****** !!!!!!!! ****************!!!!!!!!!!!!!!!! Junior version of PACE funded PI Dr Crawley

[charles shepherd]

Peer review comments from Dr Suzanne Broadbent, Southern Cross University, Australia:

http://bmjopen.bmj.com/content/6/7/e011255.reviewer-comments.pdf

 

[Keela Too]

£5 million PACE -- highly flawed study but findings of no sig between group benefit at follow up
£1.2 million FINE - null result
£840k Esther Crawley NIHR senior researcher grant + FITNET her study nearly another £1 million NIHR funding
Collin £340k- her research fellow
+ 3 reserach associates
Peter White - another NIHR million testing CBT and NIHR grant for systematic review of treatments for medically unexplained symptoms

... staggering amounts being pumped into CBT trials ...

Yet where are the biomedical trials?
Why no funding to test promising drugs?
Ampligen? LDN? Anti-virals? Anti-retrovirals?

Surely all of these have shown as much - or more - promise than CBT and/or GET, yet still money is thrown at these ineffective therapies like they are just rolling dice again and again waiting for the outcome they want.

 

[SilverbladeTE]

If this goes ahead, and a substantive number of children are made worse, I would like to see the parents, the charities and the patient community unite to ensure that both the ethics committee and the researchers are held responsible. If the ethics committee did their due diligence they would never approve this.

 

[Keith Geraghty]

Reviewer 1: Dr Suzanne Broadbent Southern Cross University Lismore NSW Australia

…she writes quite a good review of the trial and makes many important points such as:

GET, This section is very poorly written and as a protocol paper, needs a lot more information.

she then writes a very detailed 2-3 page critque with comments and suggestions for changes

group.bmj.com on July 7, 2016 - Published by http://bmjopen.bmj.com/Downloaded from

Now let’s look at Reviewer 2’s comments!

Reviewer 2 Dr Lucy Clark – of Queen Mary University – author of articles with Prof. White defending the PACE trial and assisting in other trials, such as GETSET. (independent reviewer?)

In the 1990's Dr Clark completed a both bachelor and masters degrees in Sport and Exercise Sciences, also working in health and fitness during that time. In 1998 she started working as a researcher at Kings College London on a randomised controlled trial comparing graded exercise with cognitive behaviour therapy for primary care patients with fatigue. In 2005 she completed her PhD in this field and continued to research fatigue in primary care. At this time she also assisted with some research into headache in primary care and took on some lecturing roles. In 2007 she moved to Queen Mary, to undertake a study looking at the cytokine response to exercise in secondary care patients with chronic fatigue syndrome. More recently she has been managing a trial of guided self-help for patients diagnosed with CFS in secondary care, the emphasis of the guidance being a graded return to exercise and activity. She also continues to work as a personal trainer outside of QMUL.


Here is what Dr Clark wrote in total in general comments section of what she felt about the proposal: 1 short paragraph... - really just one paragraph or am I missing something?

“This study protocol investigating the feasibility of carrying out a RCT of GET for CFS/ME is written clearly and in enough detail for it to be repeated. It includes all the information it should regarding funding and ethics, and the references seem to be relevant to this population and up-to-date. The title and abstract are clear, and it describes an interesting study that, when completed, should add to the literature on GET for CFS/ME.”

…I don’t really have words for this – all I say is compare this to Dr Broadbent’s detailed 2-3 page review?

 

[K22]

I think that it is Good another missing millions protest is planned later in the year. Much to protest against in the UK, with the lack of research dollars and comprehensive stragegy to radically improve things in the uk another. If this was MS a single, poorly designed study exploring exercise in a woolly cohort would matter less but this will be used to add to the other GET evidence derived from weak trials and extrapolated to ME when it shouldn't, whilst the MRC continue with the excuse that for some unfortunate reasons they just aren't getting many biomedical research applicatikns and that's why we are still getting so little invested.

The severe are groaning in their beds and we have had £200,000 invested by the state in the uk since the 2012 funding allocation. Utter peanuts. And yet GET research has a never ending well of funds.

Can someone please tell EC that neither CFS nor ME are unexplained chronic fatigue and that she should be very careful in how she goes encouraging kids with excercise intolerance and pain and flu like immune symptoms to increase aerobic exercise.

