Cost Effectiveness of Adding Fenfluramine to Standard of Care for Patients with Dravet Syndrome in Sweden.

OBJECTIVE: This study evaluated, in a Swedish setting, the cost effectiveness of fenfluramine (FFA) as an add-on to standard of care (SoC) for reducing seizure frequency in Dravet syndrome, a severe developmental epileptic encephalopathy. METHODS: Cost effectiveness of FFA+SoC compared with SoC only was evaluated using a patient-level simulation model with a lifetime horizon. Patient characteristics and treatment effects, including convulsive seizures, seizure-free days and mortality, were derived from FFA clinical trials. Resource use and costs included cost of drug acquisition, routine care and monitoring, as well as ongoing and emergency resources. Quality of life (QoL) estimates for patients and their caregivers were derived from clinical trial data. Robustness was evaluated by one-way sensitivity analysis, probabilistic sensitivity analysis and scenario analyses. RESULTS: Lifetime cost of FFA+SoC was ~3 million SEK per patient compared with ~1.5 million SEK for SoC only. FFA+SoC generated 15% more QALYs than SoC only (21.2 vs 18.5 over a lifetime), resulting in an incremental cost-effectiveness ratio (ICER) of ~540,000 SEK. Moreover, FFA+SoC had a higher probability of being cost effective than SoC only from a willingness-to-pay threshold of 710,000 SEK. Results remained generally consistent across scenario analyses, with only few exceptions (exclusions of carer utility or FFA effect on sudden unexpected death in epilepsy). CONCLUSION: Due to better seizure control, FFA is a clinically meaningful add-on therapy and was estimated to be a cost-effective addition to current SoC for patients with this rare disease in Sweden at a willingness-to-pay threshold of 1,000,000 SEK.

Importance of Time Point-Specific Indirect Treatment Comparisons of Osteoporosis Treatments: A Systematic Literature Review and Network Meta-Analyses.

PURPOSE: The efficacy comparison of osteoporosis treatments can be hindered by the absence of head-to-head trials; instead, network meta-analyses (NMAs) have been used to determine comparative effectiveness. This study was the first to investigate the impact of time point-specific NMAs of osteoporosis treatments on variability in treatments' onset of action caused by their different mechanisms of actions and trial designs. METHODS: A systematic literature review was conducted to identify randomized controlled trials (RCTs) of treatments for postmenopausal women with osteoporosis, including romosozumab (ROMO), teriparatide (TPTD), abaloparatide (ABL), alendronate (ALN), risedronate (RIS), ibandronate (IB), zoledronic acid/zoledronate (ZOL), denosumab (DEN), and raloxifene (RLX), on at least 1 fracture or bone mineral density (BMD) outcome. Of 100 RCTs identified in 5 databases, 27 RCTs were included for NMAs of new vertebral, nonvertebral, and hip fracture outcomes at 12, 24, and 36 months, and 47 RCTs were included for NMAs of BMD outcomes at lumbar spine, total hip, and femoral neck to compare the relative efficacy of osteoporosis treatments. Quality of included studies was assessed using the Cochrane Risk of Bias tool. FINDINGS: For vertebral fractures, TPTD (83.63%), ABL (69.11%), and ROMO/ALN (78.70%) had the highest probability to be the most effective treatment at 12, 24, and 36 months, respectively. ROMO/ALN had the highest probability (54.4%, 64.69%, and 90.29%, respectively) to be the most effective treatment for nonvertebral fractures at 12, 24, and 36 months. For hip fractures, ROMO/ALN (46.31%), ABL (61.1%), and DEN (55.21%) had the highest probability to be the most effective treatment at 12, 24, and 36 months, respectively. ROMO had the highest probability (76.06%, 44.19%, and 51.78%, respectively) to be the most effective treatment for BMD outcomes at lumbar spine, total hip, and femoral neck. IMPLICATIONS: The importance of indirectly comparing available osteoporosis treatments using time point-specific NMAs was confirmed because indirect comparison results differed substantially across time points.

Proposal for capturing patient experience through extended value frameworks of health technologies.

