UK Health Research Authority defends PACE. Answer to MP's question, February 2019.

Lucibee said:
I posted them here: https://www.s4me.info/threads/uk-he...uestion-february-2019.8045/page-7#post-142571
and in my next post below that.
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That is interestingly sketchy. It could be considered inadequate because it says nothing about patients being obliged to engage with the way the therapist wants them to see their illness. It does not say that cognitive strategies will be used to persuade the patient to see their illness differently. Also, it is unclear how a therapist can help the patient understand an illness nobody understands. And so on...
 
Jonathan Edwards said:
I think the problem is close to the comment in the RCGP document that effectively says that people with ME/CFS are exceptions to the legal position on informed consent because it may be in their best interests to be lied to.
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Which of course is clinicians playing god in the extreme. I fully appreciate a doctor will sometimes have to make decisions in situations where their patient is incapable of doing it for them self - playing god being unavoidable, but always one would hope with the greatest integrity, and concern for whether the patient really is incapable of making their own decision. An easy example might be an unconscious crash victim, whose leg needs amputating to save their life. But in completely the opposite case, playing god out of hugely increased sense of entitlement ... not good at all.
 
Here's the letter I submitted to the BMJ which didn't get accepted. It simply lists some of the main arguments which you all know and which have already been made on this forum and elsewhere.

I'm a bit curious about the reason it wasn't accepted. At one point I thought it could be because I directed my criticism at Prof. Jonathan Montgomery, chair of the HRA, in person. So I resubmitted the letter by changing that section:

"If this is indeed a responsible approach to data transparency, I would like Prof. Jonathan Montgomery, chair of the HRA, to specify what would constitute an irresponsible approach."​

Was changed into the less aggressive:

"This does not seem like a responsible approach to data transparency. The fact that the Information Commissioner’s Office accepted QMUL’s position on other requests, changes little to these shortcomings."​

But that didn't work. I got formal confirmation of my rapid response submission on email for both versions, so I don't think I did something wrong in the process of submitting.

The letter might be a bit long, but without references, it's only 680 words and I think I've seen longer rapid responses. Perhaps it focused too much on the HRA letter instead of the BMJ's reporting of it. However, I think the same can be said of letters that did get published. So I don't really know why it was refused (I didn't get an email explaining or even confirming the rejection).




I would like to comment on the NHS Health Research Authority’s (HRA) letter regarding the PACE-trial. [1,2] Due to its restricted authority, the HRA focuses on conflicts of interests, alterations in the outcome measures and availability of data for secondary analysis.

The main concern regarding conflicts of interests is that the PACE-authors violated their promise, as made in the protocol [3], to adhere to the declaration of Helsinki. The declaration requests that potential participants in a trial are “adequately informed” about researchers “possible conflicts of interest”. [4] This code of conduct seems to have been breached in the PACE-trial. Four participants in the trial have been interviewed and all said they were not informed about the lead investigators’ ties to insurance companies. Some said they would have likely refused participation in the trial if they had been informed about this information beforehand. [5] In an open letter to the Lancet, more than 40 ME/CFS researchers and expert clinicians expressed their concern about this violation of the declaration of Helsinki. They demanded, “whether the consent obtained from the 641 trial participants is legitimate.” [6] The HRA report fails to give them reassurance. In fact, the report admits that the Patient Information Sheet (PIS) did not contain information about the advisory roles of PACE trial researchers, information that was detailed in the trial protocol. [3] But instead of reaffirming concerns about this violation of the Declaration of Helsinki, the HRA argues that these advisory roles to insurance companies do not constitute a conflict of interest. This is a curious explanation. If these advisory roles were described as conflicts of interest in the main Lancet paper of 2011 [7] and in the trial protocol, why should the reporting to trial participants be any different?

Secondly, the HRA letter notes that Queen Mary University of London (QMUL) and the PACE-authors “approached the issue of transparency of data for analysis responsibly.” I would like to contest that statement. PLOS One currently issues an “expression of concern” about the economic analysis of the PACE-results (MCcrone et al. 2012) because the authors refused to share data for independent reanalysis as is required by journal policy. [8] QMUL’s rejection to share the trials’ main outcome data has been condemned within the scientific community. [9] Without the release of this data, it would still be unknown that the PACE-authors inflated their recovery rates threefold by deviating from the thresholds set out in their protocol. [10] This is relevant information for healthcare professionals. QMUL has spent 245.000 pounds to block the release of this information [11] and characterized those who demanded transparency as a “very damaging group of individuals.” [12] If this is indeed a responsible approach to data transparency, I would like Prof. Jonathan Montgomery, chair of the HRA, to specify what would constitute an irresponsible approach.

