Points of View The multifaceted value of medicines as assessed by NICE in the U.K. An Analysis of Drugs for Rare and Intractable Diseases

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The Office of Pharmaceutical Industry Research Principal Investigator
Yosuke Nakano
Visiting Associate Professor, Department of Pharmaceutical Policy, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Associate Professor, Health and Social Medicine Unit, Yokohama City University School of Medicine
Naka Igarashi

1. Introduction

At NICE in the UK, about 50 pharmaceutical products (including additional indications, etc.) are designated for medical technology evaluation each year, and after analysis and evaluation, a recommendation for use in the public healthcare system is determined. Generally, pharmaceuticals are evaluated within the framework of Technology Appraisal (TA), but a special framework called Highly Specialised Technologies (HST) has been introduced for "therapeutic technologies for very rare diseases". The first evaluation results (guidance) were published in 2015. As of February 2020, HST guidance has been released for 12 technologies.

Although various studies and surveys have been conducted on TA, there have been limited studies on HST1). This paper therefore focuses on pharmaceuticals that have been selected as HSTs, and investigates and analyzes them from the perspective of what values are taken into account and evaluated in particular.

2. Overview of the evaluation of medical technology at NICE in the U.K.

First, TA and HST are targeted at drugs with high cost or large financial impact, such as cancer drugs2), 3). HST, on the other hand, is for "technologies for the treatment of very rare diseases," and in addition to the very small number of eligible patients, all conditions must be met, including chronic and severe disorders, as well as extremely high treatment costs and long-term use4) ( Figure 1).

Figure 1 Main selection criteria for HST (excerpts from the original)

Drugs selected for TA and HST are subjected to cost-effectiveness analysis by companies and third-party organizations, and the Drug Evaluation Committee makes a final recommendation for use in the public healthcare system after considering the interpretation of the analysis results, other influences, and the opinions of clinical specialists and patients3), 4), 5) (Figure 2).

Fig. 2 Schematic diagram of the medical technology evaluation process at NICE

In the HST, the threshold for the incremental cost-effectiveness ratio (ICER), which is used to determine the recommended use of a drug, is significantly increased .3) In the TA, the threshold is 20,000 to 30,000 pounds for ordinary drugs and 50,000 pounds for drugs to which the special end-of-life treatment is applied. 3) TA is 20,000 to 30,000 pounds for ordinary drugs, and 50,000 pounds for drugs to which the end-of-life exception applies. The threshold for HST, on the other hand, is set at 100,000 to 300,000 pounds, which is determined by the QALY increment of the technology to be evaluated: 100,000 pounds for 10 QALYs or less, "incremental QALY value" x 10,000 pounds for 10 to 30 QALYs, and 300,000 pounds for 30 QALYs or more.

3-1. Overall summary of evaluation results

In researching and analyzing HST, we also examined the most recent TA evaluations for reference .6) Looking at the actual evaluations since 2015, when the HST evaluation guidance was first released, as of October 2019, when the survey was conducted, there were around 50 TA evaluations per year, for a cumulative total of 260, and 1 to 3 HST evaluations per year, for a cumulative total of 11. and a cumulative total of 11 evaluation guidance had been prepared (Table 1). Furthermore, as a benchmark, we reviewed the details of the 2019 TA (53 cases) and found that anticancer agents accounted for more than 60% of the disease breakdown. The evaluation results were as follows: recommended (including partially recommended): 51%, recommended for use with the Cancer Drug Fund: 23%, and not recommended: 26% (Figure 3).

Table 1 Number of TA and HST evaluation reports (2015-2019*)

Figure 3 Breakdown of 2019 TA evaluations (53)

3-2. Results of HST evaluation

Next, the overall evaluation of HST (11 cases) is shown in Table 2. The most common modality was macromolecular drugs such as antibody drugs and enzyme replacement therapies (4 cases), but since 2018, drugs belonging to new modalities such as gene therapies and nucleic acid drugs were also evaluated. In addition, all 11 indications were for diseases designated as intractable in Japan7), and the results of the evaluations recommended the use of these drugs in all 11 cases.

Table 2 List of evaluations of HSTs (11 cases)

3-3. Factors considered in the HST evaluation

Next, in addition to QALY and Cost, which are used to calculate ICER as an indicator of cost-effectiveness, the presence or absence of factors that were specifically mentioned during the evaluation and taken into consideration both within and outside of cost-effectiveness are summarized in the dotted lines in Table 2.

In the evaluation of TA, in addition to QALY and Cost, the following factors were taken into account: "Life-prolonging treatment for fatal diseases such as terminal stage (End of Life)," "Significant Innovation," which considers not only the technical aspects but also the magnitude of benefits to the patient, etc. Innovation" is also mentioned and considered as a value in some cases5), 8)). In this survey, in addition to the above, "Equity issue," which is rarely mentioned in terms of consideration for the socially disadvantaged, "Carer, Caregiver," which is mentioned in terms of diseases requiring care, etc., and "Caregiver," which is mentioned in terms of "burden associated with the care of patients and their families, etc.," as well as the above, are taken into account in the evaluation. The results were divided into three categories: "Equity issue," "Carer, Caregiver," and "Other factors.