BACKGROUND: Inclusion of patient experience (PEx) in health technology assessment (HTA) has become increasingly important; however, no harmonized approach exists to help manufacturers or decision makers ensure PEx considerations are fair, consistent, and thorough within global HTA frameworks. OBJECTIVE: To develop a proposal for including PEx in the HTA frameworks of health technologies. METHODS: A systematic literature review (SLR) on existing value frameworks (VFs) was conducted to capture how PEx-related value judgment is currently considered. Guided by the results of the SLR, a research group including HTA experts and patient representatives used an iterative process to develop potential value domains to capture PEx, in accordance with international guidelines. Subsequently, a panel of international payer experts was used to challenge the proposed PEx domains and provide recommendations for implementation. RESULTS: The SLR found 61 VFs and multi-criteria decision analyses (MCDAs) that considered PEx; however, PEx-related value elements were often referred to superficially, without clear definitions. Five potential PEx domains, with proposed measures for each, were developed and refined using expert feedback: (1) responsiveness to patient's individual needs, (2) improved health literacy and empowerment, (3) patient and caregiver reported outcomes, (4) household's financial burden, and (5) improved access for vulnerable patient populations. A flexible approach for framework implementation was proposed. CONCLUSIONS: Proposed PEx domains could be implemented at multiple levels of healthcare decision making to formalize consideration of PEx in the assessment of value, either through the extension of existing VFs or to create new PEx-focused VFs and more holistic decision making tools. DISCLOSURES: This study was funded and sponsored by UCB Pharma. The funding agreement ensured the authors' independence in designing the study, interpreting the data, writing, and publishing the report. Charokopou, Mountain, and Szegvari are employed by UCB Pharma. Inotai, Jakab, and Kalo are employed by Syreon Research Institute, which received funding from UCB Pharma for this research. Brixner has received fees from AbbVie, Elevar, Millcreek Outcomes Group, Novartis, Sanofi, UCB Pharma, and Xcenda. Campbell has received grants and contracts from the PhRMA Foundation and the Institute for Clinical and Economic Review. During a sabbatical leave, Campbell collaborated with Syreon Research Institute on research projects that included funding from UCB Pharma. Hawkins has received consultancy fees from UCB Pharma. Kristensen has received speakers bureau fees from Pfizer, AbbVie, Amgen, UCB Pharma, Celgene, Bristol-Myers Squibb, MSD, Novartis, Eli Lilly, and Janssen Pharmaceuticals and consultancy fees from UCB Pharma.

Early health economic modelling for a treatment candidate in hidradenitis suppurativa.

AIMS: Hidradenitis suppurativa (HS) is a chronic skin condition causing inflammatory lesions, pain, scarring, and impaired mobility. Treatment options are limited and often lack success implying the need for additional/improved treatments. This research aimed to estimate the potential economic value of a treatment candidate, explore drivers of cost-effectiveness, and highlight economic evidence requirements for successful future value assessments. MATERIALS AND METHODS: An early cost-effectiveness model was developed to assess the cost-effectiveness (cost per quality-adjusted life year (QALY) gained) of a treatment candidate compared against the only authorized biologic, adalimumab, for moderate to severe HS, from a UK National Health Service and Personal Social Service perspective. A targeted literature review of clinical and economic references and previous health technology assessments (HTA) was performed for development and validation of the early economic model used to present sensitivity analyses accompanying the base case cost-effectiveness results. RESULTS AND LIMITATIONS: Base case results revealed the candidate not to be cost-effective compared to adalimumab when considering a formal cost-effectiveness threshold of £30,000 per QALY gained. Scenario- and threshold analyses highlighted that reducing dosing or drug price by half improved the cost-effectiveness of the candidate. Cost-effectiveness was highly sensitive to health states' utility values, treatment discontinuation, and resource utilization, in line with existing HTA evidence. The paucity of economic studies and uncertainties around the candidate presented methodological constraints that were addressed through sensitivity analyses. CONCLUSIONS: Key costs and health effects drivers were highlighted to contextualize under which circumstances a treatment candidate for moderate to severe HS would reach acceptable cost-effectiveness levels. This early economic evaluation suggested promising economic perspectives for treatment candidates in HS. Exploring novel ways to use clinical endpoints to simulate the patient pathway and clinically meaningful treatment achievements in future research will facilitate the value demonstration of candidates in disease areas with high unmet care need.

