Structural equation modeling for identifying the drivers of health-related quality of life improvement experienced by patients with migraine receiving eptinezumab.

BACKGROUND: As new migraine therapies emerge, it is crucial for measures to capture the complexities of health-related quality of life (HRQoL) improvement beyond improvements in monthly migraine day (MMD) reduction. Investigations into the correlations between MMD reduction, symptom management, and HRQoL are lacking, particularly those that focus on improvements in canonical symptoms and improvement in patient-identified most-bothersome symptoms (PI-MBS), in patients treated with eptinezumab. This exploratory analysis identified efficacy measures mediating the effect of eptinezumab on HRQoL improvements in patients with migraine. METHODS: Data from the DELIVER study of patients with 2-4 prior preventive migraine treatment failures (NCT04418765) were inputted to two structural equation models describing sources of HRQoL improvement via Migraine-Specific Quality-of-Life Questionnaire (MSQ) scores. A single latent variable was defined to represent HRQoL and describe the sources of HRQoL in DELIVER. One model included all migraine symptoms while the second model included the PI-MBS as the only migraine symptom. Mediating variables capturing different aspects of efficacy included MMDs, other canonical symptoms, and PI-MBS. RESULTS: In the first model, reductions in MMDs and other canonical symptoms accounted for 35% (standardized effect size [SES] - 0.11) and 25% (SES - 0.08) of HRQoL improvement, respectively, with 41% (SES - 0.13) of improvement comprising "direct treatment effect," i.e., unexplained by mediators. In the second model, substantial HRQoL improvement with eptinezumab (86%; SES - 0.26) is due to MMD reduction (17%; SES - 0.05) and change in PI-MBS (69%; SES - 0.21). CONCLUSIONS: Improvements in HRQoL experienced by patients treated with eptinezumab can be substantially explained by its effect on migraine frequency and PI-MBS. Therefore, in addition to MMD reduction, healthcare providers should discuss PI-MBS improvements, since this may impact HRQoL. Health technology policymakers should consider implications of these findings in economic evaluation, as they point to alternative measurement of quality-adjusted life years to capture fully treatment benefits in cost-utility analyses. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT04418765 ; EudraCT (Identifier: 2019-004497-25; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004497-25 ).

Persistence to anti-CGRP monoclonal antibodies and onabotulinumtoxinA among patients with migraine: a retrospective cohort study.

BACKGROUND: To date, real-world evidence on persistence to anti-calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies (mAbs) or onabotulinumtoxinA have excluded eptinezumab. This retrospective cohort study was performed to compare treatment persistency among patients with migraine on anti-CGRP mAbs (erenumab, fremanezumab, galcanezumab, or eptinezumab) or onabotulinumtoxinA. METHODS: This retrospective study used IQVIA PharmMetrics data. Adult patients with migraine treated with an anti-CGRP mAb or onabotulinumtoxinA who had 12 months of continuous insurance enrollment before starting treatment were included. A "most recent treatment episode" analysis was used in which the most recent episode was defined as the latest treatment period with the same drug (anti-CGRP mAb or onabotulinumtoxinA) without a ≥ 15-day gap in medication supply on/after June 25, 2020, to December 31, 2021. Patients were indexed at the start of their most recent episode. Patients were considered non-persistent and discontinued the therapy associated with their most recent episode if there was ≥ 15-day gap in medication supply. A Cox proportional-hazards model estimated the discontinuation hazard between treatments. The gap periods and cohort definition were varied in sensitivity analyses. RESULTS: The study included 66,576 patients (median age 46 years, 88.6% female). More eptinezumab-treated patients had chronic migraine (727/1074), ≥ 3 previous acute (323/1074) or preventive (333/1074) therapies, and more prior treatment episodes (3) than other treatment groups. Based on a 15-day treatment gap, patients on subcutaneous anti-CGRP mAbs had a 32% (95% CI: 1.19, 1.49; erenumab), 42% (95% CI: 1.27, 1.61; galcanezumab), and 58% (95% CI: 1.42, 1.80; fremanezumab) higher discontinuation hazard than those receiving eptinezumab, with this relationship attenuated, but still statistically significant based on 30-day and 60-day treatment gaps. There was no significant difference in the discontinuation hazard between eptinezumab and onabotulinumtoxinA. Based on a 15-day treatment gap among patients who newly initiated therapy, the discontinuation hazard of subcutaneous anti-CGRP mAbs remained significantly higher compared to eptinezumab and onabotulinumtoxinA. CONCLUSION: Patients treated with eptinezumab demonstrated persistency that was higher than subcutaneous anti-CGRP mAbs and similar to onabotulinumtoxinA.

