Australian Researcher Challenges Measures of "Recovery" in PACE Trial

Alem Matthees is an Australian researcher who has investigated methods of assessing recovery in ME/CFS. (His article, "Assessment of recovery status in chronic fatigue syndrome using normative data," was published in Quality of Life Research in October 2014.) Nobody is more capable of challenging the methodology used to evaluate "recovery" in the PACE trial than he is.

(As an aside, Mr. Matthees has made repeated attempts to access the full data of the PACE trial under FOIA, but to no avail. Queen Mary refuses to release its data on the grounds that it is protecting intellectual property.)

In Mr. Matthees' response to Chalder's article in The Lancet Psychiatry, "Reducing fear avoidance beliefs key to improving symptoms and reducing disability in chronic fatigue syndrome," he once again challenges the results of the PACE trial, pointing out numerous problems with methodology, its shifting parameters for "recovery," the shortcomings of doing an unblinded test, and drawbacks in using self-reporting as an outcome measure.
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BMJ Letter, 21 January 2015
Alem Matthees, patient, Perth

Re: Tackling fears about exercise is important for ME treatment, analysis indicates

AllTrials supporters may be interested in the multiple major deviations/additions to the PACE Trial protocol, apparently occurring almost exclusively after the authors were already unblinded to the trial data and familiar with the distribution of various outcomes.

This latest paper on mediators by Chalder et al. appears to continue this tradition.[1]

The protocol was published in BioMed Central on the basis that "the authors/investigators are unlikely to be able to make revisions to their protocol". The editor(s) "strongly advise readers to contact the authors or compare with any published results article(s) to ensure that no deviations from the protocol occurred during the study."[2] BioMed Central "believes that publishing study protocols will help to improve the standard of medical research by: [...] enabling readers to compare what was originally intended with what was actually done, thus preventing both 'data dredging' and post-hoc revisions of study aims."[3] It is therefore concerning that the protocol underwent extensive, major, post-trial revisions, without adequate justification. All changes substantially decreased the stringency of the thresholds, made the tested therapies appear much more effective or less harmful than they otherwise would have, and lead to widespread media hype.

The primary endpoint was completely abandoned after the trial ended.

For fatigue this had been either 50% improvement or a Chalder Fatigue Questionnaire (CFQ) bimodal score of ≤3/11 points. For physical function this had been either 50% improvement or a Short-Form-36 physical function (SF-36/PF) score of ≥75/100 points. The "clinically useful difference" for individual participants (≥2/33 points CFQ Likert score and/or ≥8/100 points SF-36/PF) was introduced post-hoc and was significantly less stringent than the "positive outcome"(s) as previously defined.[4][5]

The recovery criteria (a secondary analysis) underwent extensive, major, post-hoc changes, which made it much less stringent to the point of being highly doubtful whether anyone genuinely recovered.[6] It became possible to be classified as completely "recovered" without clinically significant improvements to either fatigue or physical function. None of these changes, described below, were included in the statistical analysis plan that was finalized shortly before data unblinding.[7]

1) The previously required CFQ bimodal score of ≤3/11 points was changed to a CFQ Likert score of ≤18/33. The change of scoring method obscures direct comparison, but a Likert score of 18 can be a bimodal score of between 4 to 9, which the protocol regarded as abnormal or excessive fatigue. About 1% of participants simultaneously met both definitions of 'normal fatigue' (CFQ Likert ≤18/33) and 'severe fatigue' (CFQ bimodal ≥6/11) at baseline.[8] Questions have therefore arisen over the method and normative population sample used to calculate this threshold.[9-12]

2) The previously required SF-36/PF score of ≥85/100 points was lowered to ≥60; worse than trial eligibility criteria for 'significant disability' (≤65).[6] About 13% of participants simultaneously met both definitions of 'normal physical function' (a criterion for complete recovery) and 'significant disability' at baseline.[8] The post-hoc revised threshold was derived from an inappropriate statistical calculation using a non-representative population sample which included the elderly and disabled.[13] CFS occurs at all ages but in this trial of adults, 97% were aged under 60 years at baseline, and a diagnosis of CFS requires that other chronic disabling conditions which explain the fatigue etc are excluded. The stated justification for this drastic change, erroneously asserted that about half the general working age population score under 85, but it is actually 17.6%. Note that 92.3% of the 'healthy' working age English population score 85 to 100, and 61.4% score 100.[13]

3) The required CGI score of 1 ("very much better") was relaxed so that 2 ("much better") also counted towards recovery. The next option 3 ("a little better") was regarded as a non-improvement. A moderate improvement in CGI score is non-specific, could be a result of improvement to one complaint while multiple major symptoms remain, and on its own does not guarantee any clinically significant improvements to the primary efficacy measures of fatigue and physical function.[14-15]

4) No longer meeting Oxford CFS criteria did not guarantee real-world recovery, because participants who otherwise still met Oxford criteria as usually applied and still experienced either severe fatigue or significant disability, could be disqualified by failing ad hoc criteria for either, even if their CFQ and SF-36/PF scores remained abnormal or one remained unimproved.[16] (The optional requirements of not meeting CDC CFS criteria or London ME criteria were superfluous, not entry requirements, stricter than the Oxford CFS criteria, made no difference to the results, and were improperly applied.[6,17])

The technical details of the "planned" mediation analysis[1] are not adequately covered in the published protocol[4] or the statistical analysis plan.[7] It is unknown what methodological changes occurred during this exploratory analysis or whether it was influenced by 'data dredging' and 'post-hoc revisions'. Earlier results were described in 2011 as: "There was modest mediation of CBT and GET effects (approximately 20% of the total effect)."[18] Now much higher figures are being reported, even for individual mediators, including, "fear avoidance beliefs, the strongest mediator, accounted for up to 60% of the overall effect."[1] Interestingly, Chalder et al.[1] and the accompanying editorial by Knoop & Wiborg[19] conceded that the causal relationships between mediators and outcomes were unclear.

The 60% figure compared GET with a non-representative version of pacing (APT), but news articles have misrepresented this as strong evidence that patients recover by overcoming their fears and exercising. This is contradicted by "an almost complete absence of improvements in objectively measured outcomes", including the fitness step-test which indicates that participants failed to exercise more, despite GET aiming to substantially increase activity/function e.g. 30 minutes of exercise at 60-75% maximum heartrate at least 5 times per week.[20] The exception (GET walking distances) was not clinically significant and was not due to improved fitness.[19] These results dispute the deconditioning model and instead reflect an activity ceiling determined by post-exertional symptoms and abnormal (pathophysiological) responses to exercise.[21,22]

This non-blinded trial tested therapies aimed to change participants' beliefs about symptoms and impairments, so the discrepancy between subjective and objective outcomes raises plausible concerns about biases with self-reports.[23,24]

1. http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366%2814%2900...

2.http://www.biomedcentral.com/imedia/2095594212130588_comment.pdf

3. http://www.biomedcentral.com/authors/protocols

4. http://www.biomedcentral.com/1471-2377/7/6

5. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065633

6. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776285

7. http://www.trialsjournal.com/content/14/1/386

8. https://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind1303c&L=co-cure&F=&S=&P=...

9. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960...

10. http://evaluatingpace.phoenixrising.me/aps3chalder.html

11. http://www.meactionuk.org.uk/Normal-fatigue.htm

12.http://www.ncbi.nlm.nih.gov/pubmed/23363640#cm23363640_751

13. http://link.springer.com/article/10.1007%2Fs11136-014-0819-0

14. http://www.ncbi.nlm.nih.gov/pubmed/24791749

15. https://www.youtube.com/watch?v=d_7J5ELjArU

16. https://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind1303b&L=co-cure&F=&S=&P=...

