Estimating health state utilities in primary hyperoxaluria type 1: a valuation study

Abstract

Aims

Quantitative data on health state utilities in primary hyperoxaluria type 1 (PH1) are lacking. This study was conducted to estimate utility values in PH1 using 3 standard valuation techniques.

Materials and methods

Health state vignettes were developed with input from expert clinicians to describe different stages of chronic kidney disease (CKD) within the setting of PH1, along with a post-combined liver and kidney transplant (CLKT) health state ≥12 months following transplantation. The utility associated with living in each PH1 health state, as described by the vignettes, was evaluated by members of the UK general public using standard utility assessment techniques, including EQ-5D-5L, Visual Analog Scale, and Time Trade-Off.

Results

A similar pattern across the three valuation methods was observed. Utility values were roughly constant from CKD stage 1–3b and then dropped sharply from these states to CKD stage 4. Decreases in utility in the later stages of CKD (stages 4–5) were followed by a recovery in quality of life in the post-CLKT health state.

Limitations

Vignettes may not fully capture the burden of living with PH1.

Conclusions

This study serves as an informative source of data on how the burden of PH1 varies across disease stages of CKD and post-CLKT in patients with PH1. The study findings highlight the unique clinical features of PH1 compared with non-PH1-related CKD, such as the need for earlier and more intensive hemodialysis, the risk of systemic oxalosis, and the potential need for CLKT (as opposed to kidney-only transplant). The impact of PH1 on health-related quality of life, which worsens once hemodialysis is required and systemic disease manifestations occur, is captured in this study using quantitative health state utilities. These data provide an understanding of the impact of PH1 on health-related quality of life and will facilitate health economic evaluation of future treatments.

PLAIN LANGUAGE SUMMARY

Primary hyperoxaluria type 1 (PH1) is a rare genetic disease in which the body produces too much oxalate, leading to kidney damage. Over time it can affect other organs such as the bones, the heart, and the eyes. As kidney damage progresses, patients with PH1 eventually need to receive kidney dialysis. New and emerging treatments aim to reduce oxalate production. To assess the economic value of treatments, data are needed on the quality of life of patients in different stages of PH1. This study collected these data using standard valuation methods. First, we developed written descriptions of different stages of PH1 using expert clinical input and information from published studies. Then, members of the UK general public valued the descriptions in three ways: via a survey called EQ-5D-5L (which asks participants about their mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), via EQ-VAS (a visual scale, resembling a ruler, used to rate quality of life), and via time trade-off (in which participants were asked how many years of perfect health they would give up to avoid living in each disease stage described). The results show that PH1 is likely to have a considerable impact on patients’ quality of life, especially in advanced stages, when dialysis is needed and multiple organs are impacted. The study provides measurable estimates of quality of life in people with PH1, which helps healthcare providers, policy makers, and payers understand the disease burden of PH1. The results can also be used in economic evaluation of new treatments.

Keywords:

• Health-related quality of life
• oxalosis
• primary hyperoxaluria
• rare diseases
• utilities
• EQ-5D-5L
• time trade-off

JEL CLASSIFICATION CODES:

• I19
• I1
• I
• I10

Introduction

Primary hyperoxaluria (PH) is a group of autosomal recessive genetic diseases characterized by an abnormality in the metabolism of glyoxylate, leading to hepatic overproduction of oxalate¹. Oxalate is eliminated from the body mainly by the kidneys. In PH, excessive deposition of oxalate salts (i.e. calcium oxalate) in the kidneys during renal elimination can result in progressive chronic kidney disease (CKD) due to oxalate-mediated kidney damage².

PH1, which is caused by pathogenic mutations in the alanine-glyoxylate aminotransferase (AGXT) gene², is the most prevalent subtype, affecting up to 80% of people with PH³. The estimated overall prevalence of PH1 is 1–3 per million based on studies involving primarily European populations, with elevated prevalence in populations with high rates of consanguinity and/or founder mutations (e.g. Middle Eastern/North African, Canary Islander)⁴. PH1 is also the most severe subtype of PH³, with patients experiencing kidney failure by a median age of 24 years and nearly all patients experiencing kidney failure by 50–60 years of age⁵.

