Value assessment of new interventions for Alzheimer’s disease dementia in Japan based on literature review and group interview

ABSTRACT

Introduction

With an increase in the number of patients with Alzheimer’s disease dementia (ADD), new health technologies have been developed to address the problem. We propose an optimal way to assess the disease burden and treatment value of ADD in Japan by considering the characteristics of the disease.

Areas covered

We performed literature searches and a group interview with professional care workers to obtain information on the items that would facilitate the assessment of the value of ADD intervention. We determined the items as patient quality of life (QOL), medical costs, caregiver QOL, public long-term care costs, and informal care costs.

Expert opinion

There are several limitations to how QOL is measured, particularly for patients with ADD. Public long-term care costs represent a substantial proportion of total costs and should be included in the assessment and decision-making of ADD, even from the payer’s perspective. Following that, a process is required to take informal care costs into account in decision-making, regardless of whether they are included or not in a base-case analysis. The importance of other elements of care burden that cannot be quantitatively measured should also be recognized and reflected in decision-making.

KEYWORDS:

• Alzheimer’s disease dementia
• caregiver burden
• group interview
• health technology assessment
• informal care
• literature review
• patient care
• quality of life
• value assessment

1. Introduction

In most countries, the number of patients with dementia has increased owing to aging populations [1]. The social burden associated with their increase is a critical issue in rapidly aging Japan. The prevalence of dementia in Japanese individuals ≥ 65 years was estimated to be 15% in 2012, with this proportion expected to exceed 20% by 2030 and 25% by 2060, along with the increase in the older population [2]. Among different forms of dementia, Alzheimer’s disease dementia (ADD) is the most common in Japan, with a prevalence of 67.6%, followed by vascular dementia (19.5%), as of 2010 [3]. ADD follows a prolonged, progressive course that begins with pathophysiological changes in the brains of the affected individuals years before clinical manifestations are observed [4]. These changes include the accumulation of amyloid-β (Aβ) and the development of neurofibrillary tangles of tau protein [5,6]. Cholinesterase inhibitors and memantine are available for patients with mild-to-moderate ADD and those with moderate and severe ADD, respectively, for treating cognitive, behavioral, and functional symptoms of ADD (high-dose donepezil is also used for patients with severe ADD) [7–11]. New drugs, including disease-modifying therapies (DMT) that slow the progression of ADD instead of merely addressing its symptoms, have been investigated, and anti-Aβ antibodies have been found to mediate the removal of amyloid plaque from affected brains [6]. Therefore, the importance of an assessment of the value of the new health technologies is notably growing, especially for patients with ADD among the subtypes of dementia.

Patient care is imperative for ADD because it affects various cerebral functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language, and judgment. Considering the characteristics of the disease, the burden of care should be considered when assessing the value of health technologies for ADD. However, the burden of care is insufficiently considered in the health technology assessment (HTA), which has been performed in multiple countries. The role and methodology of the HTA differ across countries. In Japan, HTA is used to adjust the price after national health insurance price listing for designated health technologies. Cost-effectiveness analysis, with quality-adjusted life years (QALYs), is used as the outcome measure in principle in most countries/HTA organizations, such as those in Japan [12], the National Institute for Health and Care Excellence (NICE) in the UK [13], and the Institute for Clinical and Economic Review (ICER) in the US [14]. In terms of cost, while medical costs are included, care costs, such as those for nursing home or residential care, are not always considered. Moreover, informal care costs are not included in the guidelines in many countries/organizations, including Japan [12] and NICE [13]. Researchers in the US have reported the significance of the unpaid care provided by family caregivers. They insist that the inclusion of caregiver-relevant outcomes and informal care costs is essential to estimate the true impact of new health technologies from the societal perspective, particularly for conditions requiring constant and prolonged caregiving, such as ADD [15]. Considering the gaps between components included in the current HTA system and those considered important for ADD, it is important to understand how these components are assessed and what the challenges are in assessing ADD.

This study aims to determine an optimal way to assess the disease burden and treatment value of ADD in Japan by considering the characteristics of the condition. We obtained information about the current status and challenges of items likely to be included when assessing these burdens and values from the literature and professional care workers. Based on this information, we discussed the appropriateness and challenges of all elements and whether those elements are included in the HTA process. We also discussed how these elements should be considered in the decision-making process, within and beyond the HTA process. As HTA is only one of several schemes to identify the clinical and economic impact of drug treatments and technologies, it is meaningful to consider the elements associated with ADD’s disease burden and treatment value beyond the HTA process, regardless of whether these elements can be quantitatively assessed. We consider such discussions to be useful in determining the value of future health technologies for the prevention or treatment of ADD.

