End Of Life Criteria Research Articles

Cathode Loading Impact on PEM Fuel Cell Performance Losses in Voltage Cycling Based Accelerated Stress Tests

In order to reach the target of carbon neutrality by the end of 2050 set by the European Union, hydrogen technologies will play an important role in supporting the transition to a renewable energy economy, especially for heavy duty applications, such as trucks and airplanes.1 For the latter, hydrogen is a viable alternative fuel compared to kerosene, offering a higher specific energy density as well as zero in-flight CO2 emissions.2 However during operation, proton exchange membrane fuel cells (PEMFCs) suffer from significant performance losses due to the instability of Pt-based catalysts for the oxygen reduction reaction (ORR) via the loss of electrochemically active surface area (ECSA).3 This induces substantial decay in the H2/air performance mainly due to the increasing impact of the local O2 transport resistance (RO2,local) with decreasing cathode roughness factor (rf, in units of cm2 Pt cm-2 MEA), which is especially pronounced for low Pt-loadings.4 Thus, for heavy duty applications requiring long-term durability, higher Pt loadings are required to reduce the impact of RO2,local.In this study, we analyse the H2/air performance loss contributions during voltage cycling based accelerated stress tests (ASTs) using cathodes with different Pt-loadings. ASTs were performed using 5 cm2 MEAs with cathode Pt loadings of 0.2, 0.4, and 0.8 mgPt cmMEA -2 (48.6 wt%, TEC10V50E, Tanaka Kikinzoku K.K. (TKK)). Full characterization of the MEA performance characteristics after different numbers of voltage cycles, was performed by measuring: i) H2/O2 and H2/air polarization curves; ii) cathode rf, determined by cyclic voltammetry and CO stripping; iii) O2 transport resistances (RO2,total) via limiting current measurements; and, iv) proton conduction resistances in the cathode catalyst layer (RH+,cath) via electrochemical impedance spectroscopy (EIS). Voltage cycling was performed under H2/N2 (200/75 nccm) at 80 °C, 95% RH, and ambient pressure using square wave profiles with lower and upper potential limits of 0.60 and 0.95 V, respectively, with hold times of 1 s at each potential.A strong H2/air performance dependency on the cathode rf is visible for the same Pt/C cathode catalyst with varying Pt loading. As shown in Figure 1, the same H2/air performance is reached at similar cathode rf values, independent of number of voltage cycles. This is due to the observation that the RO2,local values only depend on the cathode rf and not on the electrode’s history.Finally, when choosing an end-of-life (EoL) criterion of a more than 20 mV deviation of the measured cell voltages at a given current density from the theoretical ORR kinetics losses (c.f. red line in Figure 1 and gray areas for accepted cell voltage range), this EoL criterion is reached for the differently loaded MEAs at the same cathode rf but after different amounts of aging cycles. For example, at 1.5 A cm2 MEA this 20 mV deviation is reached at a cathode rf of 50-70 mgPt 2 cmMEA -2. However, for the 0.8 mgPt cmMEA -2 Pt/C cathode more than 200.000 cycles are needed to reach this value, compared to only 5.000 cycles for the 0.2 mgPt cmMEA -2 loaded cathode. Consequently, a 4-fold increase of the the cathode Pt loading increases its voltage cycling stability by »40-fold.

PP451 Does NICE Reimburse Oncology Treatments Meeting End-Of-Life Criteria More Often Than Treatments That Do Not?

IntroductionThe National Institute of Health and Care Excellence (NICE) issued a supplementary advice in 2009 stating that treatments for patients with short life expectancies (<24 months) can exceed the cost-effectiveness threshold of GBP30,000 (EUR34,668) per additional quality-adjusted life-year (QALY), as long as the treatment is indicated for small patient populations and there is sufficient evidence that it extends life (≥ three months), compared with current National Health Service (NHS) treatments. This study investigated how often NICE reimburses treatments that meet end-of-life (EOL) criteria.MethodsHealth technology assessments (HTAs) conducted by NICE from 2009 to 2020 were reviewed for approved oncology drugs. Terminated appraisals were excluded. Data regarding EOL criteria in these submissions were then gathered. The HTA decisions were divided into the following categories: EOL criteria met; EOL criteria not met; and EOL criteria not applicable. A chi-square analysis was performed.ResultsA total of 316 reviews were assessed in the final sample, of which 71 percent (n = 223) of decisions were positive. Out of the positive decisions, 43 percent (n = 96), 25 percent (n = 55), and 32 percent (n = 72) of decisions were in the EOL criteria met, EOL criteria not met, and EOL criteria not applicable groups, respectively. The chi-square analysis showed a significant correlation between HTA decisions and EOL criteria (p = 0.0008). These results were consistent when the “EOL criteria not applicable” group was excluded (p = 0.001). When the analysis was performed between the “EOL criteria met” and “EOL criteria not met”, along with “EOL criteria not applicable” groups, it showed a possible correlation (p = 0.05).ConclusionsThis study showed that in oncology, NICE reimburses treatments that meet EOL criteria more often than treatments that attempt, but fail, to meet the EOL criteria.

