Download Appeal received from Alzheimer`s Society, Age Concern

Alzheimer's Society
Gordon House
10 Greencoat Place
London
SW1P 1PH
15 June 2006
Alana Miller
National Institute for Health and Clinical Excellence
MidCity Place
71 High Holborn
London
WC1V 6NA
Dear Alana
Joint Appeal from the Alzheimer’s Society, Age Concern, Counsel and Care, Dementia
Care Trust and Royal College of Nursing regarding the NICE Final Appraisal
Determination: Donepezil, rivastigmine, galantamine and memantine for the treatment of
Alzheimer’s disease.
The Alzheimer’s Society, Age Concern, Counsel and Care, Dementia Care Trust and Royal
College of Nursing wish to strongly object to the FAD and lodge an appeal against the Guidance
contained within the FAD which states that:
1) “The three acetylcholinesterase inhibitors donepezil, galantamine and rivastigmine are
recommended as options in the management of people with Alzheimer’s disease of moderate
severity only (that is, those with a Mini Mental State Examination [MMSE] score of between 10
and 20 points).”
2) “Memantine is not recommended as a treatment option for people with Alzheimer’s disease
except as part of well designed clinical studies.”
The appeal is lodged on the following grounds.
Ground One
The Institute has failed to act fairly and in accordance with the appraisal
procedure set out in the Institute’s Guide to the Technology Appraisal Process
Ground Two
The Institute has prepared guidance which is perverse in the light of the evidence submitted
The basis for the appeal and detailed evidence in support of each of these grounds of appeal are
set out in the attached document. This cover letter should be considered alongside the attached
document.
Yours sincerely
Neil Hunt,
CEO, Alzheimer's Society
Philip Hurst,
Policy Manager, Age Concern
Stephen Burke,
CEO, Counsel and Care
Louise Chambers
CEO, Dementia Care Trust
Pauline Ford
Gerontological Nursing Advisor, Royal College of Nursing
Joint Appeal from the Alzheimer’s Society, Age Concern, Counsel and Care,
Dementia Care Trust and Royal College of Nursing regarding the NICE Final
Appraisal Document: Donepezil, rivastigmine, galantamine and memantine
for the treatment of Alzheimer’s disease.
Appeal Ground One: The Institute has failed to act fairly and in accordance with the
Appraisal Procedure set out in the
Guidance to the Technology Appraisal Process
1a
The Institute has failed to act fairly in that the FAD failed to
provide adequate reasoning for a number of statements potentially
affecting the final outcome. This has made it difficult to effectively
engage in the consultation and appeal.
In order to effectively engage in the consultation and appeal it is vital that
stakeholders are given clear and detailed explanation of why and how a
decision was reached. The current FAD contains a number of statements that
are not supported by adequate explanation (in para 4.3.10.4 and 4.3.10.7).
The lack of information inevitably affects the substance and detail of the
challenge stakeholders can make to the assertions both during the
consultation period and in the appeal process.
1ai
The FAD fails to give clear reasoning for the Committee’s decision that
“it was not convinced that inclusion of an element of harm in the economic
analysis from further prescribing of antipsychotics as a result of their
recommendation was appropriate.” (para 4.3.10.4) There is clear evidence
that neuroleptics cause serious and harmful side effects and that
anticholinesterase treatment can lead to a reduction in neuroleptic
prescribing.1 The reasons why reduction in neuroleptic use is an important
benefit of anticholinesterase drugs and therefore should be included in a cost
benefit analysis are outlined in appeal point 2fii (page 9). The FAD must give
detailed explanation as to why this important benefit was dismissed.
1aii The FAD fails to give clear reasoning as to why the responder analysis,
which provides the most accurate match to the pattern of clinical use, has
been disregarded and why the Committee was not persuaded that the
responder definition would result in cost effective use of the drug treatments
(FAD, para 4.3.10.7). The benefits and importance of the ‘responder analysis’
are discussed in appeal point 2fiii (page 9).
As well as substantially improving the clinical effectiveness figures, the cost
effectiveness figures resulting from the responder analysis fall well within
NICE’s usual threshold of cost-effectiveness.2 Therefore, further explanation
is required as to why the Committee reached the counter-intuitive conclusion
1
A new meta-analysis of US and European data from clinical trials with cholinesterase
inhibitors reported a significant decrease in neuroleptic use (25 per cent to 9 per cent).
