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Introduction: Most European infant national immunization programs (NIPs) recommend pneumococcal conjugate vaccines (PCVs), which currently cover 10-15 serotypes administered in a three-dose schedule (two primary  plus one booster). Recently, a PCV covering 20 serotypes that is administered in a four-dose schedule (three primary plus one booster) was licensed., Methods: An online survey was administered to collect data from health care providers (HCPs) and caregivers of children aged 0-5 (including expectant mothers) in four European countries (Germany, France, Spain, and Greece). All caregiver respondents had a shared or full responsibility to make health decisions for their child. Data on opinions, perceptions, and openness to a change in childhood vaccination dosing schedules were collected, along with demographic information for HCPs as well as caregivers., Results: A total of 601 HCPs and 1954 caregivers were recruited across the four countries. Nearly all HCPs (93%) agreed that broader serotype coverage against pneumococcal disease for children is a significant unmet need, and 92% had a "sense of urgency" to vaccinate children. Both HCPs and caregivers were supportive of an additional PCV dose and doctor visit, assuming it provided at least 20% more serotype coverage than what is currently available. Caregivers strongly agreed on the importance of full vaccination for pneumococcal disease, even if an extra dose and visit to the doctor was required., Conclusions: HCPs and caregivers were virtually unanimous in their support for a PCV with broader serotype coverage and showed a subsequent willingness to include an extra infant dose/visit. These results can help guide broader discussions regarding public health policy and vaccine administration in the context of important efforts to reduce the global disease burden associated with pneumococcal disease., (© 2024. The Author(s).)

Introduction: A 20-valent pneumococcal conjugate vaccine (PCV20) was recently recommended for use among US children. We evaluated the cost-effectiveness of PCV20 among children aged 6 years with chronic medical conditions (CMC+) and children aged 6 years with immunocompromising conditions (IC) versus one and two doses of 23-valent pneumococcal polysaccharide vaccine (PPSV23), respectively., Methods: A probabilistic model was employed to depict 10-year risk of clinical outcomes and economic costs of pneumococcal disease, reduction in life years from premature death, and expected impact of vaccination among one cohort of children with CMC+ and IC aged 6 years. Vaccine uptake was assumed to be 20% for both PCV20 and PPSV23. Cost per quality-adjusted life year (QALY) gained was evaluated from the US societal and healthcare system perspectives; deterministic and probabilistic sensitivity analyses (DSA/PSA) were also conducted., Results: Among the 226,817 children with CMC+ aged 6 years in the US, use of PCV20 (in lieu of PPSV23) was projected to reduce the number cases of pneumococcal disease by 5203 cases, medical costs by US$8.7 million, and nonmedical costs by US$6.2 million. PCV20 was the dominant strategy versus PPSV23 from both the healthcare and societal perspectives. In the PSA, 99.9% of the 1000 simulations yielded a finding of dominance for PCV20. Findings in analyses of children with IC aged 6 years in the USA were comparable (i.e., PCV20 was the dominant vaccination strategy). Scenario analyses showed that increasing PCV20 uptake to 100% could potentially prevent > 22,000 additional cases of pneumococcal disease and further reduce medical and nonmedical costs by US$70.0 million among children with CMC+ and IC., Conclusions: Use of PCV20 among young children with CMC+ and IC in the USA would reduce the clinical burden of pneumococcal disease and yield overall cost savings from both the US healthcare system and societal perspectives. Higher PCV20 uptake could further reduce the number of pneumococcal disease cases in this population., (© 2024. Pfizer Inc. and Policy Analysis Inc.)

Background: As of June 2023, two pneumococcal conjugate vaccines, 20- (PCV20) and 15- (PCV15) valent formulations, are recommended for US infants under a 3 + 1 schedule. This study evaluated the health and economic impact of vaccinating US infants with a new expanded valency PCV20 formulation., Methods: A population-based, multi cohort, decision-analytic Markov model was developed to estimate the public health impact and cost-effectiveness of PCV20 from both societal and healthcare system perspectives over 10 years. Epidemiological data were based on published studies and unpublished Active Bacterial Core Surveillance System (ABCs) data. Vaccine effectiveness was based on PCV13 effectiveness and PCV7 efficacy studies. Indirect impact was based on observational studies. Costs and disutilities were based on published data. PCV20 was compared to both PCV13 and PCV15 in separate scenarios., Results: Replacing PCV13 with PCV20 in infants has the potential to avert over 55,000 invasive pneumococcal disease (IPD) cases, 2.5 million pneumonia cases, 5.4 million otitis media (OM) cases, and 19,000 deaths across all ages over a 10-year time horizon, corresponding to net gains of 515,000 life years and 271,000 QALYs. Acquisition costs of PCV20 were offset by monetary savings from averted cases resulting in net savings of $20.6 billion. The same trend was observed when comparing PCV20 versus PCV15, with a net gain of 146,000 QALYs and $9.9 billion in net savings. A large proportion of the avoided costs and cases were attributable to indirect effects in unvaccinated adults and elderly. From a health-care perspective, PCV20 was also the dominant strategy compared to both PCV13 and PCV15., Conclusions: Infant vaccination with PCV20 is estimated to further reduce pneumococcal disease and associated healthcare system and societal costs compared to both PCV13 and PCV15., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The research described herein was supported by Pfizer Inc. Mark Rozenbaum, Liping Huang, Johnna Perdrizet, Alejandro Cane, Adriano Arguedas, Kyla Hayford, Maria Tort, Vincenza Snow, Erica Chilson, and Ray Farkouh are employed by Pfizer Inc. Ruth Chapman and Des Dillon-Murphy are employed by Evidera, which received financial support from Pfizer Inc. for this study. Medical writing support was provided by Derek Weycker, Ahuva Averin, Mary Cecil, and Dhwani Hariharan at Policy Analysis Inc. and was funded by Pfizer., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim: The US Food and Drug Administration approved the 20-valent pneumococcal conjugate vaccine (PCV20) to prevent pneumococcal disease. In the context of routine PCV20 vaccination, we evaluated the cost-effectiveness and public health and economic impact of a PCV20 catch-up program and estimated the number of antibiotic prescriptions and antibiotic-resistant infections averted., Materials and Methods: A population-based, multi-cohort, decision-analytic Markov model was developed using parameters consistent with previous PCV20 cost-effectiveness analyses. In the intervention arm, children aged 14-59 months who previously completed PCV13 vaccination received a supplemental dose of PCV20. In the comparator arm, no catch-up PCV20 dose was given. The direct and indirect benefits of vaccination were captured over a 10-year time horizon., Results: A PCV20 catch-up program would prevent 5,469 invasive pneumococcal disease cases, 50,286 hospitalized pneumonia cases, 218,240 outpatient pneumonia cases, 582,302 otitis media cases, and 1,800 deaths, representing a net gain of 30,014 life years and 55,583 quality-adjusted life years. Furthermore, 720,938 antibiotic prescriptions and 256,889 antibiotic-resistant infections would be averted. A catch-up program would result in cost savings of $800 million. These results were robust to sensitivity and scenario analyses., Conclusions: A PCV20 catch-up program could prevent pneumococcal infections, antibiotic prescriptions, and antimicrobial-resistant infections and would be cost-saving in the US.

Introduction: Respiratory syncytial virus (RSV) is an important cause of severe respiratory illness in older adults and adults with respiratory or cardiovascular comorbidities. Published estimates of its incidence and prevalence in adult groups vary widely. This article reviews the potential limitations affecting RSV epidemiology studies and suggests points to consider when evaluating or designing them., Methods: Studies reporting the incidence or prevalence of RSV infection in adults in high-income Western countries from 2000 onwards were identified via a rapid literature review. Author-reported limitations were recorded, together with presence of other potential limitations. Data were synthesized narratively, with a focus on factors affecting incidence estimates for symptomatic infection in older adults., Results: A total of 71 studies met the inclusion criteria, most in populations with medically attended acute respiratory illness (ARI). Only a minority used case definitions and sampling periods tailored specifically to RSV; many used influenza-based or other criteria that are likely to result in RSV cases being missed. The great majority relied solely on polymerase chain reaction (PCR) testing of upper respiratory tract samples, which is likely to miss RSV cases compared with dual site sampling and/or addition of serology. Other common limitations were studying a single season, which has potential for bias due to seasonal variability; failure to stratify results by age, which underestimates the burden of severe disease in older adults; limited generalizability beyond a limited study setting; and absence of measures of uncertainty in the reporting of results., Conclusions: A significant proportion of studies are likely to underestimate the incidence of RSV infection in older adults, although the effect size is unclear and there is also potential for overestimation. Well-designed studies, together with increased testing for RSV in patients with ARI in clinical practice, are required to accurately capture both the burden of RSV and the potential public health impact of vaccines., (© 2023. Pfizer Inc., Koen B. Pouwels, Maarten Postma, Louis Bont.)

