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Introduction
Voretigene neparvovec (VN) is a gene therapy and the first approved pharmacological treatment for biallelic RPE65-mediated inherited retinal dystrophies (IRD), a rare condition that starts in early life and causes vision to progressively deteriorate towards complete blindness. In a phase III trial, treatment with VN significantly impro...
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Context 1
... Markov state transition model was constructed, with five alive health states determined based on the worst of VA and VF (i.e., whichever of VA or VF would assign the patient to a more severe health state) and death (Fig. 1); health state cut points were derived using American Medical Association guidelines (see supplementary materials for further details). The average VA and VF across both eyes were assumed, with a scenario considering health states defined based on VA and VF in the bestseeing ...
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Citations
... via questionnaires, which have been extrapolated to larger cohorts. [5,6]. ...
Background
We evaluated health care costs in patients with childhood onset visual impairment caused by inherited retinal dystrophies (IRD).
Methods
The IRD cohort, identified from the Danish Registry of Blind and Partially Sighted Children, was compared to age- and sex-matched controls from the national, Danish population registry. Information on health care expenditures for somatic and psychiatric in- and outpatient services, purchase of prescription medications and paid assistance at home were obtained from national registries for the years 2002–2017.
Results
We included 412 in the IRD cohort (6,290 person years) and 1656 (25,088 person years) in the control cohort. Average, annual health care expenditures from age 0–48 years of age were €1,488 (SD 4,711) in the IRD cohort and €1,030 (4,639) in the control cohort. The largest difference was for out-patient eye care (13.26 times greater, 95% confidence interval 12.90–13.64). Psychiatric in-patient expenditures were 1.71 times greater (95% CI 1.66–1.76) in the IRD cohort but psychiatric out-patient health care costs were comparable between groups.
Conclusions
Health care costs were approximately 40% greater in the IRD cohort compared to an age- and sex-matched sample from the general Danish population. This is relevant in the current situation with a number of trials aimed at treating IRDs using genetically based therapies. Although eye care expenditures were many times greater, they made up < 10% of the total health care expenditures even in the IRD cohort. The reduced costs related to injuries in the visually impaired cohort was a surprising finding but may reflect a reduced propensity to seek medical care rather than a reduced risk of injuries.
... One evaluation of Zolgensma and one of Luxturna elicited patient QOL from physicians. 29,44 The evaluation of Strimvelis assumed that treated patients would enjoy the same QOL as the general population for that age. A study of Luxturna used utility weights associated with other retinal disease populations, although it noted that these are often older patients. ...
... 67 There were also 4 economic evaluations of Luxturna, one of which estimated a small added benefit at high incremental cost, 43 1 estimated a very large added benefit with cost savings, 68 and 2 estimated a large added benefit with additional cost. 44,45 All used efficacy evidence from the same small 4-year RCT. 69 The economic evaluations differed in various ways (discount rates, number of health states, and perspective) but 2 factors stand out. ...
... All models affirmed that the costs of the disease increase with the severity of visual impairment, particularly the indirect (nonhealthcare) costs, and so a gene therapy that could slow the progression of visual impairment would gradually offset the high acquisition cost. Nevertheless, there were no data on the duration of effectiveness of the gene therapy beyond 4 years, so the models relied on assumptions, 1 assuming the effect gradually wanes over 10 years, 43 1 assuming it is maintained for 40 years, 44 and 2 assuming it is maintained over the lifetime. 45,68 ...
Objectives
Advanced therapy medicinal products (ATMPs) are drugs for human use for the treatment of chronic, degenerative, or life-threatening diseases that are based on genes, tissues, or cells. This article aimed to identify and critically review published economic analyses of ATMPs.
Methods
A systematic review of economic analyses of ATMPs was undertaken. Study characteristics, design, sources of data, resources and unit costs, modeling and extrapolation methods, study results, and sensitivity analyses were assessed.
Results
A total of 46 economic analyses of ATMP (from 45 articles) were included; 4 were cell therapy medicinal products, 33 gene therapy medicinal products, and 9 tissue-engineered products. 30 therapies had commercial marketing approval; 39 studies were cost-utility analysis, 5 were cost-effectiveness analysis, and 2 were cost only studies. Four studies predicted that the ATMP offered a step change in the management of the condition and 10 studies estimated that the ATMP would offer a lower mean cost.
