The herpes zoster (HZ) virus is associated with significant morbidity. Its incidence and severity are higher among older adults and immunocompromised individuals. This systematic review assessed the clinical efficacy and effectiveness of recombinant zoster vaccine (RZV) for the prevention of HZ and associated complications in adults at least 50 years of age and in adults (≥18 years) at increased risk of HZ.

Electronic searches restricted to between 2008 and July 2023 were conducted in Embase, MEDLINE, the Cochrane Library, and clinical trial registries. Two reviewers independently screened articles and extracted data. The review adhered to the PRISMA reporting guidelines. Quality appraisal was assessed using version two of the Cochrane risk-of-bias tool for randomized trials tool and the Risk of Bias in Non-Randomized Studies - of Interventions tool. Meta-analysis was undertaken using Cochrane methodology, with preference given to random effects meta-analysis because of study heterogeneity.

Twelve RCTs and five cohort studies were identified. Vaccine efficacy was defined as one minus the incidence rate ratio, multiplied by 100. For the general population, vaccine efficacy was 92 percent (n=29,311 individuals) and vaccine effectiveness was 70 percent (n=43,990,671 individuals). Based on one trial, vaccine efficacy in the general population (aged ≥50 years) waned from an initial 97.7 percent to 73.2 percent by year 10. Two RCTs reported vaccine efficacy for those at increased risk: 68.2 percent in hematopoietic stem cell transplant recipients and 87.2 percent in those with hematological malignancies. Secondary analyses were limited by sample size.

There is clear, consistent evidence that RZV is effective in reducing HZ incidence. Although the vaccine is effective in those who are least 18 years of age and are at increased risk of HZ, efficacy may be lower compared with a general population aged at least 50 years. Secondary analyses (age subgroups, HZ complications, and HZ-related hospitalizations) were limited by small sample size, leading to inconclusive results.

Influenza causes considerable morbidity and mortality. Vaccine effectiveness is variable due to the evolution of influenza viruses and antigenic mismatch. In Ireland, influenza vaccination is reimbursed for all individuals aged at least 65 years as well as those who are at increased risk of exposure or severe disease. However, it is unclear whether reimbursement should be extended from 2023 to 2024 to those aged 50 to 64 years in the general population.

A rapid health technology assessment (HTA) format was chosen due to time constraints, as the findings were to inform a decision for the upcoming influenza season only and would not result in a permanent change to the vaccination program. National sentinel surveillance data (for seasons 2010-2011 to 2022-2023) and hospitalization data for the publicly funded healthcare system (for years 2010-2022) were used. Central Statistics Office data indicated that the projected population for 2023 of those aged 50 to 64 years was 914,379. Given the one-year timeframe, the economic evaluation was limited to a costing analysis to estimate the potential cost associated with expanding the program.

Surveillance data showed year-on-year variability in influenza incidence. Excluding the years not considered representative due to the influence of COVID-19, on average 12.9 percent (range 9 to 17%) of notified cases, 11.8 percent (range 9 to 17%) of influenza-related hospital admissions, 23.2 percent (range 12 to 34%) of influenza-related intensive care admissions, and 9.6 percent (range 0 to 44%) of influenza-related deaths per year were in people aged 50 to 64 years. Data were not disaggregated according to vaccination or risk status. The estimated mean incremental cost of extending eligibility for the 2023 to 2024 season (based on a 35% uptake rate) was EUR2.27 million (range EUR1.9 million to EUR2.65 million, depending on vaccine costs).

Given the relatively modest number of influenza-related hospitalizations in the 50- to 64-year age group, and the substantial year-on-year variability in vaccine effectiveness, the potential for a reduction in demand for hospital care is likely to be small. While a rapid HTA approach facilitates timely decision support, it creates challenges for exploring the more complex facets of an intervention.

Herpes zoster (HZ), also known as shingles, is characterized by a vesicular skin rash, often associated with acute pain and itching. The safety profile of the recombinant zoster vaccine (RZV) in adults aged 50 years and older and in adults aged 18 and older who are at increased risk of HZ was assessed in this systematic review.

