How to get a flawed systematic review and meta-analysis withdrawn from publication: a detailed example

Cochrane normally requires authors to agree to withdraw completed reviews that have been published. This withdrawal in the face of resistance from the authors is extraordinary.

There is a lot to be learned from this letter and the accompanying documents in terms of Courtney calmly and methodically laying out a compelling case for withdrawal of a review with important clinical practice and policy implications.

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Robert Courtney’s wonderfully detailed cover letter probably proved decisive in getting the Cochrane review withdrawn, along with the work of another citizen scientist/patient advocate, Tom Kindlon.

Cochrane normally requires authors to agree to withdraw completed reviews that have been published. This withdrawal in the face of resistance from the authors is extraordinary.

There is a lot to be learned from this letter and the accompanying documents in terms of Courtney calmly and methodically laying out a compelling case for withdrawal of a review with important clinical practice and policy implications.

Especially take a look at the exchanges with the author Lillebeth Larun that are included in the letter.

Excerpt from the cover letter below:

It is my opinion that the published Cochrane review unfortunately fails to meet the standards expected by the public of Cochrane in terms of publishing rigorous, unbiased, transparent and independent analysis; So I would very much appreciate it if you could investigate all of the problems I raised in my submitted comments and ensure that corrections are made or, at the very least, that responses are provided which allow readers to understand exactly why Cochrane believe that no corrections are required, with reference to Cochrane guidelines.

On this occasion, in certain respects, I consider the review to lack rigour, to lack clarity, to be misleading, and to be flawed. I also consider the review (including the discussions, some of the analyses, and unplanned changes to the protocol) to indicate bias in favour of the treatments which it investigates.

robert bob courtneyAnother key excerpt summarized Courtney’s four comments on the Cochrane review that had not yet succeeded in getting the review withdrawn:

In summary, my four submissions focus on, but are not restricted to the following issues:

  • The review authors switched their primary outcomes in the review, and used unplanned analyses, which has had the effect of substantially transforming some of the interpretation and reporting of the primary outcomes of the review;

  • The review fails to prominently explain and describe the primary outcome switching and to provide a prominent sensitivity analysis. In my opinion, the review also fails to justify the primary outcome switching;

  • The review fails to clearly report that there were no significant treatment effects at follow-up for any pooled outcomes in any measures of health (except for sleep, a secondary outcome), but instead the review gives the impression that most follow-up outcomes indicated significant improvements, and that the treatments were largely successful at follow-up;

  • The review uses some unpublished and post-hoc data from external studies, despite the review-authors claiming that they have included only formally published data and pre-specified outcome data. Using post-hoc and unpublished data, which contradicts the review’s protocol and stated methodology, may have had a significant effect on the review outcomes, possibly even changing the review outcomes from non-significant to significant;

  • The main discussion sections in the review include incorrect and misleading reports of the review’s own outcomes, giving a.false overall impression of the efficacy of the reviewed therapies;

  • The review includes an inaccurate assessment of bias (according to the Cochrane guidelines for reporting bias) with respect to some of the studies included in the review’s analyses.

These are all serious issues, that I believe we should not be seeing in a Cochrane review.

Digression: My Correspondence with Tom Kindlon regarding this blog post

James Coyne <jcoynester@gmail.com>

Oct 18, 2018, 12:45 PM (3 days ago)

to Tom

I’m going to be doing a couple of blog posts about Bob, one of them about the details of the lost year of his life (2017) which he shared with me in February 2018, shortly before he died. But the other blog post is going to be basically this long email posted with commentary. I am concerned that you get your proper recognition as fully sharing the honors with him for ultimately forcing the withdrawal of the exercise review. Can you give me some suggestion how that might be assured? references? blogs

Do you know the details of Bob ending his life? I know it was a deliberate decision, but was it an accompanied suicide? More people need to know about his involuntary hospitalization and stupid diagnosis of anorexia.

Kind regards

tom Kindlon
Tom Kindlon

Tom Kindlon’s reply to me

Tom Kindlon

Oct 18, 2018, 1:01 PM (3 days ago)

Hi James/Jim,

It is great you’re going to write on this.

I submitted two long comments on the Cochrane review of exercise therapy for CFS, which can be read here:

<https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003200.pub7/detailed-comment/en?messageId=157054020&gt;

<https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003200.pub7/detailed-comment/en?messageId=157052118&gt;

Robert Courtney then also wrote comments. When he was not satisfied with the responses, he made a complaint.

All the comments can be read on the review here:

<https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003200.pub7/read-comments&gt;

but as I recall the comments by people other than Robert and myself were not substantial.

I will ask what information can be given out about Bob’s death.

Thanks again for your work on this,

Tom

The Cover Letter: Did it break the impasse about withdrawing the review?

from:     Bob <brightonbobbob@yahoo.co.uk>

to:            James Coyne <jcoynester@gmail.com>

date:     Feb 18, 2018, 5:06 PM

subject:                Fw: Formal complaint – Cochrane review CD003200Sun, Feb 18, 1:15 PM

THIS IS A COPY OF A FORMAL COMPLAINT SENT TO DR DAVID TOVEY.

Formal Complaint

12th February 2018

From:

Robert Courtney.

UK

To:

Dr David Tovey

Editor in Chief of the Cochrane Library

Cochrane Editorial Unit

020 7183 7503

dtovey@cochrane.org

Complaint with regards to:

Cochrane Database of Systematic Reviews.

Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2017; CD003200. DOI: 10.1002/14651858.CD003200.pub7

Dear Dr David Tovey,

This is a formal complaint with respect to the current version of “Exercise therapy for chronic fatigue syndrome” by L. Larun et al. (Cochrane Database Syst Rev. 2017; CD003200.)

First of all, I would like to apologise for the length of my submissions relating to this complaint. The issues are technical and complex and I hope that I have made them easy to read and understand despite the length of the text.

I have attached four PDF files to this email which outline the details of my complaint. In 2016, I submitted each of these documents as part of the Cochrane comments facility. They have now been published in the updated version of the review. (For your convenience, the details of these submissions are listed at the end of this email with a weblink to an online copy of each document.)

I have found the responses to my comments, by L. Larun, the lead author of the review, to be inadequate, especially considering the seriousness of some of the issues raised.

It is my opinion that the published Cochrane review unfortunately fails to meet the standards expected by the public of Cochrane in terms of publishing rigorous, unbiased, transparent and independent analysis; So I would very much appreciate it if you could investigate all of the problems I raised in my submitted comments and ensure that corrections are made or, at the very least, that responses are provided which allow readers to understand exactly why Cochrane believe that no corrections are required, with reference to Cochrane guidelines.

On this occasion, in certain respects, I consider the review to lack rigour, to lack clarity, to be misleading, and to be flawed. I also consider the review (including the discussions, some of the analyses, and unplanned changes to the protocol) to indicate bias in favour of the treatments which it investigates.

Exercise as a therapy for chronic fatigue syndrome is a highly controversial subject, and so there may be more of a need for independent oversight and scrutiny of this Cochrane review than might usually be the case.

In addition to the technical/methodological issues raised in my four submitted comments, I would also like you to consider whether there may be a potential lack of independence on the part of the authors of this review.

