This report summarises the work of a group of independent
scientists brought together by the Medical Research Council to develop a
strategy for taking forward research on the complex and debilitating
condition – or range of conditions - known as Chronic Fatigue Syndrome
This Research Advisory Group was set up following a report
by the Chief Medical Officer, which acknowledged the severity of suffering
associated with CFS/ME and called for research into all aspects of the
The Group’s conclusions were reached in the light of
consultation with current and former patients, carers, charity
representatives, clinicians and researchers, who were also invited to
comment on a draft of the strategy.
The final version of the research strategy aims to provide a
framework for improving understanding and treatment of CFS/ME. It sets out
the key priorities for future investigation, offers guidance on
research methods and emphasises the importance of the continuing
involvement of people with CFS/ME, their carers and the groups
Members of the Research Advisory Group were drawn from a
range of scientific disciplines associated with CFS/ME, including
immunology, muscle physiology, virology, clinical trials and psychology.
There were also two consumer representatives.
They set out to consider the areas of future research most
likely to bring benefits for patients in the light of recent reviews,
patient experiences and current knowledge In addition to their own formal
meetings held between September 2002 and March 2003, members of the Group
met with ME charities, CFS/ME patients and their carers to gain a better
understanding of their perspectives on the condition.
They also gave careful consideration to the results of two
rounds of a public consultation exercise which drew more than 200 responses
from, people with CFS/ME and people who have recovered, carers, researchers,
clinicians and specialists, and relevant voluntary organisations.
They did not, however, undertake a full review
of all the literature on CFS/ME, examine health care provision or decide how
their recommendations should be implemented.
(IiME Underline and bold type)
Responses to consultation
Responses to the public consultation exercise drew attention
to the following perceived problems:
• Problems with definition/understanding
There are many shades of opinion – and seemingly little
agreement – on what constitutes and is meant by CFS/ME. The tensions and
frustrations surrounding this issue stand in the way of effective
management and treatment of patients, as well as useful research
• Problems with communication
People with experience of CFS/ME complain of sceptical,
unhelpful and unsupportive health professionals and are critical of the
way psychiatric issues seem to dominate research. While recognising the
validity of some of these concerns, researchers and clinicians often
feel under attack from patient organisations
• Problems with research
Research hasn’t yet reached agreement on defining
the condition, let alone established its causes, symptoms, prevalence
and impact. What research there is has been short-term,
poorly-co-ordinated and lacking in patient involvement
• Obstacles to research
Respondents complained of the low status of research
into CFS/ME and an associated shortage of funding and resources.
Effective research is also hampered by lack of knowledge about people
with CFS/ME and lack of suitable measurements for symptoms like fatigue.
Key ways forward arising out of the consultation included:
• More research funding, properly directed;
• More co-operation and collaboration between
researchers, care providers and patients, including those who are
• Getting the priorities right – which for many means a
shift from psychological to biological and medical research;
• An open debate on meanings and definitions;
Many of those who responded saw the development of a
research strategy as an opportunity to improve communication and make a real
difference to the lives of those affected by CFS/ME.
It is quite ironic that the MRC pointed out that
more "properly directed" research funding was required. It is the
MRC who seem to have had their heads in the sand during this period
with regards to funding and it is precisely due to the MRC policies
on funding which has caused such a dearth of researchers who would become
interested in ME.
Indeed the MRC ought to have got their priorities right and made
a move from psychological to biological and medical research. Yet here it has
There is only one conclusion in this area
What’s in a name?
Disagreements over terminology are symptomatic of the lack
of consensus over most aspects of CFS/ME. Chronic Fatigue Syndrome (CFS) and
Myalgic Encephalomyelitis or encephalopathy (ME) are the terms that have
been used most often to describe patients with a combination of variable
symptoms, always including disabling fatigue.
The consultation elicited widely different views on how
these symptoms should be described, defined and classified. But the Research
Advisory Group decided to adopt the ‘umbrella term’ of CFS/ME, used in the
CMO report, rather than reconsider the terminology in depth.
It emphasises, though, that this term does not refer to a
specific diagnosis and that they hold no particular position on whether
CFS/ME is one condition with a variety of causes and presentations or a
number of similar conditions with different characteristics.
Although many patients and groups prefer to identify with
the term ME rather than CFS, the Group believes that research will be best
served by an ‘inclusive approach’. They accept, however, that as knowledge
and understanding increase there may come a time when this umbrella term may
no longer be appropriate.