17.http://www.ncbi.nlm.nih.gov/pubmed/21334061#cm21334061_11777

18. http://www.trialsjournal.com/content/12/S1/A144

19. http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366%2814%2900...

20. http://www.bmj.com/content/350/bmj.h227/rr-10

21. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02428.x/full

22. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004422

23. http://www.who.int/rhl/LANCET_696-700.pdf

24. https://bmg.cochrane.org/assessing-risk-bias-included-studies

Dissent from Within: A Psychologist Criticizes PACE for Doing Harm to Patients

Carolyn Wilshire has written an excellent response to the recent rehashing of the PACE trial posted in Lancet Psychiatry. Wilshire, who is a Senior Lecturer in the School of Psychology at Victoria University in New Zealand, knows what she is talking about when she says that the PACE trial did not conform to norms set for scientific trials. She points out that the PACE trial lacked adequate controls and used selective reporting. If the PACE trial had been held to usual scientific standards, she says, its results would have been "less impressive."

Even more to the point she observes that "in the case of ME/CFS, there is evidence that GET may in fact result in adverse effects for some patients [and] drawing unwarranted conclusions from behavioural intervention studies can do great harm in less direct ways. 

For example, in the case of MECFS, if policy makers and practitioners believe that there is already a valid “treatment” out there for this condition, they may be less motivated to examine other, more valid treatment options. 

Even more seriously, we have seen in the British media this week that the results of such studies may be used support a view of MECFS that minimises is severity, exaggerates its responsiveness to treatment, and places responsibly for the illness back on the patient."

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From: Carolyn E Wilshire
Senior Lecturer
School of Psychology, Victoria University of Wellington, New Zealand PO Box 600 Wellington, New Zealand

Re: Tackling fears about exercise is important for ME treatment, analysis indicates

In drug intervention studies, there is an agreed set of quality standards. These include the use of an appropriate placebo control, random allocation to treatment, and blinding of both patients and researchers. Also increasingly important is preregistration of outcome measures, so that authors do not selectively report only the most favourable outcome measures.

Studies of behavioural interventions, including the current PACE study and its predecessor, 1,2 have not consistently been evaluated by these standards, which has sometimes led to exaggerated claims as to their effectiveness. Here, I comment on this issue from the perspective of an experimental psychologist (I leave it to others to consider theoretical issues, such as validity of the authors’ underlying illness model).

The original PACE study reported that one year after a 24-week graded exercise therapy programme (GET), 61% patients improved on a combined self-rated measure of fatigue and physical function. 2 CBT yielded a similar improvement rate of 59%. On the face of it, that looks impressive. However, the control condition - specialist medical care - also yielded an impressive 45% improvement. This in itself casts doubt on the validity of the self-report measures used to assess improvement. But more importantly, this high level of baseline improvement means that conclusions rest on the differences in improvement rates between the various conditions, some 14-16% of participants. The design of the no-treatment control therefore becomes crucial.

Drug intervention studies include a placebo condition, which controls for spurious factors known to affect outcomes, such as the expectation for improvement, and the patient’s degree of investment. The baseline condition used in the PACE study (specialist medical care) is not adequate to control for either factor: patients in this condition would be unlikely to have the same expectations of improvement as those in the intervention groups (nor, arguably would those in the pacing intervention), nor would they be likely to invest as much effort into the “treatment”, or to develop the same kind of rapport with the therapist.

Recent evidence suggests that self-report measures are much more vulnerable to the placebo effect than more objective measures. 3,4 Given that treatment was unblinded, and not all factors influencing placebo responding were adequately controlled for, objective outcomes – from blinded raters – are essential in order to overcome these criticisms. However, the study reports only one such outcome: the average distance walked in six minutes increased after all treatments but reliably more so after GET. A number of other objective measures planned in the original protocol were simply never reported. 5 All other positive outcomes are from self report.

This leads us to a third major problem, the highly selective reporting of outcome measures. Selective reporting is a major criticism that has been raised against current psychological research standards. 6 The problem is quite simple: our criterion for statistical significance (less than 5% probability of obtaining a significant effect by chance alone) means that up to 1 in every 20 statistical results could very well be artefactual. The more outcomes one samples, the higher the chances of at least one effect being significant by chance alone. By measuring multiple outcomes, and selectively reporting only favourable ones, the researcher is concealing from the reader this heightened probability of a spurious result.

The most recent output from this group, the mediation study by Chalder and colleagues is therefore difficult to interpret, since it claims as its starting premise that the one-year outcomes of the original study demonstrate substantive evidence of genuine treatment effects. 1 Given the problems noted above, I would argue that this requirement has not been met.

The new paper’s most valuable contribution is that it reports one new objective measure: the fitness test (heart rate after a step exercise test). However, GET patients – the group predicted to show the greatest improvement – did not differ from the non-treatment control on this measure. This result, and its lack of prominence in the original paper, leads to further concerns about the selective reporting in the study and the heavy reliance on self-report.

One might object to these criticisms, arguing that in behavioral interventions adequate control conditions are difficult to design, and objective measures difficult to obtain. Both objections can be easily countered. Recently, Lynch, Laws and McKenna reviewed a selection of studies of CBT interventions for major depressive disorder and other severe psychiatric conditions. 7 They identified studies that: a) used control conditions meeting the requirements set out above (e.g., supportive therapy, psycho-education); and b) reported objective outcome measures, from blinded observers. Alarmingly, in a metanalysis of these studies, the treatment effect for CBT was much weaker and/or absent. When standards are raised to the same level as those required in drug interventions, outcomes look much less impressive.

Some might argue that the risk of harm is lower for behavioural than for drug interventions, so there is no need to adhere to the same rigorous standards. However, this assumption needs to be challenged:

in the case of ME/CFS, there is evidence that GET may in fact result in adverse effects for some patients. 8 Also, drawing unwarranted conclusions from behavioural intervention studies can do great harm in less direct ways. For example, in the case of MECFS, if policy makers and practitioners believe that there is already a valid “treatment” out there for this condition, they may be less motivated to examine other, more valid treatment options. Even more seriously, we have seen in the British media this week that the results of such studies may be used support a view of MECFS that minimises is severity, exaggerates its responsiveness to treatment, and places responsibly for the illness back on the patient.[Italics added]

In the Psychology literature, there has recently been much discussion of some of the more general weaknesses in psychological methodology. 6 If medical and psychiatric journals wish to continue publishing behavioural studies, they need to make themselves more aware of this literature. Behavioural research should not have a “get out of jail free” card when it comes to scientific rigour.

1. Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry 14 Jan 2015, doi:10.1016/S2215-0366(14)00069-8.

2. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, et al, for the PACE trial management group. 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.

3. Spiegel D. Kraemer H and Carlson RW. Is the placebo powerless? N Engl J Med 2001; 345: 1276-79.

4. Hróbjartsson A and Gøtzsche PC. Placebo interventions for all clinical conditions. Cochrane Database Syst Rev 2010; 1.

5. White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group. 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. BMC Neurol 2007; 7:6.

6. Simmons JP, Nelson LD and Simonsohn U. False-positive Psychology: Undisclosed flexibility in data collection and analysis allows presenting anything as significant. Psychological Science 2011; 22: 1359-1366.

7. Lynch D, Laws KR and McKenna PJ. Cognitive behavioural therapy for major psychiatric disorder: does it really work? A meta-analytical review of well-controlled trials. Psychological Medicine 2010; 40: 9-24.

8. Twisk FN and Maes M. A review on cognitive behavioral therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS. Neuro Endocrinol. Lett. 2009; 30: 284–99.

