The effectiveness and cost of integrating pharmacists within general practice to optimize prescribing and health outcomes in primary care patients with polypharmacy: a systematic review.

BACKGROUND: Polypharmacy and associated potentially inappropriate prescribing (PIP) place a considerable burden on patients and represent a challenge for general practitioners (GPs). Integration of pharmacists within general practice (herein 'pharmacist integration') may improve medications management and patient outcomes. This systematic review assessed the effectiveness and costs of pharmacist integration. METHODS: A systematic search of ten databases from inception to January 2021 was conducted. Studies that evaluated the effectiveness or cost of pharmacist integration were included. Eligible interventions were those that targeted medications optimization compared to usual GP care without pharmacist integration (herein 'usual care'). Primary outcomes were PIP (as measured by PIP screening tools) and number of prescribed medications. Secondary outcomes included health-related quality of life, health service utilization, clinical outcomes, and costs. Randomised controlled trials (RCTs), non-RCTs, interrupted-time-series, controlled before-after trials and health-economic studies were included. Screening and risk of bias using Cochrane EPOC criteria were conducted by two reviewers independently. A narrative synthesis and meta-analysis of outcomes where possible, were conducted; the certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. RESULTS: In total, 23 studies (28 full text articles) met the inclusion criteria. In ten of 11 studies, pharmacist integration probably reduced PIP in comparison to usual care (moderate certainty evidence). A meta-analysis of number of medications in seven studies reported a mean difference of -0.80 [-1.17, -0.43], which indicated pharmacist integration probably reduced number of medicines (moderate certainty evidence). It was uncertain whether pharmacist integration improved health-related quality of life because the certainty of evidence was very low. Twelve health-economic studies were included; three investigated cost effectiveness. The outcome measured differed across studies limiting comparisons and making it difficult to make conclusions on cost effectiveness. CONCLUSIONS: Pharmacist integration probably reduced PIP and number of medications however, there was no clear effect on other patient outcomes; and while interventions in a small number of studies appeared to be cost-effective, further robust, well-designed cluster RCTs with economic evaluations are required to determine cost-effectiveness of pharmacist integration. TRIAL REGISTRATION: CRD42019139679.

Neoadjuvant treatment for stage III and IV cutaneous melanoma.