All of the review authors, bar Price, are currently working in collaboration on another Cochrane project with some of the authors of the studies included in this review. (The project involves co-authoring a protocol for a future Cochrane review) [2]. One of the meetings held to develop the protocol for this new review was funded by Peter White’s academic fund [1]. White is the Primary Investigator for the PACE trial (a study included in this Cochrane review).

It is important that Cochrane is seen to uphold high standards of independence, transparency and rigour.

Please refer to my four separate submissions (attached) for the details of my complaint regarding the contents of the review. As way of an introduction, only, I will also briefly discuss, below, some of the points I have raised in my four documents.

In summary, my four submissions focus on, but are not restricted to the following issues:

  • The review authors switched their primary outcomes in the review, and used unplanned analyses, which has had the effect of substantially transforming some of the interpretation and reporting of the primary outcomes of the review;
  • The review fails to prominently explain and describe the primary outcome switching and to provide a prominent sensitivity analysis. In my opinion, the review also fails to justify the primary outcome switching;
  • The review fails to clearly report that there were no significant treatment effects at follow-up for any pooled outcomes in any measures of health (except for sleep, a secondary outcome), but instead the review gives the impression that most follow-up outcomes indicated significant improvements, and that the treatments were largely successful at follow-up;
  • The review uses some unpublished and post-hoc data from external studies, despite the review-authors claiming that they have included only formally published data and pre-specified outcome data. Using post-hoc and unpublished data, which contradicts the review’s protocol and stated methodology, may have had a significant effect on the review outcomes, possibly even changing the review outcomes from non-significant to significant;
  • The main discussion sections in the review include incorrect and misleading reports of the review’s own outcomes, giving a.false overall impression of the efficacy of the reviewed therapies;
  • The review includes an inaccurate assessment of bias (according to the Cochrane guidelines for reporting bias) with respect to some of the studies included in the review’s analyses.

These are all serious issues, that I believe we should not be seeing in a Cochrane review.

These issues have already caused misunderstanding and misreporting of the review in academic discourse and publishing. (See an example of this below.)

All of the issues listed above are explained in full detail in the four PDF files attached to this email. They should be considered to be the basis of this complaint.

For the purposes of this correspondence, I will illustrate some specific issues in more detail.

In the review, the following health indicators were used as outcomes to assess treatment effects: fatigue, physical function, overall health, pain, quality of life, depression, anxiety, and sleep. All of these health indicators, except uniquely for sleep (a secondary outcome) demonstrated a non-significant outcome for pooled treatment effects at follow-up for exercise therapy versus passive control. But a reader would not be aware of this from reading any of the discussion in the review. I undertook a lengthy and detailed analysis of the data in the review before i could comprehend this. I would like these results to be placed in a prominent position in the review, and reported correctly and with clarity, so that a casual reader can quickly understand these important outcomes. These outcomes cannot be understood from reading the discussion, and some outcomes have been reported incorrectly in the discussion. In my opinion, Cochrane is not maintaining its expected standards.

Unfortunately, there is a prominent and important error in the review, which I believe helps to give the mis-impression that the investigated therapies were broadly effective. Physical function and overall-health (both at follow-up) have been mis-reported in the main discussion as being positive outcomes at follow-up, when in fact they were non-significant outcomes. This seems to be an important failing of the review that I would like to be investigated and corrected.

Regarding one of the points listed above, copied here:

“The review fails to clearly report that there were no significant treatment effects at follow-up for any pooled outcomes in any measures of health (except for sleep, a secondary outcome), but instead the review gives the impression that most follow-up outcomes indicated significant improvements, and that the treatments were largely successful at follow-up”

This is one of the most substantial issues that I have highlighted. This issue is related to the primary outcome switching in the review.

(This relates to assessing fatigue at long-term follow-up for exercise therapy vs passive control.)

An ordinary (i.e. casual) reader of the review may easily be left with the impression that the review demonstrates that the investigated treatment has almost universal beneficial health effects. However there were no significant treatment effects for pooled outcome analyses at follow-up for any health outcomes except for sleep (a secondary outcome ). The lack of universal treatment efficacy at follow-up is not at all clear from a casual read of the review, or even from a thorough read. Instead, a careful analysis of the data is necessary to understand the outcomes. I believe that the review is unhelpful in the way it has presented the outcomes, and lacks clarify.

These follow-up outcomes are a very important issue for medical, patient and research communities, but I believe that they have been presented in a misleading and unhelpful way in the discussions of the review. This issue is discussed mainly in my submission no.4 (see my list of PDF documents at the bottom of this correspondence), and also a little in submission no.3.

I will briefly explain some of the specific details, as way of an introduction, but please refer to my attached documents for the full details.

The pre-specified primary outcomes were pooled treatment effects (i.e. using pooled data from all eligible studies) immediately after treatment and at follow-up.

However, for fatigue, this pre-specified primary outcome (i.e. pooled treatment effects for the combination of data from all eligible studies) was abandoned/switched (for what i consider to be questionable reasons) and replaced with a non-pooled analysis. The new unplanned analysis did not pool the data from all eligible studies but analysed data from studies grouped together by the specific measure used to assess fatigue (i.e. grouped by the various different fatigue questionnaire assessments).

Looking at these post-hoc grouped outcomes, for fatigue at follow-up , two out of the three grouped outcomes had significant treatment effects, and the other outcome was a non-significant effect. This post-hoc analysis indicates that the majority of outcomes ( i.e. two out of three) demonstrated a significant treatment effect , however, this does not mean that the pre-specified pooled analysis of all eligible studies would have demonstrated a positive treatment effect. Therefore switching outcomes, and using a post-hoc analysis, allows for the potential introduction of bias to the review. Indeed, on careful inspection of the minutia of the review, the pre-specified analysis of pooled outcomes demonstrates a non-significant treatment effect, for fatigue at follow-up (exercise therapy versus passive control)

The (non-significant) outcome of this pre-specified pooled analysis of fatigue at follow-up is somewhat buried within the data tables of review, and is very difficult to find; It is not discussed prominently or highlighted. Furthermore, the explanation that the primary outcome was switched, is only briefly mentioned and can easily be missed. Uniquely, for the main outcomes, there is no table outlining the details of the pre-specified pooled analysis of fatigue at follow-up. In contrast, the post-hoc analysis, which has mainly positive outcomes, has been given high prominence throughout the review with little explanation that it is a post-hoc outcome.

So, to reiterate, the (two out of three significant, and one non-significant) post-hoc outcomes for fatigue at follow-up were reported as primary outcomes instead of the (non-significant) pre-specified pooled treatment effect for all eligible studies. Two out of three post-hoc outcomes were significant in effect, however, the pre-specified pooled treatment effect, for the same measures, were not significant (for fatigue at follow-up – exercise therapy versus passive control). Thus, the outcome switching transformed one of the main outcomes of the review, from a non-insignificant effect to a mainly significant effect.

Furthermore, for exercise therapy versus passive control at follow-up, all the other health outcomes were non-significant (except sleep – a secondary outcome), but I believe the casual reader would be unaware of this because it is not explained clearly or prominently in the discussion, and some outcomes have been reported erroneously in the discussion as indicating a significant effect.

All of the above is outlined in my four PDF submissions, with detailed reference to specific sections of the review and specific tables etc.