Comparison of indirect treatment methods in migraine prevention to address differences in mode of administration.

Aim: Indirect treatment comparisons (ITCs) are anchored on a placebo comparator, and the placebo response may vary according to drug administration route. Migraine preventive treatment studies were used to evaluate ITCs and determine whether mode of administration influences placebo response and the overall study findings. Materials & methods: Change from baseline in monthly migraine days produced by monoclonal antibody treatments (subcutaneous, intravenous) was compared using fixed-effects Bayesian network meta-analysis (NMA), network meta-regression (NMR), and unanchored simulated treatment comparison (STC). Results: NMA and NMR provide mixed, rarely differentiated results between treatments, whereas unanchored STC strongly favors eptinezumab over other preventive treatments. Conclusion: Further investigations are needed to determine which ITC best reflects the impact of mode of administration on placebo.

Estimating treatment effects on health utility scores for patients living with migraine: a post hoc analysis of the DELIVER trial.

BACKGROUND: This post hoc analysis aimed to estimate eptinezumab's therapeutic effect on health utilities and determined to which extent monthly migraine days (MMDs) explain changes in health utilities. RESEARCH DESIGN/METHODS: DELIVER, a randomized, double-blind, placebo-controlled phase 3b trial (NCT04418765), investigated eptinezumab efficacy and safety in patients with 2-4 prior migraine treatment failures. Regression analysis explored the relationship between utility scores and MMDs, with eptinezumab treatment as a covariate along with MMDs to identify any MMD-independent effect on utilities. Path analysis quantified eptinezumab's impact as mediated through MMD reduction. RESULTS: The base case model showed that each reduction in MMD was associated with a mean utility score increase (0.0189; 95% CI: 0.0180, 0.0198; P < 0.001). Mean utility score was generally higher for eptinezumab versus placebo, justifying addition of treatment effect to the base case model. Patients administered eptinezumab had on average 0.0562 (95% CI: 0.0382, 0.0742; P < 0.001) higher utility versus placebo when controlling for number of MMDs. From path analysis, MMD reduction resulting from eptinezumab treatment accounted for 53% additional utility gain observed in patients. CONCLUSIONS: Changes in MMDs alone inadequately captured migraine's impact on patient utility, as there was also a positive eptinezumab-driven, treatment-specific impact on utility score. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04418765).

NASHmap: clinical utility of a machine learning model to identify patients at risk of NASH in real-world settings.

The NASHmap model is a non-invasive tool using 14 variables (features) collected in standard clinical practice to classify patients as probable nonalcoholic steatohepatitis (NASH) or non-NASH, and here we have explored its performance and prediction accuracy. The National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) NAFLD Adult Database and the Optum Electronic Health Record (EHR) were used for patient data. Model performance metrics were calculated from correct and incorrect classifications for 281 NIDDK (biopsy-confirmed NASH and non-NASH, with and without stratification by type 2 diabetes status) and 1,016 Optum (biopsy-confirmed NASH) patients. NASHmap sensitivity in NIDDK is 81%, with a slightly higher sensitivity in T2DM patients (86%) than non-T2DM patients (77%). NIDDK patients misclassified by NASHmap had mean feature values distinct from correctly predicted patients, particularly for aspartate transaminase (AST; 75.88 U/L true positive vs 34.94 U/L false negative), and alanine transaminase (ALT; 104.09 U/L vs 47.99 U/L). Sensitivity was slightly lower in Optum at 72%. In an undiagnosed Optum cohort at risk for NASH (n = 2.9 M), NASHmap predicted 31% of patients as NASH. This predicted NASH group had AST and ALT mean levels above normal range of 0-35 U/L, and 87% had HbA1C levels > 5.7%. Overall, NASHmap demonstrates good sensitivity in predicting NASH status in both datasets, and NASH patients misclassified as non-NASH by NASHmap have clinical profiles closer to non-NASH patients.