Competing interests: No competing interests

Invest in ME Delivers Scathing Response to P2P Report, Suggests Hidden Agenda

Invest in ME, a UK charity whose primary focus is on biomedical research into the causes, mechanisms, treatments for ME has made its response to the P2P Draft Report - and it is a delight to read.

The charity rightly pointed out that it was completely contradictory to declare ME/CFS as not psychogenic in one section of the Report while recommending further investigation of psychological therapies as treatments in another. Invest in ME suggested that by doing so the P2P panel had a "hidden agenda."

I would say that the agenda was not particularly well hidden. All of the speakers addressing the Session 2 Key Question ("Given the unique challenges to ME/CFS, how can we foster innovative research to enhance the development of treatments for patients?") were either psychologists or psychiatrists. 

Apart from the obvious bias in choosing speakers for this important session, the very fact that the PACE trial - with its flawed methodology and questionable outcome - was included at all in a review that was supposed to be "scientifically rigorous" is a clear indication that the P2P had something in mind from the very start.

_________________________

Invest in ME

PO Box 561, Eastleigh SO5O OGQ, Hampshire, UK

Telephone: 02380 251719 – 07759 349743

Web: www.investinme.org 

Email: info@investinme.org

Charity Nr 1114035

INVEST IN ME RESPONSE TO NATIONAL INSTITUTES OF HEALTH PATHWAYS TO PREVENTION WORKSHOP: ADVANCING THE RESEARCH ON MYALGIC ENCEPHALOMYELITIS/ CHRONIC FATIGUE SYNDROME DRAFT EXECUTIVE SUMMARY

Invest in ME would like to thank the NIH for the opportunity to submit comments on this draft report [1]. Invest in ME (IiME) is a UK charity (charity number 1114035) established in 2006 to educate the public and media about Myalgic Encephalomyelitis (ME) and raise funds for fundamental biomedical research into ME. We have links internationally and are current chair of the European ME Alliance, an umbrella organisation of 13 national European patient groups working together to improve awareness of ME. IiME have so far organised nine annual international ME/CFS conferences and four research colloquiums in London, UK, to allow researchers, clinicians, patient groups and patients to learn about the latest research, form collaborations and share experiences to advance research into this condition.

The charity strongly believes in international biomedical research collaboration and have initiated possibly the two most important research projects for ME in the UK – a gut micriobiota study [2] and a project leading to a UK clinical trial using rituximab to treat ME patients [3].


In the UK patients prefer to use the term ME to differentiate from the term CFS which is favoured by those using the Oxford criteria or who wish to use as broad a possible an umbrella to describe their particular interests. In this document we’ll use ME/CFS from here on to match your terminology and also that used in the Canadian Consensus Criteria for which IiME is UK distributor of the printed version).

Below are comments that we have concerning the draft document. We conclude this document with a summary and our recommendations.


Lines 2-4:

“Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, complex, multi-faceted condition characterized by extreme fatigue and other symptoms that are not improved by rest. 

IiME comment: 

It may be better to replace line 3 with – “…faceted condition characterized by multiple symptoms that are not improved by” We are unsure why “extreme fatigue” is highlighted here and all other symptoms are bundled together as “other symptoms” especially when later in the document fatigue is recognised as not necessarily being the main symptom.

Lines 7-11:

“ME/CFS results in major disability for a large proportion of the people affected. Limited knowledge and research funding creates an additional burden for patients and health care providers. Unfortunately, ME/CFS is an area where the research and medical community has frustrated its constituents, by failing to assess and treat the disease and by allowing patients to be stigmatized."

IiME comment: 

We strongly agree that ME/CFS leads to major disability and patients feel frustrated at no medical discipline taking responsibility for this condition despite it being classified as a neurological illness since 1969. However, the NIH have to take a portion of the responsibility for this state of affairs as “limited knowledge and research funding” directly causes the ignorance amongst the healthcare profession and leads to failure “…to assess and treat the disease and by allowing patients to be stigmatized”. NIH funds research and therefore carries some of this responsibility for the state of affairs.

Lines 38-43:

“The Oxford criteria (published in the Journal of the Royal Society of Medicine in February 1991) are flawed and include people with other conditions, confounding the ability to interpret the science. The lack of a consistent, specific, sensitive diagnostic test and set of criteria has hampered all downstream research on pathogenesis and treatment, causing harm and preventing ME/CFS from being considered as a distinct pathologic entity.“

IiME comment: 

We agree with the statement that the Oxford criteria “hampered all downstream research on pathogenesis and treatment, causing harm and preventing ME/CFS from being considered as a distinct pathologic entity”. We have stated for many years that the Oxford criteria are flawed for ME research and research related to ME which has used these criteria need to be ignored as evidence for this document.

Lines 51-53:

“Small sample sizes, the inclusion of participants with differing symptoms across studies, and the lack of inclusion of the homebound, rural residents, and a research focus on men limits the applicability of current studies.” 

IiME comment: 

Really those funding bodies including the NIH, the UKMRC, Departments of Health etc. must take responsibility for this state of affairs.

Lines 55-57:

“All this leads to inconclusive results and a lack of knowledge of ME/CFS prevalence (i.e., how many people have ME/CFS), incidence (new cases per year), and potential causes and treatments.” 

IiME comment: 

A study by Nacul at al. shows the variation in prevalence rates of 0.03 to 0.19% in three regions in England (UK) depending on criteria used. The overall estimated minimal yearly incidence rate was 0.015%. This study was not part of the review as it did not seem to fit your criteria [4].

Lines 58-59:

“Fatigue has been the defining focus of recent research, but many other symptoms need to be explored, primarily neurocognitive deficit (“brain fog”), post-exertion malaise, and pain.” 

IiME comment: 

We agree - which makes it stranger that the report specifically only highlighted fatigue in line 3. Not all ME/CFS patients find fatigue as their main or most debilitating symptom and too much research has been performed concentrating on this one symptom alone.
Fatigue is a symptom of numerous conditions and it is not specific for ME/CFS. Post Exertional Malaise is a hallmark symptom of ME/CFS and it has been shown in two day VO2Max exercise testing and is accepted as objective proof of physical disability. Larger studies are needed to find out whether this could be used as a biomarker and to find out whether there are clear subgroups for reasons for the drop in performance as indicated by the Keller et al. study [5, 6, 7].

Lines 65-73:

“Often, patients with ME/CFS are labeled as lazy, deconditioned, and disability-seeking; this hampers scientific progress. Both society and the medical profession often treat patients with ME/CFS with disdain, suspicion, and disrespect. Patients are frequently treated with psychiatric and other inappropriate drugs that may cause harm. Patients usually have to make extraordinary efforts, at extreme personal costs, to find a physician who will correctly diagnose and treat ME/CFS symptoms. In addition to high medication costs, the debilitating effects of ME/CFS can result in financial instability due to the physical consequences of the illness (e.g., the loss of employment, home, and other basic necessities). All of these factors contribute to the poor quality of epidemiologic studies.” 

IiME comment: 

All of these factors can be attributed to the lack of any serious strategy to resolve the illness – which then allows flawed research to be funded and which also leads to misinformation and poor education about this illness being perpetuated. Listen to the patients – an old adage but one which has until now not echoed in those rooms where decisions are made about research into ME/CFS.

Lines 92-95:

“Although psychological repercussions (e.g., depression) often follow ME/CFS, this is not a psychological disease in etiology. A multitude of symptoms are associated with ME/CFS, with substantial overlap with other pathologic diseases (e.g., fibromyalgia, major depressive disorder, and a variety of chronic pain or inflammatory conditions).”

IiME comment: 

Good to read it clearly stated that this is not a psychological disease. 