(Passmore P (2005) Pharmacological Treatment of Alzheimer’s Disease, at Managing
Dementia, Glasgow, March 2005 (presented meta analysis of Bullock 2001 and Cummings
2004))
2 Costs per QALY resulting from ‘responder analysis’ scenario A Donepezil £30k,
Galantamine £25k, Reminyl £19k (NICE technical report no.2)
3
Joint Appeal from the Alzheimer’s Society, Age Concern, Counsel and Care,
Dementia Care Trust and Royal College of Nursing regarding the NICE Final
Appraisal Document: Donepezil, rivastigmine, galantamine and memantine
for the treatment of Alzheimer’s disease.
that applying the responder definition would not result in cost effective use of
the AchE inhibitors.
1b
NICE have failed to act fairly because they have failed to explain how they have
taken into account clinical need of people in mild stages and late stages of Alzheimer’s
disease and the clinical priorities of the Department of Health.
The Directions to NICE from the Secretary of State3 require it to have regard
to:
(i) the broad clinical priorities of the Secretary of State and the National
Assembly for Wales (as set out for instance in National Priorities Guidance
and in National Service Frameworks, or any specific guidance on individual
referrals);
(ii) the degree of clinical need of patients with the condition or disease under
consideration.
It is not clear what discussion of these two points took place and the
appellants believe NICE have a duty to explain how they have taken these
requirements into account. This is important because the FAD contradicts
government policy in a number of key areas:
1bi
The FAD contradicts priorities set out within Government policy
on dementia care, as it will discourage the early diagnosis of
Alzheimer’s disease. The NSF for older people highlights and explains that
the importance of early diagnosis is a key part of good dementia care (NSF
para 7.35). This is restated in the DH policy document ‘Everybody’s business:
integrated mental health services for older people: a service development
guide’. The document states: “The main purpose of the memory assessment
service is to aid the early detection and diagnosis of dementia, while
identifying treatable causes of cognitive impairment. This allows early
intervention to maximise quality of life and independent functioning and to
manage risk and prevent future harm to older people with memory difficulties
and their carers. It is essential that early intervention services are integrated
with the memory assessment service.”
Availability of effective drug treatment on diagnosis (as per 2001 NICE
guidance on anticholinesterase drugs) encourages individuals to seek help
from their GP at an earlier stage of illness and GPs to refer to specialist
services for assessment for treatment. Clinicians and people with dementia
are telling us that the current FAD would have the opposite effect.
1bii
The current FAD denies access to drug treatment in the mild and
late stages of Alzheimer’s disease, despite evidence of clinical
effectiveness, thus ignoring the clinical need of people in these stages
3
National Institute for Clinical Excellence, Framework document, Appendix A, National Health
Service Act 1977, Directions to the National Institute for Clinical Excellence.
4
Joint Appeal from the Alzheimer’s Society, Age Concern, Counsel and Care,
Dementia Care Trust and Royal College of Nursing regarding the NICE Final
Appraisal Document: Donepezil, rivastigmine, galantamine and memantine
for the treatment of Alzheimer’s disease.
of the illness. NICE’s appraisal has demonstrated that the anticholinesterase
drugs are clinically effective in the mild stages of Alzheimer’s. The FAD states
that thirty-four per cent of people using donepezil in the mild stages of
Alzheimer’s would be classed as responders, as per the 2001 NICE guidance
(compared to 31% in the moderate stage). A recent Cochrane review of the
anticholinesterase drugs concluded, “there is nothing to suggest the effects
are less for those with severe dementia or mild dementia.”4
It is also clear that people with dementia and their carers want effective
treatment that can delay progression of the disease at the earliest stage,
before their illness impacts too greatly on their daily lives and the life of their
carer. The benefits that are achieved following drug treatment are most valued
in the mild stages of Alzheimer’s. In the mild stages a person will retain a level
of independence, be able to maintain social relationships, have capacity to
make future decisions around care and treatments (which has additional
importance with the introduction of the Mental Capacity Act 2005 in April
2007) and carers’ duties will be as light as they will ever be. In the moderate
stages people begin to lose insight, may require assistance or prompting with
key self care activities, behavioural symptoms such as aggression and
agitation can emerge, forgetfulness increases so that people fail to recognise
others or repeat the same phrase or question over and over. People in the
moderate stages will need much more support from their carer to manage
their day-to-day activities. Stabilisation in the mild stages of Alzheimer’s must
be the goal of treatment.
A recent Cochrane review of memantine found the treatment had modest
clinical benefits. During the severe stage of the illness, small gains such as
being able to speak a few words, retain some mobility, being able to feed
oneself can make a huge difference to quality of life. For example, people with
severe Alzheimer’s disease can often become very distressed and frightened
when being moved by a hoist or fed by someone else, particularly if they do
not understand what is happening. Based on our knowledge of individuals’
experience of memantine, the appellants are convinced of the important role
of memantine in moderate-severe stages of Alzheimer’s.