 

[user9876]

It is interesting that the reviews really don't agree. Clark seems to say that the treatments are reproducible where as Broadbent seems to raise a number of questions about the lack of detail in the exercise protocols and hence that they would be hard to reproduce.

If the protocols are not very easy to reproduce then I would argue that any results will be meaningless as such treatments that match the protocols could not be rolled out. What is worse is that even supporters of GET acknowledge if it is done wrongly then it can cause harm but having an ill defined protocol is likely to do this.

 

[user9876]

I think that it is Good another missing millions protest is planned later in the year. Much to protest against in the UK, with the lack of research dollars and comprehensive stragegy to radically improve things in the uk another. If this was MS a single, poorly designed study exploring exercise in a woolly cohort would matter less but this will be used to add to the other GET evidence derived from weak trials and extrapolated to ME when it shouldn't, whilst the MRC continue with the excuse that for some unfortunate reasons they just aren't getting many biomedical research applicatikns and that's why we are still getting so little invested.

The severe are groaning in their beds and we have had £200,000 invested by the state in the uk since 2012. Utter peanuts. And yet GET research had a never ending well of funds.

The reviews here demonstrate that there is no critical review of the protocols out side of a group of believers who are doing similar work. They all have an interest in poor methodology because they use such methodologies.

 

[Kalliope]

I read an interesting comment on peer review in Nature by Drummond Rennie.
The title is "Let's make peer review scientific". It might be of interest to some members in the forum (if it hasn't been shared already).

From the comment:
“There are scarcely any bars to eventual publication. There seems to be no study too fragmented, no hypothesis too trivial, no literature citation too biased or too egotistical, no design too warped, no methodology too bungled, no presentation of results too inaccurate, too obscure, and too contradictory, no analysis too self-serving, no argument too circular, no conclusions too trifling or too unjustified, and no grammar and syntax too offensive for a paper to end up in print”.

 

[sarah darwins]

no literature citation too biased or too egotistical

A great example the other day in Chalder et al's attempt to annexe MS, where their latest paper has 11 of 25 references pointing to papers one or more of them had a hand in writing.

link: http://forums.phoenixrising.me/inde...diatric-multiple-sclerosis.45553/#post-740525

 

[Jenny TipsforME]

How are we going to stop this before any children become sicker than they need to be?!

It seems to me that it requires influencing the right people more than making lots of noise. My partner is an academic and she thinks the ethics Committee who have just approved it is probably the best starting point. (What do you think @Keith Geraghty?) They won't be experts on ME, they'll probably just have read the proposal and approved it on its own merits as a self contained document. They should be fairly risk adverse, especially when it comes to children who will have a hard time withdrawing consent if they experience harm. Concerns raised in the peer review will be useful for this, as will the ME Association's survey and patient account of harm.

Could our concerns (to be organised into a letter to the committee) be summed up as:
1) We feel harm from GET is too high a likelihood for a study on children who are unlikely to be able to give properly informed consent and who will probably feel too coerced to be able to leave the trial at any time
2) GET is a treatment in which the majority of patients report harm rather than benefit (Inc various evidence) in conflict with claims made in this proposal
3) For this to be ethical, researchers would need to inform of potential risks to such an extent that it would undermine the study (nocebo effect or difficulties recruiting) see below
4)Similar research has cost a lot of money and produced null or negligible benefit to pwme.
5) This study is a misuse of public research money long term, because the methodology is confused meaning that replication would likely have different results. For example, some people will also have CBT in a fairly haphazard manner. More effort needs to be made to avoid bias in this controversial area, such as analysis from neutral researchers.
6) There are very promising areas of ME which could be invested in (eg...) and patient groups feel that money would be much more productive long term if it was spent on other areas of ME research

Also is this previous thread relevant

The Significance to ME/CFS of the Landmark Change to the UK Law on Consent

In March this year there was a landmark change to the UK law on consent which has significant implications for patients with ME/CFS. For full details of this change in the law please see the Supreme Court Judgement and related articles (1-8) below.

Consider the following scenario: an NHS fatigue clinic doctor prescribes CBT/GET to a patient, informing them that research (eg PACE trial, 9 ) shows that CBT/GET are moderately effective at curing ME/CFS with no serious side effects and CBT/GET are recommended by NICE.