Mendelian randomization: estimation of inpatient hospital costs attributable to obesity.

BACKGROUND: Mendelian Randomization is a type of instrumental variable (IV) analysis that uses inherited genetic variants as instruments to estimate causal effects attributable to genetic factors. This study aims to estimate the impact of obesity on annual inpatient healthcare costs in the UK using linked data from the UK Biobank and Hospital Episode Statistics (HES). METHODS: UK Biobank data for 482,127 subjects was linked with HES inpatient admission records, and costs were assigned to episodes of care. A two-stage least squares (TSLS) IV model and a TSLS two-part cost model were compared to a naïve regression of inpatient healthcare costs on body mass index (BMI). RESULTS: The naïve analysis of annual cost on continuous BMI predicted an annual cost of £21.61 [95% CI £20.33 - £22.89] greater cost per unit increase in BMI. The TSLS IV model predicted an annual cost of £14.36 [95% CI £0.31 - £28.42] greater cost per unit increase in BMI. Modelled with a binary obesity variable, the naïve analysis predicted that obese subjects incurred £205.53 [95% CI £191.45 - £219.60] greater costs than non-obese subjects. The TSLS model predicted a cost £201.58 [95% CI £4.32 - £398.84] greater for obese subjects compared to non-obese subjects. CONCLUSIONS: The IV models provide evidence for a causal relationship between obesity and higher inpatient healthcare costs. Compared to the naïve models, the binary IV model found a slightly smaller marginal effect of obesity, and the continuous IV model found a slightly smaller marginal effect of a single unit increase in BMI.

Development of a novel machine learning model to predict presence of nonalcoholic steatohepatitis.

OBJECTIVE: To develop a computer model to predict patients with nonalcoholic steatohepatitis (NASH) using machine learning (ML). MATERIALS AND METHODS: This retrospective study utilized two databases: a) the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) nonalcoholic fatty liver disease (NAFLD) adult database (2004-2009), and b) the Optum® de-identified Electronic Health Record dataset (2007-2018), a real-world dataset representative of common electronic health records in the United States. We developed an ML model to predict NASH, using confirmed NASH and non-NASH based on liver histology results in the NIDDK dataset to train the model. RESULTS: Models were trained and tested on NIDDK NAFLD data (704 patients) and the best-performing models evaluated on Optum data (~3,000,000 patients). An eXtreme Gradient Boosting model (XGBoost) consisting of 14 features exhibited high performance as measured by area under the curve (0.82), sensitivity (81%), and precision (81%) in predicting NASH. Slightly reduced performance was observed with an abbreviated feature set of 5 variables (0.79, 80%, 80%, respectively). The full model demonstrated good performance (AUC 0.76) to predict NASH in Optum data. DISCUSSION: The proposed model, named NASHmap, is the first ML model developed with confirmed NASH and non-NASH cases as determined through liver biopsy and validated on a large, real-world patient dataset. Both the 14 and 5-feature versions exhibit high performance. CONCLUSION: The NASHmap model is a convenient and high performing tool that could be used to identify patients likely to have NASH in clinical settings, allowing better patient management and optimal allocation of clinical resources.

Mapping the Kansas City Cardiomyopathy Questionnaire (KCCQ) Onto EQ-5D-3L in Heart Failure Patients: Results for the Japanese and UK Value Sets.

