Professors Peter White, Trudie Chalder and Michael Sharpe (co-principal investigators of the PACE trial) respond to the three blogÂ postsÂ by David Tuller, published hereÂ on 21st, 22nd and 23rd October 2015, about the PACE trial.
The PACE trial was a randomized controlled trial of four non-pharmacological treatments for 641 patients with chronic fatigue syndrome (CFS) attending secondary care clinics in the United Kingdom (UK) (http://www.wolfson.qmul.ac.uk/current-projects/pace-trial) The trial found that individually delivered cognitive behaviour therapy (CBT) and graded exercise therapy (GET) were more effective than both adaptive pacing therapy (APT), when added to specialist medical care (SMC), and SMC alone. The trial also found that CBT and GET were cost-effective, safe, and were about three times more likely to result in a patient recovering than the other two treatments.
There are a number of published systematic reviews and meta-analyses that support these findings from both before and after the PACE trial results were published (Whiting et al, 2001, Edmonds et al, 2004, Chambers et al, 2006, Malouff et al, 2008, Price et al, 2008, Castell et al, 2011, Larun et al, 2015, Marques et al, 2015, Smith et al, 2015). We have published all the therapist and patient manuals used in the trial, which can be down-loaded from the trial website (http://www.wolfson.qmul.ac.uk/current-projects/pace-trial).
We will only address David Tullerâ€™s main criticisms. Most of these are often repeated criticisms that we have responded to before, and we will argue that they are unjustified.
13% of patients had already â€œrecoveredâ€ on entry into the trial
Some 13% of patients entering the trial did have scores within normal range (i.e. within one standard deviation of the population means) for either one or both of the primary outcomes of fatigue and physical function â€“ but this is clearly not the same as being recovered; we have published a correction after an editorial, written by others, implied that it was (White et al, 2011a). In order to be considered recovered, patients also had to:
- Not meet case criteria for CFS
- Not meet eligibility criteria for either of the primary outcome measures for entry into the trial
- Rate their overall health (not just CFS) as â€œmuchâ€ or â€œvery muchâ€ better.
It would therefore be impossible to be recovered and eligible for trial entry (White et al, 2013).Â
Bias was caused by a newsletter for patients giving quotes from patients and mentioning UK government guidance on management. A key investigator was on the guideline committee
It is considered good practice to publish newsletters for participants in trials, so that they are kept fully informed both about the trialâ€™s progress and topical news about their illness. We published four such newsletters during the trial, which can all be found at http://www.wolfson.qmul.ac.uk/current-projects/pace-trial. The newsletter referred to is the one found at this link: http://www.wolfson.qmul.ac.uk/images/pdfs/participantsnewsletter3.pdf.
As can be seen no specific treatment or therapy is named in this newsletter and we were careful to print feedback from participants from all four treatment arms. All newsletters were approved by the independent research ethics committee before publication. It seems very unlikely that this newsletter could have biased participants as any influence on their ratings would affect all treatment arms equally.
The same newsletter also mentioned the release of the UK National Institute for Health and Care Excellence guideline for the management of this illness (this institute is independent of the UK government). This came out in 2007 and received much media interest, so most patients would already have been aware of it. Apart from describing its content in summary form we also said â€œThe guidelines emphasize the importance of joint decision making and informed choice and recommended therapies include Cognitive Behavioural Therapy, Graded Exercise Therapy and Activity Management.â€ These three (not two as David Tuller states) therapies were the ones being tested in the trial, so it is hard to see how this might lead to bias in the direction of one or other of these therapies.
The â€œkey investigatorâ€ on the guidelines committee, who was mentioned by David Tuller, helped to write the GET manuals, and provided training and supervision for one of the therapies; however they had left the trial team two years before the newsletterâ€™s publication.Â
Bias was caused by changing the two primary outcomes and how they were analyzed
These criticisms were first made four years ago, and have been repeatedly addressed and explained by us (White et al, 2013a, White 2015), including explicit descriptions and justification within the main paper itself (White et al, 2011), the statistical analysis plan (Walwyn et al, 2013), and the trial website section of frequently asked questions, published in 2011 (http://www.wolfson.qmul.ac.uk/images/pdfs/pace/faq2.pdf).