Conclusions
Comparison with historical controls, pooling of data, and use of techniques such as mixture cure fraction models should be used cautiously. Sensitivity analyses should be used across a plausible range of prices. Clinical studies need to be designed to align with health technology assessment requirements, including generic quality of life, and payers should aim for clarity of criteria. Regulators and national payers should aim for compatibility of registers to allow interchange of data. Given the increasing reliance on industry-funded economic analyses, careful critical review is recommended.
... [16] Subsequently, several countries in Europe have approved the drug for use. [17,18] In addition to RPE65, multiple other gene therapy trials for LCA are underway for the following mutations: GUCY2D (encodes retinal guanylylcyclase-1, a protein expressed in the outer PR and leading to LCA type 1), [19] and CEP290 (encodes a centrosomal protein involved in trafficking through the connecting cilia of PR cells). [20] Gene therapy for choroideremia Choroideremia is an X-linked disorder that leads to progressive degeneration of the PR, RPE, and choriocapillaris, mainly affecting males. ...
Inherited retinal diseases (IRD) are genotypically and phenotypically varied disorders that lead to progressive degeneration of the outer retina and the retinal pigment epithelium (RPE) eventually resulting in severe vision loss. Recent research and developments in gene therapy and cell therapy have shown therapeutic promise in these hitherto incurable diseases. In gene therapy, copies of a healthy gene are introduced into the host cells via a viral vector. Clinical trials for several genes are underway while treatment for RPE65 called voretigene neparvovec, is already approved and commercially available. Cell therapy involves the introduction of stem cells that can replace degenerated cells. These therapies are delivered to the target tissues, namely the photoreceptors (PR) and RPE via subretinal, intravitreal, or suprachoroidal delivery systems. Although there are several limitations to these therapies, they are expected to slow the disease progression and restore some visual functions. Further advances such as gene editing technologies are likely to result in more precise and personalized treatments. Currently, several IRDs such as retinitis pigmentosa, Stargardt disease, Leber congenital amaurosis, choroideremia, achromatopsia, and Usher syndrome are being evaluated for possible gene therapy or cell therapy. It is important to encourage patients to undergo gene testing and maintain a nationwide registry of IRDs. This article provides an overview of the basics of these therapies and their current status.
... implemented for the UK [22], to inform a Highly Specialised Technology Appraisal by NICE [23]. VN treatment was compared against the current standard of care (SoC). ...
... Health state utilities were derived from a study where EQ-5D-5L estimates for IRD patients with biallelic RPE65-mutation were elicited from clinicians (it was not considered feasible to collect EQ-5D-5L data directly from a representative sample of patients due to the rare nature of the disease) ( Table 2) [5]. Utility decrements resulting from the adverse events in Study 301/302 were included for the adverse events which occurred in at least 2 patients, could be attributed to VN treatment/administration procedure, and are associated with a utility reduction [22]. These adverse events were cataracts, eye inflammation, and increased intraocular pressure (IOP), and were incorporated into the analysis in the form of a one-off QALY loss for VN patients ( Table 3). ...
Objective
We aimed to evaluate the cost-effectiveness of voretigene neparvovec (VN) compared with standard of care (SoC) for patients with inherited retinal disease (IRD) caused by a biallelic RPE65-mutation. VN is a live, non-replicating adeno-associated virus serotype 2 (AAV2). SoC is best supportive care provided to patients with visual impairment. Patients under SoC may experience progressive vision loss leading to complete blindness.
Methods
We adapted a previously published Markov cohort model for IRD. An annual cycle length, life-long time horizon, discount rate of 3% for cost and health outcomes, and Swiss health system perspective were used. Data from a randomised controlled phase III trial of VN versus SoC (ClinicalTrials.gov: NCT00999609) were used to estimate transitions between health states in the first year, after which VN patients were assumed to remain for 39 subsequent years in the health state they were in at the end of the first year. After the 40th year for VN patients and 1st year for SoC patients, visual decline was modelled based on observational data on the natural progression of the disease. Quality-adjusted life years (QALYs) were calculated based on an external study which elicited clinicians’ EQ-5D-5L-based utility estimates for IRD patients with a RPE65-mutation. Costs (Swiss Francs (CHF), year 2018-2019) included drug acquisition/ administration, adverse events, testing for sufficient viable retinal cells, and healthcare-related costs of blindness. Societal costs of blindness were added in a complementary analysis. Robustness of the model results were tested in sensitivity and scenario analyses.