BACKGROUND: Cutaneous melanoma is amongst the most aggressive of all skin cancers. Neoadjuvant treatment is a form of induction therapy, given to shrink a cancerous tumour prior to the main treatment (usually surgery). The purpose is to improve survival and surgical outcomes. This review systematically appraises the literature investigating the use of neoadjuvant treatment for stage III and IV cutaneous melanoma. OBJECTIVES: To assess the effects of neoadjuvant treatment in adults with stage III or stage IV melanoma according to the seventh edition American Joint Committee on Cancer (AJCC) staging system. SEARCH METHODS: We searched the following databases up to 10 August 2021 inclusive: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, LILACS and four trials registers, together with reference checking and contact with study authors to identify additional studies. We also handsearched proceedings from specific conferences from 2016 to 2020 inclusive. SELECTION CRITERIA: Randomised controlled trials (RCTs) of people with stage III and IV melanoma, comparing neoadjuvant treatment strategies (using targeted treatments, immunotherapies, radiotherapy, topical treatments or chemotherapy) with any of these agents or current standard of care (SOC), were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Primary outcomes were overall survival (OS) and adverse effects (AEs). Secondary outcomes included time to recurrence (TTR), quality of life (QOL), and overall response rate (ORR). We used GRADE to evaluate the certainty of the evidence. MAIN RESULTS: We included eight RCTs involving 402 participants. Studies enrolled adults, mostly with stage III melanoma, investigated immunotherapies, chemotherapy, or targeted treatments, and compared these with surgical excision with or without adjuvant treatment. Duration of follow-up and therapeutic regimens varied, which, combined with heterogeneity in the population and definitions of the endpoints, precluded meta-analysis of all identified studies. We performed a meta-analysis including three studies. We are very uncertain if neoadjuvant treatment increases OS when compared to no neoadjuvant treatment (hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.15 to 1.21; 2 studies, 171 participants; very low-certainty evidence). Neoadjuvant treatment may increase the rate of AEs, but the evidence is very uncertain (26% versus 16%, risk ratio (RR) 1.58, 95% CI 0.97 to 2.55; 2 studies, 162 participants; very low-certainty evidence). We are very uncertain if neoadjuvant treatment increases TTR (HR 0.51, 95% CI 0.22 to 1.17; 2 studies, 171 participants; very low-certainty evidence). Studies did not report ORR as a comparative outcome or measure QOL data. We are very uncertain whether neoadjuvant targeted treatment with dabrafenib and trametinib increases OS (HR 0.28, 95% CI 0.03 to 2.25; 1 study, 21 participants; very low-certainty evidence) or TTR (HR 0.02, 95% CI 0.00 to 0.22; 1 study, 21 participants; very low-certainty evidence) when compared to surgery. The study did not report comparative rates of AEs and overall response, and did not measure QOL. We are very uncertain if neoadjuvant immunotherapy with talimogene laherparepvec increases OS when compared to no neoadjuvant treatment (HR 0.49, 95% CI 0.15 to 1.64; 1 study, 150 participants, very low-certainty evidence). It may have a higher rate of AEs, but the evidence is very uncertain (16.5% versus 5.8%, RR 2.84, 95% CI 0.96 to 8.37; 1 study, 142 participants; very low-certainty evidence). We are very uncertain if it increases TTR (HR 0.75, 95% CI 0.31 to 1.79; 1 study, 150 participants; very low-certainty evidence). The study did not report comparative ORRs or measure QOL. OS was not reported for neoadjuvant immunotherapy (combined ipilimumab and nivolumab) when compared to the combination of ipilimumab and nivolumab as adjuvant treatment. There may be little or no difference in the rate of AEs between these treatments (9%, RR 1.0, 95% CI 0.75 to 1.34; 1 study, 20 participants; low-certainty evidence). The study did not report comparative ORRs or measure TTR and QOL. Neoadjuvant immunotherapy (combined ipilimumab and nivolumab) likely results in little to no difference in OS when compared to neoadjuvant nivolumab monotherapy (P = 0.18; 1 study, 23 participants; moderate-certainty evidence). It may increase the rate of AEs, but the certainty of this evidence is very low (72.8% versus 8.3%, RR 8.73, 95% CI 1.29 to 59; 1 study, 23 participants); this trial was halted early due to observation of disease progression preventing surgical resection in the monotherapy arm and the high rate of treatment-related AEs in the combination arm. Neoadjuvant combination treatment may lead to higher ORR, but the evidence is very uncertain (72.8% versus 25%, RR 2.91, 95% CI 1.02 to 8.27; 1 study, 23 participants; very low-certainty evidence). It likely results in little to no difference in TTR (P = 0.19; 1 study, 23 participants; low-certainty evidence). The study did not measure QOL. OS was not reported for neoadjuvant immunotherapy (combined ipilimumab and nivolumab) when compared to neoadjuvant sequential immunotherapy (ipilimumab then nivolumab). Only Grade 3 to 4 immune-related AEs were reported; fewer were reported with combination treatment, and the sequential treatment arm closed early due to a high incidence of severe AEs. The neoadjuvant combination likely results in a higher ORR compared to sequential neoadjuvant treatment (60.1% versus 42.3%, RR 1.42, 95% CI 0.87 to 2.32; 1 study, 86 participants; low-certainty evidence). The study did not measure TTR and QOL. No data were reported on OS, AEs, TTR, or QOL for the comparison of neoadjuvant interferon (HDI) plus chemotherapy versus neoadjuvant chemotherapy. Neoadjuvant HDI plus chemotherapy may have little to no effect on ORR, but the evidence is very uncertain (33% versus 22%, RR 1.75, 95% CI 0.62 to 4.95; 1 study, 36 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: We are uncertain if neoadjuvant treatment increases OS or TTR compared with no neoadjuvant treatment, and it may be associated with a slightly higher rate of AEs. There is insufficient evidence to support the use of neoadjuvant treatment in clinical practice. Priorities for research include the development of a core outcome set for neoadjuvant trials that are adequately powered, with validation of pathological and radiological responses as intermediate endpoints, to investigate the relative benefits of neoadjuvant treatment compared with adjuvant treatment with immunotherapies or targeted therapies.

Tisagenlecleucel for relapsed/refractory acute lymphoblastic leukemia in the Irish healthcare setting: cost-effectiveness and value of information analysis.

