M.E. Analysis – Evaluating the results of the PACE study.

A project supported by Phoenix Rising

This is my first attempt at creating a website for people who use screen readers. Please let me know how I can improve it.

This page has an introduction, then a summary of ten areas of discussion that arise from the PACE study. There are then ten further pages, numbered one to ten, each one expanding on each of the ten areas of discussion.

At any stage, on any page, if you press your usual shortcut command keys (Alt, Control, etc) with any of the number keys 0 to 9, you will be taken to the appropriate page, where the digit zero will take you to page 10: the decimal point/dot/full stop key will bring you back to this page: the hyphen key should initiate your mail software where you can "dash" off a message to me!

Each page is set out in one long table, and each section of each page starts in a new cell, separated by an empty spacing cell.

In March 2011, a study in the U.K. into possible treatments for patients with M.E./C.F.S. (Chronic Fatigue Syndrome) was published in "The Lancet". Called the PACE trial, it was based on the hypothesis that M.E./C.F.S. is primarily a psychological illness and that therapies with a psychological basis would be highly effective in treating the condition and significantly improving the prospects of most patients to return to normal health and functioning.

Patients were split into four groups: one had approximately 5 sessions of Specialist Medical Care (S.M.C.) and nothing more: the other three groups had 3 or 4 sessions of Specialist Medical Care and approximately 12 to 15 sessions of Cognitive Behaviour Therapy (C.B.T.), Graded Exercise Therapy (G.E.T.) or Adaptive Pacing Therapy (A.P.T.), which was developed as a form of pacing.

C.B.T. was "based on the illness model of fear avoidance" (of activity); whilst G.E.T. was based on "the illness model of deconditioning and exercise avoidance". Under the NICE guidelines, C.B.T. and G.E.T. are all that are available for M.E./C.F.S. under the N.H.S. in the U.K.

All but one of the assessments reported in the trial were subjective, and were carried out by means of questionnaires. Only one objective assessment was carried out and reported upon in the study: the six-minute walking test, which measured how far the patients could walk in 6 minutes. Patients were assessed both at the start and at the end of the trial.

Only 462 out of the 640 patients actually took part in the assessment. The average distance walked in six minutes at the start of the trial was 321 metres. At the end of the year, the group that only had approximately 5 sessions of Specialist Medical Care increased their distance by 22 metres. Those that had C.B.T. in addition to S.M.C. did not manage any better. Those that had G.E.T. managed an extra 45 metres more than the S.M.C. group – a total of 67 metres improvement from their results at the start of the year.

That may sound good, but we have to remember three important facts. The first is that the G.E.T. group used walking as its main form of exercise, so these patients had been concentrating on walking for a year. The second is that a distance of less than 300 metres is medically quite grim, especially as these patients had an average age of 38. Even after a year of practising walking, the G.E.T. group average was still below 400 metres. The third is that a low estimate, taken from recent studies, of the distance that an average healthy adult should manage is at least 600 metres.

That objective result clearly indicates that even G.E.T., with its focus on walking, did not bring patients anywhere close to a normal, healthy score.

C.B.T. added nothing to the improvement obtained simply from a few sessions of Specialist Medical Care.

As part of the original application (protocol) for a grant, the authors of the trial proposed that they would use actometers (pedometers) strapped to patients' ankles, and use the data as a baseline measure. This would have produced a better objective assessment of patients' true activity levels. After the trial had got under way, they decided that "a test that required participants to wear an actometer around their ankle for a week was too great a burden at the end of the trial." We do not understand that reasoning, especially as they decided to retain the six-minute walk assessment.

The PACE report itself concentrated on two of the subjective assessments: fatigue and physical function. With such a poor objective result on the 6-minute walk, and a failure to report on how many patients were able to "return to work", their weak overall results lack conviction. Near the end of the report the authors stated: "our finding that studied treatments were only moderately effective also suggests research into more effective treatments is needed. The effectiveness of behavioural treatments does not imply that the condition is psychological in nature". We would go further: in our view the extremely poor results of this trial showed rather that the ineffectiveness of these therapies demonstrates that the condition is not psychological in nature.

The Daily Mail, prompted by the briefing from the Science Media Centre, stated: "scientists have found encouraging people with M..E to push themselves to their limits gives the best hope of recovery". Did they even look at the results? Statements like this create widespread misunderstanding and difficulties for patients.

There can be only one conclusion drawn from the PACE study: there is no support for the assumption that the main factor holding back the recovery of  M.E./C.F.S.  is psychological in nature. Therefore continuation of the automatic use of these therapies for all such patients should be halted. It must be remembered that C.B.T. and G.E.T. are closely tied to assumptions about false illness beliefs and deconditioning, and as these are the only treatments on offer in the N.H.S., they colour people's perception of the illness. In reality, it would be entirely reasonable to suggest that these small improvements in test results could be caused simply through better illness management (including pain relief and improved sleep patterns).