Results
For the base-case, VN resulted in incremental costs per patient of CHF 764’402 (VN: CHF 901’654, SoC: CHF 137’252), incremental blindness-free years of 7.67 (VN: 28.32, SoC: 20.65) and incremental QALYs of 6.73 (VN: 18.35, SoC: 11.62), leading to an incremental cost-effectiveness ratio of CHF 113’526 per QALY gained. In probabilistic sensitivity analysis, the cost-effectiveness of VN was better than CHF 100,000 per QALY gained in 41% of iterations. For the scenario analysis in which a societal perspective was adopted and for which a 50% work-related productivity loss from blindness was assumed, incremental costs of CHF 423,837 and an ICER of CHF 62’947 per QALY gained were produced. The scenario assuming VN treatment effect lasts for 20 years produced an ICER of CHF 156’171 per QALY gained, whereas assuming a life-long VN treatment effect resulted in an ICER of CHF 96’384 per QALY gained.
Conclusion
The incremental cost-effectiveness ratio of VN compared to the SoC was estimated to be CHF 113’526 and CHF 62’947 per QALY gained, respectively, from a Swiss healthcare system, and societal perspective assuming a 50% productivity loss.
... The literature comprises economic evaluations demonstrating that some advanced therapies are cost-effective, while others are not, depending on factors such as the setting and the choice of comparator. Multiple economic evaluations have found that incremental cost-effectiveness ratios of advanced therapies exceed standard cost-effectiveness threshold values Cher et al., 2020;Connock et al., 2020;Furzer et al., 2020;Viriato et al., 2020; National Institute for Health and Care Excellence, 2021a). On the other hand, there are numerous examples of advanced therapies being costeffective from a payer perspective in general or in specific "favourable" scenarios (e.g., assumption of a lifetime horizon in line with the advanced therapy promise of a cure, application of lower discount rates for costs and outcomes). ...
Background: The health economic literature has questioned the cost-effectiveness and affordability of advanced therapies, proposed adjustments to value assessment frameworks, and discussed the use of outcome-based managed entry agreements and staggered payments in the last few years. The aim of this manuscript is to conduct a critical reflection on assessment criteria and access conditions for reimbursement of advanced therapies.
Methods: A narrative review of the peer-reviewed literature and grey literature was conducted in April 2021 by searching PubMed; Google Scholar; policy and legislative documents; websites of health technology assessment agencies, advanced therapy organisations, governmental advanced therapy innovation programmes, consultancy agencies; ISPOR conference abstracts and presentations.
Results: Based on the available evidence, this manuscript argues that: a) advanced therapies can be cost-effective at high prices set by manufacturers; b) the economic evaluation framework adopted by many payers under-values these products; c) advanced therapies can be affordable and may not require spread payments; d) outcome-based managed entry agreements are theoretically attractive, but challenging in practice; e) the cost-effectiveness of advanced therapies depends on the outcome-based managed entry agreement and payment approach; f) there is a role for multinational collaborations to manage reimbursement and access of advanced therapies.
Conclusions: This manuscript shows that there is no single approach to reimbursement and access of advanced therapies. Instead, we support a more tailored assessment of health economic aspects of advanced therapies, which considers the heterogeneity of these products and their target populations.
... RPE65 mutation-associated inherited retinal degenerations (IRDs) are of great interest as an approved therapy is now available in an increasing number of countries worldwide (FDA USA 2017, EMA Europe 2018, MoHAP United Arab Emirates 2019, SFDA Saudi Arabia 2019, Swiss Medic Switzerland 2020, TGA Australia 2020, BFR Brazil 2020). Cost-effectiveness of this therapy for the national health-care system is actually discussed in a number of articles [1][2][3][4][5]. The gene was identified by 2 groups independently in 1997 [6,7], and while Marlhens et al. [6] reported mutations in patients with autosomal recessive Leber congenital amaurosis, Gu et al. [7] had found mutations in patients with autosomal recessive childhood-onset severe retinal dystrophy. ...