The two primary outcomes for the trial were the SF36 physical function sub-scale and the Chalder fatigue questionnaire, as in the published trial protocol; so there was no change in the outcomes themselves. The only change to the primary outcomes from the original protocol was the use of the Likert scoring method (0, 1, 2, 3) of the fatigue questionnaire. This was used in preference to the binary method of scoring (0, 0, 1, 1). This was done in order to improve the variance of the measure (and thus provide better evidence of any change).
The other change was to drop the originally chosen composite measures (the number of patients who either exceeded a threshold score or who changed by more than 50 per cent). After careful consideration, we decided this composite method would be hard to interpret clinically, and would not answer our main question of comparing effectiveness between treatment arms. We therefore chose to compare mean scores of each outcome measure between treatment arms instead.
All these changes were made before any outcome data were analyzed (i.e. they were pre-specified), and were all approved by the independent Trial Steering Committee and Data Monitoring and Ethics committee.
Our interpretation was misleading after changing the criteria for determining recovery
We addressed this criticism two years ago in correspondence that followed the paper (White et al, 2013b), and the changes were fully described and explained in the paper itself (White et al, 2013). We changed the thresholds for recovery from the original protocol for our secondary analysis paper on recovery for three, not four, of the variables, since we believed that the revised thresholds better reflected recovery. For instance, we included those who felt â€œmuchâ€ (and â€œvery muchâ€) better in their overall health as one of the five criteria that defined recovery. This was done before the analysis occurred (i.e. it was pre-specified). In the discussion section of the paper we discussed the limitations and difficulties in measuring recovery, and stated that other ways of defining recovery could produce different results. We also provided the results of different criteria for defining recovery in the paper. The bottom line was that, however we defined recovery, significantly more patients had recovered after receiving CBT and GET than after other treatments (White et al, 2013).
Requests for data under the freedom of information act were rejected as vexatious
Â We have received numerous Freedom of Information Act requests over the course of many years. These even included a request to know how many Freedom of Information requests we had received. We have provided these data when we were able to (e.g. the 13% figure mentioned above came from our releasing these data). However, the safe-guarding of personal medical data was an undertaking enshrined in the consent procedure and therefore is ethically binding; so we cannot publicly release these data. It is important to remember that simple methods of anonymization does not always protect the identity of a person, as they may be recognized from personal and medical information. We have only considered two of these many Freedom of Information requests as vexatious, although an Information Tribunal judge considered an earlier request was also vexatious (General Regulation Chamber, 2013).
Subjective and objective outcomes
These issues were first raised seven years ago and have all been addressed before (White et al, 2008, White et al, 2011, White et al, 2013a, White et al, 2013b, Chalder et al, 2015a). We chose (subjective) self-ratings as the primary outcomes, since we considered that the patients themselves were the best people to determine their own state of health. We have also reported the results of a number of objective outcomes, including a walking test, a stepping test, employment status and financial benefits (White et al, 2011a, McCrone et al, 2012, Chalder et al, 2015). The distance participants could walk in six minutes was significantly improved following GET, compared to other treatments. There were no significant differences in fitness, employment or benefits between treatments. We interpreted these data in the light of their context and validity. For instance, we did not use employment status as a measure of recovery or improvement, because patients may not have been in employment before falling ill, or they may have lost their job as a consequence of being ill (White et al, 2013b). Getting better and getting a job are not the same things, and being in employment depends on the prevailing state of the local economy as much as being fit for work.
There was a bias caused by many investigatorsâ€™ involvement with insurance companies and a failure not to declare links with insurance companies in information regarding consent
No insurance company was involved in any aspect of the trial. There were some 19 investigators, three of whom have done consultancy work at various times for insurance companies. This was not related to the research and was listed as a potential conflict of interest in the relevant papers. The patient information sheet informed all potential participants as to which organizations had funded the research, which is consistent with ethical guidelines.
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