10 Years of End-of-Life Criteria in the United Kingdom

ObjectivesIn January 2009, the National Institute for Health and Care Excellence introduced supplementary guidance for end-of-life (EoL) treatments, which allowed treatments with an incremental cost-effectiveness ratio over the regular threshold (£20 000-£30 000) to be recommended, if they satisfied the EoL criteria. The aims of this study were (1) to systematically review 10 years of EoL supplementary guidance implementation and explore how it could be improved, and (2) to create a framework for incorporating the uncertainty relating to EoL criteria satisfaction into model-based cost-effectiveness analyses for decision making. MethodsAll appraisals between January 2009 and 2019 were screened for EoL discussions. Data were extracted on the EoL criteria and cost-effectiveness assessment details. Additionally, a quantitative method was developed to include the EoL criteria satisfaction uncertainty into model-based cost-effectiveness analyses. A stylized example was created to provide a case study for the inclusion of EoL criteria satisfaction uncertainty. ResultsAn EoL discussion was identified in 35% of appraisals, 57% of which led to a positive EoL decision. Only 5.7% of technologies with positive EoL decisions were not recommended, versus 43.8% of technologies with negative EoL decisions. EoL criteria assessment was often reported insufficiently and evaluated inconsistently and nontransparently. A total of 54.9% of EoL decisions were made while at least 1 criterion was surrounded by considerable uncertainty. By applying the proposed quantitative method, this EoL criteria satisfaction uncertainty was accounted for in decision making. The stylized example demonstrated that the impact of EoL criteria satisfaction uncertainty can be substantial enough to reverse the reimbursement decision. ConclusionsTo improve consistency/transparency and correct reimbursement decisions’ likelihood, new guidelines on the implementation of the EoL criteria are needed.

HT3 SYSTEMATIC ASSESSMENT OF HTA DECISIONS FOR PERSONALIZED MEDICINES FOR AN ORPHAN DISEASE: ACUTE MYELOID LEUKEMIA (AML)

AML is a rare, aggressive cancer with few available personalized treatments. These high-cost drugs are in the focus of HTA bodies and reimbursement decisions globally. The present research examines HTA assessments for AML drugs. 7 HTA bodies were screened: US (ICER), England (NICE), Scotland (SMC), France (HAS), Canada (pCODR), Australia (PBAC) and Germany (G-BA) for the assessment of 4 drugs (Midostaurin, Gemtuzumab-ozogamicin, Daunorubicin/Cytarabine and Enasidenib) for AML treatment, approved in the last 5 years (since 2015). ICER assessed no drugs for AML. Midostaurin: All HTA bodies made a positive assessment for newly diagnosed FLT3+ AML. NICE and SMC with a restriction for the use [Patient Access Scheme (PAS) / Commercial agreement]. G-BA and HAS assessed the additional benefit with different gradings (Considerable and ASMR IV respectively). In Germany a price reduction of 26% was agreed after G-BA assessment. Daunorubicin/Cytarabine: NICE, SMC, G-BA and HAS made a positive assessment for newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes. In Germany, a price reduction of 18% was agreed after G-BA assessment. Gemtuzumab-ozogamicin: NICE, SMC, G-BA and HAS made a positive assessment for untreated de novo CD33+ (AML) except acute promyelocytic leukemia. NICE and SMC with a restriction for the use (PAS / Commercial agreement). G-BA assessed the added benefit as Not Quantifiable, with a price reduction of 36% after G-BA assessment. HAS rated ASMR V. Enasidenib: pCODR did not recommend reimbursement for relapsed/refractory AML (IDH2 mutation). HTA assessment depicted varying outcomes and decisions due to differences in the applicable underlying laws, and patient population across drugs assessed. Major factors driving decisions were, superior efficacy and acceptable safety for HAS and G-BA; clinical benefit and cost-effectiveness for pCODR, PBAC, NICE and SMC; and end of life criteria across HTAs. Cost-effectiveness for NICE, SMC was by PAS under a commercial agreement with manufacturers.