The importance of understanding patient and physician preferences for psoriasis treatment characteristics: a systematic review of discrete-choice experiments.

Introduction: Treatment adherence continues to be a major challenge in psoriasis. Patient preference studies, especially discrete-choice experiments, are gaining popularity to gather insights into patient reported treatment outcomes. This systematic literature review aimed to critically assess all discrete choice experiments exploring patients' and physicians' preferences for psoriasis treatment characteristics.Methods: PubMed and EMBASE databases were searched using keywords "psoriasis" and "preferences" to identify relevant literature. Discrete-choice experiments conducted in French or English from the year 2000 onwards, that focused on evaluating psoriasis treatment preferences in patients and/or physicians, were included. The relative importance of treatment attributes was assessed and studies were critically appraised using validated checklists.Results: Out of 987 articles identified, 25 articles fulfilled the inclusion criteria. Overall, patients and physicians prioritize efficacy-specific outcomes. Patients are shown to place greater importance to process attributes when compared to physicians, especially route and location of administration. Physicians focus primarily of efficacy attributes, however when the top two attributes are considered, safety outcomes increasingly become considered important. Of the studies, 60% conducted subgroup analysis, of which many reported associations between specific patient characteristics and preferences. Factors such as age, disease severity, and duration of condition significantly affected preferences for treatment attributes.Conclusions: This review provides insight into the types of attributes that patients and physicians value most, and therefore can help improve shared decision-making. The findings of this study also encourage regulatory agencies to continue integrating patient preferences in their decision-making.

Risk of major osteoporotic fracture after first, second and third fracture in Swedish women aged 50 years and older.

BACKGROUND: Osteoporosis affects approximately one in five European women and leads to fragility fractures, which result in poor health, social and economic consequences. Fragility fractures are a strong risk factor for subsequent major osteoporotic fracture (MOF), with risk of MOF being elevated in the 1-2 years following an earlier fracture, a concept described as "imminent risk". This study examines risk of subsequent MOF in patients with one, two or three prior fractures by age and type of fracture. METHODS: In this retrospective, observational cohort study, Swedish women aged ≥50 years with ≥1 any clinical fragility fracture between July 1, 2006 and December 31, 2012 were identified from Sweden's National Patient Register. Each patient was age- and sex-matched to three controls without history of fracture. Group 1 women included those with one fragility fracture during the study period; Group 2 included those with two fragility fractures; and Group 3 included those with three fragility fractures. "Index fracture" was defined as the first fracture during the study period for Group 1; the second for Group 2; and the third for Group 3. Patients in each cohort and matched controls were followed for up to 60 months or until subsequent MOF (hip, vertebra, forearm, humerus), death or end of data availability. RESULTS: 231,769 women with at least one fracture were included in the study and therefore constituted Group 1; of these, 39,524 constituted Group 2 and of those, 7656 constituted Group 3. At five years, cumulative incidence of subsequent MOF was higher in patients with a history of fracture as compared to controls (Group 1: 20.7% vs 12.3%; Group 2: 32.0% vs 15.3%). Three-year cumulative incidence for Group 3 was 12.1% (vs 10.7% for controls). After adjusting for baseline covariates, risk of subsequent MOF was highest within 0-24 months following an index fracture, then decreased but remained elevated as compared to controls. Having two prior fractures, vertebral fractures and younger age at time of index fracture were associated with greater relative risk. CONCLUSIONS: Women with a history of osteoporotic fracture are at increased risk of subsequent fracture, which is highest during the first 24 months following a fracture. Younger women and those with vertebral fractures are at greatest relative risk, suggesting that treatment should target these patients and be timely enough to impact the period of imminent risk.

Economic Value of Adjunctive Brivaracetam Treatment Strategy for Focal Onset Seizures in Finland.