Symptoms of PH1 can present in the first months of life, although the age at clinical onset of the disease is highly variable, ranging from infancy to adulthood; the median age of symptom onset is ∼4–6 years. In general, earlier onset of clinical manifestations is associated with a more rapidly progressive disease course⁴. Patients with PH1 can experience a wide range of disease manifestations, including kidney stones and nephrocalcinosis, along with progressive kidney failure ultimately leading to end-stage kidney disease (ESKD). Eventually, multiorgan damage ensues as the kidneys become unable to clear excess oxalate produced by the liver, and the excess oxalate, therefore, accumulates throughout the body (e.g. in the retina, heart, blood vessels, bone, skin, and nervous system)^4,6,7. This state of extrarenal disease involvement, known as systemic oxalosis, is a major contributor to morbidity and mortality and is observed to emerge in the later stages of renal impairment in PH1, often around the time of progression to CKD stage 4^6,8,9.

Until the approval of lumasiran by the US Food and Drug Administration and the European Medicines Agency in November 2020^10,11, there were no approved treatments for PH1. Historically, the standard of care has involved conservative management, such as increased fluid intake (i.e. hyperhydration), treatment with vitamin B₆, and the use of crystallization inhibitors⁹. Patients with advanced kidney disease have also historically required intensive (e.g. daily) hemodialysis (often initiated earlier, at a higher estimated glomerular filtration rate [eGFR], [corresponding to CKD stage 4 based on KDIGO guidelines¹²] in patients with PH1 compared with other causes of kidney failure) to limit systemic oxalate accumulation¹³, unless and until they become eligible for transplantation. Liver transplantation, which corrects hepatic oxalate overproduction, is currently the only potential cure for PH1¹⁴. In clinical practice guidelines, it is suggested that for patients with advanced kidney disease, liver transplantation should be paired (either simultaneously or sequentially) with kidney transplantation to restore lost kidney function¹⁵. Liver-kidney transplantation is associated with considerable risks, including organ rejection, infections, and death¹⁶, particularly in patients with poor pre-transplant health status¹⁷. Lifelong immunosuppression is also required after transplantation¹⁸.

With the introduction of lumasiran and ongoing development of other therapies for patients with PH1, cost-effectiveness analyses of new treatments for PH1 will be critical in helping to guide health technology assessment (HTA) and reimbursement decision-making. Currently, quantitative data on health state utilities that can be used to inform cost-effectiveness analysis in PH1 are limited. To address this gap, the present valuation study was conducted to estimate health state utilities in PH1.

Methods

This study utilized a 2-stage process to estimate health state utilities. The first stage included the development of health state vignettes (based on literature review and expert input). In the second stage of the study, the vignettes were rated by the general public in health state valuation interviews.

Literature review and expert input

Health state vignettes were developed to describe different stages of CKD (defined by glomerular filtration rate) related to PH1 along with a post-combined liver and kidney transplant (CLKT) health state at ≥12 months following transplantation (Table 1). As the management and impact of PH1 may differ between adults and children, separate health state vignettes were developed for adult patients and pediatric patients. The content of the vignettes for each PH1 health state was based on input from two expert nephrologists in the United Kingdom with experience in managing patients with PH (one specializing in adult care and the other in pediatric care). According to these experts, although KDIGO guidelines for CKD (not specific to PH1) recommend dialysis for patients with eGFR <15 mL/min/1.73 m^{2 12}, patients with PH1 often initiate dialysis earlier, at a higher eGFR (15–29 mL/min/1.73 m²) to remove oxalate from the bloodstream and protect against long-term damage from oxalosis¹³. Therefore, the vignettes for both eGFR 15–29 mL/min/1.73 m² (health states A4 and C2 in Table 1) and eGFR <15 mL/min/1.73 m² (health states A5 and C3 in Table 1) describe a patient on dialysis.

Table 1. Health states and their corresponding PH1 stage are classified by CKD stage and kidney function.