2. Methods

We determined the elements likely to be included when assessing ADD’s disease burden and treatment value as items included in the HTA process in general and those associated with patient care. These are patient QOL, medical costs, caregiver QOL, public long-term care costs, and informal care costs. Subsequently, we performed literature searches and a group interview with professional care workers to obtain information about the items related to value assessment in disease burden and the effects of interventions for ADD. The literature included published studies written in English or Japanese evaluating the disease burden or the effects of ADD interventions in Japan. The group interview was held with four professional care workers (two nurses, one care worker, and one care manager) employed at a nursing care facility on 11 October 2021, in Tokyo. We asked about the gap between current HTA procedures, including the method of outcome measurement, and the actual status of patients and their families, based on their working experiences in the nursing home. Based on the information, we discussed the appropriateness and challenges of evaluating the items and how and to what extent those items were currently included and should be included for future decision-making, including in the HTA process.

3. Results

3.1. Literature search

3.1.1. Quality of life measurement in patients and caregivers

Measurements of QOL used in the literature are summarized in Table 1. A Japanese study reported that a decrease in the QOL scores measured by EQ-5D-5L corresponded to the worsening of ADD; the average score was 0.801 for mild ADD, 0.662 for moderate ADD, and 0.436 for severe ADD [22]. In that study, an EQ-5D-5L proxy instrument was administered, and the nursing home or residential facility staff responded on the patients’ behalf. In a Japanese randomized controlled trial (RCT) evaluating the treatment effect of donepezil for patients with ADD, a significant improvement of 0.103 was recorded in the patient EQ-5D score approximately 3 months after the treatment [23]. A similar improvement in the patient EQ-5D score, 0.122, was recorded after approximately 3 months of treatment when data were collected from a larger group [24]. The patient’s score on the Quality of Life-Alzheimer’s Disease Scale (QOL-AD) [17,18] was also used in the RCT, and an improvement was noted [23,24]. In the RCT, the included patients received care from their family members or relatives staying with the patients, and these scores were measured based on the assessment by caregivers.

Table 1. Measures of the quality of life or caregiver burden for patients with Alzheimer’s disease dementia and their caregivers in the literature.

Measure	Description	Subject
EQ-5D (EQ-5D-3L, EQ-5D-5L) [16]	Most commonly-used measure to obtain QOL for QALY calculation. EQ-5D (EQ-5D-3L or EQ-5D-5L) consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. EQ-5D-3L and EQ-5D-5L have 3 and 5 levels of options, respectively, for each dimension. A score of 1 is assigned for perfect health and 0 for death.	Patients, caregivers
Quality of Life-Alzheimer’s Disease Scale (QOL-AD) [17,18]	A disease-specific measure of QOL for ADD. It includes 13 items: physical health, energy, mood, living situation, memory, family, marriage, friends, self as a whole, ability to do chores, ability to do things for fun, money, and life as a whole. Each item is rated on a 1–4-point scale, with total scores ranging from 13 to 52. The score is determined based on the responses of both patients and caregivers.	Patients
Zarit Burden Interview (ZBI) [19,20]	A measure to assess the burden on caregivers for older people. It consists of 22 items associated with physical and mental health and financial difficulties.	Caregivers
Neuropsychiatric Inventory-Caregiver Distress Scale (NPI-D) [21]	A tool for the assessment of the burden of caregivers of patients with dementia associated with the patients’ behavioral disturbance. It includes 12 domains.	Caregivers

Caregiver QOL was also included as an outcome in the aforementioned Japanese RCT (Table 1). After the treatment with donepezil, the caregiver EQ-5D score also improved, from 0.797 to 0.902 [23] or from 0.785 to 0.902 [24], when data from a larger group were collected. In that RCT, the Japanese version of the Zarit Burden Interview (ZBI) [20] and the Neuropsychiatric Inventory-Caregiver Distress Scale (NPI-D) [21] were also used to measure caregivers’ burden.