OBJECTIVES: This study evaluates the cost-effectiveness of tisagenlecleucel (a CAR T-cell therapy), versus blinatumomab, for the treatment of pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) in the Irish healthcare setting. The value of conducting further research, to investigate the value of uncertainty associated with the decision problem, is assessed by means of expected value of perfect information (EVPI) and partial EVPI (EVPPI) analyses. METHODS: A three-state partitioned survival model was developed. A short-term decision tree partitioned patients in the tisagenlecleucel arm according to infusion status. Survival was extrapolated to 60 months; general population mortality with a standardized mortality ratio was then applied. Estimated EVPI and EVPPI were scaled up to population according to the incidence of the decision. RESULTS: At list prices, the incremental cost-effectiveness ratio was EUR 73,086 per quality-adjusted life year (QALY) (incremental costs EUR 156,928; incremental QALYs 2.15). The probability of cost-effectiveness, at the willingness-to-pay threshold of EUR 45,000 per QALY, was 16 percent. At this threshold, population EVPI was EUR 314,455; population EVPPI was below EUR 100,000 for each parameter category. CONCLUSIONS: Tisagenlecleucel is not cost effective, versus blinatumomab, for the treatment of pediatric and young adult patients with R/R ALL in Ireland (at list prices). Further research to decrease decision (parameter) uncertainty, at the defined willingness-to-pay threshold, may not be of value. However, there is a high degree of uncertainty underpinning the analysis, which may not be captured by EVPI analysis.

The Utility of a Rapid Review Evaluation Process to a National HTA Agency.

BACKGROUND AND OBJECTIVE: In Ireland, similar to other jurisdictions, health technology assessment (HTA) is used to inform the health payer's drug reimbursement decisions. These HTAs are conducted by the National Centre for Pharmacoeconomics (NCPE). In 2009, the NCPE introduced the Rapid Review process to identify drugs that do not require further assessment in the form of the previously established full HTA process. METHODS: A retrospective analysis of all Rapid Reviews submitted to the NCPE from 2010 to 2019, inclusive, was conducted. Rapid Review recommendation was recorded (i.e. full HTA required or not required). For those submitted from 2012 to 2019, additional data relating to the drug, economic and clinical evidence-related factors were collected. Multivariable logistic regression methods were used to model the relationship between these factors and the likelihood of requiring a full HTA. An exploratory analysis estimated the additional NCPE appraisal time that would have been required to evaluate all drugs, had the Rapid Review process not been established. RESULTS: Of the 446 Rapid Reviews submitted, approximately half (49.6%) were deemed to require a full HTA. Drugs for cancer indications, drugs designated first-in-class status, and high-cost drugs were positively and significantly associated with the likelihood of requiring a full HTA. No significant association was found for drugs for orphan indications when factors relating to cost and clinical evidence were included in the model. Without the Rapid Review process, an estimated additional 15,631 NCPE appraisal days would have been required to evaluate all drugs submitted over the 10-year period. CONCLUSIONS: This is the first study to use data uniquely available to the NCPE to evaluate factors associated with the requirement for a full HTA following a Rapid Review. The process has reduced the NCPE appraisal time required to evaluate all submissions over the study period. The NCPE's Rapid Review process allows for appropriate resource prioritisation within a national HTA agency.

Estimating the Theoretical Cost Implications of Funding New Drugs Considered Not to Be Cost-Effective.

This study aims to estimate the theoretical excess expenditure that would be incurred by the Irish state-payer, should drugs be reimbursed at their original asking ("list") price rather than at a price at which the drug is considered cost-effective. In Ireland, all new drugs are evaluated by the National Centre for Pharmacoeconomics. For this study, drugs that were submitted by pharmaceutical companies from 2012 to 2017 and considered not cost-effective at list price were reviewed. A total of 43 such drugs met our inclusion criteria, and their pharmacoeconomic evaluations were further assessed. The price at which the drug could be considered cost-effective (cost-effective price) at the upper cost-effectiveness threshold used in Ireland (€ 45 000/quality adjusted life-year) was estimated for 18 drugs with an available cost-effectiveness model. Then, for each drug, the list price and cost-effective price (both per unit) were both individually applied to 1 year of national real-world drug utilization data. This allowed the estimation of the expected expenditures under the assumptions of list price paid and cost-effective price paid. The resulting theoretical excess expenditure, the expenditure at list price minus the expenditure at the cost-effective price, was estimated to be €108.2 million. This estimate is theoretical because of the confidentiality of actual drug prices. The estimation is calculated using the list price and likely overestimates the actual excess expenditure, which would reduce to zero if cost-effective prices are agreed. Nevertheless, this estimate illustrates the importance of a process to assess the value of new drugs so that potential excess drug expenditure is identified.