I believe that the actual treatment effects at follow-up are different to the impression gained from a casual read of the review, or even a careful read of the review. It’s only by an in-depth analysis of the entire review that these issues would be noticed.

In what i believe to be a reasonable request in my submissions, i asked the reviewers to: “Clearly and unambiguously explain that all but one health indicator (i.e. fatigue, physical function, overall health, pain, quality of life, depression, and anxiety, but not sleep) demonstrated a non-significant outcome for pooled treatment effects at follow-up for exercise therapy versus passive control”. My request was not acted upon.

The Cochrane reviewers did provide a reason for the change to the protocol, from a pooled analysis to analyses of groups of mean difference values: “We realise that the standardised mean difference (SMD) is much more difficult to conceptualise and interpret than the normal mean difference (MD) […]”.

However, this is a questionable and unsubstantiated claim, and in my opinion isn’t an adequate explanation or justification for changing the primary outcomes; personally, I find it easier to interpret a single pooled analysis than a group of different analyses with each analysis using a different non-standardised scale to measure fatigue.

Using a SMD is standard practice for Cochrane reviews; Cochrane’s guidance recommends using pooled analyses when the outcomes use different measures, which was the case in this review; Thus i struggle to understand why (in an unplanned change to methodology) using a SMD was considered unhelpful by the reviewers in this case. My PDF document no.4 challenges the reviewers’ reason, with reference to the official Cochrane reviewers’ guidelines.

This review has already led to an academic misunderstanding and mis-reporting of its outcomes, which is demonstrated in the following published letter from one of the co-authors of the IPD protocol……

CMAJ (Canada) recommends exercise for CFS [http://www.cmaj.ca/content/188/7/510/tab-e-letters ]

The letter claims: “We based the recommendations on the Cochrane systematic review which looked at 8 randomised trials of exercise for chronic fatigue, and together showed a consistent modest benefit of exercise across the different patient groups included. The clear and consistent benefit suggests indication rather than contraindication of exercise.”

However, there was not a “consistent modest benefit of exercise” and there was not a “clear and consistent benefit” considering that there were no significant treatment effects for any pre-specified (pooled) health outcomes at follow-up, except for sleep. The actual outcomes of the review seem to contradict the interpretation expressed in the letter.

Even if we include the unplanned analyses in our considerations, then it would still be the case that most outcomes did not indicate a beneficial treatment effect at follow-up for exercise therapy versus passive control. Furthermore, one of the most important outcomes, physical function, did not indicate a significant improvement at follow up (despite the discussion erroneously stating that it was a significant effect).

Two of my submissions discuss other issues, which I will outline below.

My first submission is in relation to the following…

The review states that all the analysed data had previously been formally published and was pre-specified in the relevant published studies. However, the review includes an analysis of external data that had not been formally published and is post-hoc in nature, despite alternative data being available that has been formally published and had been pre-specified in the relevant study. The post-hoc data relates to the FINE trial (Wearden 2010). The use of this data was not in accordance with the Cochrane review’s protocol and also contradicts the review’s stated methodology and the discussion of the review.

Specifically, the fatigue data taken from the FINE trial was not pre-specified for the trial and was not included in the original FINE trial literature. Instead, the data had been informally posted on a BMJ rapid response by the FINE trial investigators[3].

The review analyses post-hoc fatigue data from the FINE trial which is based on the Likert scoring system for the Chalder fatigue questionnaire, whereas the formally published FINE trial literature uses the same Chalder fatigue questionnaires but uses the biomodal scoring system, giving different outcomes for the same patient questionnaires. The FINE trial’s post-hoc Likert fatigue data (used in the review) was initially published by the FINE authors only in a BMJ rapid response post [3], apparently as an after-thought.

This is the response to my first letter…

Larun
Larun said she was “extremely concerned and disappointed” with the Cochrane editors’ actions. “I disagree with the decision and consider it to be disproportionate and poorly justified,” she said.

———————-

Larun said:

Dear Robert Courtney

Thank you for your detailed comments on the Cochrane review ‘Exercise Therapy for Chronic Fatigue Syndrome’. We have the greatest respect for your right to comment on and disagree with our work. We take our work as researchers extremely seriously and publish reports that have been subject to rigorous internal and external peer review. In the spirit of openness, transparency and mutual respect we must politely agree to disagree.

The Chalder Fatigue Scale was used to measure fatigue. The results from the Wearden 2010 trial show a statistically significant difference in favour of pragmatic rehabilitation at 20 weeks, regardless whether the results were scored bi-modally or on a scale from 0-3. The effect estimate for the 70 week comparison with the scale scored bi-modally was -1.00 (CI-2.10 to +0.11; p =.076) and -2.55 (-4.99 to -0.11; p=.040) for 0123 scoring. The FINE data measured on the 33-point scale was published in an online rapid response after a reader requested it. We therefore knew that the data existed, and requested clarifying details from the authors to be able to use the estimates in our meta-analysis. In our unadjusted analysis the results were similar for the scale scored bi-modally and the scale scored from 0 to 3, i.e. a statistically significant difference in favour of rehabilitation at 20 weeks and a trend that does not reach statistical significance in favour of pragmatic rehabilitation at 70 weeks. The decision to use the 0123 scoring did does not affect the conclusion of the review.

Regards,

Lillebeth Larun

——————

In her response, above, Larun discusses the FINE trial and quotes an effect size for post-hoc outcome data (fatigue at follow-up) from the FINE trial that is included in the review. Her quoted figures accurately reflect the data quoted by the FINE authors in their BMJ rapid-response comment [3] but, confusingly, these are slightly different from the data in the Cochrane review. In her response, Larun states that the FINE trial effect size for fatigue at 70 weeks using Likert data is -2.55 (-4.99 to -0.11; p=.040), whereas the Cochrane Review states that it is -2.12 [-4.49, 0.25].

This inconsistency makes this discussion confusing. Unfortunately there is no authoritative source for the data because it had not been formally published when the Cochrane review was published.

It seems that, in her response, Larun has quoted the BMJ rapid response data by Wearden et al.[3], rather than her own review’s data. Referring to her review’s data, Larun says that in “our unadjusted analysis the results were similar for the scale scored bi-modally and the scale scored from 0 to 3, i.e. a statistically significant difference in favour of rehabilitation at 20 weeks and a trend that does not reach statistical significance in favour of pragmatic rehabilitation at 70 weeks”.

It is not clear exactly why there are now two different Likert effect sizes, for fatigue at 70 weeks, but we can be sure that the use of this data undermines the review’s claim that “for this updated review, we have not collected unpublished data for our outcomes…”

This confusion, perhaps, demonstrates one of the pitfalls of using unpublished data. The difference between the data published in the review and the data quoted by Larun in her response (which are both supposedly the same unpublished data from the FINE trial) raises the question of exactly what data has been analysed in the review, and what exactly is the source . If it is unpublished data, and seemingly variable in nature, how are readers expected to scrutinise or trust the Cochrane analysis?

With respect to the FINE trial outcomes (fatigue at 70 week follow-up), Larun has provided the mean differences (effect size) for the (pre-specified) bimodal data and for (post-hoc) Likert data. These two different scoring methods (bimodel and Likert), are used for identical patient Chalder fatigue questionnaires, and provide different effect sizes, so switching the fatigue scoring methods may possibly have had an impact on the review’s primary outcomes for fatigue.