As a result, the most common factors that were clearly taken into account in the evaluation were the size of innovation (9 cases), caregiver burden (7 cases), other factors (3 cases), fairness (1 case), and end of life (0 case).

Comparing these endpoints between HST (11 total) and TA (53 in 2019), "magnitude of innovation" and "burden of care" were more common in HST (Figure 4).For diseases that fall under HST, the conventional treatment and In many cases, the "magnitude of innovation" was taken into account as a major change in treatment methods and disease management compared to conventional treatments for HST-eligible diseases. One of the reasons why there are few end-of-life exceptions is that the possibility of meeting the conditions for end-of-life exceptions of "life expectancy of less than 2 years and life extension of more than 3 months" becomes smaller when the HST conditions (the condition is chronic, the potential for life long use, etc.) described above are met.

Figure 4 Comparison of the number of considerations in TA and HST

4. Individual cases of evaluation

Table 3 shows what factors were considered and evaluated in the HST evaluations of "magnitude of innovation," "burden of caregiving," and "other factors" that were most frequently considered in the HST evaluations.

Table 3 Specific examples of evaluations within HST guidance

Evaluation cases related to magnitude of innovation

HST5 (magnitude of benefit from oral drugs)

The oral medication treatment option for Gaucher's disease was judged to be an innovation that could have a significant positive impact on patients, with "benefits beyond health" such as "freedom to travel and go to school" and "no need to miss work for treatment. The drug was judged to be an innovation that could have a significant positive impact on patients, with "benefits beyond health.

HST6 (magnitude of progress in treatment)

The fact that this drug is a treatment for pediatric hypophosphatasia (potentially saving the life of a small child) and will contribute significantly to progress in the management of this disease was considered an innovation that could not be captured in the Cost/QALY framework.

Evaluation cases related to caregiving burden (family, etc.)

HST9 (magnitude of caregiver burden (time))

The results of a questionnaire survey (Caregiver Impact Study) on the amount of time caregivers spend per day providing physical and emotional care to patients were used as support. The increase in the number of caregivers due to disease progression was incorporated into the cost estimates and reflected in the ICER, as well as the mention that "the reduction in caregiving and financial burden on families has benefits beyond health.

HST11 (decrease in caregiver's quality of life)

In the case of diseases that can lead to blindness, the ICER is calculated by incorporating the QALY loss of the caregiver, while using the results of a study that evaluated the relationship between the patient's condition and the caregiver's QOL (as vision deteriorates, the caregiver's QOL value also decreases), because the QOL of not only the patient but also the caregiver is greatly affected by diseases that can lead to blindness. It should be noted that the study allowed for both the caregiver's QOL loss and the patient's QOL loss to be incorporated into the calculation of the treatment outcome (QALY), which can be said to be the result of placing such importance on the impact of the care burden on family members and others9).

Evaluation cases related to other factors

HST8 (reduction in stress, risk and health care costs resulting from avoidance of surgery)

In the case of hereditary hypophosphatemia, which requires multiple surgeries to avoid fractures due to brittle bones, the possibility of avoiding surgery brought about by this therapeutic agent was evaluated to reduce patient stress and risk, and may even lead to a reduction in medical costs required for surgery. These aspects were incorporated within the cost-effectiveness analysis model and are reflected in the ICER figures. It was also mentioned that long-term post-marketing monitoring may allow for better evaluation of the above-mentioned benefits based on clear figures.

HST10 (likelihood of returning to work, active participation in home life and social activities, maintaining independence, etc.)

This treatment for amyloid polyneuropathy could enable patients to return to work, participate actively in family and social life, and maintain independence, all of which are not captured in the usual quality-of-life assessment and should be considered in the final decision-making process. These are not captured in the usual quality of life assessment and should be taken into account in the final decision-making process.

5. Summary

In the evaluation of HST, the value of treatment technologies was discussed from multiple perspectives and taken into account in the evaluation results as needed. In the case of quantitative considerations, quantified data are incorporated into the QALYs or costs when calculating ICERs. On the other hand, qualitative considerations were taken into account for factors that were difficult or impossible to quantify, and were "taken into account at the time of decision-making. At the present stage, there is a lack of data with a high level of evidence, and some value factors have not yet been quantitatively evaluated, but in this regard, research progress on new outcome indicators and measurements and reevaluation mechanisms based on post-marketing real-world data are expected.

In addition, during the evaluation, discussions were held based on "real voices" from clinical specialists and patient groups to see if there was any value that had been overlooked10), and in some cases this actually had an impact on the evaluation. We were reminded that the efficacy, QOL, and other evaluation scales used in clinical trials may not fully capture the benefits and burdens to patients, their families, and others, and we were able to read from the evaluation guidance the importance of such an evaluation process.

Finally, we focused on HST, a drug for rare and intractable diseases, and investigated and discussed the multifaceted nature of value in evaluation. However, it is believed that there are values that have not yet been fully captured or taken into account not only for drugs for rare and intractable diseases, but also for drugs for other diseases.

As the drug discovery modality expands and the creation of more innovative drugs is expected in the future, it will be important from the perspective of patient-centered medicine and innovation creation to pay attention to the multifaceted value of pharmaceutical products and to consider the value of patients and other stakeholders' opinions. This will be important from the perspective of patient-centered medicine and innovation creation.

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