The PACE-trial is a large-scale randomised controlled trial set up to investigate the efficacy of graded exercise therapy (GET) and cognitive behaviour therapy (CBT) for patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Some months ago, the Journal of Health Psychology (JHP) published an editorial that painted an unfavourable picture of the PACE trial. The PACE-authors published a response to the criticism in the same journal, and simultaneously, the JHP-editor invited me to share my view on the ongoing debate by writing a commentary article.
Acknowledging that peer-review and sound debates are important constituents of science, I accepted the invitation, and submitted a commentary article co-authored with Signe Flottorp and Aase Aamland. Our contribution was intended to bring perspectives into the debate, aiming for better understanding and lower levels of conflict. Sadly, JHP decided to reject our contribution, essentially stating our arguments to be well known and erroneous. We consider it disturbing when a closed editorial process is used to label opinions as right or wrong. For such a strategy to work, the process needs to be transparent and unbiased. JHP does not seem to satisfy this standard, and authors who are supportive to the PACE trial and the PACE-trialists may seem selectively rejected.
Despite the negative feedback from the JHP, we consider it important to share our view with a broader audience; hence we have decided to publish the commentary article on the Mental Elf. We aim to bring perspectives into the debate about the PACE trial, and also discuss the usefulness of GET and CBT in a wider context. In brief, the effect estimates associated with GET and CBT seem well documented. Whether individual patients find the expected efficacy to be useful, will to some extent, be a matter of personal preferences. Even though GET and CBT can be useful, however, it is also our view that ongoing research should aim at developing new and more efficient treatment strategies.
A large number of trials have consistently shown that cognitive behaviour therapy (CBT) and graded exercise therapy (GET) may be supportive for patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) (Larun et al, 2016; Price et al, 2008). This observation tells us nothing about the possible or plausible causes of the disease. It is worth noting that the effects of CBT and GET in CFS/ME are similar to those seen among patients with other serious diseases where fatigue is a prominent symptom, e.g. cancer (Furmaniak et al, 2016) and multiple sclerosis (Heine et al, 2015; van den Akker et al, 2016). The benefit of CBT and GET does not imply that we can conclude that cancer, multiple sclerosis or CFS/ME occur for psychological reasons. It is difficult to understand why the benefit of CBT and exercise in patients with cancer and multiple sclerosis seems widely accepted, whereas the usefulness of CBT and GET for patients with CFS/ME remains controversial.
We are researchers and clinicians who think that health personnel should meet all patients, including those with CFS/ME, with respect and empathy, and offer the best available treatment with documented effects. It is commendable that some researchers make an effort and conduct trials to determine which interventions may help. PACE is one of several trials that evaluate the effectiveness of CBT and GET for patients with CFS/ME. In a recent editorial, Dr. Geraghty (2016) issues an emotional verdict against PACE based on, what we consider, a tendentious review of the evidence. Some of his arguments would have wide reaching consequences if accepted, for example the argument that involvement in previous trials should disqualify researchers from designing new and better trials. Other arguments seem to be based on unfortunate allegations and misconceptions, which have already been corrected by the PACE authors (White et al, 2017). We consider the PACE authors’ response to be satisfactory, and think it is unnecessary to seek further details; however, we appreciate the opportunity to provide a broader perspective.
Dr. Geraghty begins his editorial citing Simon Wessely: ‘Science is not always plain sailing and sometimes the voyage is across an angry sea’. This quote gives an excellent picture of real world science and its challenges. Unfortunately, the rest of the editorial fails to follow up on this opening, and it becomes evident that we read the PACE trial (White et al, 2011) quite differently from Dr. Geraghty (2016). Where he sees dishonesty and fraud, we see a transparent, well-conducted and rigorous trial. After a thorough review, we conclude that the PACE researchers have performed professionally. They have undertaken to make detailed protocols and statistical analysis plans available for the public – an example for other researchers to follow. Transparency highlights any differences between the protocol and the final product, but this does not mean that all changes to the original plan are inappropriate. No matter how much time and resources are allocated to trial planning, challenges will arise and trade-offs are unavoidable. Hence, dedicated readers critically appraising studies can always point out some potential problems, but this is generally not sufficient to label an entire trial invalid nor to accuse the authors for dishonesty. All trials should be appraised according to the same criteria, and all possible shortcomings should be assessed with regard to the likelihood that they lead us to draw erroneous conclusions. In the case of PACE, we consider the conclusions to remain stable.