INTRODUCTION: There is an unmet need for well-tolerated antiepileptic drugs (AEDs) that effectively control focal onset seizures. This study aimed to evaluate the economic value of new AEDs in the treatment of focal onset seizure, with or without secondary generalization, in Finnish adults and adolescents with epilepsy, comparing brivaracetam with perampanel as adjunctive AEDs. METHODS: Economic value was assessed using cost-utility analysis. Periods of AED initiation, titration, response assessment (seizure freedom, ≥ 50% reduction, no response), switching in no response or treatment-emergent adverse events (TEAEs), and death were simulated using a discrete-event simulation model. Responses and switching were simulated based on a comprehensive Bayesian network meta-analysis. The primary modeled outcome was the 3%/year discounted incremental cost-effectiveness ratio (ICER). Discounted quality-adjusted life-years (QALYs), payer costs (year 2017 Euro) per patient, and net monetary benefit (NMB) were secondary outcomes. Probabilistic and comprehensive deterministic sensitivity analyses were conducted. RESULTS: Brivaracetam was more efficacious and had fewer TEAEs than perampanel and other AEDs. Modeled average 5-year QALYs and costs were 3.671 and €28,297 for brivaracetam and 3.611 and €27,979 for perampanel, respectively. The resulting ICER for brivaracetam versus perampanel was only €5345/QALY gained in a deterministic base case scenario. Brivaracetam had a positive NMB and high probability of cost-effectiveness of €1190 and 71% or €1944 and 80% with the assumed willingness to pay of €25,358 or €38,036/QALY gained, respectively. The primary result was robust, with a positive NMB persistent in all sensitivity analysis scenarios. When switching from brivaracetam to perampanel was excluded from the modeling or switching from perampanel to brivaracetam was included, brivaracetam was cost-saving and more effective than perampanel (dominant). CONCLUSION: These simulated comparisons demonstrated that brivaracetam was more effective and potentially also more affordable than perampanel. Thus, brivaracetam is likely a cost-effective and net beneficial alternative to perampanel for treatment of focal onset seizures. Plain language summary available for this article.

Relative performance of brivaracetam as adjunctive treatment of focal seizures in adults: a network meta-analysis.

Objective: To estimate the relative efficacy, safety and tolerability of adjunctive brivaracetam and other antiepileptic drugs (AEDs) using a Bayesian network meta-analysis (NMA) approach. Methods: A systematic literature review (SLR) identified randomized controlled trials of AEDs treating focal (partial-onset) seizures for ≥8 weeks and assessed them for inclusion in the NMA. Bayesian random-effects NMA was performed for several outcomes. All interventions within the licensed dose range were included in the network of evidence. Results: The SLR identified 82 studies; 65 were included in the NMA. These studies had baseline mean age 33.1-38.0 years, mean duration of epilepsy 18.7-23.0 years and median seizure frequency/28 days 8.1-11.8. All AEDs had significantly higher odds than placebo of achieving ≥50% responder rates (odds ratios 1.83-3.58) and all AEDs had a trend of higher odds than placebo of achieving seizure freedom (odds ratios 1.36-5.73), most being statistically significant. Tolerability outcomes were comparable between AEDs; most AEDs had higher odds than placebo of treatment-emergent adverse events leading to discontinuation, serious AEs, nausea, fatigue, dizziness and somnolence. Conclusions: This NMA would appear to show relative equivalence in efficacy, safety and tolerability outcomes of the included AEDs. However, patient heterogeneity within trials and in clinical practice should be considered when interpreting these results. While NMAs are based on the best available evidence the authors suggest that, due to the inability of NMAs to capture unmeasured confounding factors and population heterogeneity, NMAs must not be the sole basis for comparative treatment recommendations.

Lacosamide as a first-line treatment option in focal epilepsy: a cost-utility analysis for the Greek healthcare system.