The World Health Organisation (WHO in Europe) has classified ME as a neurological illness since 1969. It is the proponents of the biopsychosocial paradigm that try to promote the notion that ME/CFS can be classified in two separate codes either as neurological or mental illness depending on the diagnostician’s opinion which is grossly misleading and contributes to the problems patients face at all levels of society [8]. However, care should also be taken not to add on co-morbid diagnoses such as fibromyalgia or mood disorders just because ME/CFS patients report pain or feel a bit down as these can form just part of the normal ME/CFS symptomatology.

Lines 95-97:

“Focusing on fatigue alone may identify many ME/CFS cases. However, this symptom taken in isolation fails to capture the essence of this complex condition.” 

IiME comment: 

Exactly. We entirely agree.

Lines 113-117:

“Existing treatment studies (cognitive behavioral therapy [CBT] and graded exercise therapy [GET]) demonstrate measurable improvement, but this has not translated to improvements in quality of life (QOL). Thus, they are not a primary treatment strategy and should be used as a component of multimodal therapy. Overall, agreeing on a case definition and clarifying comorbidities could launch bench-to-bedside science.” 

IiME comment: 

It is at this point that we begin to wonder about the real agenda. 

We strongly disagree with the statement that CBT and/or GET demonstrate measurable improvement that makes a real difference in patients’ lives. In fact a large study in Belgium that collected data of 1655 patients attending four reference centres between 2002 and 2004 demonstrated that participants’ physical capacity did not change, their employment status decreased and the percentage of patients living off sickness allowance increased at the end of such therapies [9]. 

Also a 2007 study by Knoop et al showed that “CBT leads to a reduction in self-reported cognitive impairment, but not to improved neuropsychological test performance. The findings of this study support the idea that the distorted perception of cognitive processes is more central to CFS than actual cognitive performance.”[10]. We are very concerned about the term multimodal therapy. What does it mean and is there any evidence for such a therapy being useful for ME/CFS? 

CBT and GET should not form any more part of a treatment strategy for ME/CFS than it is for other neurological illnesses such as MS or Parkinson’s disease for example. The lamentable (some would say farcical) PACE trial in the UK that used the Oxford criteria has conclusively demonstrated the total waste of money behind these ineffectual therapies. The emphasis should be on researching and treating the core illness and not just concentrating on comorbidities which could often be avoided if the condition was treated by knowledgeable physicians to begin with. 

We emphasise this point!

Lines 130-134:

“In general, little attention was given to how self-management may empower and improve health and QOL for patients with ME/CFS. Physicians are inadequately trained to instruct patients in self-management skills (e.g., pacing, realistic goals, physical self-awareness, basic rights, understanding emotions, exercise, relaxation), and there is a lack of data demonstrating the efficacy of self-management on health outcomes.” 

IiME comment: 

We totally disagree. 

ME/CFS patients have been self-managing for decades, by necessity, and are better at doing so than many other patient groups. Even very severely ill bed bound patients may often be looked after by family members in their own homes with little supervision from health care professionals or social services. It is not self-management skills that patients are looking for when they visit their doctors. They need honest information, advice, support and follow ups to ensure there are no missed diagnoses – and hope that the miserable record of proper research may be overturned in order to provide a future.
Support for practical matters such as education, employment, social care and help with benefits would be useful in the early stages of the illness to avoid mildly affected patients ending up becoming severely affected due to overexertion resulting from ignorance about ME/CFS or negligent advice. 

If the illness was taken seriously and patients treated with respect at first point of contact then there would be less need for treating some of the subsequent comorbidities. There needs to be a clear message to the research community that the NIH considers ME/CFS a physical disease and the peer reviewers and funding committees that decide upon grant applications should hold the same view.

Lines 134-138:

“The focus on exercise programs has further stigmatized and discouraged research participation. In many cases, lack of instructions or guidance for including graded exercise therapy often causes additional suffering, creating fear of harm from a comprehensive self-management program that may include some physical activity (e.g., mild stretching).” 

IiME comment:

Patients do not have fear of harm and they have nothing against common sense advice but they do object to proscriptive CBT and GET programmes that are patronising and based on flawed research. 

The group should also be aware of harms caused by CBT and GET. This aspect has been explored in a paper titled “Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome” by T. Kindlon and he states - “Across different medical fields, authors have placed a greater emphasis on the reporting of efficacy measures than harms in randomised controlled trials (RCTs), particularly of nonpharmacologic interventions.”[11]. 

Each chronically ill patient be it ME/CFS, cancer or any other illness learns to cope in their own way and the most important thing for them is to receive support and honest and factual information to be able to adjust to their lives accordingly in the absence of effective treatments or a cure. ME/CFS patients tend to prefer research into the core aspects of the illness so that the information given to them by doctors would be based on facts rather than opinion, assumptions or vested interests. There is no problem in recruiting patients for such research. As a charity that funds biomedical research into
ME Invest in ME can categorically state that recruitment for research and trials is no issue.

Lines 169-177:

“Research priorities should be shifted to include basic science and mechanistic work that will contribute to the development of tools and measures such as biomarker or therapeutics discovery. The following questions need to be answered:
• What is the pathogenesis of ME/CFS? What is the role of virologic mechanisms, especially herpes viruses? Does mononucleosis lead to ME/CFS in adolescents?
• What is the role of other pathogenic agents?
• Is this a genetic disease? Is there a gene-environment interaction?
• Is ME/CFS a spectrum disease?
• Are different pathways responsible for different symptoms?”

IiME comment: 

The research priorities should not just shift to include basic science and mechanistic work but this should be one of the main areas of research. Once there is a biomarker that is reproducible then the field could move forward quickly. The message of ME/CFS being a physical disease and not a psychological one should be kept in mind when committees and peer reviewers are chosen to decide upon grant applications.

Lines 178-185: Future Directions and Recommendations

“ME/CFS is a chronic, complex condition of unknown cause and with no cure. We have learned some about the mechanisms of the disease, but nothing has improved the lives of the patients. Overall, there has been a failure to implement what we already know for patients with ME/CFS while it steals their health and wellbeing.” 

IiME comment: 

The biggest failure in the whole history of ME/CFS has been the lack of anyone in authority taking responsibility for this area of medicine and patients have been left to manage as best as they can. In the UK the Medical Research Council (MRC) and those in the MRC controlling policy toward ME have been seriously negligent. The NIH must take its share of the blame also. 

Researchers need to know that there is funding for them to be able to commit their careers to researching this group of patients.

Lines 183-184:

“The subjective nature of ME/CFS, associated stigma, and the lack of a standard case definition has stifled progress.” 

IiME comment: 

We suggest this could be changed to – “The subjective nature of ME/CFS, associated prejudice and ignorance about the disease, and the lack of a standard case definition has stifled progress.”

Lines 192-194:

“Potential conflicts of interest among investigators need to be properly vetted, discussed, and addressed by all stakeholders.” 

IiME comment: 

This is of paramount importance. In the UK the example of the appalling complicity of the MRC in allowing vested interests to be involved in ME research must be a thing of the past.

Lines 202 -208:

“1. Define disease parameters. Assemble a team of stakeholders (e.g., patients, clinicians, researchers, federal agencies) to reach consensus on the definition and parameters of ME/CFS. A national and international research network should be developed to clarify the case definition and to advance the field. There are tremendous opportunities on which we have not yet capitalized to learn across disciplines and from other diseases such as Gulf War Syndrome, Lyme disease, fibromyalgia, multiple sclerosis, and Parkinson’s disease, to determine commonalities and differences.” 

IiME comment: 

There have been years of meetings and working groups (CFS Advisory committee has submitted recommendations several times) and so-called expert panels and this report should not lead to yet another committee with no real action, and no power. 