Larun hasn’t provided the effect estimates for fatigue at end-of-treatment, but these would also demonstrate variance between bimodal and Likert scoring, so switching the outcomes might have had a significant impact on the primary outcome of the Cochrane review at end-of-treatment, as well as at follow-up.

Note that the effect estimates outlined in this correspondence, for the FINE trial, are mean differences (this is the data taken from the FINE trial), rather than standardised mean differences (which are sometimes used in the meta-analyses in the Cochrane review); It is important not to get confused between the two different statistical analyses.

Larun said: “The decision to use the 0123 [i.e. Likert] scoring did does [sic] not affect the conclusion of the review.”

But it is not possible for a reader to verify that because Larun has not provided any evidence to demonstrate that switching outcomes has had no effect on the conclusion of the review. i.e. There is no sensitivity analysis, despite the review switching outcomes and using unpublished post-hoc data instead of published pre-specified data. This change in methodology means that the review does not conform to its own protocol and stated methodology. This seems like a significant issue.

Are we supposed to accept the word of the author, rather than review the evidence for ourselves? This is a Cochrane review – renowned for rigour and impartiality.

Note that Larun has acknowledged that I am correct with respect to the FINE trial data used in the review (i.e. that the data was unpublished and not part of the formally published FINE trial study, but was simply posted informally in a BMJ rapid response). Larun confirms that: “…the 33-point scale was published in an online rapid response after a reader requested it. We therefore knew that the data existed, and requested clarifying details from the authors…” But then Larun confusingly (for me) says we must “agree to disagree”.

Larun has not amended her literature to resolve the situation; Larun has not changed her unplanned analysis back to her planned analyses (i.e. to use published pre-specified data as per the review protocol, rather than unpublished post-hoc data); nor has she amended the text of the review so that it clearly and prominently indicates that the primary outcomes were switched. Neither has a sensitivity analysis been published using the FINE trial’s published pre-specified data.

Note the difference in the effect estimates at 70 weeks for bimodal scoring [-1.00 (CI -2.10 to +0.11; p =.076)] vs Likert scoring [-2.55 (-4.99 to -0.11; p=.040)] (as per the Cochrane analysis) or -2.12 [-4.49, 0.25] (also Likert scoring) as per Larun’s response and the BMJ rapid response where the data was initially presented to the public.

Confusingly, there are two different effect sizes for the same (Likert) data; one shows a significant treatment effect and the other shows a non-significant treatment effect. This seems like a rather chaotic situation for a Cochrane review . The data is neither consistent nor transparent. The unplanned Cochrane analysis uses data which has not been published and cannot be scrutinised.

Furthermore, we now have three sets of data for the same outcomes. Because an unplanned analysis was used in the review, it is nearly impossible to work out what is what.

In her response, above, Larun says that both fatigue outcomes (i.e. bimodal & Likert scoring systems) at 70 weeks are non-significant. This is true of the data published in the Cochrane review but, confusingly, this isn’t true if we consider the data that Larun has provided in her response, above. The bimodal and Likert data (fatigue at 70 weeks) presented in the review both have a non-significant effect, however, the Likert data quoted in Larun’s correspondence (which reflects the data in the FINE trial authors’ BMJ rapid response) shows a significant outcome. This may reflect the use of adjusted vs unadjusted data, but it isn’t clear.

Using post-hoc data may allow bias to creep into the review; For example, the Cochrane reviewers might have seen the post hoc data for the FINE trial , because it was posted in an open-access BMJ rapid response [3] prior to the Cochrane review publication date. I am not accusing the authors of conscious bias but Cochrane guidelines are put in place to avoid doubt and to maintain rigour and transparency. Hypothetically, a biased author may have seen that a post-hoc Likert analysis allowed for better outcomes to be reported for the FINE trial. The Cochrane guidelines are established in order to avoid such potential pitfalls and bias, and to avoid the confusion that is inherent in this review.

Note that the review still incorrectly says that all the data is previously published data – even though Larun admits in the letter that it isn’t. (i.e. the data are not formally published in a peer-reviewed journal; i assume that the review wasn’t referring to data that might be informally published in blogs or magazines etc, because the review pretends to analyse formally published data only.)

The authors have practically dismissed my concerns and have not amended anything in the review, despite admitting in the response that they’ve used post-hoc data.

The fact that this is all highly confusing, even after I have studied it in detail, demonstrates that these issues need to be straightened out and fixed.

It surely shouldn’t be the case, in a Cochrane review, that we ( for the same outcomes ) have three sets of results being bandied about, and the data used in a post hoc analysis seems to vary over time, and change from a non-significant treatment effect to a significance treatment effect, depending on where it is quoted. Because it is unpublished, independent scrutiny is made more difficult.

For your information, the BMJ rapid response (Wearden et al.) includes the following data : “Effect estimates [95% confidence intervals] for 20 week comparisons are: PR versus GPTAU -3.84 [-6.17, -1.52], SE 1.18, P=0.001; SL versus GPTAU +0.30 [-1.73, +2.33], SE 1.03, P=0.772. Effect estimates [95% confidence intervals] for 70 week comparisons are: PR versus GPTAU -2.55 [-4.99,-0.11], SE 1.24, P=0.040; SL versus GPTAU +0.36 [-1.90, 2.63], SE 1.15, P=0.752.”

My second submission was in relation to the following…

I believe that properly applying the official Cochrane guidelines would require the review to categorise the PACE trial (White 2011) data as ‘unplanned’ rather than ‘pre-specified’, and would require the risk of bias in relation to ‘selective reporting’ to be categorised accordingly. The Cochrane review currently categorises the risk of ‘selective reporting’ bias for the PACE trial as “low”, whereas the official Cochrane guidelines indicate (unambiguously) that the risk of bias for the PACE data should be “high”. I believe that my argument is fairly robust and water-tight.

This is the response to my second letter…

———————–

Larun said:

Dear Robert Courtney

Thank you for your detailed comments on the Cochrane review ‘Exercise Therapy for Chronic Fatigue Syndrome’. We have the greatest respect for your right to comment on and disagree with our work. We take our work as researchers extremely seriously and publish reports that have been subject to rigorous internal and external peer review. In the spirit of openness, transparency and mutual respect we must politely agree to disagree.

Cochrane reviews aim to report the review process in a transparent way, for example, are reasons for the risk of bias stated. We do not agree that Risk of Bias for the Pace trial (White 2011) should be changed, but have presented it in a way so it is possible to see our reasoning. We find that we have been quite careful in stating the effect estimates and the certainty of the documentation. We note that you read this differently.

Regards,

Lillebeth

————————-

I do not understand what is meant by: “We do not agree that Risk of Bias for the Pace trial (White 2011) should be changed, but have presented it in a way so it is possible to see our reasoning.” …

The review does not discuss the issue of the PACE data being unplanned and I, for one, do not understand the reasoning for not correcting the category for the risk of selective reporting bias. The response to my submission fails to engage with the substantive and serious issues that I raised.

To date, nearly all the issues raised in my letters have been entirely dismissed by Larun. I find this surprising, especially considering that some of the points that I have made were factual (i.e. not particularly open to interpretation) and difficult to dispute. Indeed, Larun’s response even accepts the factual point that I made, in relation to the FINE data, but then confusingly dismisses my request for the issue to be remedied.