3.1.2. Medical costs and public long-term care costs

Medical costs and public long-term care costs estimated in the literature are shown in Table 2. Public long-term care costs were defined as the costs covered by the public caregiving insurance system in Japan. Annual medical costs for Japanese patients with ADD were estimated at JPY 297,524 (JPY 1 = USD 0.009, as of February 2022) per patient, with 86% of the costs attributable to medical costs other than ADD drug costs (14%) [25]. In this study, medical costs other than for ADD drugs increased in relation to ADD-severity: JPY 275,148 for patients with a clinical dementia rating (CDR) of 0.5 and 1, JPY 419,028 for those with CDR 2, and JPY 559,236 for those with CDR 3. Annual public long-term care costs were higher than medical costs, with the difference growing based on disease severity (JPY 253,919 per patient for CDR 0.5, JPY 919,814 for CDR 1, JPY 1,790,152 for CDR 2, and 2,733,045 for CDR 3). In another Japanese study that considered different levels of ADD severity based on patients’ Mini-Mental State Examination (MMSE) scores, the per-patient healthcare costs over 18 months were JPY 496,642, JPY 483,505, JPY 520,004, and JPY 480,130 for all patients, those with mild ADD, those with moderate ADD, and those with moderately severe or severe ADD, respectively [26]. A Japanese longitudinal cohort study that examined additional medical costs and long-term care costs attributable to ADD indicated that the monthly additional medical costs increased from the month of ADD onset to the first month after ADD onset, and decreased thereafter [27]. Meanwhile, the additional long-term care costs gradually increased, exceeding the additional medical costs from around 11 months after the onset.

Table 2. Medical costs and public long-term care costs for patients with Alzheimer’s disease dementia in the literature.

Literature	Medical costs (per patient)	Medical costs (total)	Public long-term care costs (per patient)	Public long-term care costs (total)	Estimation methods
Ikeda et al. [25]	¥297,524/year (ADD drug costs: ¥41,811/year, other than ADD drug costs: ¥255,714/year; overall) Other than ADD drug costs: ¥275,148/year (CDR 0.5 and 1), ¥419,028/year (CDR 2), ¥559,236/year (CDR 3)	¥1,073.4 billion/year (ADD drug costs: ¥150.8 billion/year, other than ADD drug costs: ¥922.5 billion/year; overall) Other than ADD drug costs: ¥127.3 billion/year (CDR 0.5), ¥153.7 billion/year (CDR 1), ¥194.6 billion/year (CDR 2), ¥446.9 billion/year (CDR 3)	¥1,325,862/year (overall), ¥253,919/year (CDR 0.5), ¥919,814/year (CDR 1), ¥1,790,152/year (CDR 2), ¥2,733,045/year (CDR 3)	¥4,783.2 billion/year (overall), ¥242.3 billion /year (CDR 0.5), ¥1,059.4 billion /year (CDR 1), ¥1,182.5 billion /year (CDR 2), ¥2,299.1 billion /year (CDR 3)	Annual costs were estimated. Medical costs other than that for ADD drugs were calculated by multiplying the estimated numbers of patients with ADD and medical costs based on a questionnaire survey of clinical physicians by disease-severity classified by CDR score. Drug costs were calculated as the total cost of ADD drugs: donepezil, rivastigmine, galantamine, and memantine. Public long-term care costs were calculated by multiplying the estimated numbers of patients with ADD and public long-term care costs based on public long-term care insurance service users’ claims data by care need levels.
Nakanishi et al. [26]	¥496,642/18 months (overall), ¥483,505/18 months (mild), ¥520,004/18 months (moderate), ¥480,130/18 months (moderately severe/ severe)				Costs from the baseline to 18 months were estimated. The patients were classified by ADD-severity based on MMSE score at baseline. Medical costs included the cost of patient medications, hospital admissions, emergency room visits, and outpatient visits. Mean costs are reported with 95% Cis, which were calculated using a bootstrapping approach with the lower CI coming from the 2.5 centiles and the upper CI from the 97.5 centiles.
Fukuda et al. [27]	$7,280/year (1st year), $3,528/year (2nd year), $3,292/year (3rd year)		$3,398/year (1st year), $4,589/year (2nd year), $4,561/year (3rd year)		Additional ADD-attributable costs were estimated over three years after the ADD onset as differences between those for patients with ADD and matched non-ADD controls by propensity score. The costs were estimated based on information on administrative claims and long-term care insurance.

ADD, Alzheimer’s disease dementia; CDR, clinical dementia rating.