A comprehensive electronic search was performed in Embase, MEDLINE, the Cochrane Library, and clinical trials registries. Searches were limited to the period from 2008 to July 2023. Article screening and data extraction were carried out by two independent reviewers. Risk of bias was assessed using the Cochrane revised Risk of Bias 2 (RoB2) tool for randomized controlled trials (RCTs). The Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool was used to assess the quality of non-randomized studies. An adapted version of the Newcastle–Ottawa Scale was used for the appraisal of quality of non-comparative studies.

Eighteen RCTs, four observational cohort studies, seven single-arm trials, and 11 single-arm observational studies were identified. Compared with placebo, solicited local (RZV: 74.1 to 84.0%; placebo: 7.9 to 11.9%) and systemic reactions (RZV: 53.0 to 66.1%; placebo: 6 to 11.4%) were more common in the vaccinated cohorts. Reactions were generally transient and mild to moderate in intensity. The most frequent reactions reported were pain at the reaction site, fatigue, and myalgia. The incidence of potential immune-mediated diseases (pIMDS), serious adverse events (SAEs), and fatalities was similar in vaccine and placebo groups. No SAEs, pIMDs, or deaths were reported as vaccine related.

The available data on RZV shows that while local and systemic adverse events are common with RZV, these are typically transient, and SAEs are uncommon in both the general population and those at increased risk of HZ.

Herpes zoster and post-herpetic neuralgia (PHN) can cause significant pain and morbidity, impacting on the health-related quality of life of those affected. This research aimed to identify primary studies that elicited health state utility values (HSUVs) relating to both acute herpes zoster and PHN, and to assess their suitability for an economic model of herpes zoster vaccination.

Cost-effectiveness analyses of herpes zoster vaccination were identified from (i) a recently published systematic review of economic evaluations of herpes zoster vaccination and (ii) an independently conducted rapid review that sought to update the results of the identified systematic review. The evaluations were hand-searched to identify original studies that elicited HSUVs of interest. Narrative synthesis of the original study characteristics was conducted and possible sources of variation in the studies identified. Appraisal of the methodological quality of the studies was undertaken using a published open response tool that outlined key quality assessment criteria for HSUV studies.

Twenty-one studies that elicited HSUVs were identified. Values related either to changes in utility resulting from increased pain severity, or to changes with time since disease onset. Heterogeneity was observed, potentially caused by differences in population size and characteristics, methods of elicitation, and preference weights used to value utility. Methodological quality varied across studies, with concerns around low sample sizes for populations with PHN, and poor reporting of both missing data and uncertainty around the HSUVs obtained. Differences in study population, time of participant recruitment, and methods of measuring utility could limit the applicability of HSUV study data.

This study highlights both the heterogeneity in HSUVs obtained for herpes zoster and the challenges associated with selecting HSUV data suitable for an economic model. An evidence base from which to select values for an economic evaluation has been created, though poor methodological quality and reporting of the primary studies may compromise the validity of point estimates obtained.

Utilization of the Emergency Department (ED) for non-urgent care increases demand for services, therefore reducing avoidable attendance is an important area for intervention in the prevention of ED crowding. This study aims to develop a consensus among clinicians across care settings about the “appropriateness” of attendance at the ED in Ireland.

The Better Data, Better Planning study was a multi-center, cross-sectional study investigating factors influencing ED utilization in Ireland. Following ethical approval, data was compiled in patient summary files which were assessed for measures of appropriateness by an academic General Practitioner (GP) and academic Emergency Medicine Consultant (EMC) National Panel. In cases where consensus was not reached charts were assessed by an Independent Review Panel (IRP). At each site all files were autonomously assessed by local GP-EMC panels.

The National Panel determined that 11% (GP) to 38% (EMC) of n=306 lower acuity presentations could be treated by a GP within 24-48h (k=0.259; p<0.001) and that 18% (GP) to 35% (EMC) of attendances could be considered “inappropriate” (k=0.341; p<0.001). For attendances deemed “appropriate” the admission rate was 47% compared to 0% for “inappropriate” attendees. There was no consensus on 45% of charts (n=136). Subset analysis by the IRP determined that consensus for appropriate attendances ranged from 0-59% and for inappropriate attendances ranged from 0-29%. For the Local Panel review (n=306) consensus on appropriateness ranged from 40-76% across sites.