Integrating clinical pharmacists within general practice: protocol for a pilot cluster randomised controlled trial.

INTRODUCTION: Managing patients with multiple conditions (multimorbidity) is a major challenge for healthcare systems internationally, particularly in older patients. Multimorbidity and subsequent polypharmacy increase treatment burden and the risk of potentially inappropriate prescribing, and both are complex to manage in primary care. Limited evidence suggests integration of pharmacists into general practice teams could improve medication management for patients with multimorbidity and polypharmacy. Building on findings from a non-randomised, uncontrolled General Practice Pharmacist (GPP) feasibility study conducted in Irish primary care, the aim of this study is to conduct a pilot cluster randomised controlled trial (cRCT) of the GPP study, to assess feasibility, intervention impact, costs and appropriateness of continuing to a definitive cRCT. METHODS AND ANALYSIS: This pilot cRCT will involve 8 general practitioner (GP) practices and 120 patients. Practices will identify and recruit patients aged ≥65 years, who are taking ≥10 regular medications. Practices will be allocated to intervention or control after baseline data collection. Intervention practices will have a pharmacist integrated within their service, working with GPs, patients and practice staff to optimise prescribing and other medication-related activities. Control practices will provide standard GP care. The primary feasibility outcomes will include recruitment rate, uptake of medication reviews and study retention. For the primary clinical outcome, the number of potentially inappropriate prescribing incidences per patient will be collected. Secondary outcomes will include medication-related outcomes, patient-reported outcome measures, and data pertaining to the role and impact of the pharmacist on prescribing. In addition, economic and process evaluations will be conducted. ETHICS AND DISSEMINATION: This trial has been approved by the Irish College of General Practitioners Research Ethics Committee and will be performed in accordance with the Declaration of Helsinki. The results will be reported in peer-reviewed journals and be presented at national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN Registry (https://doi.org/10.1186/ISRCTN18752158).

Characteristics and determinants of high volume dispensing in long-term oral nutritional supplement users in primary care: a secondary analysis.

BACKGROUND: Oral nutritional supplements (ONS) are recommended for patients who are malnourished or at risk of malnutrition. Appropriate ONS prescribing requires regular monitoring to assess its continued requirement. Previous research identified long-term ONS prescriptions (>6 months) without review, with 70% of these influenced by social factors. AIM: To investigate the characteristics of long-term ONS users in Ireland and the determinants of larger volumes of ONS dispensing. DESIGN & SETTING: Secondary analysis of anonymous dispensed pharmacy claims data of patients dispensed standard ONS for 12 consecutive months in 2018 (n = 912). METHOD: Factors showing significant (P<0.05) univariate associations with above the median consumption of ONS units were entered into a multivariable model. RESULTS: Median age was 76 (range 18 to 101) years, with 66.9% of the sample being ≥65 years. Almost 70% of the samples were on polypharmacy (45.6%; ≥5 medications) or excessive polypharmacy (21.5%; ≥10 medications). Younger age and being on polypharmacy for drugs having an effect on the central nervous system (CNS) were significantly associated with being dispensed more ONS units in univariate and multivariate analysis. Those patients in the age range 18 to 44 were 2.5 fold more likely to be prescribed more ONS units (odds ratio [OR] 2.5; 95% confidence interval [CI] 1.5 to 4.3; P<0.001). Patients using CNS drugs or on CNS polypharmacy were more likely to be prescribed more ONS units (ORs 1.2 and 2.4; 95% CI 0.9 to 1.4 and 1.3 to 4.4 respectively; P = 0.029). CONCLUSION: Older age and polypharmacy characterise long-term ONS users in this study. Younger age and CNS medication polypharmacy are predictors of more ONS units prescribed over a year.

Evaluation of the General Practice Pharmacist (GPP) intervention to optimise prescribing in Irish primary care: a non-randomised pilot study.