The reduction in behavioural and psychiatric symptoms following treatment
with memantine will also be hugely valued and these symptoms are known to
be closely related to quality of life in people with dementia5 and carers. 6
1c
The FAD has failed to have regard to the Secretary of State’s
Directions to “attach particular importance to equal opportunities issues
4
Birks J, 2006, Cholinesterase inhibitors for Alzheimer's disease, The Cochrane database of systematic
reviews, Issue 2
5
Banerjee S et al, Quality of life in dementia is more than cognition. BMJ, 2005 (submitted for
consideration for publication)
6
Shin IS, Carter M, Masterman D et al, Neuropsychiatric symptoms and quality of life in Alzheimer’s
disease, American Journal of Geriatric Psychiatry, 2005, 13 (6): 469-74
5
Joint Appeal from the Alzheimer’s Society, Age Concern, Counsel and Care,
Dementia Care Trust and Royal College of Nursing regarding the NICE Final
Appraisal Document: Donepezil, rivastigmine, galantamine and memantine
for the treatment of Alzheimer’s disease.
both as an employer and in relation to the guidance it issues.”7 The
upper treatment threshold disadvantages people with high levels of
language skills and education and the lower treatment threshold
disadvantages those with learning disabilities, poorer language skills, a
first language other than English, a different cultural background and
lower educational attainment levels.
The use of the MMSE tool to determine access to treatment is prejudicial
because race, education and language ability can affect performance on
MMSE.8,9 People with a high level of education or language skills may well
score above 20 points yet be in the moderate or even severe stage of the
illness. Similarly, for those with learning disabilities, poorer language skills, a
first language other than English, a different cultural background and lower
educational attainment levels, they may still be in the moderate stage yet have
an MMSE score well below 10.
In response to the comments on ACD2 the Committee accepted that MMSE scores of
people with learning disabilities or language problems are difficult to interpret, but
stated that these groups were not disadvantaged by the treatment entry level (FAD,
para 4.3.13). This clearly misses the point as the vast majority of people with learning
disabilities, a language other than English or severe receptive or expressive language
difficulties will score below the MMSE range currently recommended for treatment.
Furthermore, the FAD states that discontinuation level is set by
anticholinesterase licence. This is incorrect. The licenced indication is for mild
to moderate Alzheimer’s disease and does not specify MMSE threshold. It
relies on the judgement of the clinician. The current FAD leaves no room for
clinicians to decide when and if treatment should end. In particular, the FAD
seems to indicate that a MMSE of <10 is now seen as an automatic cut off,
regardless of the state of the individual’s ADL's/self care abilities. The RCN
had pointed out during the consultation on the Appraisal Consultation
Document (ACD) that MMSE is not the only indicator of the "success" of these
drugs and yet this position has been rejected out of hand. This will be
unbearably detrimental to already precarious families who will see a rapid
withering of the person with dementia and their remaining capabilities
chopped from beneath them - and for what purpose?
The Committee did not appear to consider the disadvantage experienced by people
with higher than average levels of education or langugage skills by the treatment entry
level. If the FAD stands, this group will almost inevitably be
7
National Institute for Clinical Excellence, Framework document, Appendix A, National Health
Service Act 1977, Directions to the National Institute for Clinical Excellence.
8
Wood et al, 2006, Assessing cognitive ability in research: use of MMSE with minority populations
and elderly adults with low education levels. Journal of Gerontological Nursing. 32(4):45-54
9
Tombaugh TN and McIntyre NJ, 1993, The mini-mental state examination: a comprehensive review.
Journal American Geriatric Society, 41(3):346
6
Joint Appeal from the Alzheimer’s Society, Age Concern, Counsel and Care,
Dementia Care Trust and Royal College of Nursing regarding the NICE Final
Appraisal Document: Donepezil, rivastigmine, galantamine and memantine
for the treatment of Alzheimer’s disease.
denied access to drug treatments even after they reach the moderate stages of the
illness.
1d
In the case of memantine, the FAD has failed to follow the remit of the
scope which lists health related quality of life for carers as an outcome and states
that where evidence allows combination treatment should be considered.
The appraisal has ignored important evidence that demonstrates treatment with
memantine can save carers 52 hours of caring time a month. This is discussed in
appeal point 2i.
In addition, it has excluded two trials of memantine in combination with donepezil.
This point is discussed in appeal point 2h.
Appeal Ground Two: The Institute has prepared Guidance which is perverse in the light
of the evidence submitted
2a
The reliance of the Appraisal Committee on incremental cost per
QALY is perverse.