There is more detail in the four PDF submissions which are attached to this email, and which have now been published in the latest version of the Cochrane review. I will stop this email now so as not to overwhelm you, and so I don’t repeat myself .

Again, I apologise for the complexity. My four submissions , attached to this email as PDF files, form the basis of my complaint so I ask you to consider them to be the central basis of my complaint . I hope that they will be sufficiently clear.

I trust that you will wish to investigate these issues, with a view to upholding the high standards expected from a Cochrane review.

I look forward to hearing from you in due course. Please feel free to email me at any time with any questions, of if you believe it would be helpful to discuss any of the issues raised.

Regards,

Robert Courtney.

My ‘comments’ (submitted to the Cochrane review authors):

Please note that the four attached PDF documents form the basis of this complaint.

For your convenience, I have included a weblink to a downloadable online copy of each document, and I have attached copies to this email as PDF files, and the comments have now been published in the latest updated version of the review.

The dates refer to the date the comments were submitted to Cochrane.

  1. Query re use of post-hoc unpublished outcome data: Scoring system for the Chalder fatigue scale, Wearden 2010.

Robert Courtney

16th April 2016

https://sites.google.com/site/mecfsnotes/submissions-to-the-cochrane-review-of-exercise-therapy-for-chronic-fatigue-syndrome/fine-trial-unpublished-data

  1. Assessment of Selective Reporting Bias in White 2011.

Robert Courtney

1st May 2016

https://sites.google.com/site/mecfsnotes/submissions-to-the-cochrane-review-of-exercise-therapy-for-chronic-fatigue-syndrome/pace-trial-selective-reporting-bias

  1. A query regarding the way outcomes for physical function and overall health have been described in the abstract, conclusion and discussions of the review.

Robert Courtney

12th May 2016

[ https://sites.google.com/site/mecfsnotes/submissions-to-the-cochrane-review-of-exercise-therapy-for-chronic-fatigue-syndrome/misreporting-of-outcomes-for-physical-function ]

  1. Concerns regarding the use of unplanned primary outcomes in the Cochrane review.

Robert Courtney

3rd June 2016

https://sites.google.com/site/mecfsnotes/submissions-to-the-cochrane-review-of-exercise-therapy-for-chronic-fatigue-syndrome/primary-outcome-switching

References:

  1. Quote from Cochrane reference CD011040:

“Acknowledgements[…]The author team held three meetings in 2011, 2012 and 2013 which were funded as follows: […]2013 via Peter D White’s academic fund (Professor of Psychological Medicine, Centre for Psychiatry, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London).”

  1. Larun L, Odgaard-Jensen J, Brurberg KG, Chalder T, Dybwad M, Moss-Morris RE, Sharpe M, Wallman K, Wearden A, White PD, Glasziou PP. Exercise therapy for chronic fatigue syndrome (individual patient data) (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD011040.

http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011040/abstract

http://www.cochrane.org/CD011040/DEPRESSN_exercise-therapy-for-chronic-fatigue-syndrome-individual-patient-data

 

  1. Wearden AJ, Dowrick C, Chew-Graham C, et al. Fatigue scale. BMJ Rapid Response. 2010.

http://www.bmj.com/rapid-response/2011/11/02/fatigue-scale-0 (accessed Feb 21, 2016).

End.

Cochrane complaints procedure:

http://www.cochranelibrary.com/help/the-cochrane-library-complaints-procedure.html

Before you enroll your child in the MAGENTA chronic fatigue syndrome study: Issues to be considered

[October 3 8:23 AM Update: I have now inserted Article 21 of the Declaration of Helsinki below, which is particularly relevant to discussions of the ethical problems of Dr. Esther Crawley’s previous SMILE trial.]

Petitions are calling for shutting down the MAGENTA trial. Those who organized the effort and signed the petition are commendably brave, given past vilification of any effort by patients and their allies to have a say about such trials.

Below I identify a number of issues that parents should consider in deciding whether to enroll their children in the MAGENTA trial or to withdraw them if they have already been enrolled. I take a strong stand, but I believe I have adequately justified and documented my points. I welcome discussion to the contrary.

This is a long read but to summarize the key points:

  • The MAGENTA trial does not promise any health benefits for the children participating in the trial. The information sheet for the trial was recently modified to suggest they might benefit. However, earlier versions clearly stated that no benefit was anticipated.
  • There is inadequate disclosure of likely harms to children participating in the trial.
  • An estimate of a health benefit can be evaluated from the existing literature concerning the effectiveness of the graded exercise therapy intervention with adults. Obtaining funding for the MAGENTA trial depended on a misrepresentation of the strength of evidence that it works in adult populations.  I am talking about the PACE trial.
  • Beyond any direct benefit to their children, parents might be motivated by the hope of contributing to science and the availability of effective treatments. However, these possible benefits depend on publication of results of a trial after undergoing peer review. The Principal Investigator for the MAGENTA trial, Dr. Esther Crawley, has a history of obtaining parents’ consent for participation of their children in the SMILE trial, but then not publishing the results in a timely fashion. Years later, we are still waiting.
  • Dr. Esther Crawley exposed children to unnecessary risk without likely benefit in her conduct of the SMILE trial. This clinical trial involved inflicting a quack treatment on children. Parents were not adequately informed of the nature of the treatment and the absence of evidence for any mechanism by which the intervention could conceivably be effective. This reflects on the due diligence that Dr. Crawley can be expected to exercise in the MAGENTA trial.
  • The consent form for the MAGENTA trial involves parents granting permission for the investigator to use children and parents’ comments concerning effects of the treatment for its promotion. Insufficient restrictions are placed on how the comments can be used. There is the clear precedent of comments made in the context of the SMILE trial being used to promote the quack Lightning Process treatment in the absence of evidence that treatment was actually effective in the trial. There is no guarantee that any comments collected from children and parents in the MAGENTA trial would not similarly be misused.
  • Dr. Esther Crawley participated in a smear campaign against parents having legitimate concerns about the SMILE trial. Parents making legitimate use of tools provided by the government such as Freedom of Information Act requests, appeals of decisions of ethical review boards and complaints to the General Medical Council were vilified and shamed.
  • Dr. Esther Crawley has provided direct, self-incriminating quotes in the newsletter of the Science Media Centre about how she was coached and directed by their staff to slam the patient community.  She played a key role in a concerted and orchestrated attack on the credibility of not only parents of participants in the MAGENTA trial, but of all patients having chronic fatigue syndrome/ myalgic encephalomyelitis , as well as their advocates and allies.

I am not a parent of a child eligible for recruitment to the MAGENTA trial. I am not even a citizen or resident of the UK. Nonetheless, I have considered the issues and lay out some of my considerations below. On this basis, I signed the global support version  of the UK petition to suspend all trials of graded exercise therapy in children and adults with ME/CFS. I encourage readers who are similarly in my situation outside the UK to join me in signing the global support petition.

If I were a parent of an eligible child or a resident of the UK, I would not enroll my child in MAGENTA. I would immediately withdraw my child if he or she were currently participating in the trial. I would request all the child’s data be given back or evidence that it had been destroyed.

I recommend my PLOS Mind the Brain post, What patients should require before consenting to participate in research…  as either a prelude or epilogue to the following blog post.

