Time to Reject the PACE Study
Sten Helmfrid1 and Johan Edsberg2
1associate professor of physics, senior scientist, Proximion AB, Kista
2 internal medicine specialist, medicinkliniken Mora
Declaration of Interest: The authors are members of the Swedish ME Association.
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This is a translation of an article that was published in slightly shortened form in
Läkartidningen, Stockholm, Sweden, on 28 September 2017.
http://www.lakartidningen.se/
Suggested citation: Helmfrid S, Edsberg J. Dags att förkasta PACE-studien. Lakartid-ningen. 2017;114:ETLE.
Link to the shortened article in Swedish:
http://www.lakartidningen.se/Opinion/De-batt/2017/09/Dags-att-forkasta-PACE-studien/
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The objective of the PACE trial from 2011 was to investigate the efficacy of graded exer-cise therapy and cognitive behavioral therapy for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) according to a treatment model that the investigators took part in developing [1]. It was obvious already from the pre-published protocol that the design of the study was highly problematic [2]. Only subjective primary outcomes were used, although the study was not blinded [3, 4]; the inclusion criteria selected a larger and more heterogeneous group of patients than what is normally understood by ME/CFS [5]; and there is no scientific support for the underlying illness model [6, 7].
During the study, several protocol changes that favored the preferred hypothesis were carried out. For example, a more advantageous scoring method was used for the primary outcome, fatigue [8]. The threshold for recovery was lowered and ended up below the entry criteria for some outcomes [9]. The presented objective secondary outcomes were incom-plete, and some of them were tucked away in subsequent publications [10]. There was no sensitivity analysis to verify that the findings were robust under the revised methods.
The protocol changes are particularly problematic considering that a sister trial that preceded PACE, FINE, showed no significant improvement [11]; the investigators there-fore must have suspected that the ongoing study also should turn out negative. Professor of law Steven Lubet has pointed out that it is inappropriate for researchers with strong preexisting commitment to a therapy to conduct a non-blinded study that determines the efficacy of that therapy [12].
The result of the PACE study was a modest improvement in subjective outcomes, which was described as a great success [13] despite null results in objective outcomes [14]. Pa-tients and researchers quickly pointed out the many shortcomings of the study [15–21], but the authors refused to accept the criticism. For example, they claimed that subjective
outcomes had been used because this is how the disease is defined [22]. The answer shows lack of understanding of both clinical psychology and theory of science. Subjective fatigue has objectively measurable consequences, and the point of using these is that they are not affected by systematic bias [23].
The debate about PACE heated up in 2015, when a devastating criticism was published at Virology blog [24]. In the blog post, there were reviews by six prominent researchers who were genuinely surprised that the study had been published. The blog post resulted in open letters to The Lancet and Psychological Medicine, which were signed by a number of top researchers and clinicians and demanded an open review of the study and that unsupported claims be retracted [25, 26].
There were many requests to release raw data, including one from a patient who wanted to reanalyze the recovery rates [27] according to the original protocol. Many requests were dismissed with the explanation that they would compromise patient confidentiality or were vexatious in nature—even when made by respected scientists [28]. The case about recovery data was ultimately settled in court; the arguments of the university were rejected and the court ordered the disclosure of data [29]. In the reanalysis, there was no longer any significant difference between the treatment groups and the reference group [30].
In a recent Cochrane review on exercise for ME/CFS based on PACE and seven other similar studies, all methodological issues were ignored [31]. The authors collaborated closely with the PACE team and have publicly been accused of conflicts of interest [32, 33]. A meta-analysis is only as reliable as the original studies that it is based on. The Cochrane review must therefore be questioned in the same way as PACE.
The design of the PACE study was flawed at the outset and the claim of positive results is contradicted by the data. It is time to reject the study. Agencies that issue guidelines for treatment of ME/CFS patients should beware of PACE and of meta-analyses that are based on studies with the same methodology. Otherwise, they should be prepared to an-swer the critical questions about PACE that the investigators have evaded [34], because patients and an increasing number of skeptical scientists will no doubt continue to ask these questions.
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