The PACE trial was an open-label study of graded exercise therapy and cognitive behavioural therapy for chronic fatigue syndrome that used subjective measures as its main outcomes. It is the core justification for prescribing these therapies to ME patients around the world.
In his detailed article, Tuller challenges the PACE trial authors’ claims that the therapies led to recovery for some patients.
Tuller points out multiple changes to the original, approved study protocol, including the changing of all of the methods for assessing the primary study outcomes, and the relaxation of all of the criteria for recovery.
In what Tuller describes as a “bizarre paradox”, patients’ scores at baseline for physical function and fatigue could worsen and yet they would be considered “recovered” according to the new thresholds that replaced those specified in the study protcol.
The objective measures used in the trial, including a walking test, did not, Tuller says, support the authors’ claims concerning recovery, but the study authors dismissed these measures even though they themselves had designed them.
Critics of the trial have previously pointed out that PACE patients’ average walking test scores after therapy have been exceeded by patients listed for lung transplantation and by older patients with chronic heart failure.
In further criticism, Tuller reports that patients were not informed of the main investigators’ insurance-industry conflicts of interest in the trial, in violation of the study protocol and the Declaration of Helsinki.
Principal investigators Peter White, Trudie Chalder and Michael Sharpe, and Richard Horton, the editor of The Lancet where the PACE trial was published, did not grant interviews to Tuller.
However, a number of high-profile scientists spoke to him about the trial. “I’m shocked that The Lancet published it,” said leading geneticist Ronald Davis, of Stanford University. “The PACE study has so many flaws and there are so many questions you’d want to ask about it that I don’t understand how it got through any kind of peer review”.
Jonathan Edwards, world-famous for his work in rheumatoid arthritis at University College London, told Tuller, “It’s a mass of un-interpretability to me. Within the circle who are involved in this field, it seems there were a group who were prepared to all sing by the hymn sheet and agree that PACE was wonderful. But all the issues with the trial are extremely worrying, making interpretation of the clinical significance of the findings more or less impossible.”
University of California epidemiologist Arthur Reingold said to Tuller, “Under the circumstances, an independent review of the trial conducted by experts not involved in the design or conduct of the study would seem to be very much in order.”
Tuller credits patients for much of the information and scientific insight that led to his critique.