Fitting lifetime distributions to interval censored cyclic-aging data of lithium-ion batteries

In lifetime analysis of lithium-ion batteries, the failure of a battery is commonly defined as the time point at which the battery holds only a certain percentage of its initial storage capacity. Usually, lifetime experiments are carried out to record degradation up to a certain level, and thus do not offer an appropriate data base for fitting lifetime distributions to different end-of-life (EoL) criteria by means of residual capacity. However, for a second use of batteries, e.g. in a home energy storage system, lifetime modeling for long-term usage is of specific interest. Based on real data from long-term cyclic aging experiments with lithium-ion batteries, the fitting of three of the most popular lifetime distributions, namely Weibull, lognormal and inverse Gaussian distributions, is examined with respect to some particular EoL criteria. The impact of chosen lifetime distributions on confidence intervals (CIs) for the mean lifetime and certain quantiles is studied. Moreover, since data of capacity decline are commonly interval-censored, comparisons of resulting CIs under full and interval-censored information are made by means of simulations.

A study of expected lifetime of XLPE insulation cables working at elevated temperatures by applying accelerated thermal ageing

Deterioration of cable insulation during its normal operation is a major concern. Usually, electric cables receive less periodic maintenance compared to the other electric components, although they are subjected to several environmental conditions during operation such as high temperature and oxidative atmospheres.In this study, a standardized accelerated thermal ageing technique was used, with the application of the Arrhenius model. This technique is commonly used in accelerated life testing to establish a lifetime-stress relationship and estimate cable lifetime. Two types of Cross-Linked Polyethylene (XLPE) material working at elevated temperatures between 95 and 105 °C were selected for testing. In such accelerated ageing processes, it is required for the insulation to reach a degradation level, which is considered the end of life for the material under evaluation. The end of life criteria (also called endpoint) is defined as a percentage reduction of elongation at break, which is considered in this study to be 50% retention of elongation at break. Thermal ageing was carried out according to the BS 7870-2 standard, while elongation at break was evaluated at several ageing stages. The uncertainty in the measurement was estimated. The short-term data points determined by ageing treatment is represented graphically in the Arrhenius plot. The extrapolation of such data was used to predict the long-term performance and estimate the cable lifetime. The lifetime for XLPE is expected to be between 40 and 60 years at 90 °C rated operating temperature. Experimental findings of this study show an estimated cable lifetime between 7 and 30 years for rated operating temperatures between 95 and 105 °C.

Interaction and mechanism of nitrocellulose and N-methyl-4-nitroaniline by isothermal decomposition method

The influence of N-methyl-4-nitroaniline (MNA) on the thermal stability of nitrocellulose (NC) was investigated via an isothermal decomposition dynamics research method. The Arrhenius equation and model-fitting were used to calculate the thermal decomposition kinetic parameters of NC and MNA/NC (3 wt%) composite. Results showed that the thermal decomposition activation energy of NC/MNA (3 wt%) was significantly increased compared with that of pure NC, indicating that the thermal stability of NC was increased with stabilizer MNA addition. Subsequently, the storage life of NC and MNA/NC (3 wt%) composite was estimated using Berthelot equation. It was found that if the decomposition extent reaches 0.1% as the end of life criterion, 3 wt% stabilizer MNA addition significantly extended the storage life of NC from 10.57 to 24.9 years at ambient temperature (298.15 K) with the life extension rate reaching 135.6%. Furthermore, the intermediate product produced by MNA and NC action was extracted and characterized via UV–Vis, HPLC, 1H NMR, FT-IR, and LC–MS, and a possible stabilization mechanism of MNA to NC was proposed.