Introduction: Studies that estimate the economic burden of pediatric pneumococcal disease often only report direct medical costs and omit indirect non-medical costs. Given these indirect costs are not included in most calculations, the full economic burden attributable to pneumococcal conjugate vaccine (PCV) serotypes is often underestimated. This study seeks to quantify the full broader economic burden of pediatric pneumococcal disease associated with PCV serotypes., Methods: We conducted a reanalysis of a previous study where non-medical costs associated with caregiving for a child with pneumococcal disease are considered. The annual indirect non-medical economic burden attributed to PCV serotypes was subsequently calculated for 13 countries. We included five countries with 10-valent (PCV10) national immunization programs (NIPs) (Austria, Finland, The Netherlands, New Zealand, and Sweden) and eight countries with 13-valent (PCV13) NIPs (Australia, Canada, France, Germany, Italy, South Korea, Spain, and the UK). Input parameters were derived from published literature. Indirect costs were inflated to 2021 values in US dollars (USD)., Results: The total annual indirect economic burden associated with pediatric pneumococcal diseases attributable to PCV10, PCV13, the 15-valent (PCV15), and the 20-valent (PCV20) serotypes were $46.51 million, $158.95 million, $223.00 million, and $413.97 million, respectively. The five countries with PCV10 NIPs bear a greater societal burden associated with PCV13 serotypes, whereas the residual societal burden in the eight countries with PCV13 NIPs was primarily attributable to non-PCV13 serotypes., Conclusion: The inclusion of non-medical costs nearly tripled the total economic burden compared with only including direct medical costs estimated from a previous study. The results from this reanalysis can help inform decision-makers on the broader economic societal burden associated with PCV serotypes and the need for higher-valent PCVs., (© 2023. The Author(s).)

Introduction: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI)-related hospitalizations in older adults. Without RSV-specific treatment for adults, testing is uncommon, leading to potential underestimation of RSV incidence in real-world data studies. This study aimed to quantify the frequency of RSV testing during LRTI-related hospitalizations of older adults to inform interpretation of incidence estimates., Methods: Administrative and billing data for hospitalizations of adults aged ≥ 65 years with a primary or secondary diagnosis of LRTI during the 2016-2019 RSV seasons (October-April) were extracted from the US all-payer Premier Healthcare Database (PHD). Billing codes identified RSV tests administered during eligible hospitalizations. The proportion of LRTI-related hospitalizations with a billed RSV test was calculated for each hospital in PHD, and summarized descriptively by hospital bed size, teaching status, and population served., Results: Most of the 937 study hospitals performed RSV testing infrequently during LRTI hospitalization; median percentage of LRTI hospitalizations with RSV testing was 4.3%, and 78.4% of hospitals performed RSV testing in less than 25% of LRTI-related hospitalizations. RSV testing varied extensively by hospital type. Median percentage tested was significantly higher for hospitals with ≥ 200 beds (9.1%) versus < 200 beds (1.6%), for teaching (11.0%) versus non-teaching (2.5%) hospitals, and in urban (7.4%) versus rural (0.7%) settings. The median percentage of RSV testing increased over time, from 0.8% to 6.3% between the 2016/17 and 2018/19 seasons., Conclusion: A small proportion of older adults hospitalized with LRTI are tested for RSV in US hospitals. Large variability occurs across hospital types. Consequently, retrospective database analyses likely result in a substantial underestimation of the true RSV-related hospitalization incidence. RSV incidence studies using real-world data need to assess for RSV testing frequency and adjust their results for under ascertainment associated with limited testing., (© 2023. The Author(s).)

Objectives: Cost-effectiveness analyses (CEAs) generally assume constant drug prices throughout the model time horizon, yet it is known that prices are not constant, often with price decreases near loss of exclusivity (LOE). This study explores the impact of using dynamic drug-specific prices on the incremental cost-effectiveness ratio (ICER) using selected reproduced case studies., Methods: Case studies were selected following explicit criteria to reflect a variety of drug characteristics. For each drug, a published CEA model was identified, replicated, and modified with dynamic real-world pricing data, to compare ICERs based on constant drug prices with estimates obtained when including drug life cycle pricing. The impact of dynamic real-world pricing-inclusive LOE-was analyzed using a single patient cohort and multiple cohorts over time., Results: Fluvastatin, alendronic acid + colecalciferol combination therapy, letrozole and clopidogrel were selected as case studies. Inclusion of real-world pricing data compared with applying constant prices reduced the ICER in a single-cohort setting up to 43%. In the multicohort analyses, further reductions of the ICERs were observed of up to 113%. The ICERs were sensitive to the period of drug usage relative to the models' time horizons, the relative proportions of drug costs in the overall treatment costs, and timing of LOE compared with the cost year of the original analysis., Conclusions: Assuming dynamic drug prices may lead to more representative ICER estimates. Future CEAs for drugs could account for predicted and disaggregated life cycle price developments based on retrospective data., (Copyright © 2022. Published by Elsevier Inc.)

Aim: The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) showed that tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This study aimed to estimate the impact of tafamidis on survival and quality-adjusted life-years (QALYs)., Methods and Results: A multi-state, cohort, Markov model was developed to simulate the disease course of ATTR-CM throughout a lifetime. For survival extrapolation, survival curves were fitted by treatment arm and New York Heart Association (NYHA) Class I/II (68% of patients) and NYHA Class III (32% of patients) cohorts using the individual patient-level data from both the ATTR-ACT and the corresponding long-term extension study. Univariate and multivariate sensitivity analyses were conducted. The predicted mean survival for the total population (NYHA Class I/II + III) was 6.73 years for tafamidis and 2.85 years for the standard of care (SoC), resulting in an incremental mean survival of 3.88 years [95% confidence interval (CI) 1.32-5.66]. Of the 6.73 life-years, patients on tafamidis spend, on average, 4.82 years in NYHA Class I/II, while patients on SoC spend an average of 1.60 life-years in these classes. The combination of longer survival in lower NYHA classes produced a QALY gain of 5.39 for tafamidis and 2.11 for SoC, resulting in 3.29 incremental QALYs (95% CI 1.21-4.74) in favour of tafamidis., Conclusion: Based on the disease simulation model results, tafamidis is expected to more than double the life expectancy and QALYs of ATTR-CM patients compared to SoC. Longer-term follow-up data from the ATTR-ACT extension study will further inform these findings., Clinical Trials.gov Identifier: NCT01994889 (date of registration: 26 November 2013)., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive condition caused by deposition of transthyretin amyloid fibrils in the heart and is associated with poor quality of life and a shortened lifespan. This study aimed to describe the prevalence, clinical characteristics, and mortality of patients with ATTR-CM, using multiple national health registers in Denmark, Finland, Norway, and Sweden., Methods and Results: Transthyretin amyloid cardiomyopathy patients were identified during 2008-2018 using a combination of diagnosis codes for amyloidosis and heart disease and were matched to patients with non-ATTR heart failure (HF). An identical study design was used in each country to facilitate comparison and aggregation of results. A total of 1930 ATTR-CM patients were identified from national health registers in the four countries. In 2018, prevalence of ATTR-CM per 100 000 inhabitants ranged from 1.4 in Denmark to 5.0 in Sweden; a steep increase over time was observed in Sweden and Norway. Median survival from diagnosis was 30 months for ATTR-CM patients and 67 months for matched HF patients. Survival was significantly lower for female than for male ATTR-CM patients (median survival: 22 and 36 months), while no significant difference was observed in the HF cohort., Conclusions: This study provides the first nationwide estimates of the prevalence, clinical characteristics, and mortality of patients with ATTR-CM, using identical study design across several countries. Findings corroborate previous case series showing high mortality in ATTR-CM, two-fold higher than for other HF patients and higher in women than men, highlighting the need for more precise and early diagnosis to reduce the disease burden., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) experience infiltrative cardiomyopathy and heart failure symptoms requiring costly hospitalizations. The Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT) demonstrated the efficacy of tafamidis on the frequency of cardiovascular (CV)-related hospitalizations in patients with ATTR-CM., Purpose: As length of stay can affect the total hospitalization burden, our study aimed to better understand the impact of tafamidis on the number of CV-related hospital days avoided in the management of ATTR-CM patients., Methods: Data from ATTR-ACT were used to calculate the total burden of CV-related hospitalization (days) by treatment arm in this post hoc analysis., Results: In the total trial population, patients receiving tafamidis had significantly fewer CV-related hospitalizations per year (relative risk reduction [RRR] 0.68; 0.4750 vs. 0.7025, p < 0.0001) and a shorter mean length of stay per CV-related hospitalization event (8.6250 vs. 9.5625 days) than patients receiving placebo. Taken together, tafamidis prevented 2.62 CV-related hospitalization days per patient per year. A subgroup analysis showed that with earlier treatment initiation of tafamidis, the annual number of CV-related hospitalizations was significantly lowered by 52% compared with placebo (RRR 0.48; 0.3378 vs. 0.7091, p < 0.0001). With 1.14 fewer days per hospitalization, tafamidis reduced the annual number of CV-related hospitalization days by 3.96 days per New York Heart Association class I/II patient., Conclusions: In patients with ATTR-CM, tafamidis was associated with a lower rate of CV-related hospitalizations and shorter length of hospital stay. Timely diagnosis and treatment with tafamidis could further decrease the total number of CV-related hospitalization days per year., Gov Identifier: NCT01994889., (© 2022. The Author(s).)

