PACE chronic fatigue trial was properly conducted, says UK research watchdog

The PACE trial, which compared treatments for chronic fatigue syndrome, met all the regulatory requirements of its day and exceeded transparency requirements, the Health Research Authority has concluded.1

The judgment came in the form of a letter from Jonathan Montgomery, chair of the HRA, to Norman Lamb, chair of the House of Commons Science and Technology Committee. A member of the committee, Carol Monaghan, had raised the issue with Montgomery when he gave evidence on research integrity to its inquiry last year.

Although the HRA’s intervention will come as a comfort to the team that led the trial and to the Medical Research Council, which funded it, it is unlikely to put to bed a longstanding campaign by activists to discredit it.

PACE was a trial led by Peter White of Queen Mary University of London that compared four treatments for chronic fatigue syndrome. Its conclusions, published in the Lancet in 2011,2 found that cognitive behavioural therapy and graded exercise therapy worked better than adaptive pacing therapy or specialist medical care.

Ever since, the trial has been the eye around which a hurricane of argument and personal vitriol has flowed. Activists with strong views about the nature of their disease and what does or does not work in treating it have never accepted the result and have attempted to discredit the conduct of the trial and those who led it. Many academics have also raised concerns about the trial’s conduct.3

Whenever the arguments raised are answered, they spring up anew elsewhere. In recent years US activists have discovered PACE and have repeated all the same arguments originally put in the UK, while ignoring or discounting the answers provided.

Montgomery’s four page letter does not seek to answer whether the PACE’s conclusions are right. The HRA’s role is to judge whether trials are properly approved and conducted, not their conclusions. That is the job of science, Montgomery says.

In any case, there are no grounds for considering PACE to be of poor quality, he says. The results were published in high impact journals, and a Cochrane review that considered the trial’s robustness classified it as high quality.

In transparency, it was ahead of contemporary requirements, Montgomery says, with a published protocol to which comments could be made and a publicly available statistical plan. Conflicts of interest, such as they were, were declared and were not at the time considered to be an obstacle to approval by a research ethics committee.

Nor, as critics have claimed, did Queen Mary University of London routinely deny access to data. There were certainly disagreements, some of which were referred to the Office of the Information Commissioner for England and Wales, but Montgomery does not conclude that the university acted unreasonably. The interests of the privacy of those who had taken part in the trial were important, and opinions may legitimately differ over when and if those interests may be overridden.

“In all but three of the 21 cases the judgment made by QMUL was vindicated. This suggests that the QMUL and the triallists approached the issue of transparency of data for analysis responsibly,” he says.

Finally, Montgomery looks at changes made to eligibility criteria and to outcome measures, which the opponents of PACE have claimed were manipulated to get the result that emerged. He does not agree, saying that the changes that were made were transparent and openly reported. “We have not seen evidence that outcome measures were changed in order to achieve a specific outcome,” he says.

Michael Sharpe, professor of psychological medicine at the University of Oxford and a member of the trial team, said, “The PACE trial authors welcome the findings. Patients with chronic fatigue syndrome, and the healthcare professionals who look after them, can be reassured that the evidence provided by PACE that cognitive behavioural therapy and graded exercise therapy are helpful and safe treatments for CFS is based on sound science.”

Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene and Tropical Medicine (and not a member of the PACE team), said, “When people do not like the results of randomised trials, they are prone to attempt to find faults with them which would not be raised if they liked the results. The careful scrutiny by the Health Research Authority of the processes and conduct of the PACE trial has essentially vindicated the investigators in terms of their conduct of that trial.”

But David Tuller, a US activist and senior fellow in public health and journalism at the University of California, Berkeley, responded in a blog by saying, “Any claim that the HRA has given PACE a blanket clean bill of health is going way beyond what the report itself states.

“The agency’s remit is relatively narrow—it focuses on process,” he adds. “As the report notes: ‘Our concern as a regulator is whether the study was properly approved by the research ethics committee.’”4