OBJECTIVE: Limited evidence suggests integration of pharmacists into the general practice team could improve medicines management for patients, particularly those with multimorbidity and polypharmacy. This study aimed to develop and assess the feasibility of an intervention involving pharmacists, working within general practices, to optimise prescribing in Ireland. DESIGN: Non-randomised pilot study. SETTING: Primary care in Ireland. PARTICIPANTS: Four general practices, purposively sampled and recruited to reflect a range of practice sizes and demographic profiles. INTERVENTION: A pharmacist joined the practice team for 6 months (10 hours/week) and undertook medication reviews (face to face or chart based) for adult patients, provided prescribing advice, supported clinical audits and facilitated practice-based education. OUTCOME MEASURES: Anonymised practice-level medication (eg, medication changes) and cost data were collected. Patient-reported outcome measure (PROM) data were collected on a subset of older adults (aged ≥65 years) with polypharmacy using patient questionnaires, before and 6 weeks after medication review by the pharmacist. RESULTS: Across four practices, 786 patients were identified as having 1521 prescribing issues by the pharmacists. Issues relating to deprescribing medications were addressed most often by the prescriber (59.8%), compared with cost-related issues (5.8%). Medication changes made during the study equated to approximately €57 000 in cost savings assuming they persisted for 12 months. Ninety-six patients aged ≥65 years with polypharmacy were recruited from the four practices for PROM data collection and 64 (66.7%) were followed up. There were no changes in patients' treatment burden or attitudes to deprescribing following medication review, and there were conflicting changes in patients' self-reported quality of life. CONCLUSIONS: This non-randomised pilot study demonstrated that an intervention involving pharmacists, working within general practices is feasible to implement and has potential to improve prescribing quality. This study provides rationale to conduct a randomised controlled trial to evaluate the clinical and cost-effectiveness of this intervention.

General practitioners' views on malnutrition management and oral nutritional supplementation prescription in the community: A qualitative study.

BACKGROUND & AIMS: Malnutrition or undernutrition, arising from a deficiency of energy and protein intake, occurs commonly among community-dwelling individuals in developed countries. Once identified, malnutrition can be effectively treated in the majority of cases with dietary advice and the prescription of oral nutritional supplements (ONS) for patients who can eat and drink orally. However, previous research has reported inadequate screening and treatment of malnutrition in the community. The aim of this qualitative study was to explore general practitioners' (GPs) experiences and opinions on the management of malnutrition and the prescription of ONS in the primary care/community setting in Ireland. METHODS: Sixteen semi-structured interviews including chart stimulated recalls (CSR) were conducted with GPs. The interviews and CSRs explored, among others, the following domains; barriers and facilitators in the management of malnutrition, ONS prescribing in the primary care/community setting, and future directions in the management of malnutrition and ONS prescribing. Recorded interviews were transcribed and analysed following a generic qualitative approach with inductive thematic analysis using NVIVO 12 to facilitate data management. RESULTS: Three main themes were identified. Theme 1: 'Malnutrition is a secondary concern', encapsulating the idea that the identification of malnutrition is usually secondary to other clinical issues or disease rather than an independent clinical outcome. This theme also includes the idea that obesity is viewed as a dominant nutritional issue for GPs. Theme 2: 'Responsibility for malnutrition and ONS management in the community', highlighting that GPs feel they do not know who is responsible for the management of malnutrition in the community setting and expressed their need for more support from other healthcare professionals (HCPs) to effectively monitor and treat malnutrition. Theme 3: 'Reluctance to prescribe ONS', emerging from the GPs reported lack of knowledge to prescribe the appropriate ONS, their concern that ONS will replace the patient's meals and the costs associated with the prescription of ONS. CONCLUSIONS: GPs in Ireland do not routinely screen for malnutrition in their clinics as they feel unsupported in treating and managing malnutrition in the community due to limited or no dietetic service availability and time constraints. GPs also view malnutrition as a secondary concern to disease management and prioritise referral to dietetic services for patients with overweight and obesity. GPs reported that they have insufficient knowledge to change or discontinue ONS prescriptions. This study demonstrates that there is a clear need for primary care training in malnutrition identification, treatment and management and more community dietetic services are needed in order to support GPs and deliver high quality care to patients.

Economic Evaluation of Systemic Treatments for Advanced Melanoma: A Systematic Review.

