PharmacoEconomics

Correction to: Cost-Effectiveness Analysis of Patiromer and Spironolactone Therapy in Heart Failure Patients with Hyperkalemia Correction to Bounthavong M, Butler J, Dolan CM, Dunn JD, Fisher KA, Oestreicher N, Pitt B, Hauptman PJ, Veenstra DL.

Correction to: Novel Risk Engine for Diabetes Progression and Mortality in USA: Building, Relating, Assessing, and Validating Outcomes (BRAVO) The original article can be found online.

Comment on: "Cost-Effectiveness of Niraparib Versus Routine Surveillance, Olaparib and Rucaparib for the Maintenance Treatment of Patients with Ovarian Cancer in the United States"

Dinutuximab Beta for Treating Neuroblastoma: An Evidence Review Group and Decision Support Unit Perspective of a NICE Single Technology Appraisal Abstract As part of its Single Technology Appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (EUSA Pharma) of dinutuximab beta (Qarziba®) to submit evidence of its clinical and cost effectiveness for treating neuroblastoma. The BMJ Technology Assessment Group (BMJ-TAG) was commissioned to act as the Evidence Review Group (ERG), reviewing the submission from the company. The Decision Support Unit (DSU) was commissioned to review additional evidence submitted by the company and to undertake further analyses. This article presents the critical review of the company's submissions by the ERG and DSU, further analyses undertaken by the DSU, and the outcome of the NICE guidance. The clinical effectiveness for dinutuximab beta was derived from a phase III randomised controlled trial (RCT) that assessed the safety and efficacy of the addition of interleukin (IL)-2 to dinutuximab beta plus isotretinoin. This trial did not inform the relative effectiveness of dinutuximab beta versus isotretinoin alone, which was established practice in the UK for maintenance treatment. In the absence of direct evidence, the company initially conducted a naïve indirect treatment comparison against a historical control, and later performed a matching-adjusted indirect comparison (MAIC) against the isotretinoin arm of an RCT comparing dinutuximab alpha and isotretinoin. The company submitted a partitioned survival analysis model that calculated the incremental cost effectiveness of dinutuximab beta versus isotretinoin. The company's original incremental cost-effectiveness ratio (ICER) was £22,338 per quality-adjusted life-year (QALY) gained. However, the ERG were concerned that the company's ICER was not suitable for decision making, and thus carried out initial exploratory analysis as a first step to overcome the naïve estimation of treatment effectiveness in the model. The ERG's analysis estimated an ICER of £111,858 per QALY gained. In their revised analysis incorporating the MAIC and other changes as requested by the appraisal committee, the company's ICER was £24,661 per QALY gained. When the DSU incorporated longer-term isotretinoin data and made corrections to the model, the ICER increased to between £62,886 and £87,164 per QALY gained depending on the choice of survival model. A confidential Patient Access Scheme (PAS) decreased the ICERs. The ICERs with the PAS were over £40,000 per QALY gained, but the NICE committee additionally considered the patient population and its size, the disease severity, the potential for significant survival benefit and uncaptured health benefits, and recommended dinutuximab beta as a treatment option, subject to the company providing the agreed discount in the PAS.

The Economic Burden of Cystic Fibrosis in Germany from a Payer Perspective Abstract Background Cystic fibrosis (CF) is a genetic disorder that is most common in white children and young adults. Long-term survival has improved steadily and will likely increase with the recent introduction of neonatal screening and causative treatment. However, these advances have substantial economic consequences for healthcare systems and payers. Objective This study aims to determine the economic burden of CF and to elucidate the structure of costs and the distribution of resources for different subpopulations, treatment strategies and sites of care for CF in Germany. Methods We conducted an observational cohort study to evaluate the economic burden of CF and the costs of treatment within different CF substrata from a payer perspective. Using claims data from a large German sickness fund, we identify the causal effect of CF on costs, service utilisation, and premature mortality. We compare the outcomes of a CF and a control group using entropy balancing and regression techniques, conduct further analyses for the CF group to gain insight into the economic burden associated with different levels of disease severity, and analyse pharmaceutical expenditures by collecting all CF-related expenses on outpatient drug treatment from the sickness fund database. Results Direct medical costs caused by CF in Germany in 2016 average €17,551 per patient-year and appear to be mainly driven by the cost of outpatient drug prescriptions (€12,869). We estimate that the national burden of disease totals €159 million. Costs increase with disease severity and related complications. If all eligible CF patients in the German population were to receive CF mutation-specific drugs, the economic burden of disease would more than triple to €594 million. Conclusion CF has a constant and wide-ranging economic impact on payers, with considerable differences in the distribution of costs and service utilisation between younger and older patients as well as mild vs. severe patients. Pharmaceutical expenses will increase in the future as causative treatment gains importance. We encourage the use of a control group approach for burden-of-disease studies to be able to identify causal effects and thus to obtain more precise estimates.