Thirdly, the HRA letter claims that differences between the initial plans and published results of the PACE-trial “were openly reported in the main Lancet paper of 2011.” This is factually incorrect. The Lancet paper of 2011 [7] does not clarify the changes in how the main outcome (improvement based on physical function and fatigue scores) was reported, nor was a sensitivity analysis conducted in any of the peer-reviewed publications by the PACE-authors. In 2018, a reanalysis of the data according to the trial protocol confirmed that the changes in outcome reporting significantly altered the trials’ findings. [13]

The HRA letter also claims that “the robustness of the PACE trial has been considered in a Cochrane review that classified it as high quality.” Yet, Cochrane currently issues a warning that the relevant review (Larun et al. 2017) is “substantially out of date and in need of updating.” [14] An international news outlet reported that retraction of the review is imminent. [15] It should also be noted that Larun et al. collaborated with the main PACE-authors on a Cochrane review based on individual patient data of graded exercise therapy trials and that this project has been retracted. [16]

With such errors and omissions it seems unlikely that HRA has “examined this study in detail.”

Michiel Tack.

ME/CFS patient

No conflicts of interest.


References:

[1] Hawkes N. PACE chronic fatigue trial was properly conducted, says UK research watchdog. BMJ 2019;364:l639 https://www.bmj.com/content/364/bmj.l639

[2] Montgomery J. Re: The PACE trial and the Committee’s inquiry on Research Integrity. NHS Health Research Authority. Jan 2019. https://www.parliament.uk/documents...Research-Authority-to-Chair-re-PACE-trial.pdf

[3] White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007 Mar 8;7:6. https://bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-7-6

[4] World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013 Nov 27;310(20):2191-4. https://jamanetwork.com/journals/jama/fullarticle/1760318

[5] Tuller D. Trial by error: The Troubling Case of the PACE Chronic Fatigue Syndrome Study (second installment). Virology blog. Oct 2015. http://www.virology.ws/2015/10/22/trial-by-error-ii/

[6] Tuller D. An open letter to The Lancet, again. Virology Blog. Feb 2016. http://www.virology.ws/2016/02/10/open-letter-lancet-again/

[7] White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, 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 Mar 5;377(9768):823-36. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60096-2/fulltext

[8] McCrone P, Sharpe M, Chalder T, Knapp M, Johnson AL, Goldsmith KA, White PD. Adaptive pacing, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome: a cost-effectiveness analysis. PLoS One. 2012;7(8):e40808. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040808

[9] Smith R. QMUL and King’s college should release data from the PACE trial. The BMJ Opinion. Dec 2015. https://blogs.bmj.com/bmj/2015/12/1...lege-should-release-data-from-the-pace-trial/

[10] Wilshire CE, Kindlon T, Matthees A, et al. Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial. Fatigue. 2017; 1-4. https://www.tandfonline.com/doi/abs/10.1080/21641846.2017.1259724

[11] Johnthejack. Using public money to keep publicly funded data from the public [blog]. June 2016. https://johnthejack.com/2016/06/29/using-public-money-to-keep-publicly-funded-data-from-the-public/

[12] General Regulatory Chamber. First-tier tribunal. Appeal number EA/2015/0269. April 2016. http://informationrights.decisions.tribunals.gov.uk//DBFiles/Decision/i1854/Queen%20Mary%20University%20of%20London%20EA-2015-0269%20(12-8-16).PDF

[13] Wilshire CE, Kindlon T, Courtney R, Matthees A, Tuller D, Geraghty K6, et al. Rethinking the treatment of chronic fatigue syndrome-a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC Psychol. 2018 Mar 22;6(1):6. https://bmcpsychology.biomedcentral.com/articles/10.1186/s40359-018-0218-3

[14] Cochrane Database of Systematic Reviews . Exercise therapy for chronic fatigue syndrome. What's new. Nov. 2018. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003200.pub7/information#whatsNew

[15] Kelland K. Exclusive: Science journal to withdraw chronic fatigue review amid patient activist complaints. Reuters. Oct. 2018. https://in.reuters.com/article/us-h...mid-patient-activist-complaints-idINKCN1MR2PI

[16] Cochrane Database of Systematic Reviews. Exercise therapy for chronic fatigue syndrome (individual patient data). What's new. Dec. 2018. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011040.pub2/information#whatsNew
 
Michiel Tack said:
Here's the letter I submitted to the BMJ which didn't get accepted. It simply lists some of the main arguments which you all know and which have already been made on this forum and elsewhere.