BACKGROUND: Many high cost treatments for advanced melanoma have become available in recent years. National health technology assessment agencies have raised concerns regarding uncertainty in their clinical and cost-effectiveness. OBJECTIVE: The aim of this systematic review is to identify economic evaluations of treatments for advanced melanoma and review model assumptions, outcomes, and quality as preparation for a health technology assessment. METHODS: A search of Embase, MEDLINE, EconLit, and the Cochrane Database was conducted. Only studies using decision-analytic models were included. Two authors independently completed full-text review and data extraction. RESULTS: Fifteen studies were identified. There were major differences in the structural assumptions underpinning the models. There was general agreement in study conclusions, although the predicted costs and quality-adjusted life years for each treatment varied. BRAF monotherapy (vemurafenib, dabrafenib) or BRAF/MEK combination therapy (BRAF monotherapy with cobimetinib or trametinib) has not been shown to be cost-effective in any jurisdiction. PD-1 inhibitors (pembrolizumab, nivolumab) are consistently found to be cost-effective compared with ipilimumab, although their cost-effectiveness compared with chemotherapy is not established. Combination therapy with nivolumab and ipilimumab is unlikely to be cost-effective in any setting. One study including all agents found that none of the new treatments were cost-effective relative to chemotherapy. Publication of the study in a health economics journal is associated with better reporting of and higher-quality assessment than those published in clinical journals. CONCLUSION: Despite differences in model structures and assumptions, the conclusions of most included studies were consistent. Health technology assessment has a key role in maximizing value from high-cost innovative treatments. Consideration should be given to divestment from BRAF/MEK inhibitors and ipilimumab in favor of reimbursement of PD-1 inhibitors.

Transferability of Economic Evaluations of Treatments for Advanced Melanoma.

BACKGROUND: Differing methodological requirements and decision-making criteria are recognised as barriers to transferability of cost-effectiveness analysis (CEA) across jurisdictions. OBJECTIVE: We assessed the generic and specific transferability of published CEAs of systemic treatments for advanced melanoma to the Irish setting. METHODS: CEAs of treatments for melanoma were identified by systematic review. Transferability to the Irish setting was assessed using the EUnetHTA transferability tool for Economic Evaluation. We present a narrative discussion comparing the differences in key parameter inputs and the likely impact of these differences on the model outcomes and the reimbursement recommendation. Transferability is considered within the context of the Irish cost-effectiveness threshold, using the net monetary benefit (NMB) framework. RESULTS: No published CEAs (n = 15) aligned with the Irish reference case for CEA. Changes to key parameters were unlikely to change the conclusions of the CEA when the cost-effectiveness threshold was considered. Ten studies (19 pairwise comparisons) were compared with findings by the National Centre for Pharmacoeconomics (NCPE) using NMB. Without accounting for differences in the cost-effectiveness threshold, there was alignment between the study conclusions and NCPE recommendations in 73.7% cases. When the Irish cost-effectiveness threshold was applied in the estimation of NMB, there was agreement in 89.5% of cases. CONCLUSIONS: Alignment in methodological requirements for CEA is important to facilitate joint health technology assessment (HTA) by regional collaborations in Europe. When parameter inputs are not exactly aligned, conclusions may still be comparable across jurisdictions. For international joint procurement initiatives, determining and implementing joint decision rules may be more important than trying to align rules regarding methodological and parameter inputs.

Analysis of Health Technology Assessments of Orphan Drugs in Ireland from 2012 to 2017.

BACKGROUND: In Ireland, health technology assessment (HTA) submissions for orphan drugs or drugs for rare diseases have increased in recent years but have not been explicitly analysed. All evaluations are conducted by the National Centre for Pharmacoeconomics (NCPE). OBJECTIVES: The objectives of this study were to ascertain the number of orphan drug submissions to the NCPE and determine how these drugs proceeded through the NCPE critical evaluation process compared with non-orphan drug submissions. METHODS: This was a retrospective analysis of applicant rapid review submissions made to the NCPE from January 2012 to December 2017 inclusive. Drugs were categorised according to the following definitions: orphan (non-cancer) drug, orphan (cancer) drug and ultra-orphan drug. In each of the three categories, the outcome of rapid review appraisal, and where relevant, the outcome of the subsequent HTA was recorded. RESULTS: During the period of study, 280 rapid review submissions were made to the NCPE, of which 21 were for orphan (non-cancer) drugs, 24 were for orphan (cancer) and ten were for ultra-orphan drugs. After rapid review, 44%, 78% and 100% of orphan (non-cancer) drugs, orphan (cancer) drugs and ultra-orphan products, respectively, were recommended for full HTA. When the outcome of the rapid review process was compared between orphan drugs and non-orphan drugs, a statistically significant difference was detected in the proportion of rapid reviews for which the outcome was 'HTA recommended' (Pearson's Chi-squared test; p = 0.04). CONCLUSIONS: The number of submissions to the NCPE for orphan drugs has increased in recent years. The rapid review and HTA process in Ireland plays a role in supporting the reimbursement decision-making process for orphan drugs in a similar manner to the process established for non-orphan drugs. However, the outcome of the reimbursement process for orphan drugs versus non-orphan drugs (in terms of access for patients) has yet to be quantified.