Aims: Transthyretin amyloid cardiomyopathy (ATTR-CM) is the cardiac manifestation of transthyretin amyloidosis (ATTR). The aim of this study was to estimate healthcare resource use for ATTR-CM patients compared with heart failure (HF) patients, in Denmark, Finland, Norway, and Sweden., Methods and Results: Data from nationwide healthcare registers in the four countries were used. ATTR-CM patients were defined as individuals diagnosed with amyloidosis and cardiomyopathy or HF between 2008 and 2018. Patients in the ATTR-CM cohort were matched to patients with HF but without ATTR-CM diagnosis. Resource use included number of visits to specialty outpatient and inpatient hospital care. A total of 1831 ATTR-CM and 1831 HF patients were included in the analysis. The mean number of hospital-based healthcare contacts increased in both the ATTR-CM and HF cohort during 3 years pre-diagnosis and was consistently higher for the ATTR-CM cohort compared with the HF cohort, with 6.1 [CI: 5.9-6.3] vs. 3.2 [CI: 3.1-3.3] outpatient visits and 1.03 [CI: 0.96-1.1] vs. 0.7 [CI: 0.7-0.8] hospitalizations. In the first year following diagnosis, patients with ATTR-CM continued to visit outpatient care (10.2 [CI: 10.1, 10.4] vs. 5.7 [CI: 5.6, 5.9]) and were admitted to hospital more frequently (3.3 [CI: 3.2, 3.4] vs. 2.5 [CI: 2.5, 2.6]) than HF patients., Conclusions: Transthyretin amyloid cardiomyopathy imposes a high burden on healthcare systems with twice as many outpatient specialist visits and 50% more hospitalizations in the year after diagnosis compared with HF patients without ATTR-CM. Studies to investigate if earlier diagnosis and treatment of ATTR-CM may lower resource use are warranted., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Conventional cost-effectiveness analysis-i.e., assessing pharmaceuticals through a cost per quality-adjusted life year (QALY) framework-originated from a societal commitment to maximize population health given limited resources. This "extra-welfarist" approach has produced pricing and reimbursement systems that are not well- aligned with the unique considerations of orphan drugs. This framework has been slow to evolve along with our increased understanding of the impact of rare diseases, which in turn has complicated the assessment of orphan drugs meant to treat rare diseases. Herein, we (i) discuss the limitations of conventional cost-effectiveness analysis as applied to assessing access to, as well as the pricing and reimbursement of, orphan drugs, (ii) critically appraise alternative and supplemental approaches, and (iii) offer insights on plausible steps forward., (© 2022. The Author(s).)

Background : Transthyretin amyloid polyneuropathy (ATTR-PN) is a fatal disease associated with substantial burden of illness. Three therapies are approved by the European Medicines Agency for the management of this rare disease. The aim of this study was to compare the total annual treatment specific cost per-patient associated with ATTR-PN in Spain. Methods : An Excel-based patient burden and cost estimator tool was developed to itemize direct and indirect costs related to treatment with inotersen, patisiran, and tafamidis in the context of ATTR-PN. The product labels and feedback from five Spanish ATTR-PN experts were used to inform resource use and cost inputs. Results : Marked differences in costs were observed between the three therapies. The need for patisiran- and inotersen-treated patients to visit hospitals for pre-treatment, administration, and monitoring was associated with increased patient burden and costs compared to those treated with tafamidis. Drug acquisition costs per-patient per-year were 291,076€ (inotersen), 427,250€ (patisiran) and 129,737€ (tafamidis) and accounted for the majority of total costs. Overall, the total annual per-patient costs were lowest for patients treated with tafamidis (137,954€), followed by inotersen (308,358€), and patisiran (458,771€). Conclusions : Treating patients with tafamidis leads to substantially lower costs and patient burden than with inotersen or patisiran.

Objective: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a rare, progressive and fatal condition caused by deposition of transthyretin amyloid fibrils in the heart. This study aims to identify all patients diagnosed with ATTR-CM in Sweden, estimate the prevalence of ATTR-CM, describe patient characteristics and mortality, assess the importance of early symptoms (red flags) for identification of ATTR-CM, and compare with patients with heart failure (HF)., Methods: This retrospective study combined multiple national health registers covering all specialist visits and prescriptions for the entire population of Sweden. Between January 2008 and December 2018, patients with ATTR-CM were identified retrospectively based on a combination of diagnosis codes and compared with matched, all-cause non-ATTR HF patients., Results: Overall, a total of 994 patients diagnosed with ATTR-CM were identified, with an average age at diagnosis of 73 years, and 30% of whom were female. The prevalence of diagnosed ATTR-CM cases in 2018 was 5.0 per 100 000. The median survival from diagnosis was 37.6 months (CI 33.8 to 43.8), with a lower median survival in women (27.9 months, CI 23.3 to 33.8) compared with men (43.5 months, CI 37.6 to 49.6). Patients with ATTR-CM demonstrated reduced survival compared with patients with HF (p<0.001). Compared with patients with HF, clinical identification of carpal tunnel syndrome, spinal stenosis, and atrioventricular and left bundle branch block can facilitate earlier diagnosis of ATTR-CM., Conclusions: This study provides the first nationwide estimates of ATTR-CM prevalence and risk factors. The results reinforce the severity of the disease and the importance of earlier diagnosis, especially for female patients, in order to allow effective treatment and prevention of disease progression., Competing Interests: Competing interests: REL and JLH are employed by Quantify Research and funded by Pfizer to conduct this study; Quantify Research is a consultancy and works with a range of different pharmaceutical companies. CG, MHR, AMS and MV are Pfizer employees and hold Pfizer stock and/or stock options. JK received support from Pfizer for her collaboration in this manuscript, as well as grants or contracts from Sanofi, Pfizer and Amgen, Kuopio University Hospital, and Finnish Heart Research Foundation Academy of Finland. JK also received consulting fees and honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Sanofi, Pfizer, Amicus, Bayer, Amgen and MSD, as well as support for attending meetings from Sanofi, Pfizer, Amicus, Bayer, Amgen, MSD, Shire and Novo Nordisk. JK has received support for participation on a Data Safety Monitoring Board or Advisory Board from Amgen, Pfizer, Amicus and Sanofi. JK is also President (future/present/past) of the Finnish Society of Internists (2015–2021) and is the leader of the grant board at the Finnish Society of Medicine. EG has not received personal payments or support; his institution has received grants for work on this study and honoraria for lectures from Pfizer. FG received honoraria for his consulting services from Pfizer, Alnylam and Ionis., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: Delayed diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) represents a missed opportunity for intervention. This study estimates the health benefits of timely diagnosis and treatment with tafamidis. Methods: A disease simulation model was developed to predict health outcomes under scenarios of timely and delayed diagnosis and treatment. Efficacy and quality of life (QoL) profiles were derived from the pivotal tafamidis trial and diagnostic delay durations from the literature. Results: Timely diagnosis and treatment were predicted to extend mean life expectancy by 5.46 and 7.76 years, relative to delayed diagnosis, for wild-type and hereditary ATTR-CM, respectively. Corresponding QALY gains were 4.50 and 6.22. Conclusion: Timely diagnosis and treatment with tafamidis are predicted to significantly improve survival and QoL for ATTR-CM patients.