3.1.3. Informal care costs

Informal care costs were defined as the unpaid costs for care provided by informal caregivers, mainly family members (Table 3) [25,26,28]. These costs were determined based on the time spent providing support for the activities of daily living (ADL), such as using the toilet, eating, dressing, grooming, walking, and bathing, and for the instrumental activities of daily living (IADL), comprising cognitively complex activities such as shopping, cooking, housekeeping, laundry, transportation, taking medication, and managing finances. Sado et al. [28] estimated informal care costs for dementia as JPY 6.16 trillion in 2014, with the total social cost being JPY 14.5 trillion. In the study, costs for ADL were estimated by employing a replacement cost approach, using the fee for ‘physical care’ in long-term care service as the unit cost, while costs for IADL were estimated by employing an opportunity-cost approach using the expected mean lost wages (Table 3). Ikeda et al. [25] reported that the informal care costs for ADD family caregivers were JPY 6,772 billion in 2018, much higher than the medical costs of JPY 1,073 billion and public long-term care costs of JPY 4,783 billion. The informal care costs for ADL and IADL were estimated using the unit cost of caregiving service and the average wage, respectively (Table 3). Nakanishi et al. [26] reported that informal caregiver costs represent over 50% of the societal costs for ADD, irrespective of severity level. The informal care costs per patient for 18 months were determined at JPY 2,454,987, estimated using the costs either for caregiver time or for missing work, whichever was higher (Table 3).

Table 3. Informal care costs for patients with Alzheimer’s disease dementia or dementia in the literature.

Literature	Informal care costs (per patient)	Informal care costs (total)	Estimation methods
Sado et al. [28]	¥3,822 thousand/year (for dementia)	¥6.16 trillion/year (for dementia)	The time spent on informal care by informal carers (mostly families) was predicted by using a model and conducting a regression analysis based on survey results. The costs for activities of daily living (ADL) were estimated based on the fee for ‘physical care’ in long-term care service as the unit cost. The costs for instrumental activities of daily living (IADL) were estimated based on the expected mean lost wages, which were calculated based on a nationwide survey on mean wage [29] by sex and age.
Ikeda et al. [25]	¥1,877,077/year (for ADD)	¥6,771.8 billion/year (for ADD)	The time spent on informal care by family caregivers was based on a survey report. Informal care costs for ADL were estimated using the unit cost of caregiving service, covered by long-term care insurance. The costs for IADL were estimated using the average wage by sex/age group.
Nakanishi et al. [26]	¥2,454,987/18 months (for ADD; overall), ¥1,871,647/18 months (mild), ¥2,181,331/18 months (moderate) ¥3,310,496/18 months (moderately severe/ severe)		The caregiver time was calculated from the recorded resource use, based on a questionnaire and additional data on treatments. Informal care costs were estimated using the cost of either caregivers’ time or missed work, whichever was higher, in which the same unit cost was applied. The unit cost for caregiver time was the value of the lost production time for working caregivers, based on the national average wage, and the value of the lost leisure time, which was 35% of the national average wage for the non-working caregivers.

ADD, Alzheimer’s disease dementia; ADL, activities of daily living; IADL, instrumental activities in daily living.

3.2. Group interview with professional care workers

3.2.1. Quality of life measurement in patients

The professional care workers reviewed the EQ-5D-5L questionnaire. They mentioned that the severity of ADD did not seem to be always associated with the score, particularly in the items related to mobility, self-care, and usual activities. They suggested this is because the ability to perform these activities independently seems to be more influenced by motivation rather than cognitive functions. Furthermore, even if the patients maintained their abilities to perform, their feelings/moods varied every day, affecting their daily activities. The attitude of, and their relationships with, caregivers often affected the patients’ behavioral independence. For example, patients who tended to depend on their families entirely would perform their daily activities independently when encouraged by professional care workers. In such situations, although QOL is usually assessed by caregivers rather than the patients themselves, proper assessment is difficult because the patients’ daily activity levels may differ depending on who provides care, causing the difference in the score.

Additionally, the care workers insisted that, although some patients diagnosed with ADD expressed concern about losing their memory, the questionnaire did not have relevant items to capture this concern. They believed that while the MMSE score can measure cognitive ability, it cannot measure the patients’ concerns regarding losing their memory. Nevertheless, they agreed that the MMSE score corresponded to these concerns of the patients, which was evident when the score dropped.