Purpose:
The first ocular gene augmentation therapy, voretigene neparvovec (VN) (Luxturna®), has been approved for clinical use in an increasing number of countries (FDA USA 2017, EMA Europe 2018, MoHAP United Arab Emirates 2019, SFDA Saudi Arabia 2019, Swiss Medic Switzerland 2020, TGA Australia 2020, BFR Brazil 2020). Among the EVICR.net clinical centers, we conducted the first multinational survey to understand distribution, diagnostic work-up, and management of inherited retinal degeneration (IRD) cases in Europe with a special focus on RPE65 mutation-associated IRDs.
Methods:
An electronic survey questionnaire including 35 questions specifically addressing RPE65 mutation-associated IRDs was developed and sent to the 101 EVICR.net clinical centers.
Results:
The overall response rate was 49%. Forty-two centers see IRD patients, and 22/42 follow patients with confirmed biallelic RPE65 mutations. Fifteen of the 22 centers (68%) and 3/22 (14%) follow 1-5 and 6-10 patients with homozygous RPE65 mutations, respectively. Additionally, 15/22 (68%) and 3/22 (14%) follow 1-5 and >20 patients with compound heterozygous RPE65 mutations, respectively. Fifty-nine percent of mutations were ACMG Class 4 and 5 (at least 1 allele), 82.8% reported previously and 17.2% novel. Referral diagnoses (the mean per center) were Leber congenital amaurosis (38.2%), early-onset severe retinal degeneration (16.8%), rod-cone-dystrophy/retinitis pigmentosa (RP) (28.1%), and unclassified visual impairment (17.0%). Twenty-five percent of the centers changed the referral diagnosis in >47.5% of cases; 32% follow a specific referral process for RPE65 mutation-associated IRD patients. Annual follow-up visits are done in 55% of the centers and biannual visits in 23%. In 32%, other centers also follow the patients. Kinetic perimetry is done in 82%, static perimetry in 45%, and microperimetry in 18% of the centers. Full-field light stimulus threshold testing with blue and red stimuli to quantify the rod and cone function is used in 6/22 centers (27%). A mobility course is available in one center (5%).
Conclusion:
This first multinational survey on management of patients with RPE65 mutation-associated IRDs in Europe shows that about half of the responding EVICR.net centers have such patients under care. There is heterogeneity in diagnoses and management practices. At the start of clinical practice experience with VN, these data provide a useful baseline and highlight the need for consensus/guidelines to inform standard of care in this new era of gene therapy.
... Moreover, the high upfront cost of accessing Luxturna (US $850,000 to treat both eyes) 97 has been criticised, with costeffectiveness analyses concluding both for 98,99 or against. 97,100 Cost is a major barrier for patient uptake, as was underscored by the eventual withdrawal of Glybera from the market due to commercial failure. ...
Inherited retinal diseases (IRDs) comprise a heterogeneous group of genetic disorders affecting the retina. Caused by mutations in over 300 genes, IRDs result in visual impairment due to dysfunction and degeneration of photoreceptors, retinal pigment epithelium, or the choroid. Important photoreceptor IRDs include retinitis pigmentosa and Leber congenital amaurosis. Macular dystrophies include Stargardt and Best disease. Currently, IRDs are largely incurable but the landscape of treatment options is rapidly changing for these diseases which, untreated, result in severe visual impairment and blindness.
Advances in DNA delivery to the retina and improved genetic diagnosis of IRDs have led to a new era of research into gene therapy for these vision-threatening disorders. Gene therapy is a compelling approach due to the monogenic nature of most IRDs, with the retina being a favourable target for administering genetic vectors due to its immunoprivileged environment, direct visibility, and multiple methods to assess sensitivity and function. Generally, retinal gene therapy involves a subretinal or intravitreal injection of a viral vector, which infects target cells to deliver a therapeutic gene, or transgene. A gene augmentation strategy introduces a functioning copy of a gene to restore expression of a mutated gene, whereas a gene-editing strategy aims to directly edit and correct the mutation. Common delivery vectors include adeno-associated virus (AAV) and lentivirus.