Introduction: This study investigates the gender distribution in patients diagnosed with wild-type transthyretin amyloidosis cardiomyopathy (ATTRwt)., Methods: A systematic review and meta-analysis of the male proportion in diagnosed ATTRwt patients were conducted. To avoid overlapping population, pooled estimates in the primary analysis were based on all unique studies. In secondary analyses, we considered predefined subsets of studies based on study sample size, recruitment years, geography, study design, age at diagnosis, and method of diagnosis. Additional meta-regression analyses were tested for potential determinants of gender distribution., Results: Twenty-eight unique studies (2542 patients) were included in the meta-analysis. Male proportion in patients with ATTRwt was 86.9% (95% confidence interval 81.5-91.6%). Studies, including patients older than 80 years at diagnosis, had a 29.1% (p value < 0.001) lower male proportion compared to studies, including younger patients. After adjusting for age, studies using autopsy as a method of diagnosis had a 21.1% (p value 0.002) lower male proportion compared to other studies., Conclusions: Studies conducted to date suggest ATTRwt disproportionally affects males. The proportion of males was significantly impacted by the age at diagnosis and method diagnosis, which may suggest important gender-based differences in the clinical manifestation and diagnostic challenges of ATTRwt in females that warrant future research.

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, fatal and under-recognized disease. This targeted literature review assessed the extent and consequences of diagnostic delay and misdiagnosis in ATTR-CM., Methods: The Embase database was searched together with proceedings of eight cardiology conferences to identify publications or abstracts on ATTR-CM. Outcomes of interest were time from symptom onset to diagnosis, rates of delayed diagnosis and misdiagnosis, and costs, healthcare resource use or clinical outcomes whilst undiagnosed/misdiagnosed., Results: Twenty-three articles were included. Weighted means of reported mean and median diagnostic delays were 6.1 and 3.4 years for wild-type (ATTRwt-CM) and 5.7 and 2.6 years for hereditary (ATTRv-CM). Misdiagnosis occurred in 34-57% of patients when reported. Evaluation and misdiagnosis by multiple healthcare providers before receiving an ATTR-CM diagnosis was common, and there was evidence that patients undergo unnecessary or inappropriate evaluations or treatments while misdiagnosed. Diagnostic "red flags" were reported to be underused. Data on the consequences of delay for patients and health systems were sparse, but given the progressive nature of ATTR-CM, delay is likely to have adverse consequences., Conclusion: ATTR-CM patients commonly experience diagnostic delay and misdiagnosis. Efforts are required to provide timely diagnosis so that patients can benefit from earlier access to new disease-modifying therapies.

Background : Currently literature on the impact of patent expiry on drug prices is lacking. Objective : To determine the impact of patent expiration and generic entry on drug prices in the Netherlands. Methods : Prescription and price data from 1999 up to and including December 2016 were collected from two national databases. The overall price ratio of drugs prices up to 48 months after patent expiration was compared to the price in the month before expiry. Sub-analyses were performed to provide insights in generic uptake, length of market exclusivity and price development for originators and generics separately. Results : In total 250 drugs faced patent expiration during the study period. Forty-eight months after patent expiration the median price ratio decreased to 0.59 (IQR = 0.23-0.86) compared to the month prior patent expiry. Major differences in price developments were observed depending on the level of revenue prior to patent expiration and the time of patent expiration with ratios ranging from 0.08 (IQR = 0.07-0.16) to 0.81 (IQR = 0.62-0.97). Prior to patent expiry, the price decreased by 2.3% annually while having market exclusivity for 11.3 years on average. Conclusion : This study showed that the median drug price after patent expiration decreased by 41% after 4 years. The results of this study can be used to provide more reliable estimates on drug prices over its lifecycle and can be implemented in economic evaluations to inform the cost-effectiveness and long-term budget impact of new drugs., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Introduction: Widespread use of ten-valent (Synflorix™, GSK) or 13-valent (Prevenar 13™; Pfizer) conjugate vaccination programs has effectively reduced invasive pneumococcal disease (IPD) globally. However, IPD caused by serotypes not contained within the respective vaccines continues to increase, notably serotypes 3, 6A, and 19A in countries using lower-valent vaccines. Our objective was to estimate the clinical and economic benefit of replacing PCV10 with PCV13 in Colombia, Finland, and The Netherlands., Methods: Country-specific databases, supplemented with published and unpublished data, informed the historical incidence of pneumococcal disease as well as direct and indirect medical costs. A decision-analytic forecasting model was applied, and both costs and outcomes were discounted. The observed invasive pneumococcal disease (IPD) trends from each country were used to forecast the future number of IPD cases given a PCV13 or PCV10 program., Results: Over a 5-year time horizon, a switch to a PCV13 program was estimated to reduce overall IPD among 0-2 year olds by an incremental - 37.6% in Colombia, - 32.9% in Finland, and - 26% in The Netherlands, respectively, over PCV10. Adults > 65 years experienced a comparable incremental decrease in overall IPD in Colombia (- 32.2%), Finland (- 15%), and The Netherlands (- 3.7%). Serotypes 3, 6A, and 19A drove the incremental decrease in disease for PCV13 over PCV10 in both age groups. A PCV13 program was dominant in Colombia and Finland and cost-effective in The Netherlands at 1 × GDP per capita (€34,054/QALY)., Conclusion: In Colombia, Finland, and The Netherlands, countries with diverse epidemiologic and population distributions, switching from a PCV10 to PCV13 program would significantly reduce the burden of IPD in all three countries in as few as 5 years.

Objective: The aim of this study was to evaluate the impact of patent expiry on drug prices by means of a systematic literature review., Methods: A systematic literature search was performed in PubMed to identify all published literature on the impact of patent expiration on drug prices. Additional literature was identified using a less distinct syntax in Google Scholar and EconLit. Data extraction followed a standardized assessment form containing the domains study type, study aim, reported outcomes, number of drugs and drug classes assessed, and originators or generics assessed., Results: The 16 identified studies that assessed impact of patent expiry on drug prices showed that price developments after patent expiration varied between countries. The included studies assessed price developments for the USA, Canada, Australia, the UK, the Netherlands, Germany and France, Spain, Italy, Norway, Sweden and Denmark. The number of drugs included within different studies ranged between 1 and 219. The identified studies indicated that drug prices decreased significantly after patent expiry with drug price ratios ranging from 6.6 to 66% 1-5 years after patent expiry., Conclusion: Drug prices decrease significantly after patent expiry. The extent of this price reduction varied greatly between products and countries. For this reason, country-specific analyses on price developments after patent expiry should be used when these are considered in decision making. Future research should be dedicated to gathering more country-specific data to reduce the uncertainty with regard to price developments.

Background: The aim of this study was to estimate the total economic and health related burden of breast cancer in the Netherlands., Methods: Data on incidence, prevalence, mortality and survival were extracted from the Dutch National Cancer Registry and were used to calculate the economic and health related burden of breast cancer for overall, DCIS (stage 0), early- (stage I), locally advanced- (stage II-III) and metastatic- (stage IV) breast cancer by age groups and by year (if applicable)., Results: The overall incidence of breast cancer increased from 103.4 up to 153.2 per 100,000 women between 1990 and 2014. The increase was driven by DCIS and early breast cancer as the incidence of locally advanced and metastatic breast cancer remained stable. Between 1990 and 2014, ten-year overall survival rates increased from 87% to 93% for early breast cancer, 41% to 62% for locally advanced- and from 6% to 9% for metastatic disease. Annually, breast cancer in the Netherlands is responsible for approximately 3100 deaths, 26,000 life years lost, 65,000 Disability Adjusted Life Years (DALYs) and an economic burden of €1.27 billion., Conclusions: This study provides a comprehensive assessment of the burden of breast cancer and subsequent trends over time in the Netherlands.