IiME were not in existence in 2003. Yet it is
amazing to read these statements now and wonder how the main
organisation responsible for funding of research into a neurological
illness can state in their report that '...they
hold no particular position on whether CFS/ME is one condition with
a variety of causes and presentations or a number of similar
conditions with different characteristics'.
Terminology is one of the key issues and the MRC must
differentiate between CFS and ME.
To take the last paragraph IiME
now believe the time really has come where this umbrella term of CFS is no
longer appropriate and the MRC need to get off of the fence, adopt clearly the
terminology used by the World Health Organisation - and initiate the necessary
epidemiological studies which will allow sub grouping to be made.
The way ahead
In considering the best ways to advance research on CFS/ME,
the Research Advisory Group identified a number of important considerations,
• Variability. Research must take account of the
wide variation in the intensity and nature of symptoms and the potential
overlap with other disorders. It must also encompass a large variation
in the age range of people affected, posing additional issues about the
ethics of research on children
• Inclusiveness. Given this variability, research
studies need to be as inclusive as possible in terms of range of
participants, including the most severely ill, with sample sizes large
enough to allow for different ‘subgroup’ effects;
• Integration. The group recommends an integrated
approach to studying CFS/ME, with experience and expertise from a
variety of appropriate disciplines brought together as part of a
• Scientific rigour. New findings must be
subjected to rigorous scientific analysis, published in peer-reviewed
journals and confirmed through independent replication in other centres.
Research has not been performed across the wide
variation of severity of Pwme. The MRC PACE and FINE trials exclude
severely affected patients. In any case the flawed Oxford criteria
used for selection of participants in these programs means that the
results will always be skewed toward 'positive' results for the
psychiatrists running these trials.
The exclusion of funding for biomedical research clearly shows
no suggestion of inclusivity. As for scientific rigour - the peer- reviewing
system used by the MRC needs itself to be reviewed and, indeed, overhauled. Also
more transparency needs to be shown in the MRC decisions on funding. If a
referee has vetoed a research proposal whilst two other referees have accepted
the proposal then the public should know who that referee was or, at a minimum, what their
reasons were for rejecting the proposal.
Key research priorities
The Research Advisory Group defined a number of important
areas for research, as follows:
1. Case definition
Understanding of CFS/ME has been hampered by the use of
numerous different definitions of the disorder, linked to a lack of
universally agreed diagnostic criteria. Standardised case definition is
clearly fundamental to studying the prevalence, presentation, causation
and management of any illness. And thus the development and validation
of appropriate ‘tools’ for case definition is a research priority.
Nevertheless, the Group believes that studies into other aspects of
CFS/ME should not be held up while awaiting these tools, as long as they
include a broad and clearly-defined range of participants;
Even the recent NICE Draft Guidelines accepted that
the Canadian Guidelines were the most stringent. Here is an area
where the MRC could easily resolve the issue mentioned here. It
chooses not to. Instead it has decided to fund trials based on the
continuing usage of the flawed Oxford criteria.
2. Population studies (epidemiology)
Population-based studies are important for answering
questions about the prevalence and incidence of specific conditions and
their relationship to time, place and people within populations. They are also
crucial to testing theories about causation, particularly for establishing
the respective roles of genetic and environmental influences. The group
highlighted three types of epidemiological studies for CFS/ME:
Descriptive studies on the incidence and
prevalence of the condition and its nature, duration and severity;
Studies of causation (aetiology), examining
potential causes and triggers of the disease. Such studies are
considered of primary importance by many patients and support group.
But, while the Group acknowledges their importance, members believe
such studies may not have the same immediate benefits for patients
as studies on symptoms and management, which should not be delayed
while awaiting confirmation of causation;
Outcome studies, looking at patterns of
recovery and the various factors involved.