Background. Health technology assessment bodies in several countries, including Japan and the United Kingdom, recommend mapping techniques to obtain utility scores in clinical trials that do not have a preference-based measure of health. This study sought to develop mapping algorithms to predict EQ-5D-3L scores from the Kansas City Cardiomyopathy Questionnaire (KCCQ) in patients with heart failure (HF). Methods. Data from the randomized, double-blind PARADIGM-HF trial were analyzed, and EQ-5D-3L scores were calculated using the Japanese and UK value sets. Several different model specifications were explored to best fit EQ-5D data collected at baseline with KCCQ scores, including ordinary least square regression, two-part, Tobit, and three-part models. Generalized estimating equations models were also fitted to analyze longitudinal EQ-5D data. To validate model predictions, the data set was split into a derivation (n = 4,465) from which the models were developed and a separate sample (n = 1,892) for validation. Results. There were only small differences between the different model classes tested. Model performance and predictive power was better for the item-level models than for the models including KCCQ domain scores. R 2 statistics for the item-level models ranged from 0.45 to 0.52. Mean absolute error in the validation sample was 0.10 for the models using the Japanese value set and 0.114 for the UK models. All models showed some underprediction of utility above 0.75 and overprediction of utility below 0.5, but performed well for population-level estimates. Conclusions. Using data from a large clinical trial in HF, we found that EQ-5D-3L scores can be estimated from responses to the KCCQ and can facilitate cost-utility analysis from existing HF trials where only the KCCQ was administered. Future validation in other HF populations is warranted.

Is the St. George's Respiratory Questionnaire an Appropriate Measure of Symptom Severity and Activity Limitations for Clinical Trials in COPD? Analysis of Pooled Data from Five Randomized Clinical Trials.

Purpose: The objective of this study was to examine the psychometric properties of the St. George's Respiratory Questionnaire (SGRQ) in patients with chronic obstructive pulmonary disease (COPD) using Rasch measurement theory (RMT) analyses. Materials and Methods: RMT analysis was conducted on the baseline SGRQ data from five multi-national, Phase III randomized trials investigating a fixed-dose combination of a long-acting ß2-agonist and a long-acting muscarinic antagonist in COPD patients. Analysis was performed for the SGRQ "Symptoms" and "Activity" domains. An exploratory analysis was also conducted using the different specific symptoms as defined in the reconceptualization of the SGRQ "Symptoms" domain. Differential item functioning (DIF) analysis was performed for geographical regions on the "Activity" domain, in order to explore cross-cultural validity of the SGRQ. Results: Overall, the SGRQ "Activity" domain showed good measurement property, but two items ("Sitting or lying still making feel breathless" and "Playing sports or game making feel breathless") showed very high fit residuals. The SGRQ "Symptoms" domain demonstrated good targeting; however, two items showed disordered thresholds ("Coughed" and "Brought up phlegm"). In an exploratory RMT analysis, measures for "Cough and Sputum", "Breathing difficulties" or "Wheezing attacks" showed unsatisfactory measurement properties with poor reliability (person separation index = 0.35, 0.66 and 0.16, respectively) and targeting issues. The examination of cross-cultural performances of the SGRQ "Activity" items showed a great variability in the responses to these items in different global regions. Conclusion: Our results indicated that SGRQ may not be an appropriate instrument to measure symptom severity or activity limitations in patients with COPD. Hence, there is a need to develop other relevant PRO instruments that can be used in conjunction with SGRQ to provide a holistic assessment of the health status of COPD patients in clinical research.

Patient-reported outcomes are important elements of psoriasis treatment decision making: A discrete choice experiment survey of dermatologists in the United States.