Multidisciplinary clinicians agree that “inappropriate” use of Irish EDs is an issue. However, obtaining consensus on appropriateness of attendance is challenging and there was a significant cohort of complex heterogeneous presentations where agreement could not be reached by clinicians in this study. This research again demonstrates the complexity of ED crowding, the introduction of evidence-based care pathways targeting avoidable presentations may serve to alleviate the problem in our EDs.

Economic models contain several parameters ordinarily subject to uncertainty. Unlike most other model parameters, costs can constitute numerous distinct components. For example, a surgical intervention can require a variety of disposables and reusable equipment. A micro-costing output may be disaggregated or presented as a total cost. Uncertainty could be applied to individual cost components or to total cost. We aimed to explore how disaggregation of cost data may impact on uncertainty using a case study.

A set of simulations using hypothetical scenarios were developed with uncertainty set at ± 20 percent. The simulations investigated the impact of number of cost components, balance between components, and correlation between them. A cost-utility model from an assessment of robot-assisted radical prostatectomy was analyzed; procedure cost was divided into 32 individual cost components or treated as a total cost.

Based on five equal cost components, uncertainty reduces from ± 20 percent for correlated variables to ± 9 percent for uncorrelated variables. With increasing numbers of uncorrelated cost components, the uncertainty in the total cost decreases markedly. The uncertainty around total robot-assisted surgery procedure equipment costs was ± 19.7 percent when components were correlated and ± 9.4 percent when uncorrelated. The impact on uncertainty in the incremental cost effectiveness ratio (ICER) was negligible but the ranking of parameters in the univariate sensitivity analysis changed.

Analyzing uncertainty by aggregated or disaggregated costs can have implications for presenting uncertainty in costs to decision makers. Applying uncertainty to aggregated costs essentially implies that variation in the cost of individual components is perfectly correlated. By disaggregating cost components they are being treated as uncorrelated, which can substantially reduce uncertainty in the total cost. In this case study we found that although the reduction in uncertainty could be clearly seen in the cost parameter, it had a negligible impact on uncertainty in the ICER.

Applicability of incremental cost-effectiveness ratios from another jurisdiction is often affected by a different local discount rate, creating uncertainty about the ICER using the local discount rate. The ICER is sometimes reported at additional discount rates in the sensitivity analysis. We aimed to investigate the extent to which an ICER can be predicted at a given non-differential discount rate if estimates are available for at least two discount rates.

We used six previously published economic models representing analyses with a range of time horizons and ICERs calculated at discount rates from 1% to 8%. A simulation exercise was applied whereby the ICER at a discount rate selected from the range 2% to 5% was calculated based on ICERs provided at two or three randomly selected discount rates. With two discount rates a linear model was used to predict the ICER at the selected rate. For three discount rates an exponential model was used. Error between the predicted and actual ICER was calculated as the absolute difference divided by the actual ICER.

For four of the models, ICERs could be well predicted by a linear model (i.e., with two points), with average errors of less than 5%. For the final two models the error was substantial with a linear model but substantially improved to under 15% with an exponential model (i.e., with three data points). The two models with a poor fit to a linear model assessed childhood vaccination programmes over a lifetime horizon.

For studies with a relatively short time-horizon, or where the majority of costs and benefits accrue in the short-term, a simple linear extrapolation can facilitate calculation of the ICER at a discount rate other than those reported. With longer time horizons, a third data point facilitates more reliably extrapolation of ICERs at desired discount rates.

A number of economic evaluations of gender-neutral human papillomavirus (HPV) vaccination have been published, generally finding that the cost-effectiveness is sensitive to the uptake rate in girls. In Ireland there is a girls-only program in place, but the initial high uptake rate (>85 percent) was substantially impacted by high profile negative publicity concerning perceived vaccine safety issues. Efforts to address perceived safety concerns have recently yielded a partial recovery in uptake rates. The aim of this study was to estimate the cost-utility of extending the program to include boys and explore the impact of fluctuating uptake rates.