NICE have accepted that it cannot always rely on the cost per QALY
approach (Guide for Manufacturers and Sponsors) and the scope of this
appraisal states that QALYs should be used only if possible. It is impossible
to calculate an accurate cost per QALY and therefore the approach should not
be used in this appraisal. The well-recognised uncertainties around measuring
quality of life in dementia are so great that a reliable cost per QALY cannot be
produced.
The model uses utility scores derived from a study by Neumann. However,
this paper used a method for measuring quality of life that has not been
validated for Alzheimer’s disease or proxy use and therefore the resulting
costs per QALY are unreliable. There are two key problems with the figures
from Neumann:
 Proxies are used
 Four of the six subscales in the index do not change substantially between
mild and moderate dementia.
 A linear relationship between quality of life and dementia severity is
assumed.
2ai
The use of the QALY derived only from carer proxies as a decision
making tool is both unacceptable and totally inappropriate. The HRQL
scores used in the model are based on Neumann et al in which carer proxies
responded on behalf of people with dementia using the Health Utilities Index 2
(HUI2). We have previously raised the point that using only carer proxy
measures is inappropriate and we have been referred to a number of papers.
Two of these papers, Coucill (2001) and Bryan (2005), highlight the lack of
clarity on whether physicians or carers are a more appropriate proxy. The
literature suggests that professionals may be better proxies than carers on
7
Joint Appeal from the Alzheimer’s Society, Age Concern, Counsel and Care,
Dementia Care Trust and Royal College of Nursing regarding the NICE Final
Appraisal Document: Donepezil, rivastigmine, galantamine and memantine
for the treatment of Alzheimer’s disease.
some subscales and family carers better on others. This underlines the
perversity of using the Neumann utility scores.
2aii
Four of the six subscales in the HUI2 index do not change substantially between mild
and severe dementia. The HUI2 comprises seven health domains – sensation, mobility,
emotion, cognition, self-care, pain and fertility (although fertility was discounted for this
study). Primary caregivers completed the questionnaire as proxy respondents and
responses
on each subscale are converted to a ‘global’ utility score. The HUI2 utility scores for
each subscale for mild and severe dementia are as follows:
Subscale
Cognition
Self-care
Pain
Emotion
Mobility
Sensation
Utility score in
mild dementia
0.66
0.88
0.95
0.88
0.94
0.80
Utility score in
severe dementia
0.18
0.14
0.96
0.84
0.79
0.64
Change between
stages
-0.48
-0.74
0.01
-0.04
-0.15
-0.24
Table 1: HUI2 utility scores for mild and severe dementia, provided by caregiver proxies (Neumann et al, 1999)
Only cognition and self-care scores change substantially between mild and
severe dementia. Therefore, averaging the scores across domains introduces
inaccuracy and is scientifically invalid. It inappropriately reduces the sensitivity
to change. For example, there is almost no change in the pain and emotion
subscales. Pain only becomes a particular problem for people with terminal
dementia who are bedbound. Emotional disturbance is equally common in all
stages of dementia. The fertility subscale was removed because it was
irrelevant and does not change and it would be appropriate to remove the
other subscales that do not change over time.
Of the two domains that do change, evidence suggests that self-care, but not
cognition, is associated with quality of life. 10 Therefore, it would appear valid
to use only scores from the self-care subscale. This results in scores of 0.88
for mild dementia and 0.14 for severe dementia rather than 0.60 and 0.34.
The Committee have stated that they do not consider it appropriate to alter the
QALY gains, but have not specifically addressed this key flaw in the method of
derivation of utility scores.
2b
It is perverse to promote bad practice rather than clinical excellence. The FAD does
this in two key ways:
10
Banerjee S et al, Quality of life in dementia is more than cognition. BMJ, 2005 (submitted
for consideration for publication)
8
Joint Appeal from the Alzheimer’s Society, Age Concern, Counsel and Care,
Dementia Care Trust and Royal College of Nursing regarding the NICE Final
Appraisal Document: Donepezil, rivastigmine, galantamine and memantine
for the treatment of Alzheimer’s disease.
2bi
The FAD discourages early diagnosis and treatment, which is recognised to be best
practice in dementia care. The response from both professional and patient groups to
ACD2 demonstrates the widespread support for access to anticholinesterase drugs on
diagnosis. This can achieve stabilisation at the earliest opportunity when it is most
valued and also supports early diagnosis. It is clear that the current FAD contradicts
professional opinion on best practice in dementia care.