I'm a bit curious about the reason it wasn't accepted. At one point I thought it could be because I directed my criticism at Prof. Jonathan Montgomery, chair of the HRA, in person. So I resubmitted the letter by changing that section:

"If this is indeed a responsible approach to data transparency, I would like Prof. Jonathan Montgomery, chair of the HRA, to specify what would constitute an irresponsible approach."​

Was changed into the less aggressive:

"This does not seem like a responsible approach to data transparency. The fact that the Information Commissioner’s Office accepted QMUL’s position on other requests, changes little to these shortcomings."​

But that didn't work. I got formal confirmation of my rapid response submission on email for both versions, so I don't think I did something wrong in the process of submitting.

The letter might be a bit long, but without references, it's only 680 words and I think I've seen longer rapid responses. Perhaps it focused too much on the HRA letter instead of the BMJ's reporting of it. However, I think the same can be said of letters that did get published. So I don't really know why it was refused (I didn't get an email explaining or even confirming the rejection).




I would like to comment on the NHS Health Research Authority’s (HRA) letter regarding the PACE-trial. [1,2] Due to its restricted authority, the HRA focuses on conflicts of interests, alterations in the outcome measures and availability of data for secondary analysis.

The main concern regarding conflicts of interests is that the PACE-authors violated their promise, as made in the protocol [3], to adhere to the declaration of Helsinki. The declaration requests that potential participants in a trial are “adequately informed” about researchers “possible conflicts of interest”. [4] This code of conduct seems to have been breached in the PACE-trial. Four participants in the trial have been interviewed and all said they were not informed about the lead investigators’ ties to insurance companies. Some said they would have likely refused participation in the trial if they had been informed about this information beforehand. [5] In an open letter to the Lancet, more than 40 ME/CFS researchers and expert clinicians expressed their concern about this violation of the declaration of Helsinki. They demanded, “whether the consent obtained from the 641 trial participants is legitimate.” [6] The HRA report fails to give them reassurance. In fact, the report admits that the Patient Information Sheet (PIS) did not contain information about the advisory roles of PACE trial researchers, information that was detailed in the trial protocol. [3] But instead of reaffirming concerns about this violation of the Declaration of Helsinki, the HRA argues that these advisory roles to insurance companies do not constitute a conflict of interest. This is a curious explanation. If these advisory roles were described as conflicts of interest in the main Lancet paper of 2011 [7] and in the trial protocol, why should the reporting to trial participants be any different?

Secondly, the HRA letter notes that Queen Mary University of London (QMUL) and the PACE-authors “approached the issue of transparency of data for analysis responsibly.” I would like to contest that statement. PLOS One currently issues an “expression of concern” about the economic analysis of the PACE-results (MCcrone et al. 2012) because the authors refused to share data for independent reanalysis as is required by journal policy. [8] QMUL’s rejection to share the trials’ main outcome data has been condemned within the scientific community. [9] Without the release of this data, it would still be unknown that the PACE-authors inflated their recovery rates threefold by deviating from the thresholds set out in their protocol. [10] This is relevant information for healthcare professionals. QMUL has spent 245.000 pounds to block the release of this information [11] and characterized those who demanded transparency as a “very damaging group of individuals.” [12] If this is indeed a responsible approach to data transparency, I would like Prof. Jonathan Montgomery, chair of the HRA, to specify what would constitute an irresponsible approach.

Thirdly, the HRA letter claims that differences between the initial plans and published results of the PACE-trial “were openly reported in the main Lancet paper of 2011.” This is factually incorrect. The Lancet paper of 2011 [7] does not clarify the changes in how the main outcome (improvement based on physical function and fatigue scores) was reported, nor was a sensitivity analysis conducted in any of the peer-reviewed publications by the PACE-authors. In 2018, a reanalysis of the data according to the trial protocol confirmed that the changes in outcome reporting significantly altered the trials’ findings. [13]

The HRA letter also claims that “the robustness of the PACE trial has been considered in a Cochrane review that classified it as high quality.” Yet, Cochrane currently issues a warning that the relevant review (Larun et al. 2017) is “substantially out of date and in need of updating.” [14] An international news outlet reported that retraction of the review is imminent. [15] It should also be noted that Larun et al. collaborated with the main PACE-authors on a Cochrane review based on individual patient data of graded exercise therapy trials and that this project has been retracted. [16]

With such errors and omissions it seems unlikely that HRA has “examined this study in detail.”

