Trial By Error: Professor Sharpe’s Pre-Hearing Briefing for Monaghan

By David Tuller, DrPH

Update: Lucibee has done what I didn’t want to bother to do. Here’s her annotated version of Professor Sharpe’s statement:

https://lucibee.wordpress.com/2018/07/02/sharpes-briefing-on-the-so-called-pace-trial-for-the-21-june-2018-westminster-hall-debate/

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Before last month’s hearing in Westminster Hall, Professor Michael Sharpe sent the following briefing notes to Carol Monaghan MP. To anyone who knows the details of the PACE scandal, it is immediately evident that the document is full of half-truths, untruths, misrepresentations and absurd arguments. It repeats the kind of irrelevant and non-responsive responses the PACE investigators and their defenders have raised repeatedly–and remarkably have gotten away with, at least until the last couple of years.

I could easily make a point-by-point rebuttal to these briefing notes, as I did to the arguments the PACE investigators raised after the publication of my initial 15,000-word investigation, but I’m not going to bother this time. It’s a waste of energy. The momentum is clear–the PACE era is coming to its much-deserved end. Except for the dwindling ranks of the CBT/GET ideological brigades, no one in this field takes Professor Sharpe’s assertions at face value anymore. Poor guy! He just seems incapable of acknowledging or coming to grips with the new reality. He must be having a difficult time of it.

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BRIEFING ON THE PACE TRIAL FOR “MYALGIC ENCEPHALOMYELITIS TREATMENT AND RESEARCH” DEBATE

WESTMINSTER HALL – 21ST JUNE 2018

We write as clinicians and researchers to clarify some points of scientific evidence.

Between us, we have very many decades of clinical and research experience in trying to help people with Chronic Fatigue Syndrome (CFS), also called Myalgic Encephalomyelitis (ME).

We wish to make it clear that we support all types of research to improve understanding and treatment for the condition.

Whilst the campaign to highlight the plight of such individuals is welcome, there has also been substantial misunderstanding and misinformation circulated about some of the research that has been done to help patients with this condition.

We write specifically about the so-called PACE trial, which we understand is likely to be discussed during the debate. We were part of the large team delivering that trial.

We clarify what the PACE trial was and provide rebuttals to many allegations that have been made about this study.

WHAT WAS THE PACE TRIAL?

• The PACE trial was a large clinical trial including 600 patients that was funded mainly by the Medical Research Council and published its main findings in 2011 in the Lancet.
• The trial aimed to compare four different ways of treating patients with CFS. A substantial proportion of participants also met one definition for ME.
• The treatments were:

1. Specialist medical care, comprising visits to an interested hospital doctor (SMC)
2. Adaptive Pacing Therapy, comprising seeing a therapist to help manage energy and live within limits (APT)
3. Cognitive Behaviour Therapy, comprising seeing a therapist for a psychologically-informed treatment to help patients explore if their fears about worsening symptoms by being more active is excessive (CBT)
4. Graded Exercise Therapy, probably better termed Graded Activity Therapy, comprising seeing a therapist for collaborative and gradual increases in activity (GET)

• The findings of the trial were clear. CBT and GET were superior to APT and SMC in improving both fatigue and physical function one year after entering the trial. The differences were clinically meaningful, but moderate in size (please see the graphs in the attached paper from The Lancet).
• The study looked very carefully for harms and found no excess of harms with the rehabilitative-type treatments (CBT and GET).
• Secondary trial papers reported that a modestly greater proportion of patients could be regarded as ‘recovered’ with CBT and GET that with the other treatments. Whist there is no agreed definition of recovery the figures we reported were approximately 20% with CBT and GET, and approximately 8% with the other conditions. These figures are consistent with other reports.
• We also found that if people who had had CBT and GET were followed up for 18 months after the trial had finished, the benefits in physical function and fatigue they reported at 12 months were maintained.

FALSE ALLEGATIONS ABOUT THE TRIAL

There has been many false allegation made about this research by activist groups and a small number of associated academics. The number of allegations is very large and changes over time. The main current ones are listed below along with our responses. We are happy to supply further information to back up these statements if required.

The trial finding that CBT and GET are superior to APT and standard medical care is false because it used patient rated outcomes.

• Patient-rated outcomes are the most important to patients. Bias in patient-rated outcomes is a risk if patients feel they have had greater attention from or have more faith in one treatment than another. This is an intrinsic problem for all trials of therapies of which the patient must be aware for a condition, which is defined in subjective terms, such as pain fatigue or depression.
• However, in PACE whilst CBT and GET were found to be more effective than APT, which had similar therapist contact time and similar, if not better, credibility with participants. This finding makes bias participants ratings a very unlikely explanation of the differences found between these treatments.