What you will find here is a discussion of matters that parents should consider before enrolling their children in the MAGENTA trial of graded exercise for chronic fatigue syndrome. The previous blog post [http://blogs.plos.org/mindthebrain/2015/12/09/what-patients-should-require-before-consenting-to-participate-in-research/ ]  is rich in links to an ongoing initiative from The BMJ to promote broader involvement of patients (and implicitly, parents of patients) in the design, implementation, and interpretation of clinical trials. The views put forth by The BMJ are quite progressive, even if there is a gap between their expression of views and their actual implementation. Overall, that blog post presents a good set of standards for patients (and parents) making informed decisions concerning enrollment in clinical trials.

Simon McGrathLate-breaking update: See also

Simon McGrath: PACE trial shows why medicine needs patients to scrutinise studies about their health

Basic considerations.

Patients are under no obligation to participate in clinical trials. It should be recognized that any participation typically involves burden and possibly risk over what is involved in receiving medical care outside of a clinical trial.

It is a deprivation of their human rights and a violation of the Declaration of Helsinki to coerce patients to participate in medical research without freely given, fully informed consent.

Patients cannot be denied any medical treatment or attention to which they would otherwise be entitled if they fail to enroll in a clinical trial.

Issues are compounded when consent from parents is sought for participation of vulnerable children and adolescents for whom they have legal responsibility. Although assent to participate in clinical trials is sought from children and adolescents, it remains for their parents to consent to their participation.

Parents can at any time withdraw their consent for their children and adolescents participating in trials and have their data removed, without requiring the approval of any authorities of their reason for doing so.

Declaration of Helsinki

The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data.

It includes:

In medical research involving human subjects capable of giving informed consent, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail, post-study provisions and any other relevant aspects of the study. The potential subject must be informed of the right to refuse to participate in the study or to withdraw consent to participate at any time without reprisal. Special attention should be given to the specific information needs of individual potential subjects as well as to the methods used to deliver the information.

[October 3 8:23 AM Update]: I have now inserted Article 21 of the Declaration of Helsinki which really nails the ethical problems of the SMILE trial:

21. Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be respected.

There is clearly in adequate scientific justification for testing the quack Lightning Process Treatment.

What Is the Magenta Trial?

The published MAGENTA study protocol states

This study aims to investigate the acceptability and feasibility of carrying out a multicentre randomised controlled trial investigating the effectiveness of graded exercise therapy compared with activity management for children/teenagers who are mildly or moderately affected with CFS/ME.

Methods and analysis 100 paediatric patients (8–17 years) with CFS/ME will be recruited from 3 specialist UK National Health Service (NHS) CFS/ME services (Bath, Cambridge and Newcastle). Patients will be randomised (1:1) to receive either graded exercise therapy or activity management. Feasibility analysis will include the number of young people eligible, approached and consented to the trial; attrition rate and treatment adherence; questionnaire and accelerometer completion rates. Integrated qualitative methods will ascertain perceptions of feasibility and acceptability of recruitment, randomisation and the interventions. All adverse events will be monitored to assess the safety of the trial.

The first of two treatments being compared is:

Arm 1: activity management

This arm will be delivered by CFS/ME specialists. As activity management is currently being delivered in all three services, clinicians will not require further training; however, they will receive guidance on the mandatory, prohibited and flexible components (see online supplementary appendix 1). Clinicians therefore have flexibility in delivering the intervention within their National Health Service (NHS) setting. Activity management aims to convert a ‘boom–bust’ pattern of activity (lots 1 day and little the next) to a baseline with the same daily amount before increasing the daily amount by 10–20% each week. For children and adolescents with CFS/ME, these are mostly cognitive activities: school, schoolwork, reading, socialising and screen time (phone, laptop, TV, games). Those allocated to this arm will receive advice about the total amount of daily activity, including physical activity, but will not receive specific advice about their use of exercise, increasing exercise or timed physical exercise.

So, the first arm of the trial is a comparison condition consisting of standard care delivered without further training of providers. The treatment is flexibly delivered, expected to vary between settings, and thus largely uncontrolled. The treatment represents a methodologically weak condition that does not adequately control for attention and positive expectations. Control conditions should be equivalent to the intervention being evaluated in these dimensions.

The second arm of the study:

Arm 2: graded exercise therapy (GET)

This arm will be delivered by referral to a GET-trained CFS/ME specialist who will receive guidance on the mandatory, prohibited and flexible components (see online supplementary appendix 1). They will be encouraged to deliver GET as they would in their NHS setting.20 Those allocated to this arm will be offered advice that is focused on exercise with detailed assessment of current physical activity, advice about exercise and a programme including timed daily exercise. The intervention will encourage children and adolescents to find a baseline level of exercise which will be increased slowly (by 10–20% a week, as per NICE guidance5 and the Pacing, graded Activity and Cognitive behaviour therapy – a randomised Evaluation (PACE)12 ,21). This will be the median amount of daily exercise done during the week. Children and adolescents will also be taught to use a heart rate monitor to avoid overexertion. Participants will be advised to stay within the target heart rate zones of 50–70% of their maximum heart rate.5 ,7

The outcome of the trial will be evaluated in terms of

Quantitative analysis

The percentage recruited of those eligible will be calculated …Retention will be estimated as the percentage of recruited children and adolescents reaching the primary 6-month follow-up point, who provide key outcome measures (the Chalder Fatigue Scale and the 36-Item Short-Form Physical Functioning Scale (SF-36 PFS)) at that assessment point.

actigraphObjective data will be collected in the form of physical activity measured by Accelerometers. These are

Small, matchbox-sized devices that measure physical activity. They have been shown to provide reliable indicators of physical activity among children and adults.

However, actual evaluation of the outcome of the trial will focus on recruitment and retention and subjective, self-report measures of fatigue and physical functioning. These subjective measures have been shown to be less valid than objective measures. Scores are  vulnerable  to participants knowing what condition they are assigned to (called ‘being unblinded’) and their perception of which intervention the investigators prefer.

It is notable that in the PACE trial of CBT and GET for chronic fatigue syndrome in adults, the investigators manipulated participants’ self-reports with praise in newsletters sent out during the trial . The investigators also switched their scoring of the self-report measures and produced results that they later conceded to have been exaggerated by their changing in scoring of the self-report measures [http://www.wolfson.qmul.ac.uk/current-projects/pace-trial#news ].

Irish ME/CFS Association Officer & Tom Kindlon
Tom Kindlon, Irish ME/CFS Association Officer

See an excellent commentary by Tom Kindlon at PubMed Commons [What’s that? ]

The validity of using subjective outcome measures as primary outcomes is questionable in such a trial

The bottom line is that the investigators have a poorly designed study with inadequate control condition. They have chosen subjective self-reports that are prone to invalidity and manipulation over objective measures like actual changes in activity or practical real-world measures like school attendance. Not very good science here. But they are asking parents to sign their children up.

What is promised to parents consenting to have the children enrolled in the trial?

The published protocol to which the investigators supposedly committed themselves stated

What are the possible benefits and risks of participating?
Participants will not benefit directly from taking part in the study although it may prove enjoyable contributing to the research. There are no risks of participating in the study.