PH1 stage^a	Adult health state	Child health state (∼6 years)
CKD stage 1 (GFR ≥90): normal or high kidney function	A1	C1
CKD stage 2 (GFR 60–89): mildly decreased kidney function	A1	C1
CKD stage 3a (GFR 45–59): mildly to moderately decreased kidney function	A2	C1
CKD stage 3b (GFR 30–44): moderately to severely decreased kidney function	A3	C1
CKD stage 4 (GFR 15–29): severely decreased kidney function	A4	C2
CKD stage 5 (ESKD; GFR <15): kidney failure	A5	C3
CLKT: ≥12 months post-transplant	A6	C4

CKD: chronic kidney disease; CLKT: combined liver and kidney transplant; ESKD: end-stage kidney disease; GFR: glomerular filtration rate.

GFR expressed in mL/min/1.73m².

^a PH1 stage classification by CKD stage and function based on the literature and clinical expert opinion.

A targeted literature review (Supplementary Table S-1) was also performed to inform the health state vignettes. The literature review identified published resources on PH1 symptoms and the impact of PH1 on patient quality of life (QoL). This primary review of the literature was supplemented by additional targeted literature reviews, a review of the gray literature (including websites for patient advocacy organizations), written patient or caregiver testimonies, and social media videos of patients and caregivers describing life with PH1.

Draft adult and child vignettes

Based on the literature review, draft vignettes were developed for adult patients and pediatric patients. To ensure clinical accuracy, the expert clinicians participated in an online video interview and gave initial feedback on the health state vignettes, and then provided feedback by email to confirm the changes made to the draft vignettes based on their prior feedback were correct. The vignettes were finalized after two draft iterations based on the clinical expert feedback.

PH1 health state utility assessments

The utilities associated with living in each PH1 health state, as described by the finalized vignettes, were evaluated by members of the UK general public (aged ≥18 years) using standard utility assessment techniques, including EQ-5D-5L, Visual Analog Scale (VAS), and Time Trade-Off (TTO) methods. Due to the COVID-19 pandemic, all interviews were conducted using online video (Skype or Zoom). To avoid possible bias, the vignettes were not described as corresponding to adult health states or pediatric health states. Instead, participants were asked to judge the QoL of each vignette without reference to the age of the patient depicted, as the intention of the valuation task was for participants to consider only health and QoL, independent of other considerations. It is possible that if participants were made aware that they were valuing pediatric health states, they would have considered a wider range of issues in the valuation task, such as equity and the fact that a child has not yet lived their adult life. Furthermore, the participants were adults, who may struggle to imagine themselves as the individual depicted in health states that are explicitly noted to involve children.

Descriptive statistics were calculated for participants’ sociodemographic information and participants’ own EQ-5D-5L responses (i.e. responses relating to their own health, separate from the PH1 vignettes). EQ-5D-5L, VAS, and TTO results for the PH1 health state vignettes were also summarized descriptively.

EQ-5D-5L, VAS, and TTO health state utility values

Participants were asked to complete the EQ-5D-5L for each vignette. The EQ-5D-5L has separate items covering five domains (i.e. mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), and for each item, respondents were asked to rate the status of the patient described in the vignette using a 5-level categorical scale. A validated mapping function, the results of which reflect UK preference weights¹⁹, was then used to convert each respondent’s set of categorical item-level responses to an overall estimate of utility (on a scale where 0 corresponds to death, 1 corresponds to full health, and negative values are possible for health states considered worse than death) for the health state described in the vignette. Participants were also asked to provide VAS ratings for each vignette. VAS was scored on a continuum from 0 (worst possible state) to 100 (full health).

Finally, as an additional valuation method, a standard TTO assessment was performed to derive the health state utility values in PH1²⁰. For each vignette, the TTO method sought to determine the point “X” at which the respondent was indifferent between 10 years spent in the target health state described by the vignette (CKD stages 1–5 and post-CLKT) and “X” years spent in full health. The value X was then divided by 10 to convert it to a health state utility on a scale with 1 representing full health. If participants believed a state to be worse than death (negative utility), it was assessed using the lead-time TTO approach to derive the state’s utility value^21,22 (this is referred to as the composite TTO approach²³).

