Points of View Valuation of Pharmaceuticals from the perspective of HST at NICE in the U.K.

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Yuki Miura, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute

1. Introduction

At NICE (National Institute for Health and Care Excellence; National Institute for Health and Clinical Excellence) in the U.K., about 50 pharmaceutical products (including additional indications, etc.) are designated for medical technology evaluation each year, and after analysis and evaluation, recommendations for use in the public healthcare system are ^determined1. Generally, pharmaceutical products are evaluated within the framework of Technology Appraisal (TA), but for "technologies for the treatment of very rare diseases," Highly specialized The details of HST are described below, but the results of the evaluation (guidance) were first published in 2015, and the contents of the evaluation up to February 2020 are reported in Policy Research Institute News No. 591 ^).

When evaluated under HST, cost-effectiveness criteria are raised significantly (£100,000 to £300,000/QALY), and qualitative factors other than cost-effectiveness assessment (e.g., family burden and possibility of patient social participation) are considered more frequently in the appraisals process than under ^TA3).

This paper focuses on the ^guidance4) for a total of 10 drugs (HST 12-21) that were newly covered by HST and modified as of September 2022 from that reported in Policy Research Institute News No. 59, in addition to the quantitative analysis in the cost-effectiveness assessment or newly conducted qualitatively ^.1) The following are some of the qualitative factors that were considered in the cost-effectiveness assessment. innovation," "burden of care," "end of life," and "equity," were investigated with the aim of organizing the evaluation results and identifying the factors and methods taken into account.

2-1. Overview of Health Economic Evaluation in the U.K.

TA in NICE is conducted to determine the recommended use of conventional and novel treatments (drugs) in terms of both clinical effectiveness and cost-effectiveness; medical technologies that are new to the NHS (National Health Service; National Health Service) are considered in NICE to be reviewed for cost-effectiveness and evaluated for recommended use in the NHS or not. ⁵⁾

HST will be introduced in 2017 and will meet the selection criteria (Figure 1).

2-2. Overview of NICE evaluation results and its handling

The TA performed by NICE will use a cost-effectiveness analysis. The outcome measure used here is the quality-adjusted life year (QALY), which translates into quality-adjusted life years and can be calculated as the product of survival years and health-related quality of life (utility value). The incremental cost-effectiveness ratio (ICER) is the additional cost of using a new treatment (drug) divided by the additional benefit (utility) gained. is below the upper limit of the cost-effectiveness threshold, it is generally considered to be cost-effective and is recommended.

Treatments (drugs) that are not recommended by NICE for use in the NHS will not be re-evaluated by NICE in principle; if NICE evaluates that a treatment is not cost-effective, it can no longer be used under the NHS. However, if a pharmaceutical company applies for a Patient Access Scheme (PAS) for a high-cost drug, such as an anticancer drug, and the application is approved, the drug can be used in the NHS without imposing a burden on patients. ⁵⁾

2-3 Outline of HST

HST must meet all of the selection criteria shown in Figure 1: very few patients are eligible (prevalence in the UK is 1 in 50,000 or less than 1,100 patients), the disease must be chronic and severely disabling, the cost of treatment must be high, and the drug must have potential for lifelong use. ²⁾

A cost-effectiveness threshold (£100,000/QALY) for cost-effectiveness evaluations performed on drugs selected for HST was established in FY2017. ⁶⁾ In HST, a weighting of 1 to 3 is applied depending on the QALYs gained by the new technology over the lifetime of the patient, and other measures The HST is characterized by the application of a weight of 1 to 3 depending on the QALYs gained by the new technology over the lifetime of the patient.

In addition, NICE recommends drugs for which there is a large uncertainty about therapeutic efficacy, such as rare diseases, to achieve early access by setting a time limit. This is done based on a Managed Access Agreement (MAA), which consists of a Data Collection Arrangement (DCA) and a PAS or Commercial Access Agreement (CAA) to lower prices. The CAA determines the drug price and total budget for the Managed Access period. This will be a confidential agreement between NHS England and pharmaceutical companies, but pharmaceutical companies will need to offer a valuation (price) within a reasonable range that would potentially meet the cost-effectiveness threshold determined by NICE. ⁶⁾

3. survey methodology

The scope of this study included 10 HST guidance documents (HST 12-21) published on NICE's publicly available ^website2).