The investigators changed the trial outcomes to make CBT and GET look better.

• We used the originally registered primary outcomes to report the trial findings. There was no ‘outcome-switching’.
• The precise way the outcomes were used in the analysis was changed from the initial protocol following statistical advice. Importantly this was done before looking at the data and was signed off by the Trial Steering Committee.
• Other ways of analysing the relative effects of the treatment produce similar findings.

The proportion of patients regarded as recovered was inflated and no better with CBT and GET than with the other treatments.

• We acknowledge that the definition of recovery, especially with limited data (as in a trial), is contentious.
• We published a secondary paper exploring different definitions of recovery and found about twice as many people could be considered recovered with CBT and GET (about 20%) than with APT and SMC (about 10%).
• Whilst we would accept that many definition of recovery are possible, and that these will alter the absolute percentage of those deemed recovered in each group, the relative effect of the treatments remains the same.
• Our preferred definition of recovery yields figures similar to those in the research literature.
• The allegation that people could be recovered when starting the trial is nonsense.

The trial was fraudulent or in some way influenced by the DWP or the insurance industry.
• The DWP contributed a small amount of the total cost (less than 5%) via the MRC as part of a then popular co-funding agreement. The DWP had no influence on the trial design analysis or presentation.
• Several of the investigators had done small amounts of independent consultancy for insurance companies, but this was in not relevant to the trial. The insurance companies played no part in the trial.
• The trial was run to MRC standards with an overall Trial Steering Committee and Data Monitoring Committee and independent statisticians.
• It is hard to see that if anyone had wanted to bias the results or commit fraud, how they would be able to do so.

The PACE authors refused to share or hid the trial data.

• The PACE trial data has been shared with a number of other scientists, including a Cochrane group.
• The trial data was not shared with the public, as we did not have participants consent to do this. Queen Mary University, London, which was the sponsor of the trial, therefore declined to release the data to the public in the face of dozens of Freedom of Information requests. Most of these refusals were upheld, but on one occasion, a FOI tribunal ordered the release of some of the trial data.
• This released data has been used to “reanalyse” the trial results, with a claim that the published results were misleading. The reanalysis is flawed and misleading.

The PACE trial is universally regarded as flawed and consequently discredited.

• Very lengthy critiques have been produced alleging myriad flaws in the trial. Some of these include quotes from scientists, none of whom are experts in clinical trials.
• It is important to note that experts in clinical trials, including the many peer reviewers of the paper when it was published in The Lancet, have not found the trial to be flawed. Indeed, it is regarded as a high quality trial.

WHY THE CRITICISM?

• The question arises why people are so keen to find fault with a robust trial published as long ago as 2011. We believe that this is, in part, due to a misconception.
• The finding that CBT and GET are helpful has led some to believe that the study proves an unwanted proposition, that “ME is a psychological condition”. Not only does a treatment study not do that, but the paper also explicitly says that this is not the case.
• Another reason is that patient experience of CBT and GET outside the trial is reported as often being unhelpful or even harmful. This is an interesting and worrying observation probably explained by the treatment being given to people dissimilar to those in the trial or being given incorrectly.
• These concerns, whether justified or not, do not however mean that the trial itself was flawed or fraudulent.

HAVE SIMILAR FINDINGS BEEN MADE BY OTHERS?

• It is important to note that the PACE trial does not stand alone. There have been a number of trials from different universities and different countries with similar findings.
• The key arbiter of science is replication, and the results have been replicated many times.

CONCLUSIONS

• The PACE trial and other similar trials find moderately better outcomes with CBT and GET than with SMC or APT. The evidence for CBT and GET is robust. These therapies are not a general cure, but it helps many.
• The PACE trial does not show that CFS or ME are mental illnesses and does not suggest that biomedical factors are not relevant to ME, nor does it indicate that more research should not be done into biomedical factors.
• The reported adverse effects with GET and CBT when used in routine care require investigation. They may reflect misdiagnosis or poorly delivered treatment.
• It is most unfortunate that hostility to such treatments and associated misconceptions have led patient activist groups (by not patients in general) to reject these treatments and to seek to discredit the science supporting them.

REFERENCE

White PD, Goldsmith KA, Johnson AL et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011; 377: 823-36. (Attached)

Michael Sharpe, Professor of Psychological Medicine, University of Oxford on behalf of the PACE trial investigators. 13/6/18

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