Version 7 of the information sheet provided to parents, states

Your child may benefit from the treatment they receive, but we cannot guarantee this. Some children with CFS/ME like to know that they are helping other children in the future. Your child may also learn about research.

Survey assessments conducted by the patient community strongly contradict the suggestion that there is no risk of harm with GET.

alemAlem Matthees, the patient activist who obtained release of the PACE data and participated in reanalysis has commented:

“Given that post-exertional symptomatology is a hallmark of ME/CFS, it is premature to do trials of graded exercise on children when safety has not first been properly established in adults. The assertion that graded exercise is safe in adults is generally based on trials where harms are poorly reported or where the evidence of objectively measured increases in total activity levels is lacking. Adult patients commonly report that their health was substantially worsened after trying to increase their activity levels, sometimes severely and permanently, therefore this serious issue cannot be ignored when recruiting children for research.”

See also

Kindlon T. Reporting of harms associated with graded exercise therapy and cognitive behavioural therapy in myalgic encephalomyelitis/chronic fatigue syndrome. Bulletin of the IACFS/ME. 2011;19(2):59-111.

This thorough systematic review reports inadequacy in harm reporting in clinical trials, but:

Exercise-related physiological abnormalities have been documented in recent studies and high rates of adverse  reactions  to exercise have been  recorded in  a number of  patient surveys. Fifty-one percent of  survey respondents (range 28-82%, n=4338, 8 surveys) reported that GET worsened their health while 20% of respondents (range 7-38%, n=1808, 5 surveys) reported similar results for CBT.

The unpublished results of Dr. Esther Crawley’s SMILE trial

 A Bristol University website indicates that recruitment of the SMILE trial was completed in 2013. The published protocol for the SMILE trial

[Note the ® in the title below, indicating a test of trademarked commercial product. The significance of that is worthy of a whole other blog post. ]

Crawley E, Mills N, Hollingworth W, Deans Z, Sterne JA, Donovan JL, Beasant L, Montgomery A. Comparing specialist medical care with specialist medical care plus the Lightning Process® for chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME): study protocol for a randomised controlled trial (SMILE Trial). Trials. 2013 Dec 26;14(1):1.

States

The data monitoring group will receive notice of serious adverse events (SAEs) for the sample as whole. If the incidence of SAEs of a similar type is greater than would be expected in this population, it will be possible for the data monitoring group to receive data according to trial arm to determine any evidence of excess in either arm.

Primary outcome data at six months will be examined once data are available from 50 patients, to ensure that neither arm is having a detrimental effect on the majority of patients. An independent statistician with no other involvement in the study will investigate whether more than 20 participants in the study sample as a whole have experienced a reduction of ≥ 30 points on the SF-36 at six months. In this case, the data will then be summarised separately by trial arm, and sent to the data monitoring group for review. This process will ensure that the trial team will not have access to the outcome data separated by treatment arm.

A Bristol University website indicates that recruitment of the SMILE trial was completed in 2013. The trial was thus completed a number of years ago, but these valuable data have never been published.

The only publication from the trial so far uses selective quotes from child participants that cannot be independently evaluated. Readers are not told how representative these quotes, the outcomes for the children being quoted or the overall outcomes of the trial.

Parslow R, Patel A, Beasant L, Haywood K, Johnson D, Crawley E. What matters to children with CFS/ME? A conceptual model as the first stage in developing a PROM. Archives of Disease in Childhood. 2015 Dec 1;100(12):1141-7.

The “evaluation” of the quack Lightning Treatment in the SMILE trial and quotes from patients have also been used to promote Parker’s products as being used in NHS clinics.

How can I say the Lightning Process is quackery?

 Dr. Crawley describes the Lightning Process in the Research Ethics Application Form for the SMILE study as   ombining the principles of neurolinguistic programming, osteopathy, and clinical hypnotherapy.

That is an amazing array of three different frameworks from different disciplines. You would be hard pressed to find an example other than the Lightning Process that claimed to integrate them. Yet, any mechanisms for explaining therapeutic interventions cannot be a creative stir fry of whatever is on hand being thrown together. For a treatment to be considered science-based, there has to be a solid basis of evidence that these presumably complex processes fit together as assumed and work as assumed. I challenge Dr. Crawley or anyone else to produce a shred of credible, peer-reviewed evidence for the basic mechanism of the Lightning Process.

The entry for Neuro-linguistic programming (NLP) in Wikipedia states

There is no scientific evidence supporting the claims made by NLP advocates and it has been discredited as a pseudoscience by experts.[1][12] Scientific reviews state that NLP is based on outdated metaphors of how the brain works that are inconsistent with current neurological theory and contain numerous factual errors.[13][14

The respected Skeptics Dictionary offers a scathing critique of Phil Parker’s Lightning Process. The critique specifically cites concerns that Crawley’s SMILE trial switched outcomes to increase the likelihood of obtaining evidence of effectiveness.

 The Hampshire (UK) County Council Trading Standards Office filed a formal complaint against Phil Parker for claims made on the Lightning Process website concerning effects on CFS/ME:

The “CFS/ME” page of the website included the statements “Our survey found that 81.3 %* of clients report that they no longer have the issues they came with by day three of the LP course” and “The Lightning Process is working with the NHS on a feasibility study, please click here for further details, and for other research information click here”.

parker nhs advert
Seeming endorsements on Parker’s website. Two of them –Northern Ireland and NHS Suffolk subsequently complained that use of their insignias was unauthorized and they were quickly removed.

The “working with the NHS” refers to the collaboration with Dr. Easter Crawley.

The UK Advertising Standards Authority upheld this complaint, as well as about Parker’s claims about effectiveness with other conditions, including  multiple sclerosis, irritable bowel syndrome and fibromyalgia

 Another complaint in 2013 about claims on Phil Parker’s website was similarly upheld:

 The claims must not appear again in their current form. We welcomed the decision to remove the claims. We told Phil Parker Group not to make claims on websites within their control that were directly connected with the supply of their goods and services if those claims could not be supported with robust evidence. We also told them not to refer to conditions for which advice should be sought from suitably qualified health professionals.

 As we will see, these upheld charges of quackery occurred when parents of children participating in the SMILE trial were being vilified in the BMJ and elsewhere. Dr. Crawley was prominently featured in this vilification and was quoted in a celebration of its success by the Science Media Centre, which had orchestrated the vilification.

Captured cfs praker ad

The Research Ethics Committee approval of the SMILE trial and the aftermath

 I was not very aware of the CFS/ME literature, and certainly not all its controversies when the South West Research Ethics Committee (REC) reviewed the application for the SMILE trial and ultimately approved it on September 8, 2010.

I would have had strong opinions about it. I only first started blogging a little afterwards.  But I was very concerned about any patients being exposed to alternative and unproven medical treatments in other contexts that were not evidence-based – even more so to treatments for which promoters claimed implausible mechanisms by which they worked. I would not have felt it appropriate to inflict the Lightning Process on unsuspecting children. It is insufficient justification to put them a clinical trial simply because a particular treatment has not been evaluated.

 Prince Charles once advocated organic coffee enemas to treat advanced cancer. His endorsement generated a lot of curiosity from cancer patients. But that would not justify a randomized trial of coffee enemas. By analogy, I don’t think Dr. Esther Crawley had sufficient justification to conduct her trial, especially without warnings that that there was no scientific basis to expect the Lightning Process to work or that it would not hurt the children.