Results

Literature review

The literature review identified 23 publications on the symptoms of PH1 and its impact on patients’ QoL that met the criteria for inclusion; these publications informed the development of the draft vignettes. From this literature review, it was found that PH1 can have a range of negative impacts on physical, social, and emotional well-being, as well as occupational outcomes.

Most reports on the physical impact of PH1 noted the occurrence of pain. Affected infants were reported to scream and cry more than usual²⁴. Extreme pain up to the point of losing consciousness was described in association with kidney stones^24,25. Available literature suggests that the physical impacts of PH1 take on additional dimensions with the onset of systemic oxalosis^24,25. One adult patient with PH1 described experiencing extreme pain associated with systemic oxalosis²⁴. More generally, systemic oxalosis related to PH1 can result in bone damage⁶, including severe bone pain, frequent fractures, and deformations. Children with PH1 who experience systemic oxalate deposition also tend to have growth retardation, and their growth does not fully catch up to age-specific norms even after a combined liver and kidney transplant²⁶. Patients with PH1 can also experience optic atrophy, cardiac-related disorders, treatment-resistant anemia, hepatosplenomegaly, and skin disorders, such as necrosis and rash, in association with systemic oxalosis³.

Some patients also described the impact of hyperhydration on sleep, including the need to awaken frequently during the night to drink liquids²⁴ and the possibility that children may wet their bed because of heavy fluid intake²⁷. With regard to social and emotional impacts, children and adolescents with PH1 described feeling different from their peers and having difficulties telling other people about their disease^28–30. Patients reported that this perception was due to multiple contributing factors associated with disease management (e.g. hyperhydration, dietary requirements) or with the disease itself. As PH1 is rare and its manifestations are often not outwardly evident, there is little understanding of the disease among those not affected^27,30. Furthermore, patients with PH1 reported that they often missed school due to frequent kidney stones and dialysis, which further ostracized them from their peers^13,24,25.

Patients also reported the burden of psychological stress associated with the diagnosis of an incurable disease and the constant fear of experiencing a kidney stone or kidney failure^24,28. One adult patient reported the frustrating experience of waiting to be placed on the transplant list²⁸, while another patient who received a transplant was worried about the potential need for a second transplant in the future²⁵. One young adult said her life activities were severely restricted because she was unable to travel while on dialysis; she was hoping to receive a transplant to start a normal life²⁴.

In addition to experiencing physical, social, and emotional impacts, patients with PH1 described the experience of missing out on educational and professional opportunities. One young adult with PH1 reported that he had to leave college early due to frequent hospital admissions²⁵. Two adult patients who had oxalosis despite receiving transplants reported diminished ability to work^25,30.

Draft vignettes

The literature review findings were used to develop the first draft vignettes that were presented to clinical experts for feedback. The clinicians noted differences in the impact of the disease and its treatment for adult and pediatric patients and highlighted missing information. For example, the experts noted that the passing of kidney stones is typically very painful for adults and can require medical intervention, whereas children do not always pass the stones, which instead gather in the kidneys and can cause obstructions, leading to urinary tract infections. Expert feedback on considerations, such as this, which could not be ascertained from the literature review, was incorporated into the vignettes. After incorporating two rounds of expert feedback, the vignettes were finalized, as summarized in Supplementary Table S-2.

Health state utility assessments

The participant demographics of the study sample were generally similar to those of the UK general population according to census data (Table 2)^31,32. For participants’ responses on the EQ-5D-5L regarding their own health status (Tables 3 and 4), the proportion reporting anxiety/depression was higher in the current sample compared with the general population³³. Participants reported fewer problems in mobility, self-care, and usual activities than the UK population overall.

Table 2. Sociodemographic participant characteristics (N = 100).

	UK sample (N = 100)	UK population^a
Age
Mean (SD)	41.07 (16.73)
Range	18.00–84.00
Median	41.00	39.4^a
Sex
Male	50	49%^a
Female	50	51%^a
Ethnicity
White	82	86%^a
Mixed	9	2%^a
Asian	6	8%^a
Black	2	3%^a
Other	1	1%^a
Occupation
Employed full time	52	–
Employed part time	13	–
Self-employed	8	–
Retired	12	–
Unemployed	1	–
Student	14	–
Has long-term condition
Yes	20	36%^c
Knows someone with metabolic condition^b
Yes	19	–

SD: standard deviation.