3.2.2. Burden of care

According to the professional care workers, the burden of care does not always correspond to ADD severity, as it is lower for patients with severe ADD who need complete assistance than those with MCI or mild ADD who have behavioral and psychological symptoms of dementia (BPSD). It is noted that BPSD is defined as symptoms of disturbed perception, thought content, mood, or behavior that frequently occur in patients with dementia [30], such as wandering and aggression. They stated that treatments that could stop disease progression before such symptoms appear might be directly linked to reducing the burden on caregivers.

Based on their experience with the families of care recipients in their long-term care facilities, a part of the burden seems to be caused by a negative impression (stigma) of the disease. Families sometimes do not want to accept that the care recipients have ADD and discourage patients from receiving professional evaluations of their condition, even though an ADD diagnosis is needed for treatment. Such family attitudes may indicate that ADD is still perceived rather negatively in society, increasing the burden on families and tending to cause a delay in treatment and care support. In most diseases, the burden of care is the same regardless of who provides the care; however, this is not the case with ADD, particularly regarding the mental burden on families. The greater burden on families is due to the difference in caregiving skills and experiences of professional care workers, as well as the difference in patients’ attitudes – patients tend to behave moderately with non-family members, including professional care workers. Moreover, it is difficult for families to accept that the patients can no longer do things they used to do themselves, which may contribute to their emotional burden.

4. Conclusion

We examined elements that may be included when the disease burden and intervention value for ADD are assessed to understand the current status and challenges. There are several limitations to current QOL measurements, particularly for patients with ADD. Public long-term care costs were higher than medical costs, and informal care costs contributed considerably to the economic burden.

Among the possible elements incorporated in the assessment of the disease burden and intervention value of ADD, patient QOL, included as QALY in the HTA in principle, needs to be developed or improved in terms of measurement methods that take into account the characteristics of the disease. Public long-term care costs represent a substantial proportion of total costs. Thus, it is necessary to include public long-term care costs in the assessment and decision making of ADD, even from the payer’s perspective. Informal care costs too represent a considerable portion of the care burden, making it necessary to consider how to measure them and then include them in the assessment of any process, such as an appraisal or threshold adjustment. Additionally, various elements of the care burden cannot be quantitatively measured but are essential for ADD, and should, therefore, be recognized as important and reflected in decision-making.

5. Expert opinion

In the HTA system in general, QALY is used as an outcome measure in principle [12–14]; thus, it is crucial to appropriately measure the QOL, which may be a challenge in patients with ADD. As a measure of QOL, scores determined using a preference-based measure developed for the QALY calculation can be used, and the EQ-5D score is currently employed in Japan [12]. When it is impossible to obtain patient responses, responses from a proxy, such as family members and medical or care workers, can be used [12,13]. The scores were obtained based on an assessment by caregivers in the literature [22–24]. A decrease in the EQ-5D-5L score corresponds to a worsening of ADD [22], suggesting that its progress can be inferred from a reduction in QOL. Patient EQ-5D score was used to assess treatment effects in an RCT, and the effect was observed as an improvement in the score [23,24]. Nevertheless, correctly measuring patient QOL may be a challenge in patients with ADD, considering the characteristics of the condition. Although responses provided by a proxy are acceptable, these responses may not always correctly reflect the patient’s ability. Professional care workers suggested in the group interview that the QOL assessment results may be biased owing to the person who answers for the patient. The difference in the patient QOL scores between different groups of proxies has been reported in the literature, in which the results provided by clinicians had higher construct validity for observable EQ-5D dimensions (mobility and self-care), whereas those provided by family carers had higher construct validity for less observable dimensions (pain and anxiety/depression), were suggested [31]. The professional care workers also suggested that the results are often affected by the patient’s mood. Possible causes may include BPSD and complications, such as depression, which is reportedly often complicated with ADD [32]. An increase in dependence due to aging, apart from ADD, may also be associated with this behavior. Other than the difficulty in adequately evaluating the health status of the patients, there is also the issue of which items can be used to assess the QOL for patients with ADD. In addition to the five dimensions covered by EQ-5D, it might be preferable to consider other elements when assessing QOL. The professional care workers mentioned that disease progression, particularly from MCI to mild ADD, is probably not reflected on some items in the EQ-5D score. EQ-5D + C, an extended version of the standard EQ-5D, has been constructed by adding the ‘cognitive functioning’ attribute [33,34]. As a disease-specific QOL measurement tool, the QOL-AD is used to assess the QOL of patients with ADD based on assessments by both patients and proxy responders. It is correlated with other scales associated with patients’ ADL, degree of depression, and pleasant events in daily life [17,18]. Moreover, to capture a broader range of impacts on care recipients and caregivers beyond QOL, the EQ Health and Wellbeing instrument (EQ-HWB) has been developed as a standardized measure of health and wellbeing aspects [35]. EQ-HWB and its short version (EQ-HWB-S) consist of 25 and 9 items, respectively. EQ-HWB-S covers domains recognized as potentially-important aspects of health but were not covered in EQ-5D, such as energy and cognition. These items seem to reflect the conditions of ADD. Additionally, there are important domains in social care and caring, including social relationships and control over daily life [35], which may contribute to assessing the caregivers’ QOL. To develop or improve instruments suited to ADD is desirable only by considering the characteristics of the disease and the expected benefits from its treatments.