2bii It is well established that neuroleptic use should be minimised,
however the FAD works against this principle. Appeal point 2fii discusses
the reasons why avoiding neuroleptic use wherever possible is established as
best practice. The current FAD works against this principle by preventing
access to memantine, the only alternative drug treatment to neuroleptics in
the severe stages of Alzheimer's disease. This is particularly important, given
the evidence that memantine can reduce behavioural and psychiatric
symptoms and therefore reduce the need for neuroleptic drugs.
Given that NICE’s duty is to support clinical excellence it is perverse to issue
guidance that contradicts well-established principles of good dementia care
(which are also included in the NICE dementia clinical guideline).
2c
The decision to base access to anticholinesterase treatment on
MMSE score is perverse in light of the evidence of the unsuitability of
the MMSE tool for this purpose.
An analysis of patient level data was carried out to assess whether there were
subgroups of patients for whom the drug treatments were more cost-effective.
Subgroups based on severity were examined and the drugs found to have
different cost-effectiveness profiles. The FAD recommended that only those
with an MMSE score of 10-20 should be prescribed the drug treatment.
However, there are crucial flaws in basing access to drug treatment on MMSE
score. Consultees across a wide range of professional and patient groups
were unanimous in highlighting the unsuitability of the MMSE as tool to decide
access to drug treatment.
The 2001 NICE guidance (TA019) highlighted the limitations of the MMSE because
of the impact of language and race. (TA019, para 4.3 “The MMSE score is not
without problems and reliance on this assessment is difficult in people whose AD is
complicated by dysphasia and whose first language is other than English.”) These
criticisms are repeated in the current NICE dementia draft clinical guideline (page
129, para 5-13): “Potential limitations, particularly of the MMSE, include associations
with education level and sensitivity to depression (Orrell et al., 1992). There is some
variability in terms of reliability, particularly when standardised instructions and
procedures are not followed. These screening measures may be misleading with those
with either high or low premorbid ability and with certain types of dementia
(especially fronto-temporal and vascular dementia) as well as with people with
sensory difficulties, or who are being tested in a second language.” No new
9
Joint Appeal from the Alzheimer’s Society, Age Concern, Counsel and Care,
Dementia Care Trust and Royal College of Nursing regarding the NICE Final
Appraisal Document: Donepezil, rivastigmine, galantamine and memantine
for the treatment of Alzheimer’s disease.
evidence has emerged to contradict this view and therefore the current FAD should be
consistent with this view.
The inter-rater and test-retest reliability of the MMSE is very poor11 which, if
the FAD stands, will result in access to drugs being dependent on the lottery
of what an individual scores on the MMSE on the day of assessment. In
addition, it is well recognised that race, education and language ability can
affect performance on MMSE.12,13 People with a high level of education or
language skills may well score above 20 points yet be in the moderate or even
severe stage of the illness. Similarly, for those of lower education, or when
English is not a first language, they may still be in a moderate stage yet have
an MMSE score well below 10. The resulting inequalities in access to drugs
are highlighted in appeal point 1c.
Based on this evidence it is perverse for the FAD to recommend that
treatment decisions be based on MMSE score.
2e
As the FAD stands, individuals with an MMSE of below 20 who respond
well to treatment are at risk of having effective treatment removed should their
MMSE score increase to above 20. This is perverse.
2f
It is perverse to use inaccurate assumptions within the model of cost effectiveness for
anticholinesterase drugs. Specifically the model:
i.
Does not capture benefits to carers following effective drug treatment
ii.
Ignores savings resulting from reduction in neuroleptic use
iii.
Fails to use the results of the responder analysis, which provides the most realistic
assessment of costs and benefits
iv.
Underestimates the costs of care.
2fi
It is perverse to ignore the evidence of savings to carer time
following treatment with anticholinesterase drugs. The utility gain of 0.01
assigned to carers is completely inadequate. There is a recognised lack of
published data on improvements to carers quality of life following effective
drug treatment. However, the huge response to NICE’s draft decisions to
restrict access to the drugs demonstrates the importance carers place on
these drug treatments and an overwhelming theme of carers’ letters was the
improvements that the drugs bring to carers as well as people with dementia.
Furthermore, there is direct evidence of benefits to carers, which the FAD is
perverse to ignore. Research demonstrates that treatment with
11
Bowie P et al, Should the Mini Mental State Examination be used to monitor dementia
treatments? Comment in: Lancet, 2000, 355:9200:314-5
12 Wood et al, 2006, Assessing cognitive ability in research: use of MMSE with minority
populations and elderly adults with low education levels. Journal of Gerontological Nursing.
