I have been really enjoying your continued PACE analysis, but I have to say I have a few issues with some of the finer details of this one. I of course understand you are not an expert in the ME&CFS field and the politics, history and medical findings are quite a bit to wade through, but hope you will indulge me to point out a few things...
In terms of PACE based therapies, the objections patients and ME clinicians have (beyond the poor science) is not just that the specific GET/CBT proposed is ineffective, but that it is in fact harmful to a great number of patients. The fact that exercise and a bit of talking therapy sound on their face to be something that couldn't possibly cause harm is a large part of the problem.
There is a large body of literature showing abnormal response to exertion in ME&CFS - so much so that the Institute of Medicine has proposed renaming the disease to 'Systemic Exertion Intolerance Disease'.
For an overview of some of the exercise/muscle/exertion findings try:
http://www.jacobspublishers.com/images/Physiology/J_J_Physiology_1_2_007.pdf
Every survey of ME patients ever done has shown the majority of patients reporting harms from GET, the recent MEA report shows 74% saying GET worsened their condition, and if you review the qualitative section at the end there are a large number of patients (including a few from the PACE trial) describing how GET rendered them permanently bedbound or wheelchair dependent. see:
http://www.meassociation.org.uk/wp-...No-decisions-about-me-without-me-30.05.15.pdf
and in fact in the few cases where Objective measures have been used in GET/CBT studies the results have been negative for GET, even in studies that are heavily skewed to a 'biopsychosocial' approach:
https://www.researchgate.net/public...atigue_syndrome_The_role_of_physical_activity
The Belgium government has dismantled its GET&CBT program based on results they collected showing these therapies had negative effects on employment rates and other disability measures.
In the PACE trial specifically, the “Fitness” data for GET – one of the original outcome measures – also showed GET having the worst outcomes of all trial arms. It was only ever published in a tiny graph in the supplemental materials of one of the papers, and it is impossible to tell in this format if it rose to the level of statistical significance, but it is noteworthy that this has never been addressed by the authors. In particular as an exercise therapy like GET should have improved “fitness” (in this case measured by a step-test), not worsened it.
Tom Kindlon also has some excellent analysis of harms relating to PACE specifically :
https://scholar.google.com/citations?user=CWv7ODUAAAAJ&hl=en
its worth noting as well, that the PACE investigators used their own non-standard criteria to select patients (The Oxford criteria) which doesn’t require Post-exertional symptoms, neurological symptoms, or autonomic irregularities, and requires ‘fatigue’ to be the primary complaint. They also cherry picked the 640 trial subjects from a pool of 3158 patients. So even if their results were valid, it is not a given that they can be expanded to ME or CFS patients who fit different criteria and experience Post-exertional malaise. Both the IOM report and the NIH P2P report have suggested these criteria (Oxford) should not be used for research as this overly broad definition is likely to “impair progress and cause harm”.
In terms of large RCTs, I'm not sure if PACE was indeed the largest, but would have to verify
I believe Ampligen trials were comparable size. And in fact an FDA review of Ampligen has found it to be safe, though the FDA was not convinced of efficacy despite 40% of patients reporting substantial improvement. And while there have been a lot of mis-steps in regard to Ampligen, one could argue that in this case pharmacological trials are being held to a much higher evidence standard than non-pharmacological treatments.
http://www.cortjohnson.org/blog/2015/02/05/congressional-hearing-ampligen-roadblocks-fda-called/
The ongoing phase-3 Rituximab trials are also a large RCT (for M.E.) , and judging by the extremely promising results from three previous trials, will hopefully put some of this debate to bed. Ie – if results are comparable to previous trials, the weak argument of “its all we can offer” would be off the table. Here is a summary of the Rituximab results so far:
http://simmaronresearch.com/2015/07...al-boosts-hopes-for-chronic-fatigue-syndrome/