Voretigene neparvovec-rzyl (Luxturna) became the first FDA-approved direct gene therapy in December 2017, and the Australian TGA followed suit in August 2020. More are projected to follow, with clinical trials underway for many other IRDs.
This review provides an overview of gene therapy for IRDs, including current progress and challenges. A companion article in this issue details target patient populations for IRD gene therapy, and how optometrists can assist in assessing individuals who may be eligible for current and future therapies.
... The company base case in the UK HTA submission therefore used utility values based on the HUI-3. The impact of using EQ-5D-5L instead of the HUI-3 utilities from the vignette study is shown by Viriato et al. [21], who performed comparable analyses with the company model for the UK setting, as in the NICE submission, resulting in an ICER of £95,072/QALY (compared with £86,635/QALY calculated with the HUI-3 in the NICE submission). The UK ICER was higher in the NICE submission due to larger utility decrements for HS2 compared with HS1 (the most important transition according to the one-way sensitivity analyses [21] is from HS1 to HS2) when using the HUI-3 (− 0.16, Fig. 2) compared with the UK EQ-5D-5L (− 0.09, Fig. 2). ...
... The impact of using EQ-5D-5L instead of the HUI-3 utilities from the vignette study is shown by Viriato et al. [21], who performed comparable analyses with the company model for the UK setting, as in the NICE submission, resulting in an ICER of £95,072/QALY (compared with £86,635/QALY calculated with the HUI-3 in the NICE submission). The UK ICER was higher in the NICE submission due to larger utility decrements for HS2 compared with HS1 (the most important transition according to the one-way sensitivity analyses [21] is from HS1 to HS2) when using the HUI-3 (− 0.16, Fig. 2) compared with the UK EQ-5D-5L (− 0.09, Fig. 2). In contrast, the Dutch ICER was higher if utility values were based on the Dutch EQ-5D-5L tariff compared with the HUI-3 (Table 3) because of the smaller range in utility values of HS1 to HS5 when using the HUI-3 (0.56) instead of the Dutch EQ-5D-5L (0.60). ...
... Furthermore, it is anticipated that the RPE65 gene will remain active during the lifetime of RPE cells, which normally undergo minimal proliferation (i.e. cell division) throughout life [21]. The four economic evaluations applied different assumptions on the duration of treatment effect. ...
The emergence of gene therapies challenge health economists to evaluate interventions that are often provided to a small patient population with a specific gene mutation in a single dose with high upfront costs and uncertain long-term benefits. The objective of this study was to illustrate the methodological challenges of evaluating gene therapies and their implications by discussing four economic evaluations of voretigene neparvovec (VN) for the treatment of RPE65-mediated inherited retinal disease. The checklist for economic evaluations of gene therapies of Drummond et al. was applied to the economic evaluations of VN performed by US Institute for Clinical and Economic Review, two country adaptations of the company model in the UK and the Netherlands, and another US publication. The main differences in methodological choices and their impact on cost-effectiveness results were assessed and further explored with sensitivity analyses using the Dutch model. To enable comparison between the economic evaluations, costs were converted to US dollars. Different methodological choices were made in the economic evaluations of VN resulting in large differences in the incremental cost-effectiveness ratio varying from US$79,618 to US$643,813 per QALY. The chosen duration of treatment effect, source of utility values, discount rate and model structure had the largest impact on the cost-effectiveness. This study underlines the findings from Drummond et al. that standard methods can be used to evaluate gene therapies. However, given uncertainty about (particularly long-term) outcomes of gene therapies, guidance is required on the acceptable extrapolation of treatment effect of gene therapies and on how to handle the uncertainty around this extrapolation in scenario and sensitivity analyses to aid health technology assessment research and align submissions of future gene therapies.
... In addition, we wanted to get detailed information about diagnosis, prevalence, and management of patients with RPE65 mutation-associated IRDs [3,6,7]. For the latter, an approved gene ther-apy is now available in an increasing number of countries worldwide (FDA USA 2017, EMA Europe 2018, MoHAP United Arab Emirates 2019, SFDA Saudi Arabia 2019 2019, Swiss Medic Switzerland 2020, TGA Australia 2020, and BFR Brazil 2020) at considerable cost for the national health-care system [8][9][10]. The results of that part of the survey will be reported in a separate article. ...