BACKGROUND AND AIMS: Epilepsy is the most common serious neurological disorder worldwide. Approximately 40% of patients with focal epileptic seizures remain uncontrolled with antiepileptic drug (AED) monotherapy or polytherapy. Lacosamide has been recently approved by the European Medicines Agency as monotherapy for the treatment of focal seizures. The aim of this study was to estimate the cost-effectiveness of lacosamide compared with zonisamide as first-line treatment of focal epilepsy in patients with epilepsy aged ≥ 16 years to inform clinical decision-making in Greece. METHODS: A discrete event simulation model was adapted to reflect treatment pathways and resource use within the Greek national healthcare system, as specified by clinical experts. The model captures time-varying events and patient characteristics. Clinical inputs were sourced from pivotal trials and a network meta-analysis comparing lacosamide with other AEDs. The model predicts disease progression and seizures, relevant and most common adverse events, withdrawal due to lack of efficacy or adverse events, and epilepsy-specific and all-cause mortality over a 2-year time horizon. Unit costs were retrieved from published Greek sources. Health outcomes were measured as quality-adjusted life years (QALYs); secondary outcome was the cost per seizure avoided. Robustness of the results was tested with univariate and probabilistic sensitivity analyses. RESULTS: The lacosamide treatment pathway was associated with higher costs (i.e. €1,064) and an additional 0.119 QALYs when compared with zonisamide, resulting in an incremental cost-effectiveness ratio of €8,938 per QALY gained. The sensitivity analyses demonstrated that the results are most sensitive to the efficacy and utility estimates. LIMITATIONS: There are a number of limitations which stem from the process of model adaptation and lack of local real-world evidence. CONCLUSIONS: Lacosamide is a cost-effective option at a willingness-to-pay threshold of €30,000 per QALY, representing a valuable monotherapy treatment option for patients with focal epileptic seizures in the Greek setting.

A discrete-choice experiment to elicit preferences of patients with epilepsy for self-management programs.

BACKGROUND: There is an increasing number of self-management programs developed for patients with epilepsy, with the goal of supporting treatment management and improving their quality of life. With the aim of increasing medication adherence and effectiveness of self-management programs, it is important to design programs that are engaging to, and align with the preferences of patients with epilepsy. This study aimed to evaluate and compare the preferences of patients with epilepsy for self-management programs in three European countries. This is the first cross-border evaluation of the preferences of patients with epilepsy in Europe for such programs. METHODS: Using a discrete-choice experiment, patients with epilepsy from Germany, France, and the Netherlands were surveyed, and chose repetitively between two hypothetical self-management programs. These differed in the following six characteristics: i) the thematic area which would be the main focus of the program, ii) the method of interaction, iii) the source of information or provider of the program, iv) the amount of time spent on the program per week, v) the cost, and vi) whether the program would start immediately, or if there would be a delay of 3weeks before its initiation. A Bayesian efficient design was used to construct 15 choice sets, and a mixed panel logit model was used to estimate patients' preferences. Subgroup analyses were conducted according to socioeconomic status, burden of disease, and previous activation in self-management. RESULTS: A total of 299 people with epilepsy were included in the study, with a mean age of 45.5years. Only 15% had previously made use of a self-management program, although 44.5% reported having previously heard of them. In all three countries, all attributes barring the content were significant at 10%. The cost attribute - i.e., an out-of-pocket expenditure for a program - was reported as the most important feature in each country and across subgroups (significant at 1%). This was followed by the length of program sessions per week, which ranged from 20 to 90min per week. Although there was some heterogeneity between countries and subgroups, the patients, overall, had a preference for a face-to-face meeting with a doctor. In the Netherlands, a preference for online programs and physician assistants was observed when compared with the other countries. Other attributes, including the information source - whether a program was led by a physician, another patient with epilepsy, or another combination - was also important to patients, who appear willing to trade preferences in order to gain their favored attribute level. However, 20% of the population chose consistently to not participate in any self-management program. CONCLUSION: Given the heterogeneity of the epilepsies, preferences, and dispreferences across subgroups, our study highlights that if full account is not taken of different segmentation strategies when designing a self-management program, a large proportion of the population may not be attracted to it.

Capsaicin 8% Patch Versus Oral Neuropathic Pain Medications for the Treatment of Painful Diabetic Peripheral Neuropathy: A Systematic Literature Review and Network Meta-analysis.