The patient consents to CBT/GET, trusting that what he has been told by his consultant is accurate and complete. However CBT/GET makes the patient considerably worse and he takes legal action.

Under the previous law on consent:

"a doctor would not be negligent if the information given to a patient about treatment and/or a procedure was compatible with that which would be given by a responsible body of medical opinion, provided always that standard was considered reasonable by a Court." (4)

Therefore in the above scenario the doctor could have argued that he had complied with the law as he had followed " a responsible body of opinion", i.e. the view held by the UK psychiatric establishment and the NICE guidelines.

But with this landmark change in the law, hiding behind "a reasonable body of opinion" is no longer an option:

" The doctor is under a duty to take reasonable care to ensure that the patient is aware of any material risks involved in any recommended treatment, and of any reasonable alternative or variant treatments. The test of materiality is whether, in the circumstances of the particular case, a reasonable person in the patient’s position would be likely to attach significance to the risk, or the doctor is or should reasonably be aware that the particular patient would be likely to attach significance to it" (1, para 87) (emphasis added)

Therefore a doctor can no longer just inform his patients of the risks based on the views of some researchers, he must inform his patients of all material risks found in all research and of alternative treatments. And ignorance of the facts is no excuse.

...
All doctors, researchers and health professionals who have for years prescribed CBT/GET without fully informing patients of risks, alternative treatments etc have been in breach of these GMC guidelines on consent.


* * *

In the UK , CBT is mainly prescribed as in the discredited PACE trial : "to change the behavioural and cognitive factors assumed to be responsible for perpetuation of the participant’s symptoms and disability", whilst GET is prescribed to correct the assumed deconditioning and exercise intolerance caused by these wrong cognitions. (11, 16) (emphasis added)

However, the scientific evidence clearly shows these assumptions are wrong: the disease is not perpetuated by patients' aberrant cognitions and behaviour, it is perpetuated by on-going physical disease processes and therefore the use of CBT/GET as treatments for ME/CFS is scientifically invalid and potentially harmful.

That ME/CFS is a serious organic disease has been highlighted in two major, independent reports on ME/CFS published earlier this year in the US:

1. The Institute of Medicine report: "Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness" commissioned by the HHS, NIH, CDC, AHRQ and the FDA. (12)

2. The National Institute of Health Pathways to Prevention report: "Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome". (13)

Their conclusions were based on comprehensive reviews of over 9000 peer reviewed research papers and testimony from expert researchers and clinicians in the field. Both reports concluded unequivocally that ME/CFS is a serious physical disease, not psychological:

"The literature review found sufficient evidence that ME/CFS is a disease with a physiologic basis. It is not, as many clinicians believe, a psychological problem that should not be taken seriously. A primary message of the report is that:


"Other key findings...postexertional malaise, where exertion from activity (even seemingly mild activity, such as walking or active cognition) can trigger a “collapse” or “relapse” of malaise that lasts days or longer, far in excess of what would normally be expected. There may be a delay between the trigger and the collapse. Physiologic abnormalities after exertion are seen, which supports patient reports that forcing a person to “push” themselves can lead to profound exacerbation of symptoms." (14)...

"These new criteria highlight the critical importance of postexertional malaise, which is so characteristic that the committee believes that the concept of exertion intolerance should be part of a new name." (14)

The recent MEA Illness Management Survey Report clearly illustrates not only the physical risks but also the mental and emotional risks of CBT/GET. Some might argue that the MEA Report is merely patients' subjective experiences of these treatments and therefore has limited validity, but the PACE trial and other studies on which the NICE guidelines are based, also used subjective experiences to measure outcome. A court of law would surely find that this report provides evidence of risks which any "reasonable person" (1, para87) would "attach significance to" (1, para87) and therefore patients should also be informed of this kind of evidence of risk. (15)

One patient in the survey stated:

“It was torture, and abuse. Nothing more. The idea that ME can be exercised better when in actual fact it caused me to be much worse is reckless as it put my health at serious risk. I was made bedbound by GET. I did GET because I trusted the hospital consultant, he made me believe that it would work. Therefore my informed consent to do the course was achieved through coercion – coercion that was based on misinformation, false statistics and unsupported claims directly made by X and X. This kind of claim is medical fraud, and on balance an abuse of patients’ rights. Had I known the truth about GET I never would have done it.” ( 15, Patient 676, p136)

If this patient, and others in the survey, had been fully informed as was required by GMC professional guidelines, and is now required by law, it ishighly likely they wouldn't have consented to CBT/GET and immeasurable harm and suffering would have been avoided.