ME/CFS patients need research into their disease and researchers need substantially more funding to be able to do meaningful research in a progressive manner. 

Invest in ME have been facilitating international networking for nine years and it is starting to pay off but funding is needed to keep the networking going. 

In 2012 we held the first ME/CFS Clinical Autoimmune Working Group meeting in London, UK, in collaboration with The Alison Hunter Memorial Foundation (AHMF) of Australia and that colloquium included researchers from other disciplines such as MS, Rheumatology and oncology [12]. This was a real example of international collaboration and networking – organised by patients and carers. The consensus from that meeting was that the rituximab trial by Fluge et al. in Norway provided the best leads for future research [13]. 

In 2013 our 3rd colloquium resulted in Invest in ME setting up a project to conduct a UK rituximab clinical trial to allow collaboration and sharing of experiences with the Norwegian researchers, and others. 

In 2014 our 4th Biomedical Research into ME Colloquium had almost 50 biomedical researchers from nine countries involved and many new initiatives were created. Invest in ME are now organising our fifth colloquium – a two day affair. 

These are biomedical research meetings – aligned with our biomedical research conferences. We have a basis for international research and networking – it doesn’t need to be reinvented and it doesn’t need to be described as though it is a new idea.
So action is needed not merely words. (See our Conclusion later in the document.)

Lines 271-276:

“Patients often choose clinical trials or complementary and alternative medicine because effective treatment is not available and because traditional health care is not meeting their needs. Studies investigating homeopathy, non-pharmacologic, complementary, and alternative medicine treatments are needed. Studies addressing biopsychosocial parameters (including the mind-body connection), function, and QOL should be encouraged.” 

IiME comment: 

It is quite odd to see recommendations like this within the context of your previous comments of ME/CFS not being of psychological aetiology, lacking in basic research or patients experiencing stigma from the diagnosis, including social isolation and judgement (Lines 121-122). 

Encouraging studies into homeopathy, alternative treatments or mind-body connections at the same time as declaring lack of basic research would only add to this stigma – or prejudice. There is no more need for such studies in ME/CFS than there is for cancer, MS or Parkinson’s disease for example. Scarce research funding for ME/CFS should not be used for yet more trivialities. 

The Fluge et al. rituximab research did not fit your criteria of at least 12 week duration but it has captured the interest of renowned researchers outside the field such as Invest in ME’s advisor, Professor Jonathan Edwards, who was instrumental in getting rituximab accepted as treatment for rheumatoid arthritis. If that research can identify differences between responders and non- responders then that in itself would help move the field forward considerably. ME/CFS patients are keen on taking part in clinical trials such as rituximab or Ampligen as that is their only chance of getting ‘real’ treatment, of being taken seriously, of being treated with respect. 

What is meant here by the term biopsychosocial? If it is the same paradigm that has been promoted in the UK and rest of Europe since 2005 then we can inform you that it has not worked and patients deserve better than this [14]. 

We have written before that “….we feel it is impossible to marry the views of those who believe in the deconditioning/behavioural and wrong illness belief model of ME with those from the biomedical side. The failed PACE Trial has demonstrably proven that the behavioural view of ME cannot deliver and should not continue to command more funding.” [15] 

To include ME/CFS in a broad collaborative umbrella of other fatigue will do nothing, and produce nothing but delay in treating ME/CFS seriously. A mirage of progress which will waste another few years, forcing patients down a path of complicity by trust – a tried and trusted technique used in the UK to appear to do something but in essence achieve nothing. 

Incorporating the biopsychosocial model into any future strategy of ME/CFS research is asking patients to participate in one of the worst possible examples of Stockholm syndrome one can imagine. As can be seen we feel very strongly about this topic. 

We wonder why another agenda seems to be creeping into this document - when the fine and correct words earlier in the document seemed to be moving things in the right direction.

Lines 288-291:

“Although ME/CFS is not a psychiatric disease, exploring psychiatric comorbidities such as depression, anxiety, and fear is critical to improve quality of life. Response burden must be considered; a battery of simplified measures is strongly encouraged, as well as the triangulation of qualitative and quantitative data.” 

IiME comment: 

From our experience doctors that have no expertise in ME/CFS may confuse mood disorders, burn out, overtraining syndrome or excessive tiredness caused by another illness with ME/CFS so it is extremely important to train doctors to be able to diagnose ME/CFS and know the difference between ME/CFS and depression, for example, as well as being aware of the rate of misdiagnosis. Newton et al. research from 2010 showed that 40% of the patients referred to a specialist CFS clinic in the UK turned out to have an alternative diagnosis after careful examination. “Of the 40% of patients subsequently found not to have CFS the most common diagnosis was fatigue associated with a chronic disease (47% of all alternative diagnoses); 20% had primary sleep disorders, 15% psychological/psychiatric illnesses and 4% a cardiovascular disorder. Thirteen per cent remained unexplained (5.2% of the total referrals).” [16]. 

Co morbidities could be lessened by making sure patients are being treated with respect from the first point of contact and onward – basic medical ethics.

Lines 348-351:

“The modest benefit from CBT should be studied as adjunct to other modalities of treatment such as self management. Future treatment studies should evaluate multimodal therapies. Comparative effectiveness research is also needed.” 

IiME comment: 

Again it is strange to see a recommendation for CBT or therapies that are mainly aimed at behavioural or psychiatric illnesses when you have made it clear that ME/CFS is neither psychiatric nor psychological in aetiology. 

Most patients feel that CBT and self-management have been given more than enough attention already and it is time to explore other treatments along the lines of rituximab, gamma globulin, Ampligen, LDN etc. Self-management can be easily explained in a leaflet and patients support one another on online forums or support groups so resources should be directed toward well designed clinical trials that are based on well thought out hypotheses. 

What ME/CFS is lacking is input from various medical experts such as neurologists, immunologists, infectious disease specialists and endocrinologists and pain specialists that can explain the biology of the illness. 

You mentioned (lines 38-39, 365-366) that the Oxford criteria are flawed and should be retired. Should you then not remove any research that used those criteria from this review? 

What is meant by multimodal therapies? Is there any evidence that such therapies work for ME/CFS? It is of little wonder that patients suspect there is still a hidden agenda still being set out. 

The lines above are inconsistent.

Line 351-352:

“We recommend that the NIH and the FDA convene a meeting on the state of ME/CFS treatment.” 

IiME comment: 

Haven’t there been such meetings already? How many more do you need? 

There is a list of meetings on the FDA website, the latest one having been held in March 2014 [17]. The document from March 2014 states that regarding the number of drug trials needed to prove efficacy of symptom relief is two independent trials. Why is it then that this draft document is recommending even more CBT/GET/self- management trials when these therapies have already been tested a number of times without any objective measurable improvement [9, 10]? 

The UK PACE trial that formed part of your evaluation, despite using the Oxford criteria, was meant to be a definitive trial but it turned out to be so unsuccessful that even the entry criteria and recovery had to be altered to make it seem as value for the enormous £5million expense which was wasted on it [18, 19].

Lines 364-368:

“Specifically, continuing to use the Oxford definition may impair progress and cause harm. Thus, for needed progress to occur we recommend (1) that the Oxford definition be retired, (2) that the ME/CFS community agree on a single case definition (even if it is not perfect), and (3) that patients, clinicians, and researchers agree on a definition for meaningful recovery.” 

Invest in ME comment: 

This we can entirely agree with – something we have stated for many years - and it is good to see it in print. We need a medical speciality and centres of excellence that take responsibility of ME/CFS. For any specific treatment to have a chance to be successful patients need to be carefully phenotyped and it may be that there needs to be an emphasis on personalised medicine rather than trying to find something that fits all patients diagnosed with ME/CFS.