PURPOSE: A network meta-analysis (NMA) was performed, aiming to assess the relative efficacy and tolerability of the capsaicin 179-mg (8% weight for weight) cutaneous patch (capsaicin 8% patch) compared with oral, centrally acting agents (ie, pregabalin, gabapentin, duloxetine, amitriptyline) in patients with painful diabetic peripheral neuropathy (PDPN). METHODS: A systematic search of EMBASE/MEDLINE, Cochrane Library, and the National Health Service Centre for Reviews and Dissemination Database of Abstracts of Reviews of Effects was conducted to identify all randomized controlled trials. Data from eligible studies according to predefined inclusion and exclusion criteria were extracted, and analyses were based on aggregate-level data. Efficacy outcomes were the proportions of patients with ≥30% and ≥50% reductions in pain, and tolerability outcomes were somnolence, dizziness, nausea, diarrhea, constipation, headache, fatigue, insomnia, and rate of discontinuation due to adverse events (AEs). Data were analyzed by using a Bayesian NMA. Fixed and random effects models were estimated. Relative treatment effect was presented as odds ratios (ORs) with 95% CIs. Sources of heterogeneity were assessed. FINDINGS: The NMA included 25 randomized controlled trials. For ≥30% pain reduction, the capsaicin 8% patch was significantly more effective than placebo (OR, 2.28 [95% CI, 1.19-4.03]), exhibited a numerical advantage compared with pregabalin (OR, 1.83 [95% CI, 0.91-3.34]) and gabapentin (OR, 1.66 [95% CI, 0.74-3.23]), and had similar efficacy compared with duloxetine (OR, 0.99 [95% CI, 0.5-1.79]). The evidence available was not sufficient to assess the relative efficacy of amitriptyline. In the NMA for tolerability, the capsaicin 8% patch was only included for headache because the incidence was 0% for the other outcomes. Oral, centrally acting agents had a significantly elevated risk compared with placebo for somnolence (pregabalin, gabapentin, duloxetine, and amitriptyline), dizziness (pregabalin, gabapentin, duloxetine, and amitriptyline), nausea (duloxetine), diarrhea (duloxetine), fatigue (duloxetine), and discontinuation because of AEs (pregabalin, gabapentin, and duloxetine). Compared with pregabalin and gabapentin, duloxetine had a significantly lower risk of dizziness but a significantly higher risk of nausea. IMPLICATIONS: This NMA suggests that the efficacy observed with the capsaicin 8% patch is similar to that observed with oral agents (ie, pregabalin, duloxetine, gabapentin) in patients with PDPN. The oral agents were associated with a significantly elevated risk of somnolence, dizziness, fatigue, and discontinuation because of AEs compared with placebo. The capsaicin 8% patch was as effective as oral centrally acting agents in these patients with PDPN but offers systemic tolerability benefits.

Which factors enhance positive drug reimbursement recommendation in Scotland? A retrospective analysis 2006-2013.

OBJECTIVES: To identify the factors that influence the Scottish Medicines Consortium (SMC) in deciding whether to accept pharmaceutical technologies for use within the Scottish health care system. METHODS: A database of SMC submissions between 2006 and 2013 was created, containing a range of clinical, economic, and other factors extracted from published health technology assessment reports. A binomial outcome variable was used, defined as the decision to "accept for use" or "not recommend" a technology. Univariate and multivariate analyses were conducted to assess the impact by means of odds ratios (ORs) of the submitted evidence on the recommendation decision. RESULTS: Out of 463 applications, 265 were accepted for use (57%) and 198 (43%) were not recommended for use within National Health Service Scotland. Univariate analyses showed that 13 variables significantly affected the SMC decision. Of these 13 variables, 7 variables were shown to have a meaningful impact in the multivariate analysis. Four of these concerned the outcome of cost-effectiveness analyses; the fact that a submission was supported by a cost-minimization analysis was the strongest positive variable (OR = 10.30) and a submission showing a product not being cost-effective (i.e., incremental cost-effectiveness ratio above £30,000/quality-adjusted life-year gained) was the strongest negative predictor (OR = 0.47). The other variables concerned whether the submission was related to a product indicated for a nervous system disease (OR = 0.41), whether it was indicated for nonchronic use (OR = 1.66), and whether the submission was performed by a big company (OR = 2.83). CONCLUSIONS: This study demonstrated that the outcome of cost-effectiveness analyses is an important factor affecting the SMC's reimbursement recommendation decision.