While medical costs are taken into account in the HTA process, care costs, such as public long-term care costs, are not considered [12] or not always included. In the UK, public care costs can be included according to the guidelines [13], but the costs were included only in 13 technology appraisals (including those for ADD treatments) out of 30 technology appraisals for neurological conditions [36]. In the US, long-term care costs were included in the analysis from a health care system perspective when assessing aducanumab for ADD [37]. However, while medical costs do not always increase with disease progression [26,27], public care costs often exceed the medical costs after the disease progression in the case of ADD [27]. Considering its higher impact owing to the special characteristics of the ADD, we believe that public care costs should be included in the cost-effectiveness analysis in the HTA. Here our discussion focused on public care costs, but out-of-pocket care service costs may also be considered a part of them. Moreover, regarding public care, the costs and the impact on society may also be necessary for the assessment.

The burden of care is almost not considered, though its inclusion seems an important issue in the HTA. Spouses caring for older patients with disability were referred to as hidden patients [38]; the caregiver burden includes various physical, psychological, emotional, social, and financial dimensions [39]. In Japan, the percentage of patients with dementia who received care from families was 43.8% (in 2013), higher than that for other diseases, such as cancer, stroke and Parkinson’s disease, as well as higher than that in other countries, such as the US (24.3%) and the UK (20.1%) [40]. A part of the burden of care has been evaluated using instruments, such as those to measure QOL. In Japan, caregiver QOL is not considered, but we will be able to include it in the analysis from the public healthcare and long-term care payer’s perspective in the next version of the guideline. In the UK, even though the guidelines state that carers’ QOL should be treated as an outcome if relevant, a study revealed that only 3% of NICE technology appraisals included carer health-related QOL in cost-utility analyses [41]. An improvement in caregiver QOL after ADD treatment was reported based on the EQ-5D score in Japanese RCTs [23,24]. Other instruments to measure the burden on caregivers have also been developed and employed [20,21,42]. Therefore, using such instruments to measure caregiver QOL, a part of caregiver burden can be quantified and considered in the HTA process.

Another burden of care, the time spent in unpaid care, is estimated as informal care costs. Informal care costs are excluded from HTA in Japan [12] and other countries, including the UK [13]. However, informal care costs, including unpaid caregiver-time costs, are included in the US in the base case analysis from a modified societal perspective, but not from a healthcare system perspective [37]. In the analysis from the modified societal perspective, other costs, including the cost of caregiver productivity loss and caregiver medical costs, were also included. Informal care costs were estimated in some Japanese studies to represent a significant part of the economic burden for ADD [25,26,28]. Although part of the care can be assessed as public care costs, the rest is borne by the families for informal care, which should also be included in evaluating the ADD care burden. When considering the inclusion of informal care costs, it may be challenging to estimate them, as there is no particular method to calculate the informal care costs, and estimates differ across studies. Several scenarios have been applied as sensitivity analyses; moreover, the time spent on caring duties has been considered productivity loss [25,26,28]. The time spent on informal care was considered in NICE technology appraisals [43], but it was not converted to costs.

There are other challenges in assessing informal care costs, which do not always increase with the disease progression – the burden on family caregivers may decrease when the patient’s condition worsens, and care is transferred from informal care by family to public care. Notably, informal care may have positive value for some caregivers who prefer to keep the patients at home rather than in long-term care facilities [37]. A careful discussion is necessary on how to evaluate them. In sum, as informal care plays an important role in the care of patients with ADD, its value should be included as an element when the disease burden or treatment effect is assessed, regardless of how well it can be quantitatively assessed.