Examining the Feasibility and Utility of Estimating Partial Expected Value of Perfect Information (via a Nonparametric Approach) as Part of the Reimbursement Decision-Making Process in Ireland: Application to Drugs for Cancer.

BACKGROUND: In Ireland, all new drugs for which reimbursement by the healthcare payer is sought undergo a health technology assessment by the National Centre for Pharmacoeconomics. The National Centre for Pharmacoeconomics estimate expected value of perfect information but not partial expected value of perfect information (owing to computational expense associated with typical methodologies). OBJECTIVE: The objective of this study was to examine the feasibility and utility of estimating partial expected value of perfect information via a computationally efficient, non-parametric regression approach. METHODS: This was a retrospective analysis of evaluations on drugs for cancer that had been submitted to the National Centre for Pharmacoeconomics (January 2010 to December 2014 inclusive). Drugs were excluded if cost effective at the submitted price. Drugs were excluded if concerns existed regarding the validity of the applicants' submission or if cost-effectiveness model functionality did not allow required modifications to be made. For each included drug (n = 14), value of information was estimated at the final reimbursement price, at a threshold equivalent to the incremental cost-effectiveness ratio at that price. The expected value of perfect information was estimated from probabilistic analysis. Partial expected value of perfect information was estimated via a non-parametric approach. Input parameters with a population value at least €1 million were identified as potential targets for research. RESULTS: All partial estimates were determined within minutes. Thirty parameters (across nine models) each had a value of at least €1 million. These were categorised. Collectively, survival analysis parameters were valued at €19.32 million, health state utility parameters at €15.81 million and parameters associated with the cost of treating adverse effects at €6.64 million. Those associated with drug acquisition costs and with the cost of care were valued at €6.51 million and €5.71 million, respectively. CONCLUSION: This research demonstrates that the estimation of partial expected value of perfect information via this computationally inexpensive approach could be considered feasible as part of the health technology assessment process for reimbursement purposes within the Irish healthcare system. It might be a useful tool in prioritising future research to decrease decision uncertainty.

Are new models needed to optimize the utilization of new medicines to sustain healthcare systems?

Medicines have made an appreciable contribution to improving health. However, even high-income countries are struggling to fund new premium-priced medicines. This will grow necessitating the development of new models to optimize their use. The objective is to review case histories among health authorities to improve the utilization and expenditure on new medicines. Subsequently, use these to develop exemplar models and outline their implications. A number of issues and challenges were identified from the case histories. These included the low number of new medicines seen as innovative alongside increasing requested prices for their reimbursement, especially for oncology, orphan diseases, diabetes and HCV. Proposed models center on the three pillars of pre-, peri- and post-launch including critical drug evaluation, as well as multi-criteria models for valuing medicines for orphan diseases alongside potentially capping pharmaceutical expenditure. In conclusion, the proposed models involving all key stakeholder groups are critical for the sustainability of healthcare systems or enhancing universal access. The models should help stimulate debate as well as restore trust between key stakeholder groups.

Value-of-information analysis to reduce decision uncertainty associated with the choice of thromboprophylaxis after total hip replacement in the Irish healthcare setting.