We see nothing in this area to have shown a clear
strategy has been implemented since the 2003 briefing document was
made. No epidemiological study is funded and the government and MRC
are continually embarrassed by not being able to answer the simple
question - how many people suffer from ME in the UK, let alone what
3. Disease development (pathophysiology)
A wide variety of factors have been suggested as factors in
the development of CFS/ME, but the evidence for each has been weak,
contradictory or unconfirmed. Areas discussed by the Group are as follows:
Infections. Some people are known to develop
prolonged fatigue following certain infections. Although no single
infectious cause of CFS/ME has been identified, infection may well be a
factor in a proportion of cases, and recent advances in virology and
bacteriology make it easier to study its potential role in the
development of the disease;
Neurology. Abnormal neurological signs are not
consistently reported in most patients with CFS/ME, and initial reports
of inflammation of the brain, spinal cord or muscles have not been
confirmed. New imaging techniques might help to shed more light on this
aspect of the disease;
Muscle fatigue/weakness. These symptoms are very
common in people with CFS/ME, but it is not clear whether these problems
arise in the central nervous system or the muscles themselves;
Immunology. Although there have been many reports
of immune system changes in people with CFS/ME, there is no consensus on
the nature and extent of these changes and their potential role in the
development of the disease;
Neuroendocrinology. Abnormalities in the levels
of brain hormones, such as cortisol, have been found in some CFS/ME
patients although it is not clear whether these are causes or
consequences of the disease;
Central nervous system (CNS) function. Fatigue,
intellectual impairment and sleep disturbances are all symptoms of
CFS/ME associated with CNS dysfunction, but again it is not clear
whether these are causes or consequences of the illness. ‘Longitudinal’
studies of people throughout the course of their illness may help to
resolve this issue, while modern imaging techniques could be used to
study the underlying brain pathways of these and other symptoms,
including chronic pain;
Cognitive (intellectual) performance. Although
most studies to date have shown little change in overall intellectual
functioning, there is evidence of attention, memory and concentration
problems in CFS/ME, which are hard to pin down and cannot be entirely
explained by mood variations;
Psychological factors. This is a controversial
area because many people with ME feel that researchers have tended to
focus on psychological causes of CFS/ME at the expense of physical
factors. However, the Group points out that psychological factors,
including personality, coping mechanisms and social support, play a role
in the manifestations of all illnesses, however well established
their physical causes. A key problem with CFS/ME is that it is not clear
at what point in the illness psychological factors might play a part.
On this key point of the potential role of psychological and
psychiatric factors in CFS/ME, the Group makes the following very clear
‘It is the firmly held belief of the Group that
psychiatric illnesses are no less real or debilitating than neurological
It is fitting that the end quote in this section
refers to psychiatric illness in relation to ME as the MRC's love
affair with psychiatric paradigms and the vested interests of the
psychiatric lobby have been to the disadvantage and expense of
neurological ME sufferers in the UK.
To document the clear biological factors (above) which clearly need to be
researched and provision given for funding of research into these - and then to pursue a strategy which
clearly denies any of this is quite disingenuous.
Whether the pathophysiological
factors mentioned above were lacking in evidence in 2003 is debatable - what is
not is that in 2007 there is obvious and documented proof of these factors. Look
at the recent finding by researchers in Stanford, California, USA - where clear
viral-induced dysfunction of the central nervous system has been found in
clinical trials of ME patients (http://mednews.stanford.edu/releases/2007/january/montoya.html).
Where would we be if the MRC had directed funding at biomedical research into
the above areas?
Looking back at this report, and reviewing the actions of the
MRC in the last 3-4 years, one can only shake one's head at the complete lack of
a strategy based on this report.
s for CFS/ME
The search for useful treatments
A variety of interventions (treatments) have been considered
for CFS/ME, but research so far has identified only two which consistently
appear to offer potential benefits: graded exercise therapy (GET) and
cognitive behavioural therapy (CBT).
Focusing on how the evidence base for potentially effective
treatments can be strengthened, the Group draws attention to the fundamental
importance of objective, sensitive and consistent ‘outcome measures’ (signs
of clinically important effects), which can be used to test the
effectiveness of individual treatments and to make comparisons between
Trial procedures should be made as objective as possible by
randomising participants to either active or placebo (dummy) treatment and
masking them to which treatment they are receiving where possible. Trials
should be large enough to detect clinically useful effects, last long enough
to achieve benefit and follow up all participants for long enough to
determine whether effects are sustained.
Crucially, the Group believes it is not necessary to wait
for a full understanding of the causes and development of CFSME before
exploring potential treatments. The cause of diabetes, for example, remains
unknown, but knowledge of the underlying manifestations of the disease has
allowed effective treatment to be developed and rigorously tested.
The Group calls for rigorous assessment of interventions –
1. Musculoskeletal-based interventions
There appears to be considerable confusion and
disagreement about the best approach to physical rehabilitation of
people with CFS/ME, not helped by the fact that some people improve and
others deteriorate with treatment, leading to a high degree of
scepticism among patients. The CMO’s report agreed that rehabilitation
was important but stressed that it should be graded, tailored to
individual needs and start from a low baseline. The Group believes that
an integrated package of care, including a variety of therapies – both
physical and psychological - is likely to be most beneficial;
2. Psychologically-based interventions
The Group believes that cognitive behaviour therapy
(CBT) can play an important role in the management of many
illnesses, particularly chronic ones, and that this treatment, together
with GET, deserves further study.
