We believe that for our preliminary analysis it was important to follow the protocol-specified recovery criteria, which make more sense than the revised thresholds. For example, the former required level of physical function would suggest a ‘recovered’ individual could at least do most normal activities, but may have limitations with a few of the items on the SF-36 health survey, such as vigorous exercise, walking up flights of stairs, or bending down. The revised threshold that White et al. (2013) used meant that a ‘recovered’ individual could have remained limited on four to eight out of ten items depending on severity. We found that when using the revised recovery criteria, 8% (7/87) of the ‘recovered’ participants still met trial eligibility criteria for ‘significant disability’.

Weakening the recovery thresholds increases statistical power to detect group differences because it makes the event (i.e. ‘recovery’) rates more frequent (i.e. less close to zero) but it also leads to the inclusion of patients who still, for example, have significant illness-related restrictions in physical capacity as per SF-36 physical function score. We argue that if significant differences between groups cannot be detected in sample sizes of approximately n=160 per group, then this may indicate that CBT and GET simply do not substantially increase recovery rates.

Lack of data on stratification variables

In order to increase the chance of being granted or enforced, the FOIA request asked for a ‘bare minimum’ set of variables, as asking for too many variables, or for variables that may be judged to significantly increase the risk of re-identification of participants, would have decreased the chance that the FOIA request would be granted. This was a reasonable compromise given that QMUL had previously blocked all requests for the protocol-specified recovery rates and the underlying data to calculate them. Some non-crucial variables are therefore missing from the dataset acquired under the FOIA but there is reason to believe that this would have little effect on the results.

Allocation of participants in the PACE trial was stratified [1]: “The first three participants at each of the six clinics were allocated with straightforward randomisation. Thereafter allocation was stratified by centre, alternative criteria for chronic fatigue syndrome and myalgic encephalomyelitis, and depressive disorder (major or minor depressive episode or dysthymia), with computer-generated probabilistic minimisation.”

This means that testing for statistical significance assuming simple randomisation results in p- values that are approximate and effect-size estimates that might be biased. The FOIA dataset does not contain the stratification variables. While the lack of these variables may somewhat alter the estimated treatment effects and the p-values or confidence levels, we expect the differences to be minor, a conclusion that is supported by Table 3 below. Table 1 of the publication of the main trial results (White et al., 2011) shows that the stratification variables were approximately evenly distributed between groups [1]. We have replicated the rates of “trial recovery” as previously published by White et al. (2013) [2]. We also attempted to replicate their previously reported logistic regression, without the stratification variables, and the results were essentially the same (see Table 3), suggesting that the adjustments would not have a significant impact on the outcome of our own analysis of recovery.

If QMUL or the PACE trial investigators believe that further adjustment is necessary here to have confidence in the results, then we invite them to present analyses that include stratification variables or release the raw data for those variables without unnecessary restrictions.

Lack of data on alternative ME/CFS criteria

For the same reasons described in the previous subsection, the FOIA dataset does not contain the variables for meeting CDC CFS criteria or London ME (myalgic encephalomyelitis) criteria. These were part of the original definition of recovery, but we argue that these are superfluous because:

(a) While our definition of recovery is less stringent without the alternative ME/CFS criteria, these additional criteria had no significant effect on the results reported by White et al. (2013) [2]). (b) The alternative ME/CFS criteria used in the trial had some questionable modifications [14], that have not been used in any other trial, thus seriously limiting cross-trial comparability and validation of their results. (c) The Oxford CFS criteria are the most sensitive and least specific (most inclusive) criteria, so those who fulfil all other aspects of the recovery criteria would most likely also fail to meet alternative ME/CFS criteria. (d) All participants were first screened using the Oxford CFS criteria as this was the primary case definition, whereas the additional case criteria were not entry requirements [1].

Discussion It is important that patients, health care professionals, and researchers have accurate information about the chances of recovery from CFS. In the absence of definitive outcome measures, recovery criteria should set reasonable standards that approach restoration of good health, in keeping with commonly understood conceptions of recovery from illness [15]. Accordingly, the changes made by the PACE trial investigators after the trial was well under way resulted in the recovery criteria becoming too lax to allow conclusions about the efficacy of CBT and GET as rehabilitative treatments for CFS. This analysis, based on the published trial protocol, demonstrates that the major changes to the thresholds for recovery had inflated the estimates of recovery by an average of approximately four-fold. QMUL recently posted the PACE trial primary ‘improvement’ outcomes as specified in the protocol [16] and that also showed a similar difference between the proportion of participants classified as improved compared to the post-hoc figures previously published in the Lancet in 2011 [1]. It is clear from these results that the changes made to the protocol were not minor or insignificant, as they have produced major differences that warrant further consideration. The PACE trial protocol was published with the implication that changes would be unlikely [17], and while the trial investigators describe their analysis of recovery as pre-specified, there is no mention of changes to the recovery criteria in the statistical analysis plan that was finalised shortly before the unblinding of trial data [11]. Confusion has predictably ensued regarding the timing and nature of the substantial changes made to the recovery criteria [18]. Changing study endpoints should be rare and is only rarely acceptable; moreover, trial investigators may not be appropriate decision makers for endpoint revisions [19,20]. Key aspects of pre-registered design and analyses are often ignored in subsequent publications, and positive results are often the product of overly flexible rules of design and data analysis [21,22].

As reported in a recent BMJ editorial by chief editor Fiona Godlee (3 March 2016), when there is enough doubt to warrant independent re-analysis [23]: “Such independent reanalysis and public access to anonymised data should anyway be the rule, not the exception, whoever funds the trial.” The PACE trial provides a good example of the problems that can occur when investigators are allowed to substantially deviate from the trial protocol without adequate justification or scrutiny. We therefore propose that a thorough, transparent, and independent re-analysis be conducted to provide greater clarity about the PACE trial results. Pending a comprehensive review or audit of trial data, it seems prudent that the published trial results should be treated as potentially unsound, as well as the medical texts, review articles, and public policies based on those results. Acknowledgements Writing this article in such a brief period of time would not have been possible without the diverse and invaluable contributions from patients, and others, who chose not to be named as authors. Declarations AM submitted a FOIA request and participated in legal proceedings to acquire the dataset. TK is a committee member of the Irish ME/CFS Association (voluntary position). References 1. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O’Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; 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 Mar 5;377(9768):823-36. doi: 10.1016/S0140-6736(11)60096-2. Epub 2011 Feb 18. PMID: 21334061. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065633/ 2. White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013 Oct;43(10):2227-35. doi: 10.1017/S0033291713000020. PMID: 23363640. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776285/ 3. 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 Mar 8;7:6. PMID: 17397525. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2147058/ 4. A list of articles by David Tuller on ME/CFS and PACE at Virology Blog. https://www.virology.ws/mecfs/ 5. Kindlon T, Baldwin A. Response to: reports of recovery in chronic fatigue syndrome may present less than meets the eye. Evid Based Ment Health. 2015 May;18(2):e5. doi: 10.1136/eb-2014-101961. Epub 2014 Sep 19. PMID: 25239244. http://ebmh.bmj.com/content/18/2/e5.long 6. Matthees A. Assessment of recovery status in chronic fatigue syndrome using normative data. Qual Life Res. 2015 Apr;24(4):905-7. doi: 10.1007/s11136-014-0819-0. Epub 2014 Oct 11. PMID: 25304959. http://link.springer.com/article/10.1007%2Fs11136-014-0819-0