Challenges of Cost-Effectiveness Analyses of Novel Therapeutics for Inherited Retinal Diseases.

PURPOSE: To investigate the challenges and potential improvement strategies of cost-effectiveness analyses performed for therapeutics targeting inherited retinal diseases (IRDs). DESIGN: Perspective. METHODS: A literature review was conducted with discussion of current limitations and improvement recommendations. RESULTS: Cost-effectiveness analysis (CEA) performed for IRD therapeutics has multiple limitations. First, the available methods used to measure health-related quality of life and health utilities can be inaccurate when used in IRDs. Second, the financial burden to patients and society from vision impairment associated with IRDs has been inadequately studied and includes a variety of expenditures ranging from direct costs of IRD specialty health care to indirect expenses associated with daily living activities. Third, our collective understanding is limited in the areas of IRD natural history and health benefits gained from new IRD treatments (eg, gene therapies). In addition, the therapeutic effect from a patient perspective and its duration of action are not fully understood. Due to the scarcity of data, CEA for newly approved therapies has relied on assumptions and creations of predictive models for both costs and health benefits for these new therapeutics in order to calculate the incremental cost-effectiveness ratio. CONCLUSIONS: CEA studies performed for IRD therapeutics have been limited by the established health utilities in ophthalmology and the lack of disease-specific information. The assumptions and extrapolations in these studies create substantial uncertainty in incremental cost-effectiveness ratio results. An improved framework is required for CEA of IRD therapeutics in order to determine the cost-effectiveness of each therapy brought from clinical trials to clinical practice.

Investigational plasma kallikrein inhibitors for the treatment of diabetic macular edema: an expert assessment.

Introduction: Plasma kallikrein is a  mediator of vascular leakage and inflammation. Activation of plasma kallikrein can induce features of diabetic macular edema (DME) in preclinical models. Human vitreous shows elevated plasma kallikrein levels in patients with DME. Because of the incomplete response of some patients to anti-VEGF agents, and the treatment burden associated with frequent dosing, there is still considerable need for VEGF-independent targeted pathways.Areas covered: This review covers the role of plasma kallikrein in the pathogenesis of DME and the therapeutic potential of plasma kallikrein inhibitors. It discusses early clinical studies of plasma kallikrein pathway modulation for DME, which have been associated with some improvement in visual acuity but with limited improvement in macular edema. This review also highlights KVD001, which is furthest along the development pathway, THR-149, which has recently completed a phase 1 study, and oral agents under development.Expert opinion: Plasma kallikrein inhibitors have a potential role in the treatment of DME, with mixed functional/anatomic results in early clinical trials. Given the large unmet need in DME treatment, further studies are warranted.

Cost-effectiveness of Voretigene Neparvovec-rzyl vs Standard Care for RPE65-Mediated Inherited Retinal Disease.

IMPORTANCE: Voretigene neparvovec-rzyl, the first gene therapy approved by the US Food and Drug Administration, was approved for the treatment for RPE65-mediated inherited retinal disease (IRD) in December 2017. This gene therapy is associated with high up-front costs and high efficacy, although of unknown duration, and its cost-effectiveness has not been assessed with RPE65 IRD-specific, longitudinal, patient-observation-level data. OBJECTIVE: To assess the incremental cost-effectiveness ratio (ICER) of voretigene neparvovec-rzyl compared with standard care for RPE65-mediated inherited retinal disease. DESIGN, SETTING, AND PARTICIPANTS: In this economic analysis, a health state transition model based on visual acuity and field with a lifetime horizon was developed to estimate the cost-effectiveness of voretigene neparvovec-rzyl. The model was populated with data from a clinical trial of voretigene neparvovec-rzyl to evaluate treatment outcome and a natural history study of RPE65-mediated IRD to examine disease progression. Direct costs were derived from the literature. Indirect costs, including educational attainment, productivity, caregiver burden, and governmental programs, were estimated using published literature and data analysis of public national surveys. A health utility vignette study specific to RPE65-mediated IRD was used for health utility inputs. The cost-effectiveness study described in this article was conducted from September 15, 2017, to August 23, 2018. EXPOSURES: Bilateral voretigene neparvovec-rzyl therapy or standard care. MAIN OUTCOMES AND MEASURES: Incremental cost-effectiveness ratio. RESULTS: The model population included 70 patients with RPE65-mediated IRD, with a mean age of 15 years; 42 of 70 patients (60%) were female. In the base case, voretigene neparvovec-rzyl compared with standard care was associated with lower total costs ($2.2 million vs $2.8 million) and higher quality-adjusted life-years (18.1 vs 8.6). Voretigene neparvovec-rzyl remains cost-effective if at least 8.8% of the long-term treatment effect continues after year 3 when including indirect costs and 43.3% when excluding indirect costs, assuming a cost threshold of $150 000 per quality-adjusted life-year. CONCLUSIONS AND RELEVANCE: Results of this study suggest that voretigene neparvovec-rzyl is cost-effective compared with standard care when using a lifetime horizon, excluding indirect costs, and using a threshold of $150 000 per quality-adjusted life-year.

Current and future pharmacological intervention for diabetic retinopathy.

Diabetic retinopathy (DR) is a potentially visually devastating complication of chronic hyperglycaemia. Prospective, randomised clinical trials have delineated the standard prevention protocols, including intensive glycaemic, blood pressure, and lipid control, and laser photocoagulation treatment for neovascularisation and clinically significant macular oedema. However, despite these interventions, vision loss from DR still occurs at an alarming rate. Researchers have directed their efforts towards better understanding the specific biological and chemical changes occurring in DR to develop more targeted pharmacological prevention and treatment strategies. This review of diabetic retinopathy will primarily detail the therapies in development at present, including aldose reductase inhibitors, advanced glycosylation end product inhibitors, antioxidants, supplemental oxygen, growth factor modulators including vascular endothelial growth factor inhibitors and protein kinase C inhibitors, extracellular matrix modifiers including corticosteroids, and vitreous modulators. The experimental therapies alter several different pathways that lead to DR. Future research will further delineate these pathways, and therapy is likely to involve arresting several different promoters of DR.

An update on photodynamic therapy in age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of irreversible loss of central vision in people aged > 50 years in the western world. Until recently, the only proven treatment to reduce the risk of vision loss from its more severe neovascular form was laser photocoagulation, but this treatment was suitable for only 15% of cases. Photodynamic therapy (PDT) with verteporfin was recently proposed to be effective in reducing the risk of visual loss for an estimated 20 - 30% of neovascular AMD patients. This review covers AMD epidemiology, the mechanism of PDT, the 2-year results of the two major clinical studies of PDT with verteporfin, the cost-effectiveness of PDT and the current research status of other drugs for PDT in AMD.