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Cns drugs 2007; 21 (3): 177-184

 2007 Adis Data Information BV. All rights reserved.
The National Institute for Health and
Clinical Excellence (NICE) and Drug
Treatment for Alzheimer’s Disease
Steve Iliffe
University College London, London, England Abstract
Britain’s National Institute for Health and Clinical Excellence (NICE) has recently issued guidance that restricts the use of cholinesterase inhibitors andmemantine for the treatment of Alzheimer’s disease in the National HealthService. This stance contains lessons for designers of trials, drug regulators, healtheconomists and those developing clinical guidelines for dementia care. Thedebates that took place around and within NICE were about identifying thebenefits of these medicines and the beneficiaries, clarifying the costs of themedication and whom bears them, the methods of weighing benefit against cost,and the consequences of using different approaches to cost-benefit analysis. Thisarticle discusses each of these themes and outlines the changes in research andclinical practice and policy making that might flow from NICE’s decisions onmedication use. Outcome measures that capture changes in dementia syndromesneed further development. Cost-benefit analysis needs refinement with bettertools than quality-adjusted life-years, and the policy implications of restrictingtreatments in a progressive neurodegenerative disorder need more careful consid-eration.
1. Background
drugs, particularly given the new generations ofanti-dementia drugs appearing on the horizon.
In 2001, NICE had recommended all four drugs The attention given to the cholinesterase inhibi- for use within the National Health Service (NHS) in tors donepezil, galantamine and rivastigmine, and to patients who had mild-to-moderate Alzheimer’s dis- the NMDA receptor antagonist memantine, by ease, but in a routine review of this decision in Britain’s National Institute for Health and Clinical February 2005 the Technology Appraisal Commit- Excellence (NICE), working in conjunction with the tee of NICE reversed the recommendation in a draft Social Care Institute of Excellence (SCIE), has gen- report that suggested that the drugs should no longer erated great controversy amongst scientists, clini- be made available because they were not cost effec- cians, interested citizens’ organisations and drug tive.[1] Subsequent negative feedback from stake- manufacturers. There are lessons to be learned by holders, and critical commentaries from clinicians designers of trials, drug regulators, health econo- who challenged NICE’s reliance on quality-adjusted mists and clinical guideline developers from the life-years (QALYs) as a measure of cost effective- debates that occurred during the evaluation of these ness in dementia, the use in the economic models of old data about service costs from the US, questiona- cholinesterase inhibitors and memantine supports ble approaches to finding and analysing trials, and the view that these drugs have a real, albeit modest, treatment assumptions that did not correspond with symptom-modifying effect in some people with practice,[2] led to a revision of the recommendations.
Alzheimer’s disease.[3] For example, two multicen- More trial data were obtained from pharmaceutical tre studies have shown that donepezil slows disease companies, particularly from subgroup analyses of progression for up to a year, whether measured by a responders, and this (with more up-to-date UK data global rating scale[4] or an Alzheimer-specific mea- on services) resulted in new economic analyses that sure of changing function.[5] Taking a cautious view were more favourable to the cholinesterase inhibi- of the evidence, we should note that galantamine tors, if not to memantine. The NICE guidance of produces comparable slowing of the dementia pro- 2006 restricts the use of cholinesterase inhibitors to cess, at least for 6 months, as measured by clinician those with moderate-to-severe dementia, and limits rating and cognitive performance, but has gastroin- testinal adverse effects that intensify with increasing The following four questions about developing, dosage.[6] A systematic review of the effectiveness testing and licensing medication for the treatment of of rivastigmine showed that it could produce clini- Alzheimer’s disease arose during the debate: cally meaningful improvement across a range ofeveryday activities, from managing money through • What are the benefits of using these medicines, household chores to discussing politics.[7] Thesekinds of measures may be more meaningful than • What are the costs of using these medicines, and some of the standard scales for cognitive perform-ance and more useful in clinical practice, an issue • How can we decide if the benefits of using these that I will return to later (see section 2.2.1). Meman- tine is intended for use in patients who have moder- • What are the consequences of different approach- ate-to-severe dementia and appears to reduce the need for caregiver time and possibly postpone the The attempt by NICE to answer the first three questions for three cholinesterase inhibitors and oneNMDA receptor antagonist has a relevance beyond the specific medicines, the clinical condition beingtreated and Britain’s NHS. The questions and their answers are relevant to all complex or costly symp- Alzheimer’s disease, we need to know who the tom-modifying drugs, and a broad spectrum of de- beneficiaries are before we can identify the potential generative diseases, in any healthcare system in and actual benefits of pharmacological therapies.
which a third-party payer needs to make rationing There are three broad groups of beneficiaries from I will attempt to answer all four questions, using Alzheimer’s disease: people with dementia of some of the ideas and arguments developed by predominantly the Alzheimer type; their supporters, NICE as well as a wider range of sources, and to family and close associates (carers); and service identify themes or topics for further research.
providers across a range of disciplines and agencies.