A previously published cost-utility model used in the United States of America and Norway was adapted to the Irish setting and populated with Irish epidemiological and cost data. Comparators included no vaccination, and girls-only and gender-neutral vaccination, both with either a 4-valent or 9-valent vaccine. Vaccination is at age 12 years and oropharyngeal and penile cancers were excluded in the base case analysis. Additional analyses were used to incorporate fluctuating uptake rates into the model.

A 9-valent girls-only program dominated the existing girls-only 4-valent program. The incremental cost-effectiveness ratio (ICER) for a gender-neutral 9-valent program was EUR 50,823/quality-adjusted life year (QALY). Gender-neutral vaccination would be cost-effective at a willingness-to-pay threshold of EUR 45,000/QALY when the uptake rate is below 78 percent. The ICER decreased to between EUR 41,000 and EUR 42,000/QALY when the uptake rate was allowed to fluctuate across six to 12 yearly cycles.

The cost-effectiveness of gender-neutral HPV vaccination is highly sensitive to the assumed uptake rate in girls. Large fluctuations in HPV vaccine uptake rates have been observed in a number of countries in the last decade. Incorporating fluctuating uptake rates in the model shows that a gender-neutral program may be more cost-effective than when a stable uptake is assumed.

Health technology assessment (HTA) is a resource-intensive decision support tool that is typically structured around a set of defined domains. Sometimes urgent requests for HTAs arise that may be subject to very short timeframes, creating unique challenges. This study aimed to describe some of the options for carrying out a “hasty HTA”, and the impact of those options.

We recently completed a HTA for the Department of Health in Ireland with a strict 2-month deadline. We considered the impact of the short timeline using the project management triple constraint framework whereby the quality of a project is constrained by cost, scope, and schedule.

When delivering HTAs within short timeframes the schedule is an inflexible constraint. Providing interim advice pending a full assessment may set a precedent, or may not be possible if capital expenditure is already entailed. Additional staff should enable research to be completed faster, although economies of scale may not fully apply. Frequently such resources are not readily available. The reduction of scope through the omission of domains offers the best prospect of facilitating a short timeframe for a HTA. Scope may also be reduced through a less comprehensive analytical approach, but this creates a risk of reduced accuracy. Curtailing data collection and analysis is likely to increase uncertainty in the findings. Risk management is important when comprehensive quality assurance may not be possible.

Carrying out HTAs in short timeframes has implications for content, approach, and, potentially, quality. Agencies must consider how they can meet the needs of the decision maker without overly compromising accuracy or relevance. Due to resource constraints, the best approach is likely to be judicious changes to the scope to remove assessment elements that are unlikely to have a substantive impact on the decision.

Fully probabilistic analyses are now standard for economic models, with all parameters varied according to probability distributions. Using univariate sensitivity analyses to explore the influence of different parameters on the model results are also standard. Although there are several approaches available, there has been little discussion of the merits of each or justification for the method used in any given analysis. The aim of this study was to compare three approaches to univariate sensitivity analysis using a case study.

We considered three univariate sensitivity analysis approaches: (i) set one parameter at its upper and lower bounds while all others are set at their mean value; (ii) analysis of variance; and (iii) set one parameter at its mean and vary all others. We compared these approaches using an economic model of mechanical thrombectomy for the treatment of acute ischemic stroke, considering outcomes of incremental costs, incremental quality-adjusted life-years (QALYs), and net monetary benefit (NMB).

For incremental costs and QALYs the correlation between the approaches was moderate to high, with correlation coefficients between 0.46 and 0.94. For NMB the correlation between approaches was also high (range 0.89 to 0.98), but some of the most influential parameters were ranked differently. Setting one parameter at its upper and lower bounds was the only method that facilitated an analysis of direction of influence.

The three approaches addressed different but relevant questions. Setting individual parameters at their bounds is effectively a systematic scenario analysis and may be misleading to decision makers. Analysis of variance may be more easily interpreted, but it has disadvantages. Setting a parameter at its mean, while varying other parameters, is similar to value of information analysis. As with any sensitivity analysis, it is imperative that the uncertainty associated with each parameter is adequately captured in the model.