32(4):45-54
13 Tombaugh TN and McIntyre NJ, 1993, The mini-mental state examination: a
comprehensive review. Journal American Geriatric Society, 41(3):346
10
Joint Appeal from the Alzheimer’s Society, Age Concern, Counsel and Care,
Dementia Care Trust and Royal College of Nursing regarding the NICE Final
Appraisal Document: Donepezil, rivastigmine, galantamine and memantine
for the treatment of Alzheimer’s disease.
anticholinesterase drugs can save carers an hour a day of caring.14 This data
has been presented to NICE on a number of occasions by patient and
professional groups but the Committee have not specifically addressed it. The
appellants believe it is unreasonable to discount this evidence. The
Committee have raised the risk of ‘double counting’ if both carer quality of life
gains and carer costs were incorporated into the model (FAD para 4.3.10.3).
However, the 0.01 gain in utility assigned to carers is so low that this
argument is blatantly incorrect as neither has been adequately counted.
2fii It is perverse to ignore reduction in neuroleptic use following treatment with
anticholinesterase drugs. The FAD states that Committee was “not convinced that
inclusion of an element of harm in the economic analysis from further prescribing of
antipsychotics as a result of their recommendation was appropriate.” (para 4.3.10.4)
There is clear evidence that neuroleptics cause serious and harmful side effects and that
anticholinesterase treatment can lead to a reduction in neuroleptic prescribing.15 This is
important in terms of reduced drug costs, reduced costs associated with the side effects
of neuroleptics and impact on quality of life.
The Alzheimer’s Society have estimated that additional costs of prescribing a
neuroleptic such as risperidone is £720 per year, with many people being on
such a drug for this length of time or longer. For the model to better reflect
reality, the cost savings of a decrease in neuroleptic prescription should be
considered.
Neuroleptics are also known to have considerable and expensive health risks
and none of the cognitive or other benefits of the anticholinesterase drugs.
Neuroleptics can increase the risk of falls, strokes and fractures. These side
effects will require additional therapies or expensive hospital stays and may
accelerate care home placement. The side effects of neuroleptics will also
impact on the health related quality of life of people with Alzheimer’s.
It is unreasonable for the cost effectiveness model to ignore reduction in
neuroleptic prescribing following anticholinesterase treatment.
2fiii It is perverse to ignore results of the responder analysis. Appeal
point 1a states that the FAD has not explained why “the Committee was not
persuaded that the responder definition used in TA no.19, when applied to the
results of the pivotal randomised clinical trials, would lead to a cost-effective
use of the AchE inhibitors in the NHS.” In addition to this lack of explanation,
we consider it perverse to ignore the results of this analysis given that it
Wimo A et al, Impact of donepezil treatment for Alzheimer’s disease on caregiver time,
Current Medical Research and Opinion,2004, 20(8):1221-5
15 A new meta-analysis of US and European data from clinical trials with cholinesterase
inhibitors reported a significant decrease in neuroleptic use (25 per cent to 9 per cent).
(Passmore P (2005) Pharmacological Treatment of Alzheimer’s Disease, at Managing
Dementia, Glasgow, March 2005 (presented meta analysis of Bullock 2001 and Cummings
2004))
14
11
Joint Appeal from the Alzheimer’s Society, Age Concern, Counsel and Care,
Dementia Care Trust and Royal College of Nursing regarding the NICE Final
Appraisal Document: Donepezil, rivastigmine, galantamine and memantine
for the treatment of Alzheimer’s disease.
provides the most realistic reflection of how the drug treatments are used in
clinical practice and that the results of the responder analysis fall well within
NICE’s threshold of cost-effectiveness.
The Alzheimer’s Society, as well as other consultees including the Royal
College of Psychiatrists and Department of Health, pointed out that a more
accurate cost and clinical effectiveness estimate would be achieved by
analysing the trial data according to NICE’s 2001 technology appraisal
guidance, where only people who were shown to benefit from medication
continue drug treatment beyond a 3-4 month therapeutic trial. Because only
those who respond to treatment will continue after this initial trial period, using
the mean change of responders and non-responders within the economic
model will result in a grossly over-estimated cost per QALY. Following these
comments, the NICE Guidance Executive requested that a ‘responder
analysis’ be carried out.
As expected, the responder analysis resulted in much improved costeffectiveness estimates. However, the FAD reports that the Committee were
told the responder analysis could lead to significant selection bias and that
overall they were not persuaded that using the responder definition would
lead to a cost effective use of the anticholinesterase drugs. However, the
appellants consider that the benefits of the responder analysis outweigh risk
of potential bias and, furthermore, conversations with independent
statisticians have failed to confirm NICE’s supposition. In addition, the
conclusion that the responder definition would not lead to a cost effective use
of the anticholinesterase drugs is perverse given that the scenario A estimates
are within NICE’s threshold of cost-effectiveness.16
2fiv It is perverse to use an under-estimated cost of full time care.