2. What are the Benefits and Who are
Clinicians, citizens’ organisations and the pharma- the Beneficiaries?
ceutical industry tend to focus on the first twogroups, whilst health services emphasise the thirdpotential beneficiary and define the benefits as dis- crete economic categories, such as deferment of The comprehensive review by the NICE Tech- transfer to residential care. However, both clinical nology Appraisal Committee of the trials of the and health service perspectives are problematic be-  2007 Adis Data Information BV. All rights reserved.
NICE and Drug Treatment for Alzheimer’s Disease cause of the difficulties in measuring outcomes ade- abstract reasoning) and the memory needed to assess quality of life, disease progression may render thismeasurement less and less reliable.[14] The best op- 2.2.1 People with Dementia
tion for researchers investigating treatment effects, Treatment effects of anti-dementia drugs are dif- and also for clinicians managing patients with de- ficult to measure, whether subjectively or objective- mentia syndromes, may be to use clinical global ly. There have been few systematic attempts to measures that combine cognition, behaviour and collect personal experiences from users of agents for functioning.[15] These have yet to become the norm Alzheimer’ disease, which prompted NICE to initi- in drug trials, particularly those mounted by indus- ate a systematic review of the qualitative and narra- try, but regulators are likely to require them for the tive literature in an attempt to develop a robust evaluation of future ‘anti-dementia’ drugs.
overview of patient experiences.[9] This review Finally, we cannot yet predict who will benefit found that there is little scientific literature on the from treatment with anti-dementia drugs. Although experiences of people with dementia using these most patients with baseline Mini-Mental State Ex- drugs, most evidence being anecdotal and mediated amination (MMSE) scores of 10–20 who receive either by professional providers or by voluntary these drugs achieve greater benefit in terms of cog- organisations representing carers. One immediate nitive testing and activities of daily living scales research objective should be to investigate the expe- than when receiving placebo, there seems to be no rience of treatment from the perspective of people means of predicting such responsiveness. Therefore, with dementia, with a view to permitting individual- there is no definable subgroup of ‘drug responders’ ised outcome measures to be used in intervention who, if pre-selected, would increase the benefits of studies alongside standardised tools.
treatment and alter the cost-benefit analysis.
Objective outcome measures that are widely used Characterising responders is another important re- in trials may be limited in scope, may fail to capture the impact of the disease process on the individual,may not measure responsiveness to treatment well, 2.2.2 Carers
or may produce results that are difficult to translate The benefits of anti-dementia drugs to carers are into clinical terms. For example, functional assess- more widely investigated and are usually under- ments may be crucially important in clinical terms, stood as reduced caregiver burden and reduced eco- but are not relevant in all cultures,[10] and are less nomic losses (work given up).[16] In contrast with the well developed as measures and do not seem to experiences of people with dementia themselves, a detect treatment changes well.[11] Cognitive function great deal is known about caregiver burden, which tests, whilst widely used, show small but statistically spans the domains of psychological impairment, significant changes in response to cholinesterase physical damage (e.g. diminished immune response, inhibitors that are difficult to translate into clinical hypertension) and social isolation, whilst economic gain,[12] and that may not be relevant in all cul- losses include financial loss to the individual (work tures.[13] The measurement of quality of life in de- given up) and increased use of health services.[17] mentia syndromes emphasises the individuality of Measuring outcomes for carers is less problematic patients, means more clinically than a cognitive than it is for people with dementia, but two risks function scale and allows the comparison of differ- remain for those who want to include carer benefits ent types of interventions (e.g. psychosocial and as outcomes in intervention studies. One is that medication). However, the subjective nature of depending on caregiver burden as a proxy for patient quality-of-life measurement means there is no vali- views assumes that carers’ perspectives are necessa- dating external gold standard, and group compari- rily congruent with those of people with dementia, sons are therefore difficult. Since the disease pro- which may not always be true. The second is that cess impairs awareness, executive functions (e.g.
measurements of economic losses to caregivers vary  2007 Adis Data Information BV. All rights reserved.
enormously depending on the assumptions made 3. What are the Costs, and Who
about opportunity costs (earned income foregone), Bears Them?
the definition of caring tasks and the costs attributed There are five identifiable types of cost when to caring itself (as if it were a paid occupation), as drugs are used for symptom modification in well as the sources and datedness of service utilisa- tion data. The initial economic evaluation of the • prescribing costs (the cost of the drugs and the cholinesterase inhibitors and memantine made by NICE contained a sufficient number of challengea- ble assumptions (e.g. about US cost data applying to UK services) to undermine the whole judgement • economic costs to carers through lost work op- about the value of the medication, but it would be equally possible to overstate the benefits of medica- • costs to community services providing care in the home when institutional transfer is delayed.