BACKGROUND: Psoriasis Area and Severity Index (PASI) response rates have been the benchmark for evaluating treatment efficacy in trials involving moderate-to-severe psoriasis. OBJECTIVE: To understand how dermatologists assess biologics and which trade-off rules they apply when planning psoriasis treatment. METHODS: Two online surveys of 130 and 129 US dermatologists (surveys 1 and 2, respectively) were conducted with use of direct and indirect elicitation via discrete choice experiment. Respondents were asked to choose hypothetical biologics on the basis of 6 attributes (a ≥75% reduction from baseline in PASI score or a ≥90% reduction from baseline in PASI score, infection risk, dosing frequency, and 3 patient-reported outcomes [PROs] [relief of depression, relief of itching, and impact on usual activities]). RESULTS: Most dermatologists (74% in survey 1 and 76% in survey 2) reported using both PASI and PROs when selecting a biologic. PASI response rate was the most important attribute (35%-38% of overall decision weight), whereas combined PRO attributes had similar importance (36% of decision weight). Infection risk and dosing frequency influenced the decision to a lesser extent. LIMITATIONS: Potential bias in considering 3 PROs versus 1 PASI rate and 1 safety attribute. CONCLUSION: PASI is most important for dermatologists selecting biologics, but PROs are also considered, especially when PASI response rate is similar between treatments. PRO data should be collected in trials involving moderate-to-severe psoriasis.

The Commercial Market For Priority Review Vouchers.

In 2007 the US Congress created the priority review voucher program to encourage the development of drugs for neglected diseases. Under the program, the developer of a drug that treats a neglected disease receives both a faster review of the drug by the Food and Drug Administration and a voucher for a faster review of a different drug. The developer can sell the voucher. We estimated the commercial value of the voucher using US sales of new treatments approved in the period 2007-09. A third of the commercial value of a voucher comes from capturing market share from competitors, nearly half from the value of earlier sales because of the expedited review, and less than a quarter from lengthening the time between approval and the launch of a generic competitor. We estimate that if only one priority review voucher is available in a year, it will be worth more than $200 million, but if four vouchers are available, the value could fall below $100 million. Congress should be cautious about expanding the voucher program, because increasing the number of vouchers sharply decreases the expected price. Lower voucher prices could undermine the incentive to develop new medicines for neglected diseases.

Using Patient-Level Data to Develop Meaningful Cross-Trial Comparisons of Visual Impairment in Individuals with Diabetic Macular Edema.

INTRODUCTION: The aim of this study was to assess the impact of baseline characteristics on visual outcome of patients with diabetic macular edema and compare the results of clinical trials with different patient populations. METHODS: A model was created with patient-level data from the RESPOND/RESTORE trials to estimate the impact of baseline characteristics on increases in best-corrected visual acuity (BCVA) with anti-vascular endothelial growth factor therapies, measured by letters gained on the Early Treatment Diabetic Retinopathy Study scale from baseline to month 12. Mean BCVA gains with ranibizumab 0.5 mg pro re nata or laser photocoagulation monotherapy were predicted, assuming baseline characteristics equivalent to those in the VIVID-DME/VISTA-DME trials. These results were compared with the gain with aflibercept 2.0 mg every 8 weeks in VIVID-DME/VISTA-DME. Sensitivity analyses assessed outcome robustness. RESULTS: Baseline BCVA and central retinal thickness differed significantly between trials. In unadjusted data, patients in RESPOND/RESTORE receiving ranibizumab gained an additional 6.6 letters [95% confidence interval (CI): 4.5-8.7] compared with patients receiving laser monotherapy. After adjusting data to assume baseline characteristics equivalent to VIVID-DME/VISTA-DME, patients receiving ranibizumab were predicted to gain an additional 9.9 letters (95% CI: 7.3-12.4) compared with those receiving laser monotherapy. These results were similar (0.1-letter difference in favor of aflibercept; 95% CI: -2.9 to 3.2; P = 0.94) to the gain in BCVA in patients receiving aflibercept in VIVID-DME/VISTA-DME compared with those receiving laser monotherapy (10.0 letters, 95% CI: 8.3-11.7). CONCLUSION: After adjusting for baseline characteristics, the difference in letters gained between patients receiving ranibizumab versus aflibercept was non-significant across trials, highlighting the importance of adjusting for baseline characteristics in future comparisons. FUNDING: Novartis Pharma AG.

Review and comparison of methodologies for indirect comparison of clinical trial results: an illustration with ranibizumab and aflibercept.