BACKGROUND: The National Centre for Pharmacoeconomics, in collaboration with the Health Services Executive, considers the cost effectiveness of all new medicines introduced into Ireland. Health Technology Assessments (HTAs) are conducted in accordance with the existing agreed Irish HTA guidelines. These guidelines do not specify a formal analysis of value of information (VOI). OBJECTIVE: The aim of this study was to demonstrate the benefits of using VOI analysis in decreasing decision uncertainty and to examine the viability of applying these techniques as part of the formal HTA process for reimbursement purposes within the Irish healthcare system. METHOD: The evaluation was conducted from the Irish health payer perspective. A lifetime model evaluated the cost effectiveness of rivaroxaban, dabigatran etexilate and enoxaparin sodium for the prophylaxis of venous thromboembolism after total hip replacement. The expected value of perfect information (EVPI) was determined directly from the probabilistic analysis (PSA). Population-level EVPI (PEVPI) was determined by scaling up the EVPI according to the decision incidence. The expected value of perfect parameter information (EVPPI) was calculated for the three model parameter subsets: probabilities, preference weights and direct medical costs. RESULTS: In the base-case analysis, rivaroxaban dominated both dabigatran etexilate and enoxaparin sodium. PSA indicated that rivaroxaban had the highest probability of being the most cost-effective strategy over a threshold range of &U20AC;0-&U20AC;100 000 per QALY. At a threshold of &U20AC;45 000 per QALY, the probability that rivaroxaban was the most cost-effective strategy was 67%. At a threshold of &U20AC;45 000 per QALY, assuming a 10-year decision time horizon, the PEVPI was &U20AC;11.96 million and the direct medical costs subset had the highest EVPPI value (&U20AC;9.00 million at a population level). In order to decrease uncertainty, a more detailed costing study was undertaken. In the subsequent analysis, rivaroxaban continued to dominate both comparators. In the PSA, rivaroxaban continued to have the highest probability of being optimal over the threshold range &U20AC;0-&U20AC;100 000 per QALY. At &U20AC;45 000 per QALY, the probability that rivaroxaban was the most cost-effective strategy increased to 80%. At &U20AC;45 000 per QALY, the 10-year PEVPI decreased to &U20AC;3.58 million and the population value associated with the direct medical costs fell to &U20AC;1.72 million. CONCLUSION: This increase in probability of cost effectiveness, coupled with a substantially reduced potential opportunity loss could influence a decision maker's confidence in making a reimbursement decision. On discussions with the decision maker we now intend to incorporate the use of VOI into our HTA process.

A cost-effectiveness model comparing rivaroxaban and dabigatran etexilate with enoxaparin sodium as thromboprophylaxis after total hip and total knee replacement in the irish healthcare setting.

BACKGROUND: It has been estimated that major orthopaedic surgery has the highest risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) when compared with other surgery. Two new orally active anticoagulants have recently become licensed in Ireland for the primary prevention of venous thromboembolism in adult patients undergoing elective total hip replacement (THR) or total knee replacement (TKR). Rivaroxaban (Xarelto) is a direct factor Xa inhibitor and dabigatran etexilate (Pradaxa) is a prodrug of the active compound dabigatran, which inhibits thrombin. OBJECTIVE: To evaluate the cost effectiveness of rivaroxaban and dabigatran etexilate compared with enoxaparin sodium for the prophylaxis of venous thromboembolism in patients undergoing elective THR and TKR in the Irish healthcare setting. METHODS: The evaluation was conducted from the Irish health-payer perspective. A static decision-tree model was developed with a 180-day post-surgery time horizon. Separate models for the disease states THR and TKR were run to accommodate the different venous thromboembolism risks associated with each procedure. Outcome measures were QALYs and life-years gained (LYG). Costs were valued in euro, year 2008 values. One-way sensitivity analysis of all probabilities in the model was performed. A probabilistic sensitivity analysis using second-order Monte Carlo simulation was performed to determine the probability of cost effectiveness at euro 45,000 per QALY threshold. RESULTS: In the THR base-case model, rivaroxaban dominated both dabigatran etexilate and enoxaparin sodium. The incremental cost-effectiveness ratios for dabigatran etexilate relative to enoxaparin were euro 23,934 per LYG and euro 17,835 per QALY. In the TKR base-case model, rivaroxaban dominated both dabigatran etexilate and enoxaparin sodium. Dabigatran etexilate also dominated enoxaparin sodium. In the one-way sensitivity analysis, the THR model was robust to all but four probability variations; the TKR model was robust to all variations. At a cost-effectiveness threshold of euro 45,000 per QALY, the probability that rivaroxaban was the most cost-effective strategy after THR was 39%, followed by dabigatran etexilate at 32% and enoxaparin sodium at 29%. The probability that rivaroxaban was the most cost-effective strategy after TKR was 46%, followed by dabigatran etexilate at 30% and enoxaparin sodium at 24%. CONCLUSION: Base-case analysis indicates that when both rivaroxaban and dabigatran etexilate are compared with enoxaparin sodium, rivaroxaban is the less costly and more effective option after THR and TKR. Probabilistic sensitivity analysis indicates that rivaroxaban is the most cost-effective strategy at a cost-effectiveness threshold of euro 45,000 per QALY; however, there is uncertainty regarding this strategy being more cost effective than dabigatran etexilate when both are compared with enoxaparin sodium.