A preoccupation with prescribing costs is under- 2.2.3 Service Providers
standable because they are the main drivers for the Most of the concern with the benefits of treat- rising costs of healthcare associated with population ment with agents for Alzheimer’s disease has fo- ageing. An analysis of trends in service utilisation cused on the downstream economic gains that can and healthcare costs in British Columbia, Canada, be derived from the upstream use of symptom- over 3 decades[23] suggests that the driving forces for modifying drugs, particularly with delayed institu- age-related rising costs are increased per capita tionalisation. This is not surprising given the scale of utilisation of medical services linked to perceived the clinical problem. Between 1990 and 1998 the changes in ‘capacity to benefit’, and three forms of proportion of the EU population aged >65 years increase in drug costs: (i) age-specific exposure increased from 14.5% to 15.9%, and now numbers rates or treatment patterns; (ii) changes in the vol- around 60 million people.[18] A recent review of ume and mix of drugs used by each patient; and (iii) dementia prevalence studies in the EU estimated price changes for given drug types. Medical technol- that 3.8 million people (6.4% of this age group) had ogies also ‘creep’ (expand beyond their original dementia.[19] Dementia is the fourth most common purpose), with the result that medication may be cause of death in the ≥75-year age group[20] and is a used beyond its range of demonstrated effective- huge economic burden for the community.[21] In the UK, the annual costs of Alzheimer’s disease were Monitoring costs arise when practitioners add the estimated in 1998 to lie between £5400 and £5800 work of re-assessing patients with dementia at regu- million.[22] At this time, health and social services lar intervals to evaluate the benefits of treatment, were thought to meet 42% of this, with the remain- and to make decisions about treatment continuation der met by Department of Social Security funding or modification. Although these costs may not be quantified, they still influence policy and practice.
Given the scale of expenditure on dementia care, For example, in the UK, the initiation of cholinester- it is hardly surprising that regulators have a keen ase inhibitors is a specialist function, but the review interest in demonstrating that interventions not only of treatment can be shared with the patient’s general work, but also have economic benefits by reducing practitioner, so reducing demand on outpatient clin- the high costs of downstream expenditure on care homes or high-intensity home support. This brings Adverse effects can attract costs if they cause us to consider the difficult problem of working out hospital admission, or require a family member to what the costs of treatment are, and how we would take time off work to look after the person with know that the drugs represent good value for money.
dementia at home. Although adverse effects associ-  2007 Adis Data Information BV. All rights reserved.
NICE and Drug Treatment for Alzheimer’s Disease ated with anti-dementia drugs are common and sig- appropriate, particularly when appropriate data on nificant enough to induce withdrawals from trials, quality of life are not available,[25] as is the case with there is no evidence of them causing costs to the dementia syndromes. Much of the debate between healthcare system or domestic economies.
old age psychiatrists and the NICE Technology Ap-praisal Committee centred on this issue.[26] The opportunity costs borne by carers may be difficult to estimate, and depend on whether the Even if the quality-of-life data were readily avail- economic perspective taken is that of services, or able from trials, there are doubts about whether societal. The boundary between ‘normal’ life and QALYs are valid for dementia syndromes.[27] The caring is imprecise, and the main carer (e.g. a retired use of proxy measures of quality of life that have not spouse) may not be engaged in paid work, but rather been specifically developed for dementia is chal- have a supportive role, say in the episodic care of lenged, with recent studies demonstrating major in- grandchildren. Opportunity costs in this scenario consistencies and disagreements between different will be low level, even if extra childcare has to be proxies.[28,29] Alternative methods of assessing qual- purchased. The opportunity costs will be much ity of life in dementia are being developed and higher if a son or daughter gives up paid work to be a validated, e.g. DEMQOL.[24] An alternative measure carer, but in doing so they will reduce the costs of could be ‘costs per progression-free week’, as debat-ed by the UK Royal College of Psychiatrists,[26] All the models used to predict cost and benefit of which may provide a much more meaningful and anti-dementia drugs focus on cognition as the main realistic estimate of the true costs and benefits to clinical measure in Alzheimer’s disease and institu- patients, carers and society. It may be the case that tionalisation as the main cost element. However, the there is no satisfactory technical solution to the potential benefits and risks in dementia are much problem of rationing, and that we are always re- wider, and cognition is not necessarily the most turned to the value system of the society.