Background: Immunocompromising conditions and advanced age (≥65 years) are associated with a high risk for invasive pneumococcal disease (IPD). We investigated the risk and outcomes of IPD in adults with underlying conditions in the post-PCV7 era in The Netherlands., Methods: IPD data from 2008 to 2012 was obtained from the national pneumococcal surveillance system, covering 25% of the Dutch population. Population estimates of underlying conditions were derived from the primary care data (2012). IPD incidence in adults with immunocompromising conditions (high risk group) and non-immunocompromising comorbidities (medium risk group) were compared to the "normal risk group" without diagnosed comorbidities. Case-fatality and ICU admission in the different risk groups was analyzed by logistic regression. Serotype specific propensities to affect high risk group IPD patients were calculated., Results: Adults with a high risk condition have a 18-fold (95% CI 15.6-21.2) and 3-fold (95% CI 2.6-3.9) higher risk compared to the normal risk group for IPD at age 18-64 years and 65 years and older, respectively. In case of a medium risk condition, the risk is 5-fold (95% CI 4.3-5.7) and 2-fold (95% CI 1.9-2.6) higher in age groups 18-64 and ≥65 years old. Likewise, IPD patients with a high or medium risk condition have a higher case-fatality (after adjustment for age, odds ratio: 2-fold (95% CI 1.5-3.5) and 1.4-fold (95% CI 1.0-2.1), respectively). Several serotypes (e.g. 6A, 6B, 23A and 23B) are associated with a significantly higher propensity to cause disease in high risk patients., Conclusions: The risk for IPD and death in the post-PCV7 era has remained considerably high in adults and elderly with underlying conditions. The identification of serotypes with a high propensity to affect risk groups can be important for selecting (future) vaccine serotypes., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) demonstrated the efficacy of 13-valent pneumococcal conjugate vaccine (PCV13) in preventing vaccine-type community-acquired pneumonia and vaccine-type invasive pneumococcal disease in elderly subjects. We examined the cost-effectiveness of PCV13 vaccination in the Netherlands. Using a Markov-type model, incremental cost-effectiveness ratios (ICER) of PCV13 vaccination in different age- and risk-groups for pneumococcal disease were evaluated using a societal perspective. Estimates of quality-adjusted life-years (QALYs), costs, vaccine efficacy and epidemiological data were based on the CAPiTA study and other prospective studies. The base-case was PCV13 vaccination of adults aged 65-74 years compared to no vaccination, assuming no net indirect effects in base-case due to paediatric 10-valent pneumococcal conjugate vaccine use. Analyses for age- and risk-group specific vaccination strategies and for different levels of hypothetical herd effects from a paediatric PCV programme were also conducted. The ICER for base-case was €8650 per QALY (95% CI 5750-17,100). Vaccination of high-risk individuals aged 65-74 years was cost-saving and extension to medium-risk individuals aged 65-74 years yielded an ICER of €2900. Further extension to include medium- and high-risk individuals aged ≥18 years yielded an ICER of €3100.PCV13 vaccination is highly cost-effective in the Netherlands. The transferability of our results to other countries depends upon vaccination strategies already implemented in those countries., (Copyright ©ERS 2015.)

Background: Community-acquired pneumonia (CAP) is one of the most common acute infections associated with a substantial clinical and economic burden. There have been few studies assessing incidence rate, duration of hospitalization, and costs of hospitalized CAP by age and care-setting., Methods: A retrospective study was conducted using a nationwide Dutch database containing healthcare claims data of 16.7 million inhabitants. Patients with at least one claim with a discharge diagnosis of CAP between January 2008 and December 2011 were selected. The main outcome measures considered were the incidence rate, duration of hospitalization, and the direct costs of hospitalized CAP stratified by age and care-setting., Results: In total, 195,372 CAP cases were included in the analysis resulting in an average incidence of 295 per 100,000 population per year. Sixty-three percent (123,357) of the included patients were hospitalized for 1 or more nights, of which 5.9% (n=7241) spent at least one night in the Intensive Care Unit (ICU). Overall, these 123,357 patients spent 824,985 days in the hospital of which 48,324 were spent on the ICU. The mean duration of hospitalization of ICU patients and general ward patients was 15.2 days and 6.2 days, respectively. The total costs related to all 195,372 CAP episodes during these 4 years were €711 million, with the majority (76%) occurring among those aged 50 years and older. Median (and mean) costs were dependent on age and type of care with costs ranging from €344 (€482) per episode for 0-9 year olds treated in the outpatient hospital setting up to €10,284 (€16,374) per episode for 50-64 year olds admitted to the ICU., Conclusion: There is a large variation in terms of incidence, disease burden and costs across different age groups and the treatment setting. Effective interventions, targeted at older adults, to prevent pneumonia could reduce the (financial) burden due to pneumonia., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Stroke prevention is the main goal of treating patients with atrial fibrillation (AF). Vitamin-K antagonists (VKAs) present an effective treatment in stroke prevention, however, the risk of bleeding and the requirement for regular coagulation monitoring are limiting their use. Apixaban is a novel oral anticoagulant associated with significantly lower hazard rates for stroke, major bleedings and treatment discontinuations, compared to VKAs., Objective: To estimate the cost-effectiveness of apixaban compared to VKAs in non-valvular AF patients in the Netherlands., Methods: Previously published lifetime Markov model using efficacy data from the ARISTOTLE and the AVERROES trial was modified to reflect the use of oral anticoagulants in the Netherlands. Dutch specific costs, baseline population stroke risk and coagulation monitoring levels were incorporated. Univariate, probabilistic sensitivity and scenario analyses on the impact of different coagulation monitoring levels were performed on the incremental cost-effectiveness ratio (ICER)., Results: Treatment with apixaban compared to VKAs resulted in an ICER of €10,576 per quality adjusted life year (QALY). Those findings correspond with lower number of strokes and bleedings associated with the use of apixaban compared to VKAs. Univariate sensitivity analyses revealed model sensitivity to the absolute stroke risk with apixaban and treatment discontinuations risks with apixaban and VKAs. The probability that apixaban is cost-effective at a willingness-to-pay threshold of €20,000/QALY was 68%. Results of the scenario analyses on the impact of different coagulation monitoring levels were quite robust., Conclusions: In patients with non-valvular AF, apixaban is likely to be a cost-effective alternative to VKAs in the Netherlands.

Introduction: Hepatitis C virus (HCV) infection can lead to severe liver disease. Pregnant women are already routinely screened for several infectious diseases, but not yet for HCV infection. Here we examine whether adding HCV screening to routine screening is cost-effective., Methods: To estimate the cost-effectiveness of implementing HCV screening of all pregnant women and HCV screening of first-generation non-Western pregnant women as compared to no screening, we developed a Markov model. For the parameters of the model, we used prevalence data from pregnant women retrospectively tested for HCV in Amsterdam, the Netherlands, and from literature sources. In addition, we estimated the effect of possible treatment improvement in the future., Results: The incremental costs per woman screened was €41 and 0.0008 life-years were gained. The incremental cost-effectiveness ratio (ICER) was €52,473 which is above the cost-effectiveness threshold of €50,000. For screening first-generation non-Western migrants, the ICER was €47,113. Best-case analysis for both scenarios showed ICERs of respectively €19,505 and €17,533. We estimated that if costs per treatment were to decline to €3,750 (a reduction in price of €31,000), screening all pregnant women would be cost-effective., Conclusions: Currently, adding HCV screening to the already existing screening program for pregnant women is not cost-effective for women in general. However, adding HCV screening for first-generation non-Western women shows a modest cost-effective outcome. Yet, best case analysis shows potentials for an ICER below €20,000 per life-year gained. Treatment options will improve further in the coming years, enhancing cost-effectiveness even more.

The primary objective of this meta-analysis was to estimate the prevalence of adult community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae in Europe, adjusted for possible independent covariates. Two reviewers conducted a systematic literature search using PubMed on English-language articles that involved human subjects with CAP during the period from January 1990 to November 2011 across European countries. A mixed-effects meta-regression model was developed and populated with 24,410 patients obtained from 77 articles that met the inclusion criteria. The model showed that the observed prevalence of S. pneumoniae in CAP significantly varies between European regions, even after adjusting for explanatory covariates, including patient characteristics, diagnostic tests, antibiotic resistance, and health-care setting. The probability of detecting S. pneumoniae was substantially higher in studies that performed more frequently a diagnostic polymerase chain reaction assay compared to all the other diagnostic tests included. Furthermore, S. pneumoniae was more likely to be confirmed as the cause of a CAP in studies with intensive care unit patients as compared to those with hospital- or community-treated patients. This study provides estimates of the average observed prevalence of S. pneumoniae, which could be used for projecting the health and economic benefits of pneumococcal immunization.

Background: To update a cost-effectiveness analysis of rotavirus vaccination in the Netherlands previously published in 2011., Methods: The rotavirus burden of disease and the indirect protection of older children and young adults (herd protection) were updated., Results: When updated data was used, routine infant rotavirus vaccination in the Netherlands would potentially become an even more cost-effective strategy than previously estimated with the incremental cost per QALY at only €3,000-4,000. Break-even total vaccination costs were indicated at €92-122, depending on the applied threshold., Conclusions: We concluded that the results on potentially favourable cost-effectiveness in the previous study remained valid, however, the new data suggested that previous results might represent an underestimation of the economic attractiveness of rotavirus vaccination.