The product names are given in the UK.

The assumptions reflected in the tabulation are described below. Each evaluation was included in the tally only if it could be confirmed based on the ^website2) published by NICE, which is the subject of the survey. The results of the evaluations indicate whether they are recommended or deprecated for use in the NHS. In addition to QALY and Cost, which are used when calculating ICER, the factors mentioned during the evaluation and taken into account both within and outside of cost-effectiveness were organized into four categories (magnitude of innovation, burden of care, end of life, and equity) and expressed on three scales. That is, those that were clearly taken into account ⁽²⁾ within the guidance were designated ○, those that were only mentioned were designated △, and those that were not mentioned were designated -.

These assumptions were aligned with the criteria reported by Nakano et al. ¹⁾.

4-1. Overall Overview of HST Evaluation Results

The list of HST evaluations is shown in Table 1.

Based on the results of this evaluation, all of the 10 cases under consideration were recommended for use in the NHS; 2 of the 10 cases had MAAs concluded, and all of those without MAAs had PASs applied. Combined with those as of the previous ^report1), all 20 applicable cases were recommended.

The evaluation of innovation was mentioned during guidance in 9 of the HSTs 12-21 (10 cases) surveyed, 6 of which were taken into account in the decision-making process.

All 10 evaluations of caregiving burden were clearly considered within the evaluation. Further details regarding these results are discussed below.

None of the evaluations related to life-prolonging treatment for terminal or other fatal illnesses ("end-of-life") were applicable. Since terminal stage was not compared to TA in this study, it is not possible to mention the details, but we considered that it did not fall under consideration due to the fact that many of the diseases covered by HST are young-onset diseases caused by genetic abnormalities and are likely to be treated throughout the patient's life.

Two of the fairness assessments were taken into account in the decision-making process. Since both of the diseases under study were young-onset diseases, this aspect was taken into consideration.

In the previous ^report1), the study covered the period up to October 2019. This time, the survey covered the period through August 2022, and a comparison was made to see if there were any differences in value assessment between the two periods (Figure 2). The previous ^report1) referred to 11 cases, while this survey covered 10 cases. For comparison, the ratio was calculated by dividing the sum of the number of circles, which are clearly considered in the evaluation in the HST guidance, and the number of crosses, which are only mentioned, by the number of surveys. Statistical tests were not performed due to the limited sample size of the survey (11 cases in the previous ^report1) and 10 cases in the current survey.

The results are presented in Figure 2. Although there were various differences between the previous ^report1) and the current survey in terms of diseases covered, therapeutic modalities and routes of administration, the trends were very similar.

4-2. Individual HST Evaluation Cases

This section details the factors that led to the considerations presented in Table 1. In particular, we discuss evaluation cases for representative examples of innovation and care burden (e.g., family members), which are mentioned in most of the HSTs. Please refer to Supplement 1 at the end of this report for a summary of the causes and pathologies in each guidance.

HST12 (neurocellular polyphthymia type 2)

In this case, the number of patients was very small and the available evidence was limited. Pain and other factors important to patients, their families, and caregivers were not included in the analytical model. These included unforeseen costs such as emotional impact on caregivers, family relationships, and siblings of the disease.

Looking at the burden of family caregiving, which was assumed in the cost-effectiveness analysis, utility values for health states 1 to 2 were set based on the opinions of clinical experts because no data were available (Table 3), and subsequent health states were assumed to have a linearly increasing utility value for caregivers. A model was added to show the impact of siblings' quality of life as well as the burden felt by family caregivers (Table 3). A utility value of 0.09 for siblings was applied to health state 7 (intermediate between health states 3 and 9) based on the difference between the utility value of 0.91 obtained from ^CHU-9D7), with the normal situation set at 1. Between health states 3-9, utility values were assumed according to a linear model. Medication is expected to reduce the worsening of the medical condition (health status). Insofar as there was a potential to reduce the burden on caregivers and family members, it was assumed to have a potential impact on the following four (1) the emotional and psychological impact of the caregiver caring for the patient (child), (2) the impact of family and social relationships (including the impact of siblings as well as the patient), (3) the education and social interaction of the patient (child), and (4) the economic situation of the family, which are not all reflected in the utility values presented in Table 3 and are not considered in the decision-making process. The utility values for family (parents and siblings) care burden were as follows.