“What’s fair to an individual is not always fair to a population”: A qualitative study of patients and their health professionals using the Cancer Drugs Fund

ObjectiveTo understand the values attached to cancer treatment at the end of life (EoL) to inform policy decisions around the Cancer Drugs Fund (CDF) and the National Institute for Health and Care Excellence (NICE) EoL criterion. DesignSemi-structured interviews with patients and health professionals.Purposive recruitment was performed iteratively alongside analysis of interview transcripts using constant comparison. ParticipantsPatients with incurable prostate and colorectal cancer (n = 22) who received drugs funded through the CDF and oncologists and palliative care professionals (n = 16) treating patients on CDF drugs. ResultsWhile the majority of patient and oncologist participants expressed gratitude for access to the CDF, some patient participants reported experiencing a sense of guilt, and many oncologists admitted to concern about the justice of a ring-fenced fund solely for anti-cancer drugs. For patient and professional participants, cancer drugs were not necessarily seen as a funding priority over other calls on the NHS purse. Overall, patients and health professionals emphasised prioritising quality over quantity at the end of life, with only a minority describing improved quality of life at the end of life which added value. ConclusionWhile patients and oncologists appreciated the drugs available through the CDF, most expressed concern about its fairness. Competing participant views about the added value of the end of life is challenging for resource allocation.

(Invited) Changes in Thermal Stability of Cyclic Aged Commercial Lithium-Ion Cells

It is well-known that lithium-ion cells can have safety issues. A large number of battery fire incidents have been reported. Of the more famous ones are fires in the APU battery of Boeing Dreamliner [1], fires in the Chevrolet Volt battery [2] and the Samsung Galaxy Note 7 recall (2016). Thermal stability is one of several factors affecting the safety aspects of lithium ion cells. The thermal stability for uncycled cell materials and cells is well-documented, but the effect of cyclic ageing on thermal stability is far less studied [3-6] and only in 18650 sized cells. In this presentation, we describe a systematic approach on how different temperature and current loads are affecting the thermal stability during cyclic aging of three different sized commercial cylindrical lithium-ion power cells. The cells were heated in an Accelerating Rate Calorimeter (ARC) with a heat-wait-seek procedure and temperature steps of 5 °C. Decrease in thermal stability was found in all three cyclic ageing test series as a function of relative high current and low temperature (5 °C) even though the cells were tested within the limits specified by the cell manufacturers. The decrease in thermal stability was minor for one of the test series but rather large and potentially dangerous for the other two test series. As a result, one of the cells with decreased thermal stability experienced severe disintegration of the cell can during the ARC test. A picture of the disintegrated cell that was cycled at 5 °C and 1C/1C condition is presented in Figure 1. New and potentially dangerous safety related alterations have been found in cyclic aged lithium-ion batteries. The decrease in thermal stability could be dangerous and should be an end of life criteria. An uncycled cell in a battery module may withstand the heat from a neighboring thermal runaway cell, while a cycled cell may be driven into thermal runaway. It is of vital importance to develop new diagnostic tools capable of detecting a dangerous drop in thermal stability in cyclic aged lithium-ion cells. Auxiliary Power Unit Battery Fire, Japan Airlines Boeing 787-8, JA829J, Boston, Massachusetts, January 7, 2013. . 2014, National Transportation Safety Board.Smith, B., Chevrolet Volt Battery Incident Overview Report. 2012, NHTSAFleischhammer, M., et al., Interaction of cyclic ageing at high-rate and low temperatures and safety in lithium-ion batteries. Journal of Power Sources, 2015. 274: p. 432-439.Börner, M., et al., Correlation of aging and thermal stability of commercial 18650-type lithium ion batteries. Journal of Power Sources, 2017. 342: p. 382-392.Friesen, A., et al., Impact of cycling at low temperatures on the safety behavior of 18650-type lithium ion cells: Combined study of mechanical and thermal abuse testing accompanied by post-mortem analysis. Journal of Power Sources, 2016. 334: p. 1-11.Friesen, A., et al., Al2O3 coating on anode surface in lithium ion batteries: Impact on low temperature cycling and safety behavior. Journal of Power Sources, 2017. 363: p. 70-77 Figure 1

Tisagenlecleucel for the Treatment of Relapsed or Refractory B-cell Acute Lymphoblastic Leukaemia in People Aged up to 25Years: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the National Institute for Health and Care Excellence's (NICE's) Single Technology Appraisal (STA) process, Novartis submitted evidence on the