Despite childhood vaccination programs, pertussis remains endemic. To reduce the burden of pertussis, various extended pertussis vaccination strategies have been suggested. The aim of this article is to evaluate dynamic models used to assess the cost-effectiveness of vaccination. In total, 16 studies using a dynamic model were included, of which four also studied the cost-effectiveness of extended pertussis vaccination strategies. Generally, adolescent vaccination was found to be cost effective, but not highly effective in protecting infants too young to be vaccinated. The models also predicted that owing to age shifts, reduced pertussis disease in adolescents and young adults comes with an increase in later stages of life. This underpins the use of dynamic transmission models for interventions directed against pertussis. In future, dynamic transmission models for pertussis should be used widely to further enhance understanding of pertussis epidemiology and of extended pertussis vaccination programs that are currently considered in various countries.

The aim of the current study is to estimate the epidemiological and economical consequences of several extended pertussis booster vaccination strategies and to explore the impact of parameters surrounded by large uncertainty on the cost-effectiveness. We developed an age structured transmission dynamic model to evaluate the impact of programs targeting (i) adolescents or adults using a single booster dose, (ii) a combination of adolescent and adult vaccination, and (iii) an every 10 years booster dose. The base case analysis, that is a single adolescent booster administered at the age of 12 years, resulted in a reduction of pertussis infections. However, due to an increase in the number of symptomatic infections in adults, the benefits in terms of QALYs gained and costs saved in children were partly offset. Despite these negative indirect effects in the adult population, administering an additional booster dose could still be considered cost effective with an ICER of €4200 per QALY gained. Combining an adolescent booster dose at the age of 10 (most cost-effective age for a single adolescent booster dose) with an adult (18-30 years) booster dose always resulted in favorable ICERs (<€10,000/QALY). Finally the every 10 year booster dose resulted in an ICER of €16,900 per QALY. The impact of different assumptions regarding the disease epidemiology, disease-related parameters, and vaccination program-related issues was limited. To conclude, we show that extended pertussis booster vaccination strategies are likely to be considered as cost-effective., (Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.)

Objective: To estimate the cost effectiveness of vaccinating people with high risk conditions against invasive pneumococcal disease using the 13 valent pneumococcal conjugate vaccine., Design: Economic evaluation using a cohort model from the perspective of healthcare providers., Setting: England., Participants: People aged 2 years and older at increased risk of invasive pneumococcal disease due to chronic kidney disease; splenic dysfunction; HIV infection; a compromised immune system; chronic heart, liver, or respiratory disease; or diabetes., Main Outcome Measures: Costs, gains in life years and quality adjusted life years (QALYs), and incremental cost effectiveness ratios., Results: Increasing indirect protection resulting from the vaccination programme of infants using the 13 valent pneumococcal conjugate vaccine means that the burden of disease preventable by targeting high risk groups will diminish in time. Under base case assumptions--that is, no overall impact on non bacteraemic pneumonia in high risk groups and assuming the high risk vaccination programme would be launched two to three years after the infant programme--the incremental cost effectiveness ratio was estimated to be more than £30,000 (€37,216; $48,210) per QALY gained for most risk groups. If, however, the vaccine does not offer protection against non-bacteraemic pneumococcal pneumonia or the vaccine was introduced concomitantly with the infant 13 valent pneumococcal conjugate vaccination programme then vaccinating high risk people would (more) likely be cost effective. Sensitivity analyses showed that the cost effectiveness was particularly sensitive to assumed herd benefits and vaccine efficacy estimates., Conclusion: Under base case assumptions it is unlikely that a pneumococcal vaccination programme aimed at risk groups could be considered cost effective. Uncertainty could be substantially reduced by establishing the effectiveness of the 13 valent pneumococcal conjugate vaccine against non-bacteraemic pneumococcal pneumonia, particularly in at risk groups.

The aim of this study was to investigate the optimal pertussis booster vaccination strategy for The Netherlands. A realistic age-structured deterministic model was designed. Assuming a steady-state situation and correcting for underreporting, the model was calibrated using notification data from the period 1996-2000. Several sensitivity analyses were performed to explore the impact of different assumptions for parameters surrounded by uncertainty (e.g. duration of protection after natural infection, underreporting factors, and transmission probabilities). The optimal age of an additional booster dose is in the range of 10-15 years, and implementation of this booster dose will reduce both symptomatic and asymptomatic infections, although the incidence of symptomatic infections in older age groups will increase. The impact of the different assumptions used in the model was in general limited. We conclude that over a wide range of assumptions, an additional booster dose can reduce the incidence of pertussis in the population.

Introduction: Respiratory syncytial virus (RSV) infection is one of the major causes of respiratory illness in infants, infecting virtually every child before the age of 2 years. Currently, several Phase 1 trials with RSV vaccines in infants are ongoing or have been completed. As yet, no efficacy estimates are available for these vaccine candidates. Nevertheless, cost-effectiveness estimates might be informative to enable preliminary positioning of an RSV vaccine., Methods: A decision analysis model was developed in which a Dutch birth cohort was followed for 12 months. A number of potential vaccination strategies were reviewed such as vaccination at specific ages, a two- or three-dosing scheme and seasonal vaccination versus year-round vaccination. The impact of the assumptions made was explored in various sensitivity analyses, including probabilistic analysis. Outcome measures included the number of GP visits, hospitalizations and deaths, costs, quality-adjusted life years and incremental cost-effectiveness ratios (ICERs)., Results: Currently, without vaccination, an annual number of 28,738 of RSV-related GP visits, 1623 hospitalizations, and 4.5 deaths are estimated in children in the age of 0-1 year. The total annual cost to society of RSV in the non-vaccination scenario is €7.7 million (95%CI: 1.7-16.7) and the annual disease burden is estimated at 597 QALYs (95%CI: 133-1319). In case all infants would be offered a potentially safe and effective 3-dose RSV vaccination scheme at the age of 0, 1 and 3 months, the total annual net costs were estimated to increase to €21.2 million, but 544 hospitalizations and 1.5 deaths would be averted. The ICER was estimated at €34,142 (95%CI: € 21,652-€ 87,766) per QALY gained. A reduced dose schedule, seasonal vaccination, and consideration of out-of-pocket expenses all resulted in more favorable ICER values, whereas a reduced vaccine efficacy or a delay in the timing of vaccination resulted in less favorable ICERs., Discussion: Our model used recently updated estimates on the burden of RSV disease in children and it included plausible utilities. However, due to the absence of clinical trial data, a number of crucial assumptions had to be made related to the characteristics of potential RSV vaccine. The outcomes of our modeling exercise show that vaccination of infants against RSV might be cost-effective. However, clinical trial data are warranted., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: Discounting has long been a matter of controversy in the field of health economic evaluations. How to weigh future health effects has resulted in ongoing discussions. These discussions are imminently relevant for health care interventions with current costs but future benefits. Different approaches to discount health effects have been proposed. In this study, we estimated the impact of different approaches for discounting health benefits of human papillomavirus (HPV) vaccination., Methods: An HPV model was used to estimate the impact of different discounting approaches on the present value of health effects. For the constant discount approaches, we varied the discount rate for health effects ranging from 0% to 4%. Next, the impact of relevant alternative discounting approaches was estimated, including hyperbolic, proportional, stepwise, and time-shifted discounting., Results: The present value of health effects gained through HPV vaccination varied strongly when varying discount rates and approaches. The application of the current Dutch guidelines resulted in a present value of health effects that was eight or two times higher than that produced when using the proportional discounting approach or when using the internationally more common 4% discount rate for health effects, respectively. Obviously, such differences translate into large variations in corresponding incremental cost-effectiveness ratios., Conclusion: The exact discount rate and approach chosen in an economic evaluation importantly impact the projected value of health benefits of HPV vaccination. Investigating alternative discounting approaches in health-economic analysis is important, especially for vaccination programs yielding health effects far into the future. Our study underlines the relevance of ongoing discussions on how and at what rates to discount., (Copyright © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

The BCG vaccine was introduced in 1921 and remains the only licensed vaccine for the prevention of TB worldwide. Despite its extensive use, the BCG vaccine lacks the ability to fully control the TB-endemic and -pandemic situations. The BCG vaccine is most effective in preventing pediatric TB, in particular, miliary TB and tuberculous meningitis. However, it has a limited effect in preventing pulmonary TB, which occurs more frequently in adults. BCG vaccination has now been implemented in more than 157 countries worldwide. For various countries, the benefits of vaccination are only limited and potentially not cost effective. The International Union Against Tuberculosis and Lung Diseases had set the criteria for discontinuation of BCG vaccination in 1994. This decision, however, was not based on economic considerations. Many developed countries have met the criteria set by the International Union Against Tuberculosis and Lung Disease and stopped universal BCG vaccination. For developing countries, the BCG vaccine is still an effective intervention in protecting young children from TB infection. A lot of effort has been spent on R&D of new TB vaccines, the first of which are expected to be available within 5-7 years from now. Novel TB vaccines are expected to be better and more effective than the current BCG vaccine and should provide a viable strategy in controlling TB morbidity and mortality. In this review, the aim is to explore economic evaluations that have been carried out for vaccination against TB worldwide. In addition to epidemiological evidence, economic evidence can play a crucial role in supporting the governments of countries in making proper public health decisions on BCG vaccination policies, in particular, to implement, continue, or discontinue.