Accounting for Capacity Constraints in Economic Evaluations of Precision Medicine: A Systematic Review Abstract Background and Objective Precision (stratified or personalised) medicine is underpinned by the premise that it is feasible to identify known heterogeneity using a specific test or algorithm in patient populations and to use this information to guide patient care to improve health and well-being. This study aimed to understand if, and how, previous economic evaluations of precision medicine had taken account of the impact of capacity constraints. Methods A meta-review was conducted of published systematic reviews of economic evaluations of precision medicine (test–treat interventions) and individual studies included in these reviews. Due to the volume of studies identified, a sample of papers published from 2007 to 2015 was collated. A narrative analysis identified whether potential capacity constraints were discussed qualitatively in the studies and, if relevant, which quantitative methods were used to account for capacity constraints. Results A total of 45 systematic reviews of economic evaluations of precision medicine were identified, from which 222 studies focusing on test–treat interventions, published between 2007 and 2015, were extracted. Of these studies, 33 (15%) qualitatively discussed the potential impact of capacity constraints, including budget constraints; quality of tests and the testing process; ease of use of tests in clinical practice; and decision uncertainty. Quantitative methods (nine studies) to account for capacity constraints included static methods such as capturing inefficiencies in trials or models and sensitivity analysis around model parameters; and dynamic methods, which allow the impact of capacity constraints on cost effectiveness to change over time. Conclusions Understanding the cost effectiveness of precision medicine is necessary, but not sufficient, evidence for its successful implementation. There are currently few examples of evaluations that have quantified the impact of capacity constraints, which suggests an area of focus for future research.

Is Reclassification of the Oral Contraceptive Pill from Prescription to Pharmacist-Only Cost Effective? Application of an Economic Evaluation Approach to Regulatory Decisions Abstract Background and Objective Unplanned pregnancies can lead to poorer maternal and child health outcomes. The Australian Therapeutic Goods Administration committee rejected reclassifying a range of oral contraceptive pills (OCPs) from prescription to pharmacist-only medicines in 2015, mainly based on safety concerns. Improving access to OCPs may encourage some women to use contraceptives or switch from other contraceptive methods. However, some adverse events may increase and some women may stop using condoms, increasing their risk of sexually transmitted infections. This study aimed to estimate the cost effectiveness of reclassifying OCPs from prescription to pharmacist-only. Perspective Healthcare system. Setting Australian primary care. Methods A Markov model was used to synthesise data from a variety of sources. The model included all Australian women aged 15–49 years (N = 5,644,701). The time horizon was 35 years. Contraceptive use before reclassification was estimated using data from the Household, Income and Labour Dynamics in Australia (HILDA) survey, while survey data informed use after reclassification. Health outcomes included pregnancies, pregnancy outcomes (live birth, miscarriage, stillbirth, ectopic pregnancy and abortion), sexually transmitted infections, adverse events (venous thromboembolism, depression, myocardial infarction and stroke), ovarian cancer cases and quality-adjusted life-years. Costs included those related to general practitioner and specialist consultations, contraceptives and other medicines, pharmacist time, hospitalisations and adverse events. All costs were reported in 2016 Australian Dollars. A 5% discount rate was applied to health outcomes and costs. Results Reclassifying OCPs resulted in 85.70 million quality-adjusted life-years experienced and costs of $46,910.14 million over 35 years, vs. 85.68 million quality-adjusted life-years experienced and costs of $50,274.95 million with OCPs remaining prescription-only. Thus, reclassifying OCPs was more effective and cost saving. However, a sensitivity analysis found that more research on the probability of pregnancy in women not using contraception and not trying to conceive is needed. Conclusion Reclassifying OCPs is likely to be considered cost effective by Australian decision makers.

A Q-TWiST Analysis Comparing Nivolumab and Therapy of Investigator's Choice in Patients with Recurrent/Metastatic Platinum-Refractory Squamous Cell Carcinoma of the Head and Neck Abstract Objectives In the CheckMate 141 trial (NCT02105636), nivolumab demonstrated survival, health-related quality of life, and healthcare resource utilization benefits vs single-agent therapy of investigator's choice (IC) (methotrexate, docetaxel or cetuximab) in patients with platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). We assessed between-treatment differences in quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST). Methods Survival data from CheckMate 141 (nivolumab, n = 240; IC, n = 121) was partitioned into toxicity (TOX), time without symptoms or toxicity (TWiST), and relapse (REL). TOX was defined as time spent with all-cause grade 3–4 adverse events after randomization, before disease progression. TWiST was defined as time not in TOX or REL. REL was defined as time between disease progression and death. Utility values derived from three-level EuroQol five-dimensional questionnaire data from CheckMate 141 were used to calculate Q-TWiST as the utility-weighted sum of the mean duration in each health state. Results The between-group difference in Q-TWiST score was 1.23 months (95% confidence interval 1.17–1.29) favoring nivolumab (p < 0.001). The nivolumab group experienced significantly longer mean time in TWiST (3.82 vs 2.78 months) and REL (4.02 vs 3.30 months) compared with the IC group (p < 0.001). Mean time in TOX was lower for nivolumab vs IC (0.30 vs 0.37 months, p < 0.001). Conclusions In CheckMate 141, nivolumab resulted in statistically significant and clinically meaningful gains (relative difference > 10%) in quality-adjusted survival vs standard of care in patients with R/M SCCHN.