However, many studies to date have focused on less
severe cases of CFS/ME and further research should aim to focus on the
effects of these treatments across the spectrum of the condition.
The recommendation of CBT and GET as deserving of
further study is like looking back at one of those quaint, but
clearly outdated fashions of 30 years ago. With the exception that
the results of this recommendation may be far more deadly and still
pervade the decision-making on ME today.
Continued trust in GET and CBT today ignore results of trials
and what patients are saying. The human rights issues of forcing GET and CBT
against patients' (and doctors') wishes has been the subject of sections of
IiME's response to the NICE Draft Guidelines (see
One could be forgiven for thinking that the current mess with
NICE's approach to ME may be traced back to the MRC briefing of 2003.
Delivering the best health care
Health services research is a specific branch of research,
examining the best, most cost-effective ways of organising and delivering
effective care. But the Group acknowledges that this type of research needs
to wait on more basic findings about the incidence and prevalence of CFS/ME
and the value of individual treatments.
Once this information becomes available, further research
will be needed to establish:
Which groups of patients are likely to benefit from
which types of treatment;
How the appropriate care services are distributed
Cost-effectiveness, appropriateness and
acceptability of various ‘technologies’, or treatments;
How services should be organised and delivered,
including staff training and the relative role of general and
The above would indicate a strategy. The only
strategy seen to be demonstrated is one to save money or to force
patients back to work, regardless of their true state of health.
More to follow here but the result has to be -
Collaboration in research
The Group sees a need to attract high-quality researchers
from basic science and specialised clinical disciplines to undertake
research into CFS/ME and is keen to promote multidisciplinary collaboration,
including allied health professionals, around shared research goals.
Such research teams will need strong links with the health
service in order to recruit and gain access to trial participants –
particularly those most severely affected by the disease.
A patent failure by the MRC in this area. ME is not
seen as a desirable area for researchers to enter - unless, of
course, they are of the psychiatric persuasion, in which case funding
seems to have been liberally supplied for research projects.
Some ME charities share the blame for this also by allowing
participation in areas which have doubtful relevance or benefits for
ME affected patients.
Attracting high-quality researchers is unlikely to occur if the
MRC repeatedly reject high-quality applications from biomedical researchers and
ME research UK and CFS Research foundation are tow
charities responsible for funding and initiating high-quality studies.
Invest in ME believe the MRC need to work jointly with these two
organisations to facilitate the identification, planning and implementation of
high-quality biomedical research into ME.
There is the challenge to the MRC. The ME community is waiting -
still four years on from your report.
Patient and public involvement
The participation of patients, carers and support
organisations has enriched the process of developing this research strategy,
and their continuing involvement in research offers important two-way
Researchers can gain access to user perspectives,
which will help them both frame their research questions
appropriately and work towards the most relevant outcomes;
Patients and support groups can help to set the
research agenda as well as gaining access to scientific expertise.
In terms of involvement with specific research studies, the
Group believes consumers have several important roles to play:
Getting involved at an early stage so that multiple
perspectives can be taken into account in the design and
interpretation of individual studies;
Liaising with broader groups to raise awareness of
research studies and ensuring their results are widely disseminated
and recommendations implemented;
Helping to identify potential study participants –
particularly those who are severely ill – and involve them in
Fine words but little action seen to have taken
place. The struggle that ME charities specialising in biomedical
research have is testimony to the failure of any of the major
healthcare bodies to listen to patients or advocates of biomedical
The MRC CFS/ME research strategy was published on May 1
2003, and the full document is available on the MRC website (www.mrc.ac.uk).
Future grant applications to fund research into any aspects of this
condition are likely to be judged according to how well they fit within the
proposed framework in addition to their scientific quality.
When announcing the completion of the strategy, the Chair of
the Research Advisory Group, Professor Nancy Rothwell, said:
‘Improving health and quality of life for those who
are ill with CFS/ME is clearly very important. We’ve made our
recommendations based on what is attainable in the short term, and what
has to be developed over a longer period.
‘We recognise that there are many varied views about
research needs and priorities and it has been our job to strike a
balance. Our recommendations will be a stimulus for research, and the
field will then evolve naturally as more is done and other possibilities