Michiel Tack.

ME/CFS patient

No conflicts of interest.


References:

[1] Hawkes N. PACE chronic fatigue trial was properly conducted, says UK research watchdog. BMJ 2019;364:l639 https://www.bmj.com/content/364/bmj.l639

[2] Montgomery J. Re: The PACE trial and the Committee’s inquiry on Research Integrity. NHS Health Research Authority. Jan 2019. https://www.parliament.uk/documents...Research-Authority-to-Chair-re-PACE-trial.pdf

[3] White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007 Mar 8;7:6. https://bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-7-6

[4] World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013 Nov 27;310(20):2191-4. https://jamanetwork.com/journals/jama/fullarticle/1760318

[5] Tuller D. Trial by error: The Troubling Case of the PACE Chronic Fatigue Syndrome Study (second installment). Virology blog. Oct 2015. http://www.virology.ws/2015/10/22/trial-by-error-ii/

[6] Tuller D. An open letter to The Lancet, again. Virology Blog. Feb 2016. http://www.virology.ws/2016/02/10/open-letter-lancet-again/

[7] White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, 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 Mar 5;377(9768):823-36. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60096-2/fulltext

[8] McCrone P, Sharpe M, Chalder T, Knapp M, Johnson AL, Goldsmith KA, White PD. Adaptive pacing, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome: a cost-effectiveness analysis. PLoS One. 2012;7(8):e40808. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040808

[9] Smith R. QMUL and King’s college should release data from the PACE trial. The BMJ Opinion. Dec 2015. https://blogs.bmj.com/bmj/2015/12/1...lege-should-release-data-from-the-pace-trial/

[10] Wilshire CE, Kindlon T, Matthees A, et al. Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial. Fatigue. 2017; 1-4. https://www.tandfonline.com/doi/abs/10.1080/21641846.2017.1259724

[11] Johnthejack. Using public money to keep publicly funded data from the public [blog]. June 2016. https://johnthejack.com/2016/06/29/using-public-money-to-keep-publicly-funded-data-from-the-public/

[12] General Regulatory Chamber. First-tier tribunal. Appeal number EA/2015/0269. April 2016. http://informationrights.decisions.tribunals.gov.uk//DBFiles/Decision/i1854/Queen%20Mary%20University%20of%20London%20EA-2015-0269%20(12-8-16).PDF

[13] Wilshire CE, Kindlon T, Courtney R, Matthees A, Tuller D, Geraghty K6, et al. Rethinking the treatment of chronic fatigue syndrome-a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC Psychol. 2018 Mar 22;6(1):6. https://bmcpsychology.biomedcentral.com/articles/10.1186/s40359-018-0218-3

[14] Cochrane Database of Systematic Reviews . Exercise therapy for chronic fatigue syndrome. What's new. Nov. 2018. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003200.pub7/information#whatsNew

[15] Kelland K. Exclusive: Science journal to withdraw chronic fatigue review amid patient activist complaints. Reuters. Oct. 2018. https://in.reuters.com/article/us-h...mid-patient-activist-complaints-idINKCN1MR2PI

[16] Cochrane Database of Systematic Reviews. Exercise therapy for chronic fatigue syndrome (individual patient data). What's new. Dec. 2018. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011040.pub2/information#whatsNew
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To facilitate the sharing of this on Twitter and Facebook:

 
A couple of things I noticed on a quick read of this letter:
1. Stating ‘No conflicts of interest’, I assume, was ironically intended as, being an ME sufferer, wouldn’t the author be considered to have a conflict of interest? That may not have been helpful.
2.
It should also be noted that Larun et al. collaborated with the main PACE-authors on a
Cochrane review based on individual patient data of graded exercise therapy trials and that this project has been retracted. [16]
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The wording used by Cochrane was: ‘Protocol for a Cochrane Review withdrawn from publication’ - I assume that Cochrane would prefer the use of an exact quote, or at least the exact terminology (‘protocol’, ‘withdrawn’), rather than a paraphrase of the wording used in the reference cited.