^a Figures based on data from the 2011 UK national census³¹.

^b This included relatives/family (partner, child, parent, sibling, other relative) and friends.

^c Figure based on data from the 2013 UK Opinions and Lifestyle Survey (Office for National Statistics)³².

Table 3. Vignette study participants’ self-reported EQ-5D-5L responses on their health (N = 100) compared with normative data.

EQ-5D-5L dimension	N, %	UK population, %^a
Mobility problems	12	18
Self-care problems	1	4
Usual activity problems	8	16
Pain problems	34	33
Anxiety/depression problems	38	21
Overall/any dimension problems	55	43

^a Kind et al.³³.

Table 4. Study participants’ mean self-reported EQ-5D-5L index score and VAS rating of their own health (N = 100).

	Mean (SD)	Range	95% CI
EQ-5D-5L	0.89 (0.11)	0.56–1.00	0.87–0.91
VAS	88.61 (9.80)	45–100	86.69–90.53

CI: confidence interval; SD: standard deviation.

Values for EQ-5D-5L, VAS, and TTO weights for vignettes representing the range of PH1 health states are shown in Table 5.

Table 5. EQ-5D-5L scores, VAS scores, and TTO weights of adult and child health state vignettes and their corresponding PH1 stage (N = 100).

Health state	PH1 stage	EQ-5D-5L, mean (SD)	VAS, mean (SD)	TTO, mean (SD)
Adult vignettes
A1	CKD 1–2	0.68 (0.10)	75.02 (10.73)	0.88 (0.11)
A2	CKD 3a	0.63 (0.13)	71.26 (12.53)	0.86 (0.14)
A3	CKD 3b	0.57 (0.17)	67.69 (13.56)	0.80 (0.17)
A4	CKD 4	0.33 (0.23)	49.32 (16.12)	0.51 (0.41)
A5	CKD 5—end-stage kidney disease	0.02 (0.23)	38.38 (17.66)	0.39 (0.42)
A6	Post combined liver and kidney transplant	0.68 (0.12)	65.22 (14.69)	0.77 (0.26)
Child vignettes
C1	CKD 1–3b	0.59 (0.13)	64.36 (14.62)	0.76 (0.17)
C2	CKD 4	−0.02 (0.24)	37.60 (17.84)	0.34 (0.44)
C3	CKD 5—end-stage kidney disease	−0.05 (0.23)	35.97 (17.40)	0.33 (0.41)
C4	Post-combined liver and kidney transplant	0.80 (0.11)	73.35 (13.54)	0.86 (0.13)

CKD: chronic kidney disease; PH1: primary hyperoxaluria type 1; SD: standard deviation.

EQ-5D-5L

The mean EQ-5D-5L utility scores for the adult patient health states ranged from 0.68 (CKD stage 1–2 health state) to 0.02 (CKD stage 5 health state). The CKD stage 4–5 health state utilities for adults were rated substantially worse by participants when compared with CKD stage 1–3b. The adult patient post-CLKT health state mean EQ-5D-5L utility score (0.68) was the same as that for the CKD stage 1–2 health state. The EQ-5D-5L utility scores for the pediatric patient health states ranged from 0.80 (post-CLKT health state) to −0.05 (CKD stage 5 health state). As with the adult health states, the pediatric CKD stage 4–5 vignettes were rated as having substantially lower health state utilities relative to the pediatric CKD stage 1–3b vignette. The pediatric post-CLKT health state mean EQ-5D-5L utility score (0.80) was higher than that for the CKD stage 1–3b health states (0.59).

VAS

The mean adult VAS scores ranged from 75.02 (CKD stage 1–2 health state) to 38.38 (CKD stage 5 health state). The mean pediatric VAS scores ranged from 73.35 (post-CLKT health state) to 35.97 (CKD stage 5 health state). VAS scores showed that the utility associated with the CKD stage 1–2 health state was similar to that for the CKD stage 3b health state. The CKD stage 4–5 health states for adults and children were rated worse by participants when compared with CKD stage 1–3b; for the post-CLKT health state, the utility scores were higher than for the CKD stage 4–5 health states, and generally more comparable to those for the CKD stage 1–3b health states.