Introduction: Rotavirus is the most common cause of severe diarrhoea worldwide. Vietnam is situated in the region of high rotavirus infection incidence and eligible for financial support to introduce rotavirus vaccines into the Expanded Program of Immunization (EPI) from the GAVI. This study was designed to assess the cost-effectiveness of rotavirus immunization in Vietnam, explicitly the use of Rotateq(®) and to assess the affordability of implementing universal rotavirus immunization based on GAVI-subsidized vaccine price in the context of Vietnamese healthcare system for the next 5 years., Methodology: An age-structured cohort model was developed for the 2009 birth cohort in Vietnam. Two strategies were compared: one being the current situation without vaccination, and the other being mass universal rotavirus vaccination. The time horizon of the model was 5 years with time cycles of 1 month for children less than 1 year of age and annual analysis thereafter. Outcomes included mild, moderate, severe cases and death. Multiple outcomes per rotavirus infection are possible in the model. Monte Carlo simulations were used to examine the acceptability and affordability of the rotavirus vaccination. All costs were expressed in 2009 US$., Results: Rotavirus vaccination would not completely protect young children against rotavirus infection due to partial nature of vaccine immunity, however, would effectively reduce severe cases of rotavirus by roughly 55% during the first 5 years of life. Under GAVI-subsidized vaccine price (US$ 0.3/dose), the vaccine cost would amount to US$ 5.5 million per annum for 3-dose of the Rotateq(®) vaccine. In the base-case, the incremental cost per quality-adjusted-life-year (QALY) was US$ 665 from the health system perspective, much lower than per-capita GDP of ∼US$ 1150 in 2009. Affordability results showed that at the GAVI-subsidized vaccine price, rotavirus vaccination could be affordable for Vietnamese health system., Conclusion: Rotavirus vaccination in Vietnam would be a cost-effective health intervention. Vaccination only becomes affordable if the country receives GAVI's financial support due to the current high market vaccine price. Given the high mortality rate of under-five-year children, the results showed that rotavirus immunization is the "best hope" for prevention of rotavirus-related diarrhoeal disease in Vietnam. In the next five years, Vietnam is definitely in debt to financial support from international organizations in implementing rotavirus immunization. It is recommended that new rotavirus vaccine candidates be developed at cheaper price to speed up the introduction of rotavirus immunization in the developing world in general., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Introduction: Cervical cancer is caused by infection with human papillomavirus (HPV). Several countries have implemented vaccination programs against HPV for teenage girls before sexual debut. However, recent clinical trials have demonstrated that vaccination of older women is highly effective as well. Accordingly, it has been suggested that these older women should also be offered vaccination. Here, the cost-effectiveness of HPV vaccination for older women was assessed., Methods: A Markov model was used to estimate age-specific health benefits and cost savings of HPV vaccination for women 12-50 years of age, in the Netherlands. Sensitivity analyses were performed to test the robustness of the outcomes. State-of-the-art health-economic methods were used, and international health-economic guidelines were followed., Results: HPV vaccination is highly cost-effective for girls aged 12-16 years. Remarkably, cost-effectiveness only slowly declines with increasing age of the vaccinees up to 25 years. Indeed, substantial health benefits can be obtained by vaccinating women in this age group at acceptable costs. Beyond this age, cost-effectiveness of HPV-vaccination rapidly declines., Conclusions: Not only HPV vaccination of girls before sexual debut is a highly effective and cost-effective strategy for prevention of cervical cancer, but also vaccination of women until the age of 25 years is generally cost-effective.

Background: This study aims to critically review available cost-effectiveness models for rotavirus vaccination, compare their designs using a standardized approach and compare similarities and differences in cost-effectiveness outcomes using a uniform set of input parameters., Methods: We identified various models used to estimate the cost-effectiveness of rotavirus vaccination. From these, results using a standardized dataset for four regions in the world could be obtained for three specific applications., Results: Despite differences in the approaches and individual constituting elements including costs, QALYs Quality Adjusted Life Years and deaths, cost-effectiveness results of the models were quite similar. Differences between the models on the individual components of cost-effectiveness could be related to some specific features of the respective models. Sensitivity analysis revealed that cost-effectiveness of rotavirus vaccination is highly sensitive to vaccine prices, rotavirus-associated mortality and discount rates, in particular that for QALYs., Conclusions: The comparative approach followed here is helpful in understanding the various models selected and will thus benefit (low-income) countries in designing their own cost-effectiveness analyses using new or adapted existing models. Potential users of the models in low and middle income countries need to consider results from existing studies and reviews. There will be a need for contextualization including the use of country specific data inputs. However, given that the underlying biological and epidemiological mechanisms do not change between countries, users are likely to be able to adapt existing model designs rather than developing completely new approaches. Also, the communication established between the individual researchers involved in the three models is helpful in the further development of these individual models. Therefore, we recommend that this kind of comparative study be extended to other areas of vaccination and even other infectious disease interventions.

Diarrhea is a leading cause of mortality for children under 5 years of age, and rotavirus is identified as the main cause of severe diarrhea worldwide. Since 2006, two rotavirus vaccines, Rotarix and Rotateq, have been available in the market. These vaccines have proved to have high efficacy in developed countries. Clinical trials are being undertaken in Asia and Africa, and early clinical results found that the vaccine significantly reduces severe diarrhea episodes due to rotavirus (48.3% for Asia and 30.2% for Africa). The WHO recommended that rotavirus immunization be included in all national immunization programs. Based on WHO's recommendations, the Global Alliance for Vaccines and Immunization decided to provide financial support for rotavirus immunization in the developing world. In this article, we attempted to ascertain the cost-effectiveness of universal rotavirus immunization in developing countries. After an extensive literature search, we identified and evaluated 15 cost-effectiveness studies conducted in the developing world. The results from these studies showed that rotavirus immunization is a cost-effective strategy and one of the best interventions to prevent rotavirus-related diarrheal disease. However, rotavirus vaccines are expensive and the vaccine price appears to be the most challenging and crucial factor for decision-makers regarding whether to introduce this vaccine into developing countries' immunization schedules. All the studies concluded that rotavirus immunization is cost effective but may not be affordable for the developing world at present. Developing countries will definitely rely on financial support from international organizations to introduce rotavirus vaccination. It is recommended that more research on cost-effective rotavirus immunization with updated data be conducted and new rotavirus vaccine candidates be developed at a cheaper price to speed up the introduction of rotavirus immunization to the developing world.

Background: Each year rotavirus gastroenteritis results in thousands of paediatric hospitalisations and primary care visits in the Netherlands. While two vaccines against rotavirus are registered, routine immunisation of infants has not yet been implemented. Existing cost-effectiveness studies showed inconsistent results for these vaccines because of lack of consensus on the impact. We aimed to investigate which factors had a major impact on cost-effectiveness and were primarily responsible for the large differences in previously estimated cost-effectiveness ratios., Methods: Based on updated data on health outcomes and cost estimates, we re-assessed the cost-effectiveness of routine paediatric rotavirus vaccination within the National Immunization Program for the Netherlands. Two consensus meetings were organised with national and international experts in the field to achieve consensus and resolve potential controversies., Results: It was estimated that rotavirus vaccination in the Netherlands could avert 34,214 cases of rotavirus gastroenteritis in children aged less than 5 years. Notably, 2,779 hospitalisations were averted of which 315 were extensions of existing hospital stays due to nosocomial rotavirus infection. With a threshold varying from 20K € - 50K € per QALY and according to the base-case scenario, the full vaccination costs per child leading to cost-effectiveness was € 57.76 -€ 77.71. Results were sensitive to the inclusion of potential vaccine induced herd protection, QALY losses and number of deaths associated with rotavirus gastroenteritis., Conclusions: Our economic analysis indicates that inclusion of rotavirus vaccination in the Dutch National Immunization Program might be cost-effective depending on the cost of the vaccine and the impact of rotavirus gastroenteritis on children's quality of life.