In Conclusion

Thank you for allowing us to submit our comments and we hope our views are taken on board as this affects not only US citizens but everyone diagnosed with ME or CFS across the world. Whilst it was good to see an outside group of experts trying to get an overview of ME/CFS research it is clearly not possible to do this successfully by just using a scoring method that works for a well-established disease that everyone agrees upon without any knowledge of the underlying history. It does not help that research into ME/CFS has two opposite viewpoints and this document consequently tries to facilitate both.

This is a major mistake and is contrary to any common sense.

It is illogical to do this and if the statement is made that ME/CFS is a physical disease then recommendations should follow logically from that statement. If there are co-morbidities they should be dealt with in the same way as one would do with co-morbidities in MS, cancer or Parkinson’s disease or any other disease.

We also found it difficult to comprehend what the real objective of this workshop was and we sincerely hope that this is not yet another paper exercise to keep the patient community seemingly happy whilst the authorities do nothing concrete to remedy the current situation.

It would be well for the NIH NOT to follow the UK example and repeat the mistakes and failures of the last generation where an insincere effort to change is portrayed as real progress but just results in wasted years. The mediocrity in terms of provision of correct and up to date definitions and guidelines, scientific research and development of treatments and perception of ME is a direct result, and failure, of the policies of the past.

The first part of this report started well describing the situation and what needs to be done. However, it begins to fall apart with instances where inexplicable references to bringing in components which have contributed to the abysmal situation in which ME/CFS patients find themselves. Whether intentional or actual, or not, It suggests that another agenda may be at play here.

We believe future research into ME must be based on collaboration. But it would seem quite meaningless to base the strategy on those failed policies and directions of the past - which have served patients so poorly and caused such suffering [20].

Research into ME needs a strategic approach - but it may be destined to fail completely by attempting to establish the way forward on foundations which include so much of what has been wrong in the past.

If we are seriously to have a way forward for proper research into ME then we need not just funding, but correctly defined cohorts, standardisation on diagnostic criteria and a collaborative of researchers who will not blur science with politics.

The NIH have a unique possibility to be bold, to fix this problem once and for all.

We therefore suggest the following –

We suggest that the NIH finally and totally abandon all links to the biopsychosocial model with regard to ME research funding.

We also suggest that instead of relying on alternative funding streams elsewhere that the NIH take responsibility themselves for ME/CFS. We suggest that the NIH invest $50 million per year for the next five years in biomedical research into ME/CFS, and provide correct and current education into the disease which will, in turn, raise appropriate awareness.

This would mean an investment of $250 million over 5 years. This amount will still be less than the documented annual cost of ME/CFS of $1 billion as noted in line 6.

This will create scores of biomedical research projects, lots of potential international collaboration, new ideas and new skills to enter the ME/CFS research area.

This will facilitate the harnessing of the full potential of academic and research institutes.

This will attract new, young researchers into the field of ME/CFS – this the charity has proven already with our BCell/rituximab project with UCL where a young researcher is drawn into this exciting area of research [21]

It will galvanise science and eventually form pockets of expertise which will create the centres of excellence for the future.

We suggest trying this for a 5 year period.

A yearly review of progress can inform every one of the status.

After 5 years of such funding a new conference/workshop/committee can be convened and progress can be examined.

This will provide the best chance possible for resolving this illness to the benefit of patients.

Our guess is that so much progress will have been made in research, in perception and possibly in treatments during that period that the money will be recouped with the added benefit of giving some people their lives back.

The stigma mentioned above – which is actually, in our opinion, just ignorant prejudice created by corrupt organisations and individuals, would be swept away.

$50 million per year is really not much.

After 5 years it will probably have so much momentum that it could carry on by itself through savings in welfare, through new discoveries and, yes, through private donations/funding

To begin this we invite NIH to be represented at our fifth Biomedical Research into ME Colloquium in London on 27-28th May 2015.

The charity will shortly announce the agenda – which will include most of the necessary areas to be looked at as well as the major research initiatives underway or planned.

We invite the NIH to be represented there in London – in order to join our international collaboration effort to resolve this illness in a way that brings hope to patients, brings responsible and proper science to the research area and brings a raising of awareness that will obliterate the monstrous distortions about ME/CFS which have poisoned all chance of making progress in the last generation.

What needs to be emphasised to all – something that is rarely acknowledged and which we see ignored by almost every organisation – is the urgency of the need for action and change.

This is urgent, lives are dependent on it – Treat it as being urgent!

• To make progress we need not mere words and a slow undeliberate action plan.
• Progress is a fine word – but change is its motivator
• To progress this illness we need to make a bold changes.

Invest in ME is a small charity with a BIG cause.

If such a small charity and its supporters can organise ten international conferences with delegates from 20 countries, if it can organise 5 biomedical research colloquiums attracting participants from top research organisations in a dozen countries, if it can initiate possibly the two most important research projects for ME in the UK (22) then the NIH should be able to do far, far better – and in a far shorter period of time.

In the words of the charity’s advisor Dr Ian Gibson: “Things do not have to be the way they are – we can change things.”

Let’s Do Change.

Let’s Do (biomedical) Research.

Let’s Do It For ME.

References:

1. https://prevention.nih.gov/programs-events/pathways-to-prevention/workshops/me-cfs

2. http://www.investinme.org/LDR%20UK%20Gut%20Microbiota.htm

3. http://www.ukrituximabtrial.org

4. Nacul LC, Lacerda EM, Pheby D, Campion P, Molokhia M, Fayyaz S, Leite JC, Poland F, Howe A, Drachler ML: Prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in three regions of England: a repeated cross-sectional study in primary care.

5. BMC Med 2011, 9:91.

6. Snell CR, Stevens SR, Davenport TE, Van Ness JM. Discriminative validity of metabolic and workload measurements to identify individuals with chronic fatigue syndrome. Phys Ther.2013;93:1484–1492. doi: 10.2522/ptj.20110368

7. Vermeulen RC, Kurk RM, Visser FC, Sluiter W, Scholte HR. Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity. J Transl Med. 2010;8:93. doi: 10.1186/1479-5876-8-93.Keller BA, Pryor JL, Giloteaux L. Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO2 peak indicates functional impairment. J Transl Med. 2014 Apr 23;12:104. doi: 10.1186/1479-5876-12-104.

8. White P D, Rickards H, Zeman A Z J. Time to end the distinction between mental and neurological illnesses BMJ 2012; 344:e3454

9. Sabine, Stordeur; Nancy, Thiry; Marijke, Eyssen (2008). Chronisch Vermoeidheidssyndroom: diagnose, behandeling en zorgorganisatie [Fatigue Syndrome: diagnosis, treatment and organisation of care] (Technical report) (in Dutch). KCE (Belgian Healthcare Knowledge Center). 88A

10. H. Knoop et al., “The effect of cognitive behaviour therapy for chronic fatigue syndrome on self-reported cognitive impairments and neuropsychological test performance,” J Neurol Neurosurg Psychiatry, vol. 78, no. 4, pp. 434–6 (2007).

11. Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Bull IACFS/ME. 2011;19:59–111.

12. http://www.investinme.org/IIME%20Statement%202012-05-31.htm5

13. Fluge O, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Næss H, Dahl O, Nyland H, Mella O. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome: a double-blind and placebo-controlled study. PLoS ONE.2011;6:e26358.