TTO

The TTO utility scores showed a pattern similar to that of the VAS results, with the lowest utility scores observed in the CKD stage 4–5 health states. Similar to the VAS ratings, the TTO scores increased in the post-CLKT health state relative to CKD stages 4–5 and were generally more comparable to those seen in CKD stage 1–3b. The mean adult patient TTO utility scores ranged from 0.88 (CKD stage 1–2 health state) to 0.39 (CKD stage 5 health state). The mean pediatric patient TTO utility scores ranged from 0.86 (post-CLKT health state) to 0.33 (CKD stage 5 health state).

Discussion

Quantitative data on health state utilities in PH1 are lacking. The current study was conducted to address this gap and inform future health economic analyses of treatments for PH1. This study provides results from a valuation exercise to estimate utilities for health states describing various stages of CKD as well as the post-transplantation health state in PH1. Overall, a similar pattern (albeit with different utility values) emerged across the different valuation methods (EQ-5D-5L, VAS, and TTO) for both adult and pediatric health states. Utility values were generally constant from CKD stage 1–3b and then decreased sharply moving from these earlier CKD stages to CKD stage 4. With the EQ-5D-5L valuation method, adult health state utilities approached 0 by CKD stage 5, suggesting that respondents regarded this health state as being comparable to death in terms of its desirability, while the health state utilities for both CKD stage 4 and CKD stage 5 in pediatric patients were rated as having utility scores <0, suggesting that respondents considered these health states worse than death. The observed decreases in utility in the later stages of CKD were followed by a large increase in QoL for the post-CLKT health state in both adults and children.

Overall, these results demonstrate the considerable impact of PH1 on health-related QoL, as measured by health state utilities, particularly once patients reach health states (CKD stages 4–5) in which the need for hemodialysis and the risk of systemic oxalosis arise. Hemodialysis may impact QoL due to the associated time burden and the restrictions placed on patients’ daily lives, particularly in PH1, in which intensive (e.g. daily) dialysis regimens are required as early as CKD stage 4 in order to slow systemic accumulation of oxalate. This contrasts with non-PH1-related CKD, which typically requires less frequent dialysis starting in CKD stage 5. Moreover, systemic oxalosis itself, a unique feature of PH1-related CKD that often arises in CKD stage 4, can cause significant morbidity (e.g. bone pain, skin lesions) that further impairs the QoL. The sharply pronounced burden perceived in the later stages of CKD suggests that a treatment that mitigates progression from early-stage CKD to later stages of disease could have a large impact on preserving QoL for patients with PH1 in whom substantial disease progression has not yet occurred. Similarly, a treatment that reduces the need for dialysis and addresses systemic oxalosis in patients with late-stage CKD could help preserve QoL by easing the constraints that dialysis places on these patients’ daily lives and by improving their physical condition.

The utility scores observed were generally similar across methods for any given health state, but EQ-5D-5L values were consistently lower than the corresponding TTO weights. Although the reasons for this disparity are unclear, this finding has been observed in previous research³⁴. In the TTO task, participants indicate the quality or value of a health state in terms of the extent to which they are willing to trade life years in the exercise, whereas the completion of the EQ-5D-5L requires people to simply rate the level of impairment on a descriptive categorical scale. The differences between the tasks may explain the differences in results; however, the EQ-5D-5L weights are derived from a mapping function for which TTO values are the underlying basis, and so it is unclear why there is a systematic difference between TTO and EQ-5D-5L results.