... This translates to an annual cost per patient of £ 20,000 on average. Development of effective therapies for the most frequent forms in the future may alleviate this burden, although actual therapies are associated with high cost for the medication, yet with measurable gain in quality-adjusted life years [8,10,12]. The effect on disability-adjusted-life-years may be (3), Canada (1), and USA (1) work together [13]. ...
Purpose:
An increasing number of gene therapies are developed for Inherited Retinal Degenerations (IRD). To date, one treatment has been approved for clinical use (FDA USA 2017, EMA Europe 2018, MoHAP UAE 2019, SFDA Saudi Arabia 2019, Swiss Medic Switzerland 2020, TGA Australia 2020, BFR Brazil 2020). Whilst such therapies do not provide complete cure, they may halt degeneration or partially restore function. Identification of well-characterized patients is an emerging need. We conducted the first multinational survey to understand the management of IRDs in Europe.
Methods:
An electronic survey questionnaire containing 112 questions was developed and sent to the 101 EVICR.net Clinical Centers (14 European Countries and Israel).
Results:
The overall response rate was 49%. Only 14% of responding centers do not see IRD patients; 52% that manage IRD patients follow ≥200 patients, 16% >1000. Databases exist in 86% of the centers; of these 75% are local files, 28% local web-based database and 19% national web-based. IRD patients are referred to EVICR.net centers mainly by general ophthalmologists, patient self-referrals and medical retina specialists. Most IRD patients are first seen in adulthood. Most prominent signs and symptoms depend on age of onset, e.g. nystagmus in infancy, or night blindness and reduced visual acuity at older age. The time from inquiring for first appointment and clinical diagnosis varies among countries: in 29% of centers, the mean time is < 4 weeks, although can be up to 35 months in others. The time to genetic diagnosis is ≥4 weeks, the maximum 10 years, likely depending on access to genetic testing, and the improvement of the tests available. Comprehensive eye examination always includes autofluorescence imaging and perimetry (86% static; 76% kinetic; 21% microperimetry), and frequently optical coherence tomography (95%), electroretinography (93%) and fundus photography (93%). Identified genotypes were reported in 40 to 80% patients by 69% of centers, and in 80 to 100% by 5%. Genetic testing is provided by public health insurance in 77% of centers, private health insurance in 38%, center budget in 13%, research funds in 18%; 15% of centers do not have access to genetic testing.
Conclusion:
At the start of this era of ocular gene therapy for IRD patients, this first international survey on management of IRDs in Europe highlights significant heterogeneity between centers and across countries and provides important baseline data for researchers, clinicians, pharmaceutical companies and investors.
... The study found a final ICER of 95,072 euros per QALY. 66 A major limitation in all these studies is the use of VA and VF as the primary outcomes representing benefit from therapy. These two markers have been found to be extremely variable and are unlikely to be accurate reflections of the benefits gained from gene therapy in RPE65-associated IRDs. ...
Subretinal gene therapy trials began with the discovery of RPE65 variants and their association with Leber congenital amaurosis. The RPE65 protein is critical for the normal functioning of the visual phototransduction cascade. RPE65 gene knockout animal models were developed and showed similar diseased phenotypes to their human counterparts. Proof of concept studies were carried out in these animal models using subretinal RPE65 gene replacement therapy, resulting in improvements in various visual function markers including electroretinograms, pupillary light responses, and object avoidance behaviors. Positive results in animal models led to Phase 1 human studies using adeno-associated viral vectors. Results in these initial human studies also showed positive impact on visual function and acceptable safety. A landmark Phase 3 study was then conducted by Spark Therapeutics using a dose of 1.5 x10¹¹ vector genomes after dose-escalation studies confirmed its efficacy and safety. Multi-luminance mobility testing was used to measure the primary efficacy endpoint due to its excellent reliability in detecting the progression of inherited retinal diseases. After the study met its primary endpoint, the Food and Drug Administration approved voretigene neparvovec (Luxturna®) for use in RPE65-associated inherited retinal diseases.