The NICE guidelines state clearly that they do "not regard C.B.T. or other behavioural therapies as curative or directed at the underlying disease process, which remains unknown. Rather, such interventions can help some patients cope with the condition and experience improved functioning, and consequently an improved quality of life".

Yet only very recently has the U.K. government started to fund biomedical research into M.E./C.F.S. The experience of patients both with the benefit system and with their medical care shows that the pervasive belief that the illness is primarily psychological in nature continues to be a major negative influence.

The PACE trial has cost in excess of £5 million. It has amassed a large amount of data, the likes of which we have not seen before for M.E./C.F.S., nor are we likely to see such a similar size of study in the near future. So what lessons can we learn from it? How should we proceed? What should we do with the information that this trial contains?

These are the questions we asked ourselves as we looked deeper into one of the biggest treatment trials ever carried out for ME/CFS. Here are our conclusions:

The 10 Areas

1. Future studies should not use the Oxford Criteria.

The U.K. is the only country to use the Oxford criteria as a matter of course, and then only in psychological studies of M.E./C.F.S. According to the PACE figures, 38% of the patients participating in this trial would not be classified as having M.E./C.F.S. if judged by international standards. However, studies using the Oxford criteria have historically played a major role in shaping both opinion and treatment of M.E./C.F.S. in this country. Putting all of these patients together does not help with any analysis: all patients deserve treatments appropriate to their particular needs.

2. Future studies should use additional measures of average and variation.

The way in which averages were used in the PACE trial significantly overstated the effectiveness of the therapies used in the trial.

When results form a smooth and balanced distribution (such as people's heights), it can be useful to use the arithmetic mean as an average, and the standard deviation as a measure of variation between results. However, these measures can be quite deceptive when a distribution is unusual, as it is with the key measures in the PACE trial.

For example, the average number of fingers for everyone must be below 10: there are not enough with 11 or 12 to offset those born with few or none. But it would be misleading for me to say simply that I had more than the average number of fingers.

A more useful picture can be obtained by using the middle value (the median) as an average, and the quarter-way points (the quartiles) as a measure of variation.

3. It has not been proven that we should continue to use G.E.T. and C.B.T. with all M.E./C.F.S. patients.

The authors of the PACE study concluded that "C.B.T. and G.E..T can safely be added to S.M.C. (Specialist Medical Care) to moderately improve outcomes for chronic fatigue syndrome...". The evidence does not support this.

It is not enough for a therapy or treatment to be safe: it also must be effective, and here the use of the term "added to" is highly significant. The average improvement added on to S.M.C. by either G.E.T. or C.B.T. is far too small to justify the universal investment either of resources or of patients' time. In fact, even for the key subjective measures chosen by the authors, the improvement in scores of patients who had only about 5 sessions of S.M.C. was greater than the additional effect of the therapies. This is rather like having a minimum height requirement of 5 feet 10 inches for joining the police, then allowing applicants to stand on a box 3 feet high.

G.E.T. and C.B.T. are effective therapies for a proportion of patients satisfying the Oxford criteria. The factors that define these patients need to be obtained from the vast wealth of the PACE data, so that these patients can continue to benefit.

It would, therefore, seem inappropriate for psychological theories to maintain any more importance to M.E./C.F.S. than they do for any other illness in which fatigue is a factor.

4. All patients with M.E./C.F.S. should have better access to a specialist.

Patients in the PACE trial who received only Specialist Medical Care showed some improvement in all areas (more than the authors had anticipated). In fact, that improvement was generally greater than the extra improvement added on by giving the patients about 12 sessions of G.E.T. or C.B.T. (which in turn was much less of an improvement than the authors had anticipated). The level of Specialist Medical Care experienced by the patients in the PACE study is not normally provided at M.E. centres.

An analysis by the Newcastle N.H.S. C.F.S. Service found that 40% of patients sent to them with a provisional diagnosis of M.E./C.F.S. in 2008/09 did not have the condition, but had another, often treatable, condition. A similar proportion of people attending six specialist chronic fatigue centres who were screened for entry into the PACE trial were rejected because they did not have C.F.S. These findings underline the importance of ensuring that those diagnosed with M.E./C.F.S. are assessed more rigorously by specialists, rather that simply being referred for C.B.T. and G.E.T.

5. We must find the factors that identify those patients who benefit from these therapies.

The trial was based upon the model that patients with C.F.S. (which includes patients with M.E.) suffer primarily from fear avoidance, deconditioning and exercise intolerance, and the authors clearly expected that the chosen therapies (C.B.T. and G.E.T.) would produce a much greater improvement in patients' health. Given such a small average improvement, it would be sensible to conclude that this model is no longer useful for C.F.S. as a whole, nor for M.E./C.F.S. in particular. In conclusion 6, we offer an alternative model.