* * *


REFERENCES

References 3, 4 and 5 provide an overview of this change in the law and are a good starting place.

1. Full UK Supreme Court Judgement, UK Supreme Court documentation on Montgomery (Appellant) v Lanarkshire Health Board (Respondent) Case ID UKSC 2013/0136, 11th March 2015
https://www.supremecourt.uk/cases/docs/uksc-2013-0136-judgment.pdf

2. UK Supreme Court Press Summary, Montgomery (Appellant) v Lanarkshire Health Board (Respondent) Case ID UKSC 2013/0136
https://www.supremecourt.uk/decided-cases/docs/UKSC_2013_0136_PressSummary.pdf

3. UK Supreme Court Video of Judgement Summary 2013/0136 Montgomery (Appellant) v Lanarkshire Health Board (Respondent) 11th March 2015
https://www.supremecourt.uk/watch/uksc-2013-0136/judgment.html

4. Medical Defence Union legal guidance and advice - Doctors must ensure patients are aware of material risks, 16 March 2015, Ian Barker, MDU senior solicitor
http://www.themdu.com/guidance-and-...t-ensure-patients-are-aware-of-material-risks

5. Montgomery in the Supreme Court: a New Legal Test for Consent to Medical Treatment.
Lauren Sutherland, Junior Counsel for the appellant in the Supreme Court case of Montgomery analyses the case.
http://www.scottishlegal.com/2015/0...-legal-test-for-consent-to-medical-treatment/

6. UK Supreme Court Blog: Case Comment: Montgomery v Lanarkshire Health Board [2015] UKSC 11, Emily Dorotheou, 27th March 2015
http://ukscblog.com/case-comment-montgomery-v-lanarkshire-health-board-2015-uksc-11/

7. BMJ Observations Ethics Man - Update on the UK law on consent, BMJ 2015;350:h1481, Daniel K Sokol, 16 March 2015
http://dx.doi.org/10.1136/bmj.h1481

8. BMJ News - Doctors should not cherry pick what information to give patients, court rules. BMJ 2015; 350, Clare Dyer, 13 March 2015
http://www.bmj.com/content/350/bmj.h1414

9. PACE: a randomised trial, Professor PD White et al, Lancet, Vol 377, No.9768, p823-836, 5 March 2011.
http://dx.doi.org/10.1016/S0140-6736(11)60096-2

10. Clinical Negligence: A Change to the Law of Informed Consent, Robbie Wilson, May 05, 2015
http://www.drummondmiller.co.uk/new...ence-a-change-to-the-law-of-informed-consent/

11. TRIAL BY ERROR: The Troubling Case of the PACE Chronic Fatigue Syndrome Study, By David Tuller, DrPH, 21 October 2015
Part 1 http://www.virology.ws/2015/10/21/trial-by-error-i/
Part 2 http://www.virology.ws/2015/10/22/trial-by-error-ii/
Part 3 http://www.virology.ws/2015/10/23/trial-by-error-iii/

12. US National Academies of Science, Institute of Medicine report: "Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness" http://iom.nationalacademies.org/Reports/2015/ME-CFS.aspx

13. National Institutes of Health Pathways to Prevention Workshop: "Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome"Ann Intern Med.2015;162(12):860-865.
http://annals.org/article.aspx?articleid=2322804

14. Redefining the Chronic Fatigue Syndrome, Professor Theodore G. Ganiats MD, Ann Intern Med.2015;162(9):653-654.
http://dx.doi.org/10.7326/M15-0357

15. ME Association ME/CFS Illness Management Survey Results, 2015 http://www.meassociation.org.uk/2015/05/23959/

16. A request for data from the PACE trial
http://www.virology.ws/2015/12/17/a-request-for-data-from-the-pace-trial/

....................................................................................................................................