14. http://www.meactionuk.org.uk/PROOF_POSITIVE.htm

15. Tale of Two Collaboratives http://www.investinme.org/IIME-Newslet-1304-01.htm

16. Newton JL, Mabillard H, Scott A, Hoad A, Spickett G The Newcastle NHS Chronic Fatigue Service: not all fatigue is the same. J R Coll Physicians Edin 2010;40:304–7

17. http://www.fda.gov/Drugs/NewsEvents/ucm319188.htm

18. White, PD 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. The Lancet , Volume 377 , Issue 9768 , 823 – 836.

19. http://www.pacetrial.org/

20. Diane’s Story – LILI http://www.investinme.org/mestory1010.htm

21. ME/CFS – Through The Eyes of a Young Researcher http://www.ukrituximabtrial.org/Rituximab%20newsJan15%2001.htm

22.http://www.investinme.org/IIME-Newslet-1410-01%20Possibly%20Most%20Important.htm

IACFS/ME Critiques P2P Draft Report, Insists on Increased Funding

ME/CFS is somewhere below that black line.

In a brief but hard-hitting letter to the P2P panel, the International Association for CFS/ME (IACFS/ME) has thrown down the gauntlet.

"To make significant progress," the letter said, "funding needs to be provided on par with that of other diseases that are similarly prevalent and disabling."

In order to do all the things the P2P panel has recommended in its Report, more funding is needed. But not only did the Draft Report fail to include amounts for future NIH research, it suggested funding avenues that were entirely inadequate for meeting current research needs.

The IACFS/ME letter also made a point of recommending that ME/CFS be moved from the Office for Research on Women’s Health (ORWH) to an Institute that actually has funds.

"We respectfully suggest either NINDS or NIAID as the primary Institute as multiple studies demonstrate that neurologic, infectious, and autoimmune components are present in this illness."

Nothing has been more detrimental to ME/CFS research grants than its current location under the auspices of ORWH. Back in the 1980s, when CFS was considered a contagious illness, it was represented by NIAID (National Institute of Allergy and Infectious Diseases). Funding, at that time, was devoted mainly to investigating viral etiology, but other biomedical research was pursued as well. Once CFS was moved to the ORWH, funding for serious biomedical research all but vanished.

The IACFS/ME's suggestion to house ME in the National Institute of Neurological Disorders and Stroke (NINDS), which has a budget of $1.5 billion, or NIAID, with its budget of over $4.4 billion makes perfect sense - provided that the NIH has more than a token interest in advancing research into the causes, mechanisms, and treatment of ME/CFS. 

____________________

Dear NIH P2P Panel Members,

As board members of the International Association for Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (IACFS/ME), the largest international group of clinicians, researchers, and other professionals dedicated to the care and research of patients with ME/CFS, we hope that your report will have a positive influence on the field, our organization’s members, and the patients/ families we serve.

Generally we agree with the majority of the Panel’s recommendations but believe that the elephant in the room – research funding –  alluded to in the report (e.g. Line 8) needs to be addressed more strongly and specifically. Federal funding for ME/CFS research over the last 3 decades has been inadequate to the broad-ranging and complex challenges presented by this illness. In recent years, only $5-$6 million annually has been awarded on an extramural basis, resulting in ME/CFS being the least-funded out of 240+ conditions that NIH tracks annually.

(http://report.nih.gov/categorical_spending.aspx) Over the last 25 years that IACFS/ME has been in existence, we have seen few new researchers enter the field, a flat publication rate over the past decade, and continuing stigma surrounding the illness. 

This state of affairs is particularly concerning given the costs to society of this illness with respect to lost productivity and high health care costs. To whom do the one million US patients with ME/CFS turn to be reassured that their illness is being taken seriously with substantive commitments to scientific research?  Only the federal government, and NIH in particular, has the ability to make such commitments.

Many of the same recommendations and concerns highlighted by the Panel have been brought up by members of our organization over the years.  For example, last Spring, several of our board members who also served on DHHS’ CFS Advisory Committee suggested that NIH establish and support a data/ biobank-sharing platform and/or issue a Request for Applications focusing on specific areas to jumpstart research. Unfortunately, the recommendations were not accepted or acted upon by NIH. (http://www.hhs.gov/advcomcfs/recommendations/hhs-cfsac-recommendations-response.pdf)

The reasons given were that there were too few ME/CFS researchers to invest the funds for such a platform, that such funding would take away money from other ME/CFS projects, and that since so little was known about ME/CFS, a RFA was not the right mechanism for funding.  Interestingly, the letter then went on to state “RFAs are designed to build upon recommendations that have been identified……. [through] workshops and conferences” yet no RFA was issued for ME/CFS after NIH’s State-of-the-Knowledge Workshop on ME/CFS in 2011 despite the efforts of then-Trans-NIH-Working-Group head Dr. Dennis Mangan. The letter concludes by suggesting that mentored career development, student, and post-doctoral training grants be used.

(The last time NIH issued and RFA for ME/CFS, in 2007, a number of successful projects were funded.) (http://www.hhs.gov/advcomcfs/recommendations/06142014.html)

The essential message conveyed is that the US government does not want to invest additional funds because not enough is known about the disease and there are not enough researchers. Yet a critical  reason why we have a dearth of researchers and knowledge is because of the poor funding situation, which has endured for the past 3 decades. Lack of investment in basic research by the government also impacts other sources of ME/CFS research funding. In April of 2013, the US Food and Drug Administration hosted a Drug Development workshop for ME/CFS. The pharmaceutical representatives who attended cited poor understanding of the basic pathophysiology of ME/CFS as a major reason for the reluctance of their companies to invest in ME/CFS clinical research.

Finally, we believe it would be beneficial to change the institutional affiliation of ME/CFS from the Office for Research on Women’s Health (ORWH) to an Institute with research funds to distribute.  ME/CFS may have been placed under ORWH originally so that funding could be coordinated across institutes but that has not been successful. In fact, the Program Announcement for ME/CFS includes an October 2014 note that several Institutes – including NIA, NIDDK, NIEHS, and NCCAM – have withdrawn their participation. (http://grants.nih.gov/grants/guide/pa-files/PAR-12-032.html)   

Thus we encourage the NIH to consider assigning the management of CFS/ME research to a single NIH Institute and provide that Institute with the responsibility and appropriate funding to effectively manage the research effort in this disease. We respectfully suggest either NINDS or NIAID as the primary Institute as multiple studies demonstrate that neurologic, infectious, and autoimmune components are present in this illness. To make significant progress, funding needs to be provided on par with that of other diseases that are similarly prevalent and disabling. For example, multiple sclerosis and systemic lupus erythematosus are both funded at more than ten times the level ($112-$152 million and $92-$127 million annually respectively) of ME/CFS although ME/CFS, even using a conservative estimate, may be more common.

Thus we respectfully ask that the NIH Panel highlight the inadequate research funding of ME/CFS and link this core premise to specific recommendations for new funding initiatives, with dollar amounts, mechanisms, and deadlines, to begin to address the current underfunded status of this illness.

We also agree with the Panel’s suggestion that carefully constructed and operationalized case definitions are needed for research but disagree that the main issue is lack of agreement on a single research case definition. A single case definition, the 1994 Fukuda case definition, has been used for the majority of the studies worldwide.  However, there are concerns that Fukuda is neither sensitive nor specific enough to capture the patient population it is meant to capture; furthermore, it has not been updated in 20 years to reflect clinician/ patient experience, substantial new evidence from more recent studies on symptom frequencies, and newer case definitions in ME/CFS.

Thus, we ask that the Panel instead emphasize that any research case definition used be based on clinician/ patient experience and the scientific literature, be operationalized well enough that it is easily duplicated across studies by different researchers, and that it be validated and reassessed in a timely manner.

Thank you for this opportunity to comment on the Draft Executive Summary.  We hope that you will take our suggestions into account and will feel no hesitation in contacting us if we can be of further service.

