359105317697323
  14. Brimmer DJ, Maloney E, Devlin R, et al., A pilot registry of unexplained fatiguing illnesses and chronic fatigue syndrome, BMC Res. Notes 6 (2013) 309. https://doi.org/10.1186/1756-0500-6-309
  15. Gladwell PW, Pheby D, Rodriguez T, Poland F. Use of an online survey to explore positive and negative outcomes of rehabilitation for people with CFS/ME. Disabil Rehab. 2014;36:387-94. https://doi.org/10.3109/09638288.2013.797508
  16. Dougall D, Johnson A, Goldsmith K, Sharpe M, Angus B, Chalder T, White P. Adverse events and deterioration reported by participants in the PACE trial of therapies for chronic fatigue syndrome. J Psychosom Res. 2014;77:20-26. DOI: https://doi.org/10.1016/j.jpsychores.2014.04.002
  17. Clark LV, Pesola F, Thomas JM, Vergara-Williamson M, Beynon M, White PD. Graded exercise therapy guided self-help versus specialist medical care for chronic fatigue syndrome (GETSET): a randomised controlled trial. Lancet. 2017;390:363–73. https://doi.org/10.1016/S0140-6736(16)32589-2
  18. White PD, Etherington J. Adverse outcomes in trials of graded exercise therapy for adult patients with chronic fatigue syndrome. Journal of Psychosomatic Research 2021; 147: 110533. https://doi.org/10.1016/j.jpsychores.2021.110533
  19. Sharpe M, Goldsmith KA, Johnson AL, et al. Rehabilitative treatments for chronic fatigue syndrome: long-term follow-up from the PACE trial. Lancet Psychiatry 2015; 2: 1067–74. https://doi.org/10.1016/S2215-0366(15)00317-X
  20. Crawley E, Collin SM, White PD, et al. CFS/ME National Outcomes Database, Treatment outcome in adults with chronic fatigue syndrome: a prospective study in England based on the CFS/ME National Outcomes Database, QJM: An International Journal of Medicine, Volume 106, Issue 6, June 2013, Pages 555–565, https://doi.org/10.1093/qjmed/hct061
  21. Adamson, J, Ali, S, Santhouse, A, Wessely, S, Chalder, T. Cognitive behavioural therapy for chronic fatigue and chronic fatigue syndrome: outcomes from a specialist clinic in the UK. J R Soc Med 2020; 113: 394–402. https://doi.org/10.1177%2F0141076820951545
  22. Smakowski A, Adamson J, Turner T, Chalder T. (2021) Graded exercise therapy for patients with chronic fatigue syndrome in secondary care – a benchmarking study, Disability and Rehabilitation 2021 , https://doi.org/10.1080/09638288.2021.1949049
  23. Patients’ power and PACE. Lancet 2011; 377: 1808, May 28. https://www.thelancet.com/journals/lancet/issue/vol377no9780/PIIS0140-6736(11)X6022-1
  24. Montgomery J. The PACE trial and the Committee’s inquiry on Research Integrity. 2019. Available on: https://www.parliament.uk/documents/commons-committees/science-technology/Correspondence/190129-Sir-Jonathan-Montgomery-Health-Research-Authority-to-Chair-re-PACE-trial.pdf (last accessed Feb 7th, 2022)
  25. Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. The Lancet Psychiatry 2015; 2: 141-152 , http://dx.doi.org/10.1016/S2215-0366(14)00069-8
  26. Sharpe M, Chalder T, White P. Evidence-Based Care for People with Chronic Fatigue Syndrome and Myalgic Encephalomyelitis. J Gen Intern Med 2022; 37, 449–452. https://doi.org/10.1007/s11606-021-07188-4