S.Campbell

October 2015

BTW this took ages to write so I'm not up to speed on the thread

 

[Keela Too]

Well said @Jenny TipsforME

I think the ethics committee need to see the other side of the story. I'm not sure if they can act retrospectively to withdraw their approval once given, but that MEA survey certainly needs as much coverage as we can muster - and certainly the peer reviewers would do well to read it in its entirety.

http://www.meassociation.org.uk/wp-...No-decisions-about-me-without-me-30.05.15.pdf

And @Daisymay's comment seems highly relevant

 

[Daisymay]

Well said @Jenny TipsforME

I think the ethics committee need to see the other side of the story. I'm not sure if they can act retrospectively to withdraw their approval once given, but that MEA survey certainly needs as much coverage as we can muster - and certainly the peer reviewers would do well to read it in its entirety.

http://www.meassociation.org.uk/wp-...No-decisions-about-me-without-me-30.05.15.pdf

And @Daisymay's comment seems highly relevant

Yes Keela Too and Jenny TipsforME, I think the law on consent issue may be highly relevant here and indeed should be being used by the ME charities to ensure patients at fatigue clinics and research participants are fully informed before they decide whether or not to undertake CB/GET.

Personally I think the UK charities should be coming together and taking legal advice to see how this change in the law can be used to stop the likes of MAGENTA and to protect patients in fatigue clinics..

And it would be interesting too to find out where ethics committee members stand legally if they have passed a trial protocol without ensuring that trial participants are fully informed of the risks of a treatments ie are they legally responsible as well as the researchers or indeed the therapists who provide CBT/GET?

Surely charities shoud be looking into this?

 

[Jenny TipsforME]

Well said @Jenny TipsforME

. I'm not sure if they can act retrospectively to withdraw their approval once given,
And @Daisymay's comment seems highly relevant

Just had a quick look at University of Bristol ethics policy and does have provision to "revoke approval of research if dissatisfied with the conduct of the research" which sounds like it is possible to over turn a decision. Do we know if there are precedents of this happening before research has started, either from Bristol, NHS (presumably this research has to pass NHS ethics too?) or the funding body? Yesterday I saw it had passed a regional ethics Committee meeting for the South West but can't remember what that was right now, feeling a bit ☁.

Does anyone know if the UK charities plan to do something (eg ME Association @charles shepherd). They'd have a lot more clout than us as individuals. Also would other ME researchers be prepared to sign a letter do you think?

I feel that we need to be wise in how this is approached. A likely outcome is we could get people's backs up and they just close ranks. Academics are inclined to support each other even if they don't full heartedly agree.

Something effective needs to be done though. We can't just grumble from the sidelines as children are pressured into 'treatment' likely to make them worse and £1,000,000 ME research money goes down the drain.

 

[user9876]

Reviewer 1: Dr Suzanne Broadbent Southern Cross University Lismore NSW Australia

…she writes quite a good review of the trial and makes many important points such as:

GET, This section is very poorly written and as a protocol paper, needs a lot more information.

Did they add the additional information for the GET protocol based on the reviewers comments. This seems to be an important question from these perspectives.
1) Can the treatments be repeated if they work. If the protocol is not well defined then clearly if cannot be.
2) From a safety perspective it is not clear what they are testing so it is hard to conclude that GET could be safely rolled out.
3) Those supporting GET have often used the excuse that deterioration happens when GET is done by those without experience. However, having an ill defined protocol that is not easy to repeat will encourage much variation in treatments and hence any positive or spun results are likely to lead of a wide variety of treatments and hence increased danger to patients even if those in the implied protocol are safe.

 

[Jenny TipsforME]

@user9876 I don't have the spoons to check what changes were made today, when I skimmed through yesterday I didn't feel the issues were satisfactorily resolved.

Lack of standardised repeatability seems to an issue on a few levels. The protocol doesn't seem to have anywhere near enough detail to expect someone else to be able to do the same as them. Even within the trial they seem to accept quite a bit of variation (but interpreted as positive, a sort of personalised approach). You are right that this is then hard to assess in terms of safety.

 

[Keela Too]

Just had a quick look at University of Bristol ethics policy and does have provision to "revoke approval of research if dissatisfied with the conduct of the research" which sounds like it is possible to over turn a decision.

That is interesting...

What can we all do???