 I am concerned about clinical trials that have little likelihood of producing evidence that a treatment is effective, but that seemed designed to get these treatments into routine clinical care. it is now appreciated that some clinical trials have little scientific value but serve as experimercials or means of placing products in clinical settings. Pharmaceutical companies notoriously do this.

As it turned out, the SMILE trial succeeded admirably as a promotion for the Lightning Process, earning Phil Parker unknown but substantial fees through its use in the SMILE trial, but also in successful marketing throughout the NHS afterwards.

In short, I would been concerned about the judgment of Dr. Esther Crawley in organizing the SMILE trial. I would been quite curious about conflicts of interest and whether patients were adequately informed of how Phil Parker was benefiting.

The ethics review of the SMILE trial gave short shrift to these important concerns.

When the patient community and its advocate, Dr. Charles Shepherd, became aware of the SMILE trial’s approval, there were protests leading to re-evaluations all the way up to the National Patient Safety Agency. Examining an Extract of Minutes from South West 2 REC meeting held on 2 December 2010, I see many objections to the approval being raised and I am unsatisfied by the way in which they were discounted.

Patient, parent, and advocate protests escalated. If some acted inappropriate, this did not undermine the righteousness of others legitimate protest. By analogy, I feel strongly about police violence aimed against African-Americans and racist policies that disproportionately target African-Americans for police scrutiny and stoppng. I’m upset when agitators and provocateurs become violent at protests, but that does not delegitimize my concerns about the way black people are treated in America.

Dr. Esther Crawley undoubtedly experienced considerable stress and unfair treatment, but I don’t understand why she was not responsive to patient concerns nor  why she failed to honor her responsibility to protect child patients from exposure to unproven and likely harmful treatments.

Dr. Crawley is extensively quoted in a British Medical Journal opinion piece authored by a freelance journalist,  Nigel Hawkes:

Hawkes N. Dangers of research into chronic fatigue syndrome. BMJ. 2011 Jun 22;342:d3780.

If I had been on the scene, Dr. Crawley might well have been describing me in terms of how I would react, including my exercising of appropriate, legally-provided means of protest and complaint:

Critics of the method opposed the trial, first, Dr Crawley says, by claiming it was a terrible treatment and then by calling for two ethical reviews. Dr Shepherd backed the ethical challenge, which included the claim that it was unethical to carry out the trial in children, made by the ME Association and the Young ME Sufferers Trust. After re-opening its ethical review and reconsidering the evidence in the light of the challenge, the regional ethical committee of the NHS reiterated its support for the trial.

There was arguably some smearing of Dr. Shepherd, even in some distancing of him from the action of others:

This point of view, if not the actions it inspires, is defended by Charles Shepherd, medical adviser to and trustee of the ME Association. “The anger and frustration patients have that funding has been almost totally focused on the psychiatric side is very justifiable,” he says. “But the way a very tiny element goes about protesting about it is not acceptable.

This article escalated with unfair comparisons to animal rights activists, with condemnation of appropriate use of channels of complaint – reporting physicians to the General Medical Council.

The personalised nature of the campaign has much in common with that of animal rights activists, who subjected many scientists to abuse and intimidation in the 1990s. The attitude at the time was that the less said about the threats the better. Giving them publicity would only encourage more. Scientists for the most part kept silent and journalists desisted from writing about the subject, partly because they feared anything they wrote would make the situation worse. Some journalists have also been discouraged from writing about CFS/ME, such is the unpleasant atmosphere it engenders.

While the campaigners have stopped short of the violent activities of the animal rights groups, they have another weapon in their armoury—reporting doctors to the GMC. Willie Hamilton, an academic general practitioner and professor of primary care diagnostics at Peninsula Medical School in Exeter, served on the panel assembled by the National Institute for Health and Clinical Excellence (NICE) to formulate treatment advice for CFS/ME.

Simon Wessely and the Principal Investigator of the PACE trial, Peter White, were given free rein to dramatize their predicament posed by the protest. Much later, in the 2016 Lower Tribunal Hearing, testimony would be given by PACE

Co-Investigator Trudie Chalder would much later (2016) cast doubt on whether the harassment was as severe or violent as it was portrayed. Before that, the financial conflicts of interest of Peter White that were denied in the article would be exposed.

In response to her testimony, the UK Information Officer stated:

Professor Chalder’s evidence when she accepts that unpleasant things have been said to and about PACE researchers only, but that no threats have been made either to researchers or participants.

But in 2012, a pamphlet celebrating the success of The Science Media Centre started by Wessely would be rich in indiscreet quotes from Esther Crawley. The article in BMJ was revealed to be part of a much larger orchestrated campaign to smear, discredit and silence patients, parents, advocates and their allies.

Dr. Esther Crawley’s participation in a campaign organized by the Science Media Center to discredit patients, parents, advocates and supporters.

 The SMC would later organize a letter writing campaign to Parliament in support of Peter White and his refusal to release the PACE data to Alem Mattheees who had made a requestunder the Freedom of Information Act. The letter writing campaign was an effort to get scientific data excluded from the provisions of the freedom of information act. The effort failed and the data were subsequently released.

But here is how Esther Crawley described her assistance:

The SMC organised a meeting so we could discuss what to do to protect researchers. Those who had been subject to abuse met with press officers, representatives from the GMC and, importantly, police who had dealt with the  animal rights campaign. This transformed my view of  what had been going on. I had thought those attacking us were “activists”; the police explained they were “extremists”.

And

We were told that we needed to make better use of the law and consider using the press in our favour – as had researchers harried by animal rights extremists. “Let the public know what you are trying to do and what is happening to you,” we were told. “Let the public decide.”

And

I took part in quite a few interviews that day, and have done since. I was also inundated with letters, emails and phone calls from patients with CFS/ME all over the world asking me to continue and not “give up”. The malicious, they pointed out, are in a minority. The abuse has stopped completely. I never read the activists’ blogs, but friends who did told me that they claimed to be “confused” and “upset” – possibly because their role had been switched from victim to abuser. “We never thought we were doing any harm…”

 The patient community and its allies are still burdened by the damage of this effort and are rebuilding its credibility only slowly. Only now are they beginning to get an audience as suffering human beings with significant, legitimate unmet needs. Only now are they escaping the stigmatization that occurred at this time with Esther Crawley playing a key role.

Where does this leave us?

stop posterParents are being asked to enroll in a clinical trial without clear benefit to the children but with the possibility of considerable risk from the graded exercise. They are being asked by Esther Crawley, a physician, who has previously inflicted a quack treatment on their children with CFS/ME in the guise of a clinical trial, for which he is never published the resulting data. She has played an effective role in damaging the legitimacy and capacity of patients and parents to complain.

Given this history and these factors, why would a parent possibly want to enroll their children in the MAGENTA trial? Somebody please tell me.

Special thanks to all the patient citizen-scientists who contributed to this blog post. Any inaccuracies or excesses are entirely my own, but these persons gave me substantial help. Some are named in the blog, but others prefer anonymity.

 All opinions expressed are solely those of James C Coyne. The blog post in no way conveys any official position of Mind the Brain, PLOS blogs or the larger PLOS community. I appreciate the free expression of  personal opinion that I am allowed.