The assessment of utilities is required for the calculation of quality-adjusted life-years (QALYs), a common denominator that is used in cost-effectiveness analysis as required by HTA agencies, such as the National Institute for Health and Care Excellence (NICE) in the United Kingdom. Utility measurement for rare diseases remains a challenging area. In prevalent conditions, utility data for use in cost-effectiveness analyses can be readily obtained from primary research (e.g. clinical trials)³⁵. In rare diseases, however, direct measurement of health state utilities in affected patients is often difficult, as the number of patients available for assessment would likely be too small to obtain reliable estimates, especially when considering that this small number of patients may need to be divided up over several different health states within the broader condition of interest. Accordingly, clinical trials in PH1 and other rare diseases have included assessments to elicit health state utilities directly from affected patients^36–38, but the value of this approach has been limited by the aforementioned issues. In PH1 and other rare conditions, such limitations are largely unavoidable (e.g. due to low prevalence). Therefore, studies in which a larger general population sample (i.e. individuals not affected by the disease of interest) is asked to value disease-related health states (as described by written vignettes) may be preferred for determining health state utilities in these types of conditions³⁹.

Despite the usefulness of vignette-based health state utility valuation studies in rare diseases, such as PH1, it is important to note certain limitations. In addition to clinical input, efforts were made to interview patients and caregivers, but due to the rarity of the disease, it was not possible to identify interested interview participants. Thus, a limitation of the current analysis is the lack of feedback from patients or caregivers on the health states to evaluate the accuracy of the health states from their perspectives.

Another limitation is that due to a high degree of symptom variability, the use of vignettes may not fully capture the burden of living with PH1. Moreover, vignettes are subject to different interpretations, and it is inherently difficult for members of the general public to fully understand the patient experience. To address this issue, expert clinical opinion and insights from previously published literature were obtained to try to inform the development of health states that were as accurate and representative as possible of patients in those health states. Nonetheless, there is a high degree of heterogeneity in how PH1 manifests, even for different patients within the same health state. This heterogeneity presents challenges in developing a single representative case that captures all possible scenarios and the full range of QoL impacts in a given health state in PH1.

There were also several strengths of the analysis. Overall, the participants in the study sample were similar to the UK general population (with the exception of a higher prevalence of anxiety/depression in the study sample), thereby supporting the generalizability of the results. Another strength of the study was the relatively large sample size. Additionally, this study includes the use of well-established vignette-based methods for eliciting utilities, reasonable agreement across valuation methods, and consistency with expectations based on the clinical understanding of the disease. Overall, despite the limitations described above, this study employed a rigorous and reproducible methodology and provides useful information that will enhance the understanding of health state utilities for different clinical profiles of patients with PH1.

Conclusions

Although the clinical burden of PH1 has been described in some detail, published data on the humanistic burden of PH1—particularly quantitative data on health state utilities—are limited. The current valuation study serves as a robust source of data that can facilitate a better understanding of how the health-related QoL of PH1 varies across disease stages of CKD and post-CLKT in patients with PH1. These data can enhance understanding of the impact of PH1, with its unique clinical features (e.g. need for earlier and more intensive hemodialysis compared with non-PH1-related CKD, risk of systemic oxalosis, potential need for CLKT), on health-related QoL, as captured by quantitative health state utilities, and will facilitate health economic evaluation of future treatments.

Transparency

Declaration of funding

This study was sponsored by Alnylam Pharmaceuticals.

Declaration of financial/other relationships

HDF was an employee of Acaster Lloyd Consulting Ltd. DD and SL are employees and stockholders of Alnylam Pharmaceuticals. LH is an employee of Acaster Lloyd Consulting Ltd. AL is an employee and stockholder of Acaster Lloyd Consulting Ltd, which was paid a fixed fee for their time on this project by Alnylam.

Author contributions

DD, AL, and HDF: concept and design. HDF: acquisition of data. DD, AL, LH, and HDF: analysis and interpretation of data. AL, LH, and HDF: drafting of the manuscript. HDF, DD, LH, AL, and SL: critical revision of the paper for important intellectual content. LH: statistical analysis. DD, LH, and HDF: provision of study materials or patients. DD: obtaining funding. DD, LH, and HDF: administrative, technical, or logistic support. DD and AL: supervision.

Role of the funder/sponsor

The sponsor provided input into the study design, provided logistical support as needed, and participated in the interpretation of results.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Previous presentations

ISPOR 2022; May 15–18, 2022; National Harbor, Maryland.

Acknowledgements

Writing and editorial assistance were provided by Larry Radican, PhD, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA, and was funded by Alnylam Pharmaceuticals.