The pathophysiology of this case presents with delayed language development, followed by seizures and motor dysfunction (e.g., increased falls). Most patients were listed in the guidance as being unable to sit without support by the age of 6 years. Other patients also develop visual impairment, leading to blindness. As symptoms progress, patients become increasingly dependent on caregivers. Surveys conducted by the companies show that in order to provide full-time care for patients, they have to stop working, which affects their financial situation. It was mentioned that family members are reported to be receiving various allowances and benefits, and that the family members are under a heavy physical and emotional burden to process and apply for these benefits. Families caring for patients must deal with many difficult emotional (psychological), physical, and financial challenges. These challenges continue until after the child's death and are seen as long-term effects. The Guidance also recognizes that there is an unmet need for an effective treatment, and after reviewing the available evidence and the opinions of clinical experts and patient ^experts8), the Guidance finds this agent to be innovative.

HST13 (Familial chylomicronemia (FCS))

The case mentioned not only the psychological impact of acute pancreatitis and constant hospitalization, but also the unpredictable hospitalization, which affects the family's work, the inability to have a normal family life due to the patient's dietary restrictions, and the financial impact of the family giving up their job and The study was conducted in the United States and Canada. A utility value of -0.02 was included for the burden of care. However, it was noted that there is uncertainty regarding the protective effect on acute pancreatitis and the utility values used in the model. The decision-making process took into account the benefits that were not fully captured in these analytical models. Other factors mentioned included innovation. It was explained that the establishment of a cure would give hope to the patients themselves, as well as to their families and caregivers.

HST14 (Lipodystrophy)

The case consists of six Markov submodels: pancreatic, liver disease, cardiovascular disease, renal, neuropathy and retinopathy. Details are not mentioned here, but the guidance mentions improved caregiver burden using ^EQ-5D9) and the need for 1.67 caregivers, depending on various scenarios, including patient complications, both of which were reflected in the ICER.

HST15 (spinal muscular atrophy (SMA))

SMA is a serious disease. When the child is small, the patient must be managed in a variety of ways, including changing positions every hour to support breathing, regular temperature control, longer meal times due to choking hazards, and other invasive treatments and medical devices at home. The guidance acknowledged the impact of caregiving burden. On the other hand, the analysis did not include the caregiving burden in the economic evaluation. The reason for this is that the inclusion of caregiver burden may lead to uncomfortable results, since the negative impact on caregiver productivity and ^HRQoL10) is unknown if a child who needs care lives longer.

In the actual analysis conducted, the ICER increased when caregiver burden was included in the analysis, as drug treatment may reduce the burden of caregiving in the short term and increase the amount of caregiving over the lifetime of the patient due to longer survival. We conclude that it is difficult to include all of this in the economic analysis because there was uncertainty about the level of caregiving needed in the long term. Concluded that caregiver utility should be considered in decision making, but that it is extremely difficult to quantify.

HST17 (Progressive Familial Intrahepatic Cholestasis (PFIC))

PFIC has an early onset (usually in infancy), rapidly progresses to liver failure, and generally does not survive beyond age 20 without surgery or liver transplantation. While we will not discuss the results of the analysis in detail, it was noted in the guidance that there were factors that were not captured in the model for the cost-effectiveness evaluation analysis in this case. Specifically, they are as follows. (1) the health benefits of delaying or discontinuing immunosuppressive medications after liver transplantation, (2) the impact on the quality of life of caregivers of patients with PFIC, (3) the invasiveness of other treatment options, (4) the low age of onset of PFIC, and (5) the innovative nature of this drug, all five factors were taken into account in the recommendation and The decision was made based on all five factors.