Obinutuzumab in Combination with Chemotherapy for the First-Line Treatment of Patients with Advanced Follicular Lymphoma Abstract The National Institute for Health and Care Excellence (NICE), as part of the institute's single technology appraisal (STA) process, invited the company that makes obinutuzumab (Roche Products Limited) to submit evidence of the clinical and cost effectiveness of the drug in combination with chemotherapy, with or without obinutuzumab as maintenance therapy for adult patients with untreated, advanced follicular lymphoma (FL) in the UK. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company's submission, the ERG review, and NICE's subsequent decisions. The clinical evidence was derived from two phase III, company-sponsored, randomised, open-label studies. Most evidence on obinutuzumab was based on the GALLIUM trial that compared obinutuzumab in combination with chemotherapy as induction followed by obinutuzumab maintenance monotherapy with rituximab in combination with chemotherapy as induction followed by rituximab maintenance monotherapy in previously untreated patients with FL (grades 1–3a). Long-term clinical evidence was based on the PRIMA trial, studying the benefit of two years of rituximab maintenance after first-line treatment in patients with FL. The cost-effectiveness evidence submitted by the company relied on a partitioned survival cost-utility model, implemented in Microsoft® Excel. The base-case incremental cost-effectiveness ratio (ICER) presented in the company submission was <£20,000 per quality-adjusted life-year (QALY) gained. Although the ERG concluded that the economic model met the NICE reference case to a reasonable extent, some errors were identified and several assumptions made by the company were challenged. A new base-case scenario produced by the ERG suggested an ICER that was higher than the company base case, but still below £30,000 per QALY gained. However, some ERG scenario analyses were close to or even above the threshold. This was the case in particular for assuming a treatment effect that did not extend beyond trial follow-up. These results led to an initial negative recommendation by the appraisal committee. Subsequently, the company submitted a revised base case focusing on patients at intermediate or high risk of premature mortality. Simultaneously, a further price discount for obinutuzumab was granted. In addition to the company's revised base case, the ERG suggested a restriction of the treatment effect to 5 years and implemented biosimilar uptake and cheaper prices for rituximab. All of these adjustments did not exceed £30,000 per QALY gained and therefore the use of obinutuzumab for patients with advanced FL and a Follicular Lymphoma International Predictive Index (FLIPI) score of two or more could be recommended.

Cost Effectiveness of Treatments for Diabetic Retinopathy: A Systematic Literature Review Abstract Background Diabetic retinopathy (DR) affects approximately one-third of people diagnosed with diabetes, can be sight-threatening, and generates significant human and economic burden. Over the last 2 decades, newer therapies have emerged, offering significant clinical benefits, however at a cost. Given the scarcity of available budgets, the cost effectiveness of these newer treatments is of vital importance to policy makers. Methods A systematic review was conducted in the PubMed, EMBASE, Cochrane, HEED and CRD databases to find and evaluate economic evaluations assessing the cost effectiveness of alterative DR treatments. Studies were assessed for their eligibility, findings and quality, and are presented in this systematic review. Results Of the 5254 studies retrieved from the literature search, 17 were included in this review. For patients with proliferative DR, when early pars plana vitrectomy was compared with pan-retinal laser photocoagulation, similar cost per quality-adjusted life-year (QALY) was observed between the two. Treatment with either intravitreal ranibizumab (IVR) or intravitreal bevacizumab (IVB) falls within acceptable cost-effectiveness thresholds in the diabetic macular oedema (DMO) population; however, in the non-DMO population, the marginal benefit of IVR or IVB in relation to the marginal cost relative to laser does not justify their use. Among the anti-vascular endothelial growth factor (VEGF) therapies, IVB appears more attractive from an economic point of view due to its lower cost. For patients with DMO, studies indicate that a combination therapy of IVR or IVB with laser and, to a lesser degree, as monotherapy, are cost effective relative to laser monotherapy; IVR plus laser is cost effective relative to laser plus triamcinolone; and laser combined with triamcinolone injections is reportedly more cost effective over IVR for pseudophakic eyes only. Moreover, fluocinolone implants appear cost effective compared with sham implants, or when treating refractory DMO. IVR administered either pro re nata (PRN) or as 'treat and extend' dominated intravitreal aflibercept (IVA) in a few studies. On the other hand, IVR monotherapy or with laser (as well as IVA) does not compare favourably relative to IVB monotherapy or with laser. Conclusions Interpretation of cost-effectiveness data should be treated with caution in this case; details of the therapeutic regimen, such as dosage and frequency, and clinical efficacy of the treatments should be considered in relation to policy-making decisions. Given the scarcity of resources, the ever-increasing significance of health technology assessment, and the substantial differences in the methodologies of the studies presented in this review, there is a pressing need for more advanced and standardised approaches to assessing the effectiveness and cost effectiveness of the emerging anti-VEGF pharmacotherapies for the treatment of DMO.

Alexandros Sfakianakis
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alsfakia@gmail.com