Sincerely,

Fred Friedberg, Ph.D.                                                                               
President, IACFS/ME

Staci R Stevens, M.A.
Founder: Workwell Foundation; Ripon, CA
Co-Vice President, IACFS/ME

Rosamund Vallings, MNZM, MBBS
Howick Health and Medical Center; Auckland, New Zealand
Secretary, IACFS/ME

Julia Newton, MD, PhD
Dean of Clinical Medicine & Professor of Ageing and Medicine
Clinical Academic Office, The Medical School, Newcastle University; New Castle upon Tyne,
United Kingdom
Board member, IACFS/ME

Jon D. Kaiser, MD
Clinical Faculty, Dept. of Medicine, UCSF Medical School; San Francisco, CA
Medical Director, K-PAX Pharmaceuticals, Inc.
Board Member, IACFS/ME

Steven P. Krafchick MPH, JD
Krafchick Law Firm PLLC, Legal Services for Injured and Disabled People; Seattle, WA
Board member, IACFS/ME

Tom Kindlon blasts "fear avoidance of exercise" in the British Medical Journal

It seems as if the most prestigious medical journals in the UK can't get enough of the PACE trial, even when the results are not only old hat, but a very bad fit with good scientific method.

The article, originally appearing appearing in Lancet Psychiatry on January 13, is entitled "Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial." The authors conclude their study with the following statement:

"Our main finding was that fear avoidance beliefs were the strongest mediator for both CBT and GET. Changes in both beliefs and behaviour mediated the effects of both CBT and GET, but more so for GET. The results support a treatment model in which both beliefs and behaviour play a part in perpetuating fatigue and disability in chronic fatigue syndrome."

The article, whose conclusions have been widely circulated in the media, has met with overwhelming criticism from the ME/CFS community, including the ME Association and ME/CFS Research UK. There is, as Mr. Kindlon points out in his letter to the BMJ (below), no objective evidence that GET and CBT actually improve life for ME/CFS patients. Even more to the point, there is objective evidence that "fear avoidance" is not a relevant factor in ME/CFS.

In his December 9 presentation to the P2P, Dr. Snell found that after administering a CPET to ME/CFS patients and controls, the patients not only worked up to capacity, but did not show signs of deconditioning. What was more, in both groups, perceived exertion and workload were correlated. Essentially, there were no differences between objective and subjective measures of exertion for either patients and controls. Dr. Snell concluded that the assumptions underlying both GET and CBT are not supported by objective scientific research.

In Tom Kindlon's thorough critique of the most recent salvo in favor of GET and CBT, he raises many excellent points, all of which should have been considered by the AHRQ before they allowed a study as fundamentally flawed as the PACE trial to be included in their literature review.

____________________

Objective measures found a lack of improvement for CBT & GET in the PACE Trial: subjective improvements may simply represent response biases or placebo effects in this non-blinded trial.

By Tom Kindlon, BMJ, 1/14/15

This BMJ article and a flurry of articles in the lay media this week followed the publication in Lancet Psychiatry of an analysis of the mediators of change in the important PACE Trial, a chronic fatigue syndrome (CFS) trial which cost UK taxpayers £5 million[1,2]. What seems to have been lost in the coverage is that, although there were some modest improvements in the self-report measures, there was an almost complete absence of improvements in objectively measured outcomes for cognitive behavioural therapy (CBT) and graded exercise therapy (GET) compared to the control group (specialist medical care only (SMC)).

This is a non-blinded trial, where participants were told CBT and GET had previously been found to be effective in CFS and other conditions[3,4]: one way to look at the mediation results for subjective measures when there was a lack of objective improvements is that they may merely tell us how response biases and/or placebo effects are mediated[5].

The focus on subjective measures in some CFS studies was previously criticised in a systematic review published back in 2001 (long before the PACE Trial started)[6]. They suggested instead "a more objective measure of the effect of any intervention would be whether participants have increased their working hours, returned to work or school, or increased their physical activities."

The model presented for cognitive behaviour therapy (CBT) in the PACE Trial manuals posits that the impairments and symptoms are reversible with the therapy[3,7]. However, the latest paper shows that fitness, as measured by a step test, didn't improve following CBT[2]. An earlier PACE Trial publication reported that the addition of CBT to SMC did not result in an improvement in 6-minute walking test scores compared to SMC alone[8].

The PACE Trial was part funded by the UK Department of Work and Pensions, a rare move for them, presumably done due to an expectation that the therapies would improve measures of employment and levels of benefit receipt. However, again CBT brought about no improvement using objective measures, such as days of employment lost, levels of disability benefits received and levels of receipt of insurance payments[9].

These results are in line with earlier studies of CBT. For example, an analysis of three randomized controlled trials of CBT interventions for CFS found no improvement in objectively measured activity, despite participants reporting a reduction in (self-reported) fatigue and (sometimes) functional impairments[10]. Similar results were found in another uncontrolled trial where changes in objectively measured activity did not predict fatigue levels, and objectively measured activity on completion remained low compared to population norms[11]. An uncontrolled study found improvements in self-reported physical functioning and fatigue were reported despite a numerical decrease in (objectively measured) activity[12]. In another study, the level of self-reported cognitive impairment in CFS patients decreased significantly after CBT, however, cognition had not improved when it was measured objectively using neuropsychological test performance[13].

It is unsurprising that 15 sessions of CBT (and the associated homework exercises and management program) might alter how participants respond to self-report questionnaires. A PACE Trial manual itself says "the essence of CBT is helping the participant to change their interpretation of symptoms": this could lead to altered or biased fatigue scores, one of the two primary outcome measures[14]. Also, one of the aims of CBT (for CFS) has been said to be "increased confidence in exercise and physical activity"[15]. The possible responses for the other primary outcome measure, the SF-36 physical functioning subscale, are "yes, limited a lot", "yes, limited a little" and "no, not limited at all" to questions on a range of physical activities. Such responses could be easily be artificially altered following a therapy like CBT for CFS.

The results were not that different with the GET cohort in the PACE Trial. Again the manuals predicted that the impairments and symptoms are reversible using the intervention[4,15]. The model said there was no reason participants should not be able to get back to full functioning. Deconditioning was posited to be an important maintaining factor. However, GET did not result in an improvement in fitness, as measured by the step test. GET did result in a small improvement on the six minute walking test to a final distance of 379 metres, or 35 metres more than the SMC-only group[7]. However, as Knoop and Wiborg commented in an accompanying editorial in Lancet Psychiatry: "an increase in distance walked during a test situation without an increased fitness suggests that patients walk more because of a change in cognitive processes (eg, daring to do more or an increased self-efficacy with respect to activity), not because of a change in physiological capacity”[16]. The result remained very poor given that normative data would suggest a group of similar age and gender should walk an average of 644 or so metres[17]. The distance walked remained comparable to people with many serious conditions[18-21], and considerably worse than the distance walked by healthy elderly adults[22,23], despite the PACE trial cohort having a mean age of only 40[8]. Also, to be allowed entry into CFS research studies such as the PACE Trial one can not have a range of chronic illnesses so with genuine recovery one would expect results comparable to healthy people[8].

As with CBT, measures relating to employment showed no improvement following GET in days of work missed, which remained very high, nor a reduction in levels of benefits (financial support from the state) or payments from insurance companies[9].

These results are in line with an audit of Belgian rehabilitation centres for CFS offering CBT and GET[24-26]. Some improvements in subjective measures were found, but there was no improvement in the results of the exercise test and hours in employment actually decreased.

Probably the main contribution of the PACE Trial has been to add to a growing body of evidence that while CBT and GET for CFS have resulted in some changes on subjective measures, they haven't lead to improvements on objective measures.

References:

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Competing interests: I am a committee member of the Irish ME/CFS Association and perform various types of voluntary work for the Association