This section describes the process by which the impact on the quality of life of caregivers of patients with PFIC was taken into account.

Essentially, the impact of caregivers should be incorporated into the model, but it was concluded that the extent of this impact was uncertain; however, patient ^experts8) and clinical experts commented on the time burden associated with caregiving (reduced work hours and the need for extended time off for caregiving), financial burden, hospital visits, and the The potential for medication to reduce these burdens was recognized and taken into account. Other factors mentioned included innovation. In this case, the guidance mentioned that the drug can be administered orally (non-invasive), has a novel mechanism of action that improves pruritus, lowers bile acid levels, and has no interactions, which are innovative compared to standard therapy, and that there is a high unmet need in this patient population.

HST18 (heterochromatic leukodystrophy (MLD))

MLD is a genetic disease that exhibits an autosomal recessive form of inheritance caused by a deficiency of allylsulfatase A, resulting in central and peripheral neuropathy. As the disease progresses, it is mentioned to require 24-hour care, including painful seizures, epilepsy, dementia, breathing problems, incontinence, and gastrointestinal problems. They concluded that this has a significant impact on the lives of MLD patients, their families, and caregivers due to the physical and psychological effects, as well as the inability to work. With regard to innovation, it was acknowledged that treatment options for MLD are limited and that there is an unmet need in the treatment of MLD; they would welcome this drug as a treatment option for MLD. It was noted that some of these factors were included in the economic analysis, but not all of them were quantified and considered in the decision making.

HST19 (Mucopolysaccharidosis type IV A (MPS4A))

MPS4A is a disease that causes joint and bone abnormalities, respiratory symptoms, pain, fatigue, and dependence on wheelchairs, and has a significant impact on the quality of life of patients, their families, and caregivers. While we will not discuss the results of the analysis in detail, the following uncertainties existed in the analytical model of this case. The following four points were pointed out: 1) the patient relies on the wheelchair as the disease progresses, but it is unclear how the disease progresses, 2) the model was based on uncertain assumptions to capture long-term benefits, 3) the data was incomplete, and 4) utility values based on only a few data were used (especially for the wheelchair). The following four points were pointed out. In addition to this, the evaluation of the innovation acknowledged that it has a novel mechanism of action, is the only treatment for MPS4A, and has a therapeutic effect brought by the drug. The evaluation of innovation, as well as the above, suggested that it could be included in future analytical models if the data were properly measured and analyzed. Given these uncertainties, and based on the cost-effectiveness analysis (ICER/QALY was less than £300,000), it was recommended because it was within the threshold range.

HST21 (POMC, PCSK1 or, LEPR deficiency obesity)

While this case is guidance on POMC, PCSK1, or LEBP deficiency obesity, the guidance does address the impact of obesity on the patient/family. Specifically, the patient's need to stop asking for food and to manage his/her diet was mentioned. The caregiving burden in this case was included in the economic analysis, although negative utility values were applied in part based on the values used in HST14, some of these, such as the significant impact on family members (caregivers, siblings, and other family members) (including psychological impact) and the economic impact on the family, were included in the economic analysis, but the health benefits beyond the health benefits were not quantified and were considered qualitatively in the decision-making process. Based on the cost-effectiveness analysis (ICER/QALYs were less than £300,000), they were within the threshold and therefore recommended. Other factors were described regarding innovation. It was concluded that the drug may be innovative because it is the first drug to treat the underlying mechanisms of obesity and overeating and is a high unmet need in the patient population.