AIM: To review and compare methods for indirect comparison of aflibercept and ranibizumab in patients with diabetic macular edema. METHODS: Post-stratification, inverse probability weighting based on simulated data, weight optimization, and regression model techniques were used to compare pooled individual patient-level data from the RESTORE and RESPOND (ranibizumab 0.5 mg as needed after 3 initial monthly doses) studies with summary-level data from the VIVID and VISTA (aflibercept 2.0 mg every 8 weeks after 5 initial monthly doses, 2q8) studies. The impact of adjusting for up to two baseline characteristics was assessed. RESULTS: All methods provided similar results. After adjustment for baseline best-corrected visual acuity and central retinal thickness, no statistically significant difference in average gain in baseline best-corrected visual acuity from baseline at month 12 was found between ranibizumab 0.5 mg and aflibercept 2q8. CONCLUSIONS: Weight optimization and regression methods are useful options to adjust for more than one baseline characteristic.

Comparative efficacy and safety of approved treatments for macular oedema secondary to branch retinal vein occlusion: a network meta-analysis.

OBJECTIVE: To compare the efficacy and safety of approved treatments for macular oedema secondary to branch retinal vein occlusion (BRVO). DESIGN: Randomised controlled trials (RCTs) evaluating the efficacy and safety of approved treatments for macular oedema secondary to BRVO were identified from an updated systematic review. SETTING: A Bayesian network meta-analysis of RCTs of treatments for macular oedema secondary to BRVO. INTERVENTIONS: Ranibizumab 0.5 mg pro re nata, aflibercept 2 mg monthly (2q4), dexamethasone 0.7 mg implant, laser photocoagulation, ranibizumab+laser, or sham intervention. Bevacizumab and triamcinolone were excluded. OUTCOME MEASURES: Efficacy outcomes were mean change in best corrected visual acuity (Early Treatment Diabetic Retinopathy Study scale) and the percentage of patients gaining ≥ 15 letters. Safety outcome was the percentage of patients with increased intraocular pressure (IOP)/ocular hypertension (OH). RESULTS: 8 RCTs were identified for inclusion with 1743 adult patients. The probability of being the most efficacious treatment at month 6 or 12 based on letters gained was 54% for ranibizumab monotherapy, 30% for aflibercept, 16% for ranibizumab plus laser (adjunctive or prompt), and 0% for dexamethasone implant, laser or sham. The probability of being the most efficacious treatment for patients gaining ≥ 15 letters was 39% for aflibercept, 35% for ranibizumab monotherapy, 24% for ranibizumab plus laser, 2% for dexamethasone implant, and less than 1% for laser or sham. There was no statistical difference between ranibizumab monotherapy and aflibercept for letters gained (+1.4 letters for ranibizumab vs aflibercept with 95% credible interval (CrI) of -5.2 to +8.5 letters) or the OR for gaining ≥ 15 letters: 1.06 (95% CrI 0.16 to 8.94)). Dexamethasone implant was associated with significantly higher IOP/OH than antivascular endothelial growth factor agents (OR 13.1 (95% CrI 1.7 to 116.9)). CONCLUSIONS: There was no statistically significant difference between ranibizumab and aflibercept.

Cost-effectiveness of ranibizumab versus aflibercept in the treatment of visual impairment due to diabetic macular edema: a UK healthcare perspective.

