PACE chronic fatigue trial was properly conducted, says UK research watchdogBMJ 2019; 364 doi: https://doi.org/10.1136/bmj.l639 (Published 07 February 2019) Cite this as: BMJ 2019;364:l639
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Mitochondrial dysfunction and ME/CFS Re: PACE chronic fatigue trial was properly conducted, says UK research watchdog
John McLaren-Howard, Sarah Myhill and Norman Booth have shown that myocardial dysfunction is an important diagnosable and potentially treatable cause of myalgic encephalitis or chronic fatigue syndrome. It is not sensible to expect patients with severe mitochondrial dysfunction to exercise before the underlying causes of mitochondrial dysfunction have been diagnosed and treated. These usually include important essential nutrient deficiencies and toxic metals like nickel, cadmium, or dental mercury amalgams.1-3
Mitochondrial dysfunction in ME/CFS needs testing and treating and four women are affected for every one man. In my experience, this is because most have taken progestogens and/or oestrogens for contraception or HRT. Hormone use lowers zinc, increases copper levels, lowers copper stores and increases toxic DNA adducts.4,5
Mitochondrial dysfunction and essential nutrient testing should become more widely available and must be more cost effective than the PACE trial which did not investigate abnormal or correct biochemistry.
1 Myhill S, Booth NE, McLaren-Howard J. Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) - a clinical audit.
Int J Clin Exp Med. 2013;6(1):1-15. Epub 2012 Nov 20.
2 Booth NE, Myhill S, McLaren-Howard J. Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).Int J Clin Exp Med. 2012;5(3):208-20.
3 Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction.Int J Clin Exp Med. 2009;2(1):1-16. Epub 2009 Jan 15.
4 Grant ECG. The pill, hormone replacement therapy, vascular and mood over-reactivity, and mineral imbalance. J Nutr Environ Med 1998;8:105-116.
5 Howard JM. The detection of DNA adducts (risk factors for DNA damage. A method for genomic DNA, the results and some effects of nutritional intervention, J Nutr Environ Med 2002;12:19-31.
Competing interests: No competing interests
Nigel Hawkes makes some interesting rhetorical moves in presenting this news report.
Firstly, whilst PACE supporters are quoted giving their full academic credentials e.g. Professor Sharpe of U of Oxford, Prof Evans of LSHTM, the major PACE critic mentioned is (in contrast) introduced as 'a US Activist', without noting his doctorate in public health or his academic position at UC Berkeley.
More subtly, Mr Hawkes interprets Prof. Montgomery's as providing a completely clean bill of health to the PACE study.
Hawkes reports "In any case, there are no grounds for considering PACE to be of poor quality, he says.". In fact Prof Montgomery’s letter is far more balanced, carefully deflecting questions of scientific robustness to other agencies and detecting both: “indications that the science is sound, as well as evidence of concern”. He recommends that “The range of views suggests that the debate needs to be continued …”[ibid]. I do not understand how Hawkes translates this to Montgomery saying there are “no grounds” for concern.
For those who are not familiar with this debate, it might help if Hawkes had mentioned any of the primary scientific criticisms of PACE, for example: that it was (ultimately) an unblinded trial using subjective outcome measures as the primary endpoint, and thus wide open to placebo effects; or that the very broad recruitment criteria could result in quite diverse responses to any treatment from different patient subgroups. It is not surprising that so many patients, advocates (or ‘campaigners’ in Hawkes’s vocabulary) and concerned scientists/clinicians argue that the PACE trial is inadequate as a basis for clinical recommendations, even if the HRA concludes that the ethical oversight was satisfactory.
Science journalists have an important role in summarising research and sharing knowledge. Their words can have a significant impact on clinical decisions and policy development. It is disappointing to see such an important story apparently being mis-reported in your pages.
 Health Research Authority. Letter from the HRA to Norman Lamb MP, 29 January 2019. https://www.parliament.uk/documents/commons-committees/science-technolog....
 Hawkes, N. PACE chronic fatigue trial was properly conducted, says UK research watchdog. BMJ, 2019; 364:l639. https://doi.org/10.1136/bmj.l639
Competing interests: I have a relative who would meet the inclusion criteria of the PACE trial.
It is an outrage that 85% of research is wasted because "it asks the wrong questions, is badly designed, not published or poorly reported" ( http://rewardalliance.net ). Much remains to be done by funders, regulatory authorities, research sponsors and the scientific community. But this observation also shows that it is very difficult to do good research. Indeed no trial is perfect and if examined closely enough criticisms can be found and emphasised for almost any piece of research.
The PACE trial represents work in a clearly contentious area where there is significant disagreement between some medical/research professionals and some patient groups. But, with peer reviewed publications, public access to (critically reviewed) protocols, and access to some original data, this research does not seem to fall into the 85% of research waste. It was not a perfect trial, but whenever it has been scrutinised by organisations experienced in judging research (initial research council review, Cochrane review, and most recently the HRA) the process, methodology, analysis and the research team have been found to be well within, and acting within, the accepted norms of clinical research. Unfortunately the social context of this work means that it is unlikely that any trial on this topic could have been carried out without magnified criticism. That there is criticism (or at least still scientific questions that need answering) is not indicative that something has gone wrong. Indeed there is a famous quote (attributed alternatively to Asimov, Kekule and Flemming) that goes along the lines of: "The most exciting phrase to hear in science, the one that heralds new discoveries, is not “Eureka!” but “That’s funny …”". The community needs to move on from PACE and focus efforts on designing and conducting the next research.
When reviewing research, ethics committees do not try to judge whether a trial is perfect. Instead (and once any legal review obligations are considered for certain types of studies) we try to form an opinion on the proposed research based around the principles of Autonomy, Beneficence, Non-maleficence and Justice. The reason why a committee is needed is because these decisions cannot be reduced to an algorithm as they are necessarily complex, necessarily grey. Research Ethics Committees can be held accountable for not following process, or being inconsistent with previous decisions (or decisions made by similarly constituted committees), but the nature of the "opinion" is to provide confidence, call it a safeguard, that "outside eyes" have reviewed the research. While definitely not infallible, this system has shown itself to be sufficient, certainly to the task of protecting participants and ensuring research is publicly acceptable. What is now needed is more critical analysis of how research ethics committees can help to reduce research waste. But, as the PACE example perhaps shows, any such efforts must always be tempered by the reminder that no study, no matter how well funded or designed, is likely to be perfect in every way. While more can certainly be done to address research waste, we must not let the mythical concept of "perfect research" get in the way of the practical reality of "good research".
Competing interests: I am chair of two UKECA recognised research ethics committees, an academic with a research focus on the role and function of research ethics committees, and involved with the REWARD Alliance Regulation and Governance Working Group.