Within the cost model presented by NICE, the cost estimate (£355 per week)
of full time institutional care is an underestimate. The model does not include
the two most intensive types of care, and is based only upon the proportion
that is reimbursed by social services rather than NHS. Available care strata in
the UK include:






Residential care
Specialist (EMI) residential care
Nursing home care
Specialist (EMI) nursing home care
Specialist units for people with specific needs
NHS continuing care.
The last two categories cost more than £1,000 per week. Care for younger
people with dementia may exceed £1,500 per week. Specialist residential or
Costs per QALY resulting from ‘responder analysis’ scenario A Donepezil £30k,
Galantamine £25k, Reminyl £19k
16
12
Joint Appeal from the Alzheimer’s Society, Age Concern, Counsel and Care,
Dementia Care Trust and Royal College of Nursing regarding the NICE Final
Appraisal Document: Donepezil, rivastigmine, galantamine and memantine
for the treatment of Alzheimer’s disease.
nursing home care is usually required when psychiatric and behavioural
symptoms are prominent. As these symptoms are a very frequent reason for
the need for full time care, people with dementia often require this level of
support from the time of first admission to a care facility. In addition, people
with dementia may be moved from less to more specialist facilities when their
level of need increases, with approximately 12.5 per cent of care facility
residents moving to alternative facilities over a 12-month period (figures from
Ballard et al, 2002).17
In addition, 10 per cent of the people moving care facilities require a period of
time in psychiatric in-patient facilities (a standard admission would be four to
eight weeks) to stabilise the situation before the transfer to a new care facility
can be achieved. We therefore suggest that an estimated cost of 0.5 days per
annum of psychiatric in-patient care should be added to the per patient per
annum cost.
In response to the Alzheimer's Society comments relating to full time care
costs the Committee state that they have used the best available data.
However, these data relates only to residential and nursing home costs borne
by social services and does not include the two most expensive types of care
used by people with Alzheimer's disease, which are often funded by the NHS.
It is unreasonable to exclude these costs when calculating an average cost of
full time care.
2g
The conclusion that there is insufficient evidence to determine the
clinical efficacy of memantine is perverse in light of the evidence.
This conclusion is unreasonable both because (1) one pivotal trial has been
excluded and potentially important data from three other trials are not
considered. And (2) convincing data regarding the sub-group of people with
the syndromes of agitation or psychosis have been ignored.
(1) The exclusion of the memantine plus donepezil trial is unreasonable and
leads to an unfair final conclusion. This was pointed out by a number of
consultees, including patient and professional groups as well as the
manufacturers, but NICE have failed to give adequate response to the points
raised. As has been pointed out:
 This Tariot trial was accepted as a pivotal trial by the FDA
 It was previously accepted by the Appraisal Committee
 It is harder to demonstrate efficacy in patients already stabilised on an
anticholinesterase drug treatment
The memantine plus donepezil trial was a high quality placebo controlled trial
that compared treatment with memantine and donepezil to donepezil and
17
Ballard, C et al (2002) Can psychiatric liaison reduce neuroleptic use and reduce health
service utilisation for dementia patients residing in care facilities? Int J Ger Psych 17:140-5
13
Joint Appeal from the Alzheimer’s Society, Age Concern, Counsel and Care,
Dementia Care Trust and Royal College of Nursing regarding the NICE Final
Appraisal Document: Donepezil, rivastigmine, galantamine and memantine
for the treatment of Alzheimer’s disease.
placebo. It is a particularly good design that will become increasingly used in
the context of already licensed drugs, as most ethical committees would not
permit withholding licensed drugs. Therefore it is perverse to exclude a trial
that utilises a design that is being heralded as an ideal design for future trials
of new therapies for Alzheimer's disease.
A pooled analysis of the two monotherapy trials showed statistically significant
improvements on a range of measures. When the results of the memantine
plus donepezil trial were included the results were more favourable towards
memantine. Given the points raised above, the Appraisal Committee should
give greater weight to this trial.
(2) Data was presented regarding the sub-group of people with agitation or
psychosis, demonstrating very favourable clinical effectiveness and costeffectiveness, probably because people with these syndromes experience a
more rapid course of decline and therefore more likely to benefit from
intervention. These data were ignored because NICE did not consider people
with these syndromes to represent a meaningful sub-group. This is perverse
both because NICE specifically were charged with examining sub-groups with
preferential treatment response and because these syndromes are well
established and recognized by international professional bodies such as the
International Psychogeriatric Association and licensing authorities, and are
associated with distinct clinical outcome and underlying biology (genetic
profiles, brain neurochemistry and neuropathology). It was particularly
perverse to ignore the data suggesting a favourable treatment response in the
people within this group who experienced clinically significant agitation, as
there are currently no licensed treatments for this syndrome, usual practice is
to prescribe drugs that are dangerous and more expensive than memantine
and identifying new, effective and safe treatments for this syndrome has been
identified by people with dementia, their carers and all professional bodies as
an urgent and imperative objective. This is an opportunity to substantially
improve clinical excellence which has been perversely ignored.