BACKGROUND: Ranibizumab and aflibercept are alternative anti-vascular endothelial growth factor agents approved for the treatment of visual impairment (VI) due to diabetic macular edema (DME). OBJECTIVE: To estimate, from a UK healthcare perspective, the cost-effectiveness of ranibizumab 0.5 mg pro re nata (PRN) and ranibizumab 0.5 mg treat and extend (T&E) compared with aflibercept 2 mg every 8 weeks after five initial monthly doses (2q8) in the treatment of VI due to DME. METHODS: A Markov model previously reviewed by the National Institute for Health and Care Excellence was used to simulate the long-term outcomes and costs of treating DME. Health states were defined by increments of ten letters in best-corrected visual acuity (BCVA), with a 3-month cycle length. Patients could gain (or lose) a maximum of two health states between cycles. A 3-year treatment time frame and a lifetime horizon were used. Future costs and health outcomes were discounted at 3.5% per annum. Patient baseline characteristics and the efficacy of ranibizumab PRN were derived using data from the RESTORE study. The relative efficacies of ranibizumab PRN, ranibizumab T&E, and aflibercept were assessed with a network meta-analysis. Different utilities were assigned based on BCVA and whether the treated eye was the better- or the worse-seeing eye. Sensitivity analyses tested the robustness of the model. RESULTS: Lifetime costs per patient of treating DME were £20,019 for ranibizumab PRN, £22,930 for ranibizumab T&E, and £25,859 for aflibercept 2q8. Ranibizumab was dominant over aflibercept, with an incremental gain of 0.05 quality-adjusted life-years (QALYs) and cost savings of £5,841 (PRN) and £2,930 (T&E) compared with aflibercept. Ranibizumab PRN and ranibizumab T&E had 79% and 67% probability, respectively, of being cost-effective relative to aflibercept at a willingness-to-pay threshold of £20,000/QALY. When assuming the higher end of PRN injection frequency (15.9 over 3 years), the cost savings associated with ranibizumab were £3,969. CONCLUSION: From a UK healthcare perspective, ranibizumab provides greater health gains with lower overall costs than aflibercept in patients with VI due to DME.

Potential impact of vaccination against Neisseria meningitidis on Neisseria gonorrhoeae in the United States: results from a decision-analysis model.

Components in 4CMenB vaccine against Neisseria meningitidis serogroup B have shown to potentially cross-react with Neisseria gonorrhoeae. We modeled the theoretical impact of a US 4CMenB vaccination program on gonorrhea outcomes. A decision-analysis model was populated using published healthcare utilization and cost data. A two-dose adolescent vaccination campaign was assumed, with protective immunity starting at age 15 years and a base-case efficacy against gonorrhea of 20%. The 20%-efficacy level is an assumption since no clinical data have yet quantified the efficacy of 4CMenB against Neisseria gonorrhoea. Key outcome measures were reductions in gonorrhea and HIV infections, reduction in quality-adjusted life-years (QALYs) lost, and the economically justifiable price assuming a willingness-to-pay threshold of $75,000 per QALY gained. Adolescent vaccination with 4CMenB would prevent 83,167 (95% credible interval [CrI], 44,600-134,600) gonorrhea infections and decrease the number of HIV infections by 55 (95% CrI, 2-129) per vaccinated birth cohort in the USA. Excluding vaccination costs, direct medical costs for gonorrhea would reduce by $28.7 million (95% CrI, $6.8-$70.0 million), and income and productivity losses would reduce by $40.0 million (95% CrI, $8.2-$91.7 million). Approximately 83% of the reduction in lost productivity is generated by avoiding HIV infections. At a cost of $75,000 per QALY gained, and incremental to the vaccine's effect on meningococcal disease, a price of $26.10 (95% CrI, $9.10-$57.20) per dose, incremental to the price of the meningococcal vaccine, would be justified from the societal perspective. At this price, the net cost per infection averted would be $1,677 (95% CrI, $404-$2,564). Even if the cross-immunity of 4CMenB vaccine and gonorrhea is only 20%, the reduction in gonorrhea infections and associated costs would be substantial.

How does drug coverage vary by insurance type? Analysis of drug formularies in the United States.

OBJECTIVES: To quantify how access to on-patent drugs by tier placement varies by insurance type and therapeutic area. STUDY DESIGN: Retrospective analysis of insurance plan drug coverage data. METHODS: Drug coverage information was collected from the Fingertip Formulary database in May 2011 for 3 drug classes (statins, angiotensin II receptor blockers, and protein-tyrosine kinase inhibitors) across 3 therapeutic areas with varying levels of generic drug availability. A generalized linear model was used to estimate the percentage of available on-patent drugs covered in the formulary tiers with lowest copay requirements (tiers 1 and 2) in different types of healthcare insurance plans in the United States. RESULTS: There were substantial differences between insurance types in the number of on-patent drugs reimbursed in tiers 1 and 2 (ie, with a low copay). Compared with commercial plans, there were more on-patent drugs reimbursed with a low copay in employer plans, union plans, and with pharmacy benefit management companies, and substantially fewer on-patent drugs with a low copay in Medicare plans (Medicare Advantage, special needs, prescription drug plans) and discount prescription programs. These results were expected, as union plans are known for their generosity and Medicare plans rely heavily on cost containment (eg, cost sharing). For commercial Medicaid and municipal plans, the findings were dependent on the therapeutic class, or were inconclusive. The number of competitors a plan faces did not consistently affect the coverage of on-patent drugs. CONCLUSIONS: The degree of coverage of on-patent drugs in the lowest copay tiers varies dramatically between insurance types, especially for expensive protein-tyrosine kinase inhibitors.