The positive findings in PACE span across several outcomes. Dr. Geraghty (2016) does not appreciate the consistency of these results, but rather conveys a general criticism against the widespread use of patient reported outcome measures (PROMs). Keeping in mind that CFS/ME is diagnosed based on subjectively reported symptoms, it is not strikingly odd that trials focus on patient reported outcomes. There is also a paucity of reliable objective outcomes for this condition. Even though PACE demonstrates that maximum heart rate or lactate levels remains constant or improves slightly following GET, it is appropriate to ask what it means for the patient. PROMs are often more important to patients than objectively assessed outcomes, and researchers should therefore avoid devaluing PROMs on a general basis. PROMs are increasingly used in areas with a tradition of using more objective outcome (Anker et al, 2014), and they may even have long-term prognostic importance (Norekvål et al, 2010). One would therefore expect some degree of correlation between reliable and valid patient reported outcomes and objectively assessed activity levels, as substantiated by recent validation studies (Mahieu et al, 2016).
The criticism made against the PACE trial primarily refers to the author’s definition of improvement and recovery, terms that can be somewhat ambiguous. Chemo- and radiotherapy may cure cancer patients of their cancer, but many patients may struggle with side effects for years. When is it appropriate to say that patients have recovered? When they are cured of cancer, when their health condition allows them to return to work or when they feel as well as they did before they were sick? There is no single correct answer, but one has to be aware of the thresholds when interpreting the results. Retaining this perspective, PACE shows that some patients will improve very much following CBT or GET, and the majority will experience some improvement. Some patients will not experience improvements at all. There is a lack of reliable methods to predict who will respond and who will not. This is unfortunate, but this is by no means unique for CFS/ME, GET and CBT.
It will be a major step forward if researchers succeed in developing alternative treatment strategies that work more efficiently than CBT or GET for some patients, e.g. Rituximab (Fluge et al, 2011). Some opponents claim that it is possible to use existing case definition to predict treatment response, and they often shorten debates by circular arguments like stating that people who are diagnosed with ME and report improvement following CBT or GET must have been misdiagnosed with ME in the first place. There is actually no evidence that existing case criteria for CFS/ME are suitable for this purpose (Brurberg et al, 2014), and the PACE trial contributes important data on the relationship between case definitions and the effectiveness of CBT and GET. Some critics devaluate the findings in PACE because patients were recruited according to the Oxford criteria, forgetting that PACE participants were stratified according to much narrower case definitions similar to the CDC-1994 and London ME criteria (White et al, 2011). The effectiveness of CBT and GET was consistent no matter what case criteria that were used (White et al, 2011).
The take home message from PACE is that patients with CFS/ME are expected to benefit from CBT and GET. These results are consistent across several outcomes within PACE, and across several other independent trials as confirmed by systematic reviews (Larun et al, 2016; Price et al, 2008). An effect seen at an aggregated level does not imply that all patients will experience a benefit. Regardless of the type of disease or the type of treatment it rarely does. In the absence of evidence of efficacy for other interventions, health professionals should offer patients with CFS/ME the opportunity to try CBT or GET. Clinicians should talk with patients about available treatment options, and patients can then decide whether they want to try CBT, GET or other approaches. It is sad that some patients have had bad experiences with GET, but it is important to recognise that other case reports, as well as our own clinical experience, suggest that many patients with CFS/ME benefit from these interventions. To maximise the positive effects and avoid side effect, however, it is important that these interventions are led by health professionals with sufficient expertise and experience.
Peer-review and debate are important constituents of science, but we are concerned that tendentious criticism and allegations as set forth by Dr. Geraghty (2016) are counterproductive and may discourage further research. Patients who could benefit from these treatment strategies, and actually want to try, may also lose the opportunity because they lose the courage to try or because health personnel avoid offering them. It is important that patients, clinicians and researchers continue their efforts to acquire knowledge and improve our understanding of the disease.
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