Some aspects may be difficult to measure quantitatively. The professional workers mentioned that the burden on caregivers depends on who cares for the patients. The physical and mental burden is particularly significant for certain family members close to the patients, and the difference among individuals may be difficult to evaluate. The importance of the time spent with the patient may also differ among individuals. Considering that families do not often accept their members as having ADD, as reported by professional care workers, social prejudices surrounding the disease may add to the burden. There are various factors associated with the burden on caregivers, and some of them seem difficult to measure quantitatively. Nevertheless, we consider it important to understand the impact of these factors and work on including them as much as possible in the assessment, regardless of whether they can be quantitatively measured.

We summarize the status of inclusion of each element in the HTA process in general and in Japan, NICE, and ICER in Table 4.

Table 4. Summary of current inclusion status of value assessment elements in health technology assessment system for Alzheimer’s disease dementia.

		HTA system in each country
Elements	HTA system in general	Japan	NICE (UK)	ICER (US)*
Patient QOL	++	++	++	++
Patient medical costs	++	++	++	++
Informal caregiver QOL	+	-	+	+*
Informal caregiver medical costs	-	-	-	+*
Public long-term care costs	+	-	+	+
Informal care costs/ informal caregiver productivity loss	-	-	-	+*

⁺⁺, always included; +, possible, but not always included; -, not/almost not included.

HTA, health technology assessment; ICER, Institute for Clinical and Economic Review; QOL, quality of life; UK, United Kingdom; US, United States.

*ICER: Modified societal perspective only.

We point to the limitations of this study. We only included studies performed in Japan in the literature review to discuss the elements for value assessment of ADD intervention in the country. Therefore, the results may not be generalizable to other countries. While we performed a comprehensive literature review, we interviewed only one group working together in one nursing care facility, affecting generalizability. Additionally, we found that such group interviews can provide important findings that cannot be captured in a literature review; so it is desirable to do it for a diverse group of people, such as patients, family members, physicians. Consequently, interviewing several groups of care workers from different types of facilities and in different areas, as well as a much more diverse group of people would allow us to better understand ADD’s nationwide status.

Looking ahead 5–10 years from this review, the percentage of older people (≥ 65 years) is estimated to rise from 28.9% in 2020 to 30.0% in 2025 and 31.2% in 2030 [44]. By then, it is expected that DMT will be in the market, and the need to properly assess their value from a broader perspective will be greater. To ensure preparedness, it is necessary to initiate the discussions immediately.

Article highlights

• With an increase in the number of patients with Alzheimer’s disease dementia (ADD), new health technologies have been developed; optimally assessing the disease burden and treatment value of ADD by considering its characteristics is crucial.

• Patient quality of life (QOL)—included as quality-adjusted life years—is, in principle, an outcome measure in the health technology assessment (HTA). However, current QOL measurements are subject to limitations, specifically for patients with ADD.

• Public long-term care costs represented a substantial proportion of the total costs; thus, they should be included in the assessment and decision-making of ADD, even from the payer’s perspective.

• Informal care costs comprise a considerable share of the care burden; consequently, they should be included in the assessment of any process.

• The importance of other elements of care burden—including those that cannot be quantitatively measured—should be recognized and reflected in decision-making.

Declaration of interest

A Igarashi received consulting fees from Biogen Inc., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Novartis Pharma K.K., and Eli Lilly Japan K.K., outside of this research. S Ikeda received consulting fee from Eisai Co., Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One peer reviewer has worked with Biogen and TauRx in their role at EVERSANA. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Author contributions

All authors were involved in the conception and design of the study; interview, literature review and interpretation of the results; critical revision of the manuscript; and the final approval of the version to be published. All authors agree to be accountable for all aspects of the work. All authors agree for the final version of the manuscript to be published.

Acknowledgments

We are grateful to Life Co. Ltd. for cooperating with the group interview. We thank Tomomi Takeshima, CMPP, PhD, of Milliman Inc., for writing and editorial support, and Editage (www.editage.coom) for English language editing, which were funded by Eisai Co., Ltd and Biogen Japan Ltd.

Additional information

Funding

This paper was funded by Eisai Co., Ltd and Biogen Japan Ltd.