Drug versus vaccine investment: a modelled comparison of economic incentives.

BACKGROUND: Investment by manufacturers in research and development of vaccines is relatively low compared with that of pharmaceuticals. If current evaluation technologies favour drugs over vaccines, then the vaccines market becomes relatively less attractive to manufacturers. METHODS: We developed a mathematical model simulating the decision-making process of regulators and payers, in order to understand manufacturers' economic incentives to invest in vaccines rather than curative treatments. We analysed the objectives and strategies of manufacturers and payers when considering investment in technologies to combat a disease that affects children, and the interactions between them. RESULTS: The model confirmed that, for rare diseases, the economically justifiable prices of vaccines could be substantially lower than drug prices, and that, for diseases spread across multiple cohorts, the revenues derived from vaccinating one cohort per year (routine vaccination) could be substantially lower than those generated by treating sick individuals. CONCLUSIONS: Manufacturers may see higher incentives to invest in curative treatments rather than in routine vaccines. To encourage investment in vaccines, health authorities could potentially revise their incentive schemes by: (1) committing to vaccinate all susceptible cohorts in the first year (catch-up campaign); (2) choosing a long-term horizon for health technology evaluation; (3) committing higher budgets for vaccines than for treatments; and (4) taking into account all intangible values derived from vaccines.

Respiratory syncytial virus immunization program for the United States: impact of performance determinants of a theoretical vaccine.

OBJECTIVES: To inform strategic decisions on respiratory syncytial virus (RSV) vaccine development and identify critical endpoints likely to drive the vaccine's medical and economic impact. DESIGN: A decision-analysis model populated using healthcare utilization data and costs from the literature; vaccine efficacy and duration based on assumptions. SETTING: Vaccination in the physician office setting in the USA. PARTICIPANTS: A hypothetical cohort of newborn infants. INTERVENTION: Vaccination of children at low and high risk of respiratory sequelae with a theoretical RSV vaccine vs palivizumab prophylaxis for children at high risk. OUTCOME MEASURES: Medical and economic value of RSV vaccination, including cost per quality adjusted life-year (QALY) gained. RESULTS: Using base-case assumptions (efficacy 50% at birth; half-life 12 months), RSV vaccination would prevent 23,069 hospitalizations and 66 deaths per vaccinated birth cohort in the USA. Excluding vaccination costs, direct medical costs for RSV would reduce by $236 million, and income and productivity losses by $134 million. Assuming a vaccine cost per course similar to Rotarix® in the USA ($232 including administration fees), the cost per QALY gained would be $93,401 (95% CI: $65,815-$126,060) from the healthcare system perspective and $65,115 (95% CI: $41,003-$93,679) from the societal perspective. The net cost (healthcare system perspective) per life-year saved would be $216,120 (95% CI: $161,184-$263,981); the cost per hospitalization averted would be $19,172 (95% CI: $14,679-$22,093). Aside from efficacy, the vaccine's impact is sensitive to the start of protective immunity and the duration of protection. CONCLUSIONS: Development of an RSV vaccine would substantially reduce inpatient hospitalizations and outpatient visits. It would also have an impact on infant mortality. To demonstrate the full medical and economic value of the vaccine, appropriate endpoints or endpoint surrogates for hospitalization, mortality, and total case reductions should be collected during vaccine development.