[16] Cochrane Database of Systematic Reviews. Exercise therapy for chronic fatigue syndrome (individual patient data). What's new. Dec. 2018. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011040.pub2/information#whatsNew
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Richard Smallfield said:
A couple of things I noticed on a quick read of this letter:
1. Stating ‘No conflicts of interest’, I assume, was ironically intended as, being an ME sufferer, wouldn’t the author be considered to have a conflict of interest? That may not have been helpful.
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We have discussed this in the past and I think it is fair to say that being a patient is not a conflict of interest. The interest of the individual patient is prima facile the interest of all patients , which is the only legitimate interest to 'conflict' with. Irony may have been intended but without implying misrepresentation I think.
 
Richard Smallfield said:
Stating ‘No conflicts of interest’, I assume, was ironically intended as, being an ME sufferer, wouldn’t the author be considered to have a conflict of interest? That may not have been helpful
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Thanks for your feedback Richard. I agree with Jonathan Edwards that being a patient is not a conflict of interest (which interest would be conflicting with what?).

I should say that I left out this section of my submission
Michiel Tack said:
Michiel Tack.

ME/CFS patient

No conflicts of interest
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Because BMJ asked about this information before submitting. In one of my attempts to submit my comment, I've actually listed being a ME/CFS patient as a conflict of interest (wanted to know if that might be the reason for rejection), but it didn't help.
 
Richard Smallfield said:
1. Stating ‘No conflicts of interest’, I assume, was ironically intended as, being an ME sufferer, wouldn’t the author be considered to have a conflict of interest? That may not have been helpful.
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It can seem confusing, but NICE (as an example) makes it very clear in their 2018 "Policy on declaring and managing interests for NICE advisory committees":

https://www.nice.org.uk/Media/Defau...rocedures/declaration-of-interests-policy.pdf
11. For the avoidance of doubt, a person living with a disease or condition relevant to the matter under discussion, or who has a family member in that position, is not seen as an interest and this does not need to be declared.
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Richard Smallfield said:
1. Stating ‘No conflicts of interest’, I assume, was ironically intended as, being an ME sufferer, wouldn’t the author be considered to have a conflict of interest? That may not have been helpful.
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As Jonathan said, patients have an inherent interest in whether treatments work. This is not a conflict of interest. There is no primary or secondary gain in this case.
 
Snow Leopard said:
As Jonathan said, patients have an inherent interest in whether treatments work. This is not a conflict of interest. There is no primary or secondary gain in this case.
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Yes. One has to consider what the primary interest is, and what interests might conflict with that. Well the overriding primary interest is surely the overall best outcomes for patients, and it would be very hard to argue that the essential interests of pwME conflicts with ... the overall best interests of pwME. The interests are congruent, not conflicting.
 
Esther12 said:
Also, someone just sent me this HRA response to the committee's more general concerns. I've not read it yet, but it looked like there were signs of hypocrisy in there:

https://publications.parliament.uk/pa/cm201719/cmselect/cmsctech/1961/1961.pdf
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Sanctions
Recommendation: We recommend that the HRA introduce a system of sanctions to drive
improvements in clinical trials transparency, such as withdrawing favourable ethical opinion
or preventing further trials from taking place. The Government should consult specifically on
whether to provide the HRA with the statutory power to fine sponsors for non-compliance.
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I can think of a few people this should apply to, although maybe is closing the door after the horse has bolted(?)
https://www.s4me.info/threads/horse...ent-2018-david-mccormack-trudie-chalder.6385/
 
Trial By Error: The UK Health Research Authority’s Missteps on PACE and the Declaration of Helsinki

"The PACE authors and their allies routinely cite the UK’s Health Research Authority as having given this boondoggle of a trial a clean bill of health. The HRA, which oversees research ethics processes and procedures, conducted a review of PACE and issued its findings in January, 2019. The agency assessed PACE as having been conducted properly, but it noted that its purview was limited to “whether the study was properly approved by the Research Ethics Committee (REC),” and questions about the “quality of the study” were beyond its scope.

Even within its remit, the report was deficient in multiple respects. It has therefore had the unfortunate effect of obscuring some of the trial’s unacceptable flaws.

These deficiencies are apparent in the report’s section on “conflicts of interest” and its analysis of whether the PACE investigators should be held to account for not disclosing their advisory and/or financial ties with major insurance companies to prospective trial subjects."

https://www.virology.ws/2022/04/14/...w-up-on-pace-and-the-declaration-of-helsinki/
 
I had a tab opened with a file 'Response to Sir Jonathan Montgomery.pdf', but by the time I went to read it it had been purged from my temporary files, and now I can't find it online. Anyone know what this may have been? I've got no info on it other than the file name.
 
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