When it comes to offering patients high-quality care for a poorly understood disease, solid, well-funded research, medical education, and respect go a long way. In a masterful report today in STAT, Julie Rehmeyer sets the record straight on chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME). She specifically covers the many pitfalls in the landmark UK PACE trial. Rehmeyer is far from the only critic of this research.
The trial serves as a model for how not to conduct a clinical trial and criticism of it has been abundant, as Rehmeyer explains. Worse still, its conclusions that exercise and cognitive behavior therapy are effective have underpinned clinical practice guidelines around the world. That’s a bad thing because the conduct of the trial was questionable, making its recommendations moot and harmful to patients. Read her story. It’s a longread, but well worth the effort.
But I’d like you to take away from this post key problems with the PACE trial. People with ME and their caregivers need all the help and understanding that they can get. Also, many people won’t read Rehmeyer’s piece. Therefore, the more outlets that understand the neglect and misunderstanding about it, the better. Also, this blog is quite interested in the patient point of view on how to be cared for, a topic that remains undercovered and unappreciated. Note well: Rehmeyer and other ME patients add a lot to the discussion and many research scientists agree with her concerns.
Patient Experience Departs from the Trial
As Rehmeyer explains, when she first got wind of the trial, its sheer breadth made it seem potentially valuable. “It seemed like a great study – big controlled, peer-reviewed…,” she wrote. But she delved deeper because the findings did not jibe with her experience and others living with CFS/ME. She continues: “The hallmark of ME/CFS is that even mild exertion can increase all the other symptoms of the disease, including not just profound fatigue, but also cognitive deficits, difficulties with blood pressure regulation, unrestorative sleep, and neurological and immune dysfunction, among others.”
The trial concluded that graded exercise works – the exact opposite of how patients with CFS/ME describe their endurance. “Staying within my ever changing limits” seemed the safest course for Rehmeyer and others to stop them from spinning down into phenomenal debilitating illness.
The other cornerstone conclusion, that cognitive behavioral therapy, or training oneself to think positive, become more active, and ignore their symptoms, felt enormously insulting to Rehmeyer and other patients, especially when other science pointed to other clues to what underpins the disease.
What’s become abundantly clear is that besides patients like Rehmeyer, immunologists have identified important patterns in the immune system and physiologists have found “highly unusual physiological changes in ME/CFS patients after exercise,” Rehmeyer points out.
There’s certainly been a long history in medicine of viewing some patients as malingerers, i.e. that they don’t want to get well. Although I haven’t seen Rehmeyer and others discuss this quite this way, I wonder whether the investigators were predisposed to viewing the patients as malingerers. I’ll be honest: I am all for making the best of a situation and trying to look on the bright side, but I am closer to Barbara Ehrenreich here, who wrote the recent book Brightsided: How Positive Thinking is Undermining America. I’ll leave it to others to explore whether the PACE investigators were unfairly biased from the get-go to think cognitive behavioral therapy must work. I am sure that many similar and some different incentives motivate health researchers pinning their hopes on it, but that’s just a hunch.
But when trials like PACE become the quintessential trial for teaching clinical practice guidelines, explanations grounded in science are tossed to the wind or not pursued.
Wouldn’t it be wonderful if research funds were allocated into the pathophysiology of ME/CFS and effective treatments were developed? Slowly, this is starting, and with more attention to the disease, more is bound to come.
What’s worse is the highly unorthodox way the trial was conducted. Above, I mentioned moving the goal posts to catch the ball. In midstream, investigators lowered the bar for self-reported recovery. Rehmeyer writes:
“Their revised definition of “recovery” was so loose that patients could get worse over the course of the trial on both fatigue and physical function and still be considered “recovered.” The threshold for physical function was so low that an average 80-year-old would exceed it.”
Rehmeyer also raises questions about the interaction between the researchers and the patients. Specifically, the way patients were asked about their self-reported symptoms also seemed questionable in leading to unfounded conclusions of marked improvement.
It Takes A Movement
To bring you up to date, PACE has been a moving target. Since the trial findings were published in 2011, patients, scientists, and critics have fought over the merits of the trial in newspapers, peer-reviewed journals, and blogs. The times they are a changing, albeit slowly.
A Freedom of Information Request for the trial investigators to release all the data to patients succeeded in the UK. Alem Matthees, a patient from Perth, Australia, who obtained the data and led the analysis, said that the differences between groups were within the range of chance variation, and indicated no benefit of the therapies.
Together with patients, statistics professors Bruce Levin of Columbia University and Philip Stark of the University of California Berkeley have recalculated “recovery” statistics. In contrast to the study authors’ claims of recovery rates of 22%,
the new analyses found that only 4% of patients who received exercise therapy, and 7% who received cognitive behavioral therapy (CBT) recovered, while 3% of a no-therapy comparison group did so.
An evidence review sponsored by the US Agency for Healthcare Research and Quality and finished this year, also reveals that PACE and other research into ME is wanting. “More definitive studies are needed to fill the many research gaps in diagnosing and treating ME/CFS,” write the authors of the systematic review. On key criteria, the evidence to back widespread adoption of recommendations from previous research remains weak.
ME/CFS is just the kind of topic that the US Patient Centered Outcomes Research Institute (PCORI)might support, if patients mounted a successful campaign for it as a priority topic.
A movement has grown and patients have every right to be indignant. All along the way, proponents of the trial have raised questions about tactics and anger coming from irate patients. But patients have been largely helpless and disrespected until now, and quibbling about their tactics sounds like a side show.
On September 27, rallies are being organized in 25 cities around the world to press for research funding for ME/CFS. The battle to garner attention to this poorly understood illness is moving forward.