Healthcare decisions on vaccination programs mainly rely on the direct burden of illness and related costs of the disease. Next to the expected direct beneficial effect of pediatric immunization programs against Streptococcus pneumoniae, worldwide implementation of these programs has also been driven by the indirect beneficial impact as observed among various nontargeted age groups in Northern America. In this article, we provide a descriptive overview of the post-marketing surveillance and show that there are large differences in the observed disease epidemiology after implementation of pediatric pneumococcal immunization programs across countries. Possible factors responsible for these differences may include vaccine-serotype coverage, implemented vaccination schedules, antibiotic resistance rates and pneumococcal disease incidence prior to vaccination. A potential limitation can be found in the installation or enhancement of existing surveillance systems as well as other potential confounding bias, which may have influenced observed disease rates in the included observational studies. We conclude that the health and economic impact should be addressed in light of the country specific pneumoccocal disease epidemiology to support decisions on immunization programs.

Background: Pharmacoeconomic evaluations of new drug therapies are often required for reimbursement or guidance decisions. However, for orphan drugs, country-specific requirements exist. In the Netherlands, orphan drug developers can be exempted from providing a full pharmacoeconomic evaluation, whereas in Scotland, no such exceptions can be made, although additional modifying factors specific to orphan products may be considered., Objective: The aim of the present work was to identify differences in the outcomes of the recommendations for orphan drugs for rare diseases between 2 European countries: Scotland and the Netherlands., Methods: All orphan drug reports to the Dutch Committee for Pharmaceutical Assistance (Commissie Farma-ceutische Hulp [CFH]) and orphan drugs guidance issued by the Scottish Medicines Consortium (SMC) through May 2009 were reviewed from the respective organizations' Web sites. The following were gathered from the pharmacoeconomic analyses and recommendations for reimbursement in the Netherlands or guidance for drug use in Scotland: drug indication, outcome of pharmacoeconomic evaluation, recommendation, and exact date., Results: Dossiers for 38 orphan drugs were submitted to the CFH; 37 were submitted to the SMC. Only 1 submission to the CFH included a full pharmacoeconomic analysis; all other reports included only a cost analysis. Twenty-four submissions to the SMC were accompanied by a full pharmacoeconomic evaluation; no information could be obtained for 4 drugs. The remaining reports either did not include a cost-effectiveness analysis or were deemed insufficient by the SMC. Forty-three percent (10/23) of the cost-utility analyses submitted to the SMC reported an unfavorable outcome of more than £30,000/ quality-adjusted life-year (QALY) gained; of these, only 2 (20%) reporting incremental cost-utility ratios of £43.717 to £81.000 were granted a restricted positive recommendation. The CFH gave positive recommendations for reimbursement for 36 of 38 submissions (95%). Of the 37 orphan drugs submitted to the SMC, 19 (51%) received a positive recommendation for use. Seventy-three percent (8/11) of submissions to the SMC with an unfavorable cost-effectiveness estimate (ie, more than £30,000 [€34,000 or US $48,000] per QALY gained) received a negative recommendation for reimbursement., Conclusions: Ninety-five percent of orphan drug submissions were approved for reimbursement in the Netherlands, compared with 51% in Scotland, during the period of interest. Moreover, cost-effectiveness or cost-utility analyses were included in 24 of 37 submissions in Scotland, compared with only 1 of 38 in the Netherlands., (Copyright © 2010 Excerpta Medica Inc. All rights reserved.)

Background: Community-acquired pneumonia and invasive pneumococcal disease are common among older people (ie, those aged > or =65 years). A new 13-valent pneumococcal conjugate vaccine (PCV-13) is under study in the Netherlands., Objective: The aim of this work was to model the cost-effectiveness of PCV-13 vaccination among those aged > or =65 years in the Netherlands, both in the total population and in those at increased risk for pneumonia, for various levels of efficacy (30%-90%) assumed., Methods: Our previously published cost-effectiveness model was updated to include age-specific epidemiologic data and health-care utilization and costs for a hypothetical cohort of adults aged > or =65 years in the Netherlands. This cohort was followed twice-once as unvaccinated and once as vaccinated-over a time period of 5 years, with differences between both analyses reported. Outcome measures included costs, life-years gained (LYGs), quality-adjusted life-years, and incremental cost-effectiveness ratios (ICERs). All analyses were performed from a societal perspective., Results: In the model, the ICER for vaccination remained below euro80,000/LYG, except when the vaccine was assumed to protect only against bacteremic pneumonia, with a relatively low effectiveness (40%) in combination with a high vaccine price (euro65), and indirect effects of serotype replacement would largely offset the direct effect of vaccination. For various assumptions, introduction of widespread PCV-13 vaccination (assuming a 60% efficacy against invasive and noninvasive disease because of vaccine serotypes, and a cost of euro50 per vaccinated person) was associated with the ICERs varying from cost-saving to euro50,676/LYG., Conclusions: In this model analysis of a hypothetical cohort in the Netherlands, vaccination with PCV-13 might be considered cost-effective, both for the total population and for the high-risk population aged > or =65 years, from a societal perspective, over a 5-year time horizon. The main limitation of this study was uncertainty regarding how great a proportion of pneumonia could be attributed to pneumococcal disease., (2010 Excerpta Medica Inc. All rights reserved.)

Objectives: To update cost effectiveness estimates for the four dose (3+1) schedule of the seven valent pneumococcal conjugated vaccine (PCV-7) in the Netherlands and to explore the impact on cost effectiveness of reduced dose schedules and implementation of 10 valent and 13 valent pneumococcal vaccines (PCV-10 and PCV-13)., Design: Economic evaluation comparing PCV-7, PCV-10, and PCV-13 with no vaccination using a decision tree analytic model built from data in previous studies., Setting: The Netherlands. Population A cohort of 180,000 newborns followed until 5 years of age., Main Outcome Measures: Costs; gains in life years and quality adjusted life years (QALYs); and incremental cost effectiveness ratios., Results: Under base case assumptions-that is, assuming a five year protective period of the vaccine and no assumed net indirect effects (herd protection minus serotype replacement) among children aged over 5 years-vaccination with PVC-7 in a four dose (3+1) schedule was estimated to prevent 71 and 5778 cases of invasive and non-invasive pneumococcal disease, respectively, in children aged up to 5 years. This corresponds with a total net gain of 173 life years or 277 QALYs. The incremental cost effectiveness ratio of PCV-7 was estimated at euro113,891 ( pound98,300; $145,000) per QALY, well over the ratio of euro50,000 per QALY required for PCV-7 to be regarded as potentially cost effective. A three dose (2+1) schedule of PCV-7 reduced the incremental cost effectiveness ratio to euro82,975 per QALY. For various assumptions and including 10% of the maximum net indirect effects among individuals aged 5 years and over, PCV-10 and PCV-13 had incremental cost effectiveness ratios ranging from euro31,250 to euro52,947 per QALY., Conclusions: The current Dutch infant vaccination programme of four doses of PCV-7 is not cost effective because of increases in invasive disease caused by non-vaccine serotypes, which reduces the overall direct effects of vaccination and offsets potential positive herd protection benefits in unvaccinated individuals. The 10 valent and 13 valent pneumococcal vaccines could have better net health benefits than PCV-7 through less replacement disease and increased herd protection. Both these effects could substantially reduce the incremental cost effectiveness ratio to possibly acceptable levels, if total programme costs can be lowered by reduced schedules, reductions in vaccine prices, or both.

Several recently published European cost-effectiveness studies on the 7-valent pneumococcal conjugate vaccine (PCV-7: Prevnar((R))) have included net-indirect vaccine benefits for non-vaccine protected groups into their studies, which might be too optimistic an approach given recent data. Net-indirect effects result from herd protection minus serotype replacement effects. In this study we analyze the impact of net-indirect effects in non-vaccine protected groups of 5 years of age and older with updated assumptions regarding epidemiologic data and health care unit costs. Without net-indirect benefits for non-vaccine protected groups included the cost-effectiveness ratio is estimated at euro72,360 per QALY. In order to obtain cost-effectiveness ratios below the threshold of euro50,000 per QALY - which is in the middle of the range that is often referred to in the Netherlands - the net-indirect protective effect should at least be 16% of which has been observed in the USA after the introduction of PCV-7.