4-3. Discussion from Individual Cases

Considerations for Evaluation of Innovation

The cases in which innovation was evaluated were evaluated because of the presence or high unmet need for the targeted disease. In addition, the innovation was evaluated as having a change in dosage form or route of administration, having a new mechanism of action, or being able to provide a treatment that is not part of the current standard of care, as factors that cannot be captured by the analytical model. However, these factors may not necessarily correspond to the change in therapeutic efficacy and safety, the improvement in quality of life, and the value perceived by the patient because of the new mechanism of action. Some may believe that maintaining or improving quality of life is more valuable to patients than improving laboratory values. Since cost-effectiveness actually assesses improvement or increase in quality of life, it is difficult to quantitatively reflect the value that evaluation of innovation brings, such as high unmet need for treatment or severity of disease, and in this survey, there were cases where high unmet need was considered in the decision-making process. Innovations in dosage forms that improve patient adherence, the establishment of treatments for diseases for which there is a high therapeutic need, and the emergence of drugs with new mechanisms of action are very important factors to increase treatment options and treatment satisfaction. In this sense, we considered that the future issue will be how to build up innovation as a value apart from cost-effectiveness.

Considerations for the evaluation of burden of care

Regarding the impact of the burden of care, in many cases, the utility values set for each health condition and complication were reflected in the ICER by maintaining or improving them through drug treatment. We believe that this was because the longer duration of treatment and the chronic and severely disabling nature of the disease among the HST selection conditions made it a more readily apparent factor. However, the impact on the burden of care was found to be an important factor that could not be captured only in the cost-effectiveness assessment, but was recognized as an important factor and reflected in the decision-making process, although various factors such as limitations in data acquisition, small number of patients, and uncertainty in the analytical model were considered. This factor was qualitatively taken into account in decision-making based on the opinions of clinical experts and patient ^experts8) during the appraisals process, when data variability was high, when credible data did not exist, and when costs could not be accurately determined at the end of the clinical trial. In addition to this, with regard to uncertainties in the analytical model and data acquisition, the MAA has established a system whereby future data collection and analysis, safety information, etc. are checked, and the guidance is updated again and a decision is made to recommend or not to recommend. These measures contributed to the recommendation/non-recommendation decision so as not to impede patient access.

Patients' own quality of life is now able to quantify its value in terms of the extent to which it impedes patients' daily lives. The indexes have been improved and are now more in line with the values of the Japanese ^people11). On the other hand, it seems difficult to quantify the quality of life of family members and siblings who care for patients in a comprehensive and uniform manner. The ^EQ-5D9) was also ^{used to} measure quality of life in the cases discussed in this study. We thought that further study would be needed to determine how to measure the influence of the patient's family.

In some cases, such as HST15, although drug treatment reduced the burden of caregiving in the short term, the amount of caregiving increased over the patient's lifetime due to longer survival, making it difficult to cover the burden of caregiving in the analytical model. Although it would be good if the accumulation of data could be incorporated into the analytical model, further case studies are needed in the future to determine how to evaluate the evidence obtained from long-term treatment as the value of drugs within a limited period of data collection and analysis.

5. summary

In this news item, some of the factors and evaluation processes that were considered separately from the cost-effectiveness evaluation were clarified in the case studies evaluated in the HST at NICE in the U.K., although they were within the framework of intractable diseases. In particular, there were some scattered qualitative considerations in the factors taken into account for innovation and care burden decision-making.

Based on these survey results, we believe that we have recognized that the value of pharmaceuticals is more than just the accumulation of quantifiable elements, although many assumptions are different when referring to the value evaluation of pharmaceuticals in Japan, such as target diseases, the position of HTA in each country, and economic conditions. We hope that you have now recognized that the value of pharmaceuticals lies in more than just the accumulation of quantifiable elements. The challenge, then, is how to evaluate these values. In the present guidance for rare diseases, especially because of the limited scope of the survey, such as intractable diseases, cases with limitations in data acquisition and uncertainties in the analytical model were identified in which the opinions of clinicians and patient ^experts8) were taken into account in decision making. Although it is difficult for all drugs to be evaluated uniformly, in cases such as rare and intractable diseases, such as those covered in this survey, it is important that the evaluation proceeds while the opinions of various stakeholders are taken into account, and that the public is able to receive medical care in diseases with high unmet needs without impeding patient access. This would be a highly convincing value evaluation for the public.

Further case studies are expected to be accumulated on how and when to reflect this unquantifiable value in prices, as described in this paper, since it is necessary to consider various conditions such as constraints on data acquisition, the degree of contribution to QALYs for each disease, and access to new drugs.

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