2h
The failure to consider reduction in neuroleptic use following
treatment with memantine is unreasonable.
Research demonstrates that memantine is effective in reducing agitation and
aggression, thus reducing the need for neuroleptic drug treatments.18 The
importance of incorporating neuroleptic sparing into an economic analysis of
Alzheimer’s drug treatment is explained in appeal point 2fii in relation to
anticholinesterase. These points apply equally in the case of memantine.
Reduction in neuroleptic use was not discussed in relation to memantine,
when it is arguably most relevant given that agitation and aggression are more
Gauthier S et al, 2005, Effects of memantine on behavioural symptoms in Alzheimer’s
disease patients: an analysis of the Neuropsychiatric Inventory (NPI) data of two randomised,
controlled studies, International Journal of Geriatric Psychiatry, 20:459-64
18
14
Joint Appeal from the Alzheimer’s Society, Age Concern, Counsel and Care,
Dementia Care Trust and Royal College of Nursing regarding the NICE Final
Appraisal Document: Donepezil, rivastigmine, galantamine and memantine
for the treatment of Alzheimer’s disease.
prevalent in the stages of illness licensed for treatment with memantine.
Indeed, the scope specifically states that the drug treatments should be
compared to standard treatment, which for behavioural symptoms in
Alzheimer’s is currently neuroleptic drugs. We therefore argue that the
analysis of memantine should include a comparison with neuroleptic drug
treatments in terms of cost and clinical effectiveness and that the model
should include reduction in neuroleptic prescription following treatment with
memantine.
2i
Excluding benefits of memantine treatment to carers is perverse
in light of the evidence.
Evidence demonstrates that treatment with memantine can reduce the
amount of time carers spend caring by 52 hours per month.19 This is an
important benefit of treatment that has been ignored by the Committee. The
appellants and other consultees have raised this in response to previous
ACDs but NICE have responded that the manufacturer did not submit
evidence on carer benefits (Response to consultee and commentator
comments on the Appraisal Consultation). However, this does not preclude
NICE from considering the evidence on carer benefits submitted by other
consultees and we consider it unreasonable that NICE did not include these
data within the cost-effectiveness analysis of memantine.
In particular, under ‘appraisal methodology and criteria’, NICE's Framework
Document states that 'its [NICE's] task is to assess the evidence of all of the
clinical and other heath-related benefits of an intervention - taking this in a
wide sense, to include quality of life, relief of pain or disability etc as well as
any impact on likely length of life'. Saving around an hour and a half a day of
carer time is clearly an important quality of life benefit of memantine and
therefore falls within this requirement.
Furthermore, the scope for this appraisal stated that benefits to carers’ health
related quality of life should be considered where evidence allowed. A
reduction in hours of caring duties is relevant and should be considered.
2j
NICE have been unreasonable in their interpretation of comments
from the Alzheimer's Society on the behavioural subgroup.
The comments made in the Alzheimer's Society’s response to the ACD2 have
been taken out of context by the Appraisal Committee and this
misunderstanding appears to have contributed to the FAD (para 4.3.17). The
point the Alzheimer’s Society made about NPI threshold for clinically
significant agitation was in relation to memantine as a treatment for
behavioural symptoms, in particular agitation. In this context we suggested a
higher threshold that would indicate an approximate severity that clinicians
19
Wimo A et al, 2003, Resource utilisation and cost analysis of memantine in patients with
moderate to severe Alzheimer's disease, Pharmacoeconomics, 21:327-40
15
Joint Appeal from the Alzheimer’s Society, Age Concern, Counsel and Care,
Dementia Care Trust and Royal College of Nursing regarding the NICE Final
Appraisal Document: Donepezil, rivastigmine, galantamine and memantine
for the treatment of Alzheimer’s disease.
would consider reflected a clinically significant problem requiring treatment. It
is for this group of individuals, who currently would usually be prescribed an
atypical neuroleptic, where the Alzheimer’s Society argued that treatment with
memantine would be of particular value.
This does not negate the evidence that both agitation and psychosis are
sentinel symptoms that identify the person with dementia as a member of the
subgroup who will do better in all outcomes than the general population of
patients on memantine.
16