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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