important aspect of the disease process. Data fromthe development of the DEMQOL instrument, a 5. Policy Issues in Technology
disease-specific measure of health-related quality of Assessment in Dementia
life in dementia,[24] suggest that decreased quality of If social values are the final arbiter of decisions life is significantly correlated with higher levels of about resource allocation, we need to think about the behavioural and psychological disturbance, but not development of the NICE/SCIE guidelines in such with cognitive decline. Measuring quality of life in terms. There are at least nine possible consequences dementia is complex and modelling on a single of a decision to discontinue the prescription of a measure such as cognition is likely to miss impor- group of effective symptom-modifying drugs for tant factors shaping the illness experience, the im- pact of the disease on carers and effects on service Withholding treatment on cost grounds implies that the health service cannot meet public expecta-tions about appropriate treatment, because it is de- 4. How do We Know if the Benefits are
nying vulnerable people with progressive neurologi- Worth the Costs?
cal disorders treatments that can relieve their symp- Health utility measures such as QALYs are based on the values that people place on different health Restricting the use of medication for Alzheimer’s states, and are central to NICE’s judgements about disease may contradict specific policies and service the cost effectiveness of treatments. NICE uses a developments in dementia care. For example, in rule of thumb that treatments with QALYs costing England, the National Service Framework for Older <£30 000 are affordable for the NHS. This is not a People and the Audit Commission have both called fixed rule, as there are circumstances when it is not for early identification and treatment of people with  2007 Adis Data Information BV. All rights reserved.
dementia. There is a real risk that policy will appear flown principles, particularly commitments to anti- discriminatory practices. Advocates of older peo-ples’ interests will join forces with the dementia The proposal will shift costs of medication to lobby to campaign against adverse decisions, per- people with dementia and their families because haps claiming violation of human rights by the gov- people will buy the medication for themselves or ernment if it accepts and adopts such recommenda- their relative. This is inequitable, if personal income tions. Legal action, launched by the pharmaceutical or savings are used, and could also reduce people’s industry and supported by a voluntary organisation, ability to spend money on other important things, was announced during the writing of this paper.
In the period between the decision to discontinue Curtailing the prescription of these drugs may medication availability and any curtailment of new undermine current service development in dementia prescribing, doctors may opt to offer these care. For example, in the UK, old age psychiatry has medicines to people whose diagnosis is suspected become an important and dynamic discipline within rather than confirmed, since they could continue medicine, partly through its growing community with medication begun before the curtailment dead- role, but this role may now be diminished through line. Perversely, prescribing costs could increase loss of an effective form of treatment. The recruit- temporarily, and individuals and families may chal- ment and retention of clinicians specialising in old lenge clinical decisions, during this window of op- age psychiatry may be compromised in the longer portunity, if the drugs are not prescribed.
term. The growth of dementia care services forpeople with early dementia may go into reverse, and Decisions about using supposedly expensive treatments inevitably prompt debates about publicexpenditure priorities. For example, why should the Voluntary organisations may feel that their per- public health service bear the costs of antifungal spectives and concerns are being ignored in the treatment for infected toenails (a form of cosmetic policy development process. A huge amount of ef- therapy) but not for reduction of dementia symp- fort has been put into inclusiveness in policy makingin the UK, with stakeholder opinion being sought toms? More invidiously, some will question why the assiduously by the Department of Health and NICE taxpayer should pay for immigrants’ healthcare but itself. Whilst this apparent rejection of the strong not for that of veterans of World War II? The interest of organisations such as the Alzheimer’s political arguments that flow from this kind of eco- Society in the treatments for dementia may strength- nomic logic are not likely to be ones welcomed by en their campaigning role it does not strengthen the any political party in government, particularly if it idea of ‘partnership working’. In one move, an ad- wants to emphasise improvements in healthcare and verse decision about medication could propel the voluntary sector from partnership with the health- The irony of this proposal in England is that it care system into conflict. The message to individu- coincides with the establishment by the Department als may be that the relief of symptoms is simply not of Health of a national dementia research network to worth attention from public services. It is difficult to subsidise further studies (including large trials of think of an easier way to trigger a sense of abandon- new medicines) and to limit the drift of drug re- ment amongst people with newly diagnosed demen- search from the UK to cheaper countries of Eastern Europe and Asia. Could a government send a clearer Rightly or wrongly many will see the proposals signal to inhibit pharmaceutical industry investment to restrict access to cholinesterase inhibitors and in the UK than allowing one of its agencies to curtail memantine as evidence that older people are deval- the use of medication of proven effectiveness, on ued. Charges of ageism will be compared to high-  2007 Adis Data Information BV. All rights reserved.
NICE and Drug Treatment for Alzheimer’s Disease 6. Conclusion
The author was a member of the NICE/SCIE Dementia The outcome of much debate about the use of Guidelines Development Group 2004–6, and in the past has cholinesterase inhibitors and memantine in England received unrestricted research funding from Eisai/Pfizer. No is that the former can be prescribed by NHS doctors sources of funding were used in the preparation of this for people with moderate-to-severe Alzheimer’s dis- ease, and that memantine can only be prescribed aspart of a well designed trial. However, the definition References
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