The PACE trial found that cognitive behavioral therapy and graded exercise therapy were effective treatments for chronic fatigue syndrome and could produce recovery in 22% of patients. It seems they got it wrong.
Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), and the recently-suggested IOM term systemic exertion intolerance disease (SEID), is characterized by long-term fatigue and a host of other symptoms that impair the patient’s ability to function. It sometimes develops after a flu-like illness, but can also come on gradually with no apparent antecedent. The cause is unknown. There is controversy about the diagnostic criteria, and treatment has not been very successful. Between 8-63% of patients improve during follow-up, but fewer than 10% of adult patients return to pre-illness levels of functioning.
A 2001 review in the Journal of the American Medical Association (JAMA) found that cognitive behavioral therapy (CBT) and graded exercise therapy (GET) were the most promising treatments, but the evidence was mixed and the supporting studies had methodological inadequacies. They warned that positive results on subjective measures in these studies did not mean the participants had actually improved their physical capacities. The PACE trial was designed to look for better evidence.
The PACE trial
The PACE trial was published in The Lancet in 2011.
641 patients meeting Oxford criteria for CFS were randomized to four groups:
- Specialist medical care alone (SMC): explanation of CFS, generic advice such as avoiding extremes of activity and rest, specific advice on self-help, and symptomatic pharmacology.
- SMC plus adaptive pacing therapy (APT): helping the patient achieve optimum adaptation to the illness by planning and pacing activities.
- SMC plus cognitive behavioral therapy (CBT): based on the fear avoidance theory that regards CFS as reversible and says fear leads to avoidance of activity, which interacts with physiological processes to perpetuate fatigue.
- SMC plus graded exercise therapy (GET): based on the theory that CFS patients suffer from deconditioning that is reversible with systematic gradual increase in physical activity.
Primary outcomes were rated by subjects who filled out standard questionnaires to assess fatigue and physical function.
Percentage of subjects with improvement in fatigue from baseline:
- SMC: 65%
- APT: 65%
- CBT: 76%
- GET: 80%
Percentage of subjects with improved physical function from baseline:
- SMC: 58%
- APT: 49%
- CBT: 71%
- GET: 70%
Adverse events were monitored and serious deterioration did not vary significantly between groups.
A second PACE report was published in 2013 in Psychological Medicine. It claimed that 22% of subjects treated with CBT or GET recovered, as defined by a score within the range of mean plus or minus one standard deviation of a healthy person’s score.
Together, the two PACE reports concluded that CBT and GET, when added to SMC, were safe and effective treatments for CFS, with a moderate effect size; and with those treatments, a substantial number of patients could achieve recovery from CFS.
Criticism of the PACE study by patients
There was an extensive reaction from patient and advocacy communities. CFS patients were offended by the suggestion that their symptoms were psychological: they knew there was a large body of research indicating that CFS was a biological condition. CFS patients could not accept the results of the study, because in their experience, even mild exertion could increase all the other symptoms of the disease, and they knew that their exercise tolerance varied from day to day. They knew that starting low and building slowly simply wouldn’t work for them. They had learned to rest as soon as they felt tired.
There was evidence to support them. A 2011 study compared CFS patients to normal controls on two maximal exercise tests done 24 hours apart. There were no significant differences on the first test, but the CFS patients had significantly worse performance on the second test, indicating an atypical recovery response and protracted malaise in CFS.
One patient, Julie Rehmeyer, pointed out the problem with subjective reports:
But the subjective reports from patients seemed suspect to me. I imagined myself as a participant: I come in and I’m asked to rate my symptoms. Then, I’m repeatedly told over a year of treatment that I need to pay less attention to my symptoms. Then I’m asked to rate my symptoms again. Mightn’t I say they’re a bit better — even if I still feel terrible — in order to do what I’m told, please my therapist, and convince myself I haven’t wasted a year’s effort?
Criticism of the PACE study by scientists
Dr. David Tuller, writing on the Virology blog, identified several major flaws:
- 13% of subjects already met the criteria for “recovery” at the start of the study.
- In the middle of the study, subjects were given a newsletter including glowing testimonials about how the treatments had helped patients.
- During the trial, the researchers deviated from the protocol. They changed methods and relaxed the criteria for “recovery.”
- They violated their own protocol by failing to tell prospective participants about their conflicts of interest: connections to government and insurance interests.
Tuller quoted several top researchers who agreed that the study was fraught with indefensible methodological problems. Comments included statements like “I’m shocked that The Lancet published it” and “It’s a mass of uninterpretability.”
The struggle to access the trial data
Critics pushed for an independent review of the trial data. They submitted dozens of freedom-of-information (FOI) requests for PACE-related documents and data. The National Institutes of Health (NIH) and the Institute of Medicine (IOM) chimed in, and experts said the deconditioning hypothesis was flawed and untenable. The authors claimed they were being persecuted by patients and advocacy groups. They had received death threats and a phone threat of castration, and one had been stalked by a woman who brought a knife to one of his lectures.
When the trial data were finally made available (only after long persistence, many FOI requests, and a court order), an independent group did a preliminary analysis of “recovery” from CFS using individual participant data. It found that the previously reported recovery rates had been inflated by an average of four-fold. Re-analyzing the data according to the published trial protocol revealed that the recovery rate was 3.1% for SMC alone, 6.8% for CBT, 4.4% for GET, and 1.9% for APT. These differences were not statistically significant.
Fiona Godlee wrote in an editorial in the British Medical Journal (BMJ) that when there is enough doubt to warrant independent re-analysis, “Such independent reanalysis and public access to anonymised data should anyway be the rule, not the exception, whoever funds the trial.”
The authors of the re-analysis said,
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.
An open letter calling for the article to be retracted went unheeded. The original open letter to Psychological Medicine was reposted with a total of 142 signatories.
An article in the Journal of Health Psychology includes an impressive number of references and concludes:
Science is not always plain sailing and sometimes the voyage is across an angry sea. A recent clinical trial of treatments for chronic fatigue syndrome (the PACE trial) has whipped up a storm of controversy. Patients claim the lead authors overstated the effectiveness of cognitive behavioural therapy and graded exercise therapy by lowering the thresholds they used to determine improvement. In this extraordinary case, patients discovered that the treatments tested had much lower efficacy after an information tribunal ordered the release of data from the PACE trial to a patient who had requested access using a freedom of information request.
Conclusion: A flawed study with lessons to be learned
Studies like the PACE trial can have a strong impact on patient care, and flawed studies can result in harm to patients. Conventional peer review is obviously not enough: the effective peer review in this case came after publication. Numerous flaws were found that should have been addressed before publication. Critics called for the study to be retracted; so far, it hasn’t been. This unfortunate episode can serve as a wake-up call and it points out the value of freely sharing raw data with other researchers. Good scientists want to know if they are wrong. They want to have their work scrutinized and should be willing to share their data without the requesters having to resort to a court order.
ADDENDUM: The tribunal that finally resulted in the release of the data found that the researchers’ claims of death threats were false. Their complete report is available online.
This article was originally published in the Science-Based Medicine Blog.