Another petition? Or are there too many of those these days?
Persuade all our experts to write in?
I really can't understand how they can ignore the now substantial evidence of harms...

Meh

 

[Jenny TipsforME]

@Keela Too perhaps work on the assumption that the people approving this haven't actually seen the evidence of harms? The reviewers have a wider knowledge, but in terms of the ethics committees is it plausible the only information they have is what EC put in the proposal? I imagine that they sort of plough through one proposal after another in an already hectic schedule. This might be incorrect.

Has anyone here ever been on an ethics approval Committee to know how they operate? Perhaps @Jonathan Edwards?

There do seem to be a lot of petitions. I can't keep track of which ones I've signed! Unless we can get 100,000 UK signatures and get it to Parliament - not likely - I think that petitions feel a bit tired (and ME isn't about being a bit tired ).

Perhaps a joint letter from patients and experts? To people who can reverse the decision and/or letter to the editor type of thing
Perhaps enlisting ME friendly journalists to write about it?

Trying to find any examples of similar research being rejected might be informative. On what grounds do committees reverse decisions? How did people go about persuading them?

 

[JaimeS]

What can we do?

1) It is possible to do a petition through #MEAction or any other platform. While it might seem like there are a lot of petitions out there about ME, the University of Bristol likely hasn't seen them. It will be news to them that people are out there, and concerned. Look at the number of exclamation points in the heading here. I think people will be pretty infuriated and sign, and send to their friends to sign. I think we can expect to see signatures in the thousands; if we don't, it will be because we didn't promote it 'hard enough'.

2) Check this out: http://www.bristol.ac.uk/research/integrity/

We might be able to send letters to the guy at the bottom of this page, expressing our concerns. Perhaps a letter signed by scientists who oppose PACE. We might be able to combine this approach with a petition, and put patient 'signatures' at the bottom of the letter (i.e. attach the letter to the petition results). We should send this letter to:

research-governance@bristol.ac.uk

(I believe. Please do feel free to double-check.)

3) Why, look, they have a Twitter about engaging with the public: University of Bristol Engage. We could also refer to them in tweets, link them to PACE and its problems -- link everything back to the patient survey that shows harms.

I might use this ONLY once we've started the petition, and use Twitter to link to the patient survey that shows harms, AND the petition. It would be really amazing to tweet them each time we reach milestone signatures: 500, 1000, etc.

As much as it might seem I am, I'm not speaking as '#MEAction' here, since I haven't spoken with others at #MEAction on this matter to reach consensus. Rather, these are my thoughts as a concerned individual.

Input?

-J

 

[user9876]

What can we do?

When there were questions about the Smile trial Crawley accused patients of harassment for daring to contact the ethics committee to say she was testing a therapy (the lightening process) on children first rather than adults. I assume Bristol university got behind her to support her in that. She claimed that paediatric CFS is different although I've never seen evidence of that.

She has recently just got her professorship which I think is shocking.

https://twitter.com/i/web/status/751367677978013696

What is perhaps interesting for this is this tweet:

https://twitter.com/i/web/status/751024991957811201

It suggests that the protocol was written by someone quite junior who has just got a PhD studentship

https://twitter.com/i/web/status/751027287236218881

I guess they would claim that it was supervised and reviewed

 

[user9876]

Looking through their protocol there is very little about how GET is done or what happens when a relapse happens. For example this is the piece for a relapse from the appendix

Managing setbacks will be discussed prior to discharge in the context of physical
exercise (how much this should be reduced and when they should start to do
exercise again).

Instead the refer to the PACE GET manuals (although several of the urls are broken) along with the NICE Guidelines. I don't know if they are the same or what happens when their is contradictory advice.

Also they talk about things like

Participants will be advised to stay within the target heart rate zones of 50–70% of their maximum heart rate.

With references to NICE guidelines and the PACE lancet paper. Maybe it is well known how to establish a target heart rate but it seems to be left to the abilities and knowledge of the therapist.

This lack of detailed protocol would seem to leave a lot to the imagination of those implementing them and as such would lead to a wide variety of deployments if rolled out as a service rather than in a trial.

This seems more like a sketch of a trial than anything I would think of as a protocol but then maybe my expectations that a protocol is basically a formal(ish) and complete specification varies from the expectations within the medical community.