But it would be wrong to deny these therapies to those patients who could benefit from them. The PACE trial has amassed a great deal of information about these patients. Priority should be given to determining how to recognise the characteristic symptoms of patients who benefit from these therapies, and to determining whether, in fact, it is these specific therapies that help, or whether other factors are at play.

6. We need better information on the prognosis of this illness.

There was no proper control group in the PACE trial. One group received just 5 sessions of Specialist Medical Care; the others received 3 or 4 sessions of S.M.C. and a further dozen sessions with a therapist. If we were to assess G.E.T. and C.B.T. (and their associated psychological assumptions), then we would need to start the assessment at the end of the sessions of Specialist Medical Care, and have a control group that experienced an equal number of sessions of a therapy which did not address those psychological assumptions. Only then could we separate out the specific effects of G.E.T. and C.B.T.

Results from our own survey have revealed a number of interesting points. For people with M.E./C.F.S. the natural variation between good and bad spells is often quite marked. Any focus in lessening the frequency and intensity of the bad spells, whether through medical means or through better management, would be welcomed by patients.

7. Future analysis of the results of the PACE trial should focus on individual improvement.

If everyone in a doctor's waiting room were given anti-depressants, there would probably be a weak overall benefit. Some people would benefit a lot, most would not and a few would be harmed. It would be a remarkably stupid and lazy idea: anti-depressants should only be given to an individual after a thorough and appropriate diagnosis has indicated that they are needed.

The PACE trial demonstrated weak overall improvements from therapies that were not selected on the basis of thorough, appropriate, individual diagnosis. It would be helpful if the individual data were to be released. There is so much information in this study that it would be a pity if it were not available for general analysis, and with modern technology it should be possible to analyse and present the results in a much more informative manner.

8. We need to find reliable bio-markers for M.E.

While certain biomarkers and other assessments have been suggested for use in M.E./C.F.S. patients, agreement on which tests are diagnostic, or even useful in a majority of patients, has been complicated by a devastating lack of funding and by the use of varying definitions, some of which are overly broad.

It is not possible to identify biomarkers in a population that has been lumped together based on the failure to diagnose an alternate condition and on the manifestation of a single common, exceedingly vague symptom (or even a small group of symptoms which could arise from a number of causes).

In order to determine diagnostic biomarkers for M.E./C.F.S, it will be essential to carefully perform differential diagnosis. We recommend the use of the International Consensus Criteria for the purpose of identifying which patients have M.E. (Many people have started to use the term M.E. rather than M.E./C.F.S. when describing patients identified under tighter criteria.) These are the most up-to-date modern criteria supported by multiple researchers interested in differential diagnosis. Differential diagnosis also includes the careful identification of conditions other than M.E., which might be causing fatigue.

9. There needs to be much more research and support for the seriously affected.

It doesn't say much for our society that we have done so little for the people who are the most affected by this illness. It is just too convenient to ignore those who remain trapped in their homes, and remain unnoticed – a view that was eloquently endorsed by the Countess of Mar in an address to the House of Lords (UK).

Out of over 2400 studies and articles concerning M.E. that are listed in the A.f.M.E. archives from 2000 onwards, only one specifically focuses on those whose needs are the greatest.

10. Future studies should aim for a more rigorous scientific structure.

The common advice for scientific studies is that if you want to prove that something is so, go out of your way to prove that it is not so. By beginning an experiment with the intention of confirming what you already believe to be true, you are likely to miss important possibilities, create misunderstandings, or make errors.

In our opinion, research into M.E./C.F.S. has been conducted on a piecemeal basis. The PACE trial is one of a very small number of comprehensive studies conducted since the analysis of pupil absences by Dowsett and Colby, published in 1997. Unfortunately, despite the authors' hopes, the results of the PACE trial have not taken us any further forward in terms of treatment, but at least they have made the limitations of the psychological model for M.E./C.F.S. quite clear. We hope that further analysis of individual data will enable doctors to target these therapies more appropriately for the small proportion of patients that might find them useful.

We also hope that the Medical Research Council's decisions on funding M.E. research, in November 2011, will result in a more integrated approach, especially in the selection of patients and in the consistency and quality of objective assessments.

Credits

The contents of this website were put together by Graham McPhee and Janelle Wiley, together with contributions, analysis, and support from Mark Berry, Robert Courtney, Tom Kindlon, Simon McGrath, Alex Young, and many others who prefer to remain in the background, and with lots of patient support and suggestions from friends both at Phoenix Rising and elsewhere. All of the contributors have M.E., which is why the project has taken so long to complete.

The project was created as a way to consolidate some of the analysis on a Phoenix Rising thread discussing the PACE trial, together with analysis elsewhere, into a more accessible format. Phoenix Rising made Wiki software available to support collaboration on this project.

If you wish to contact Graham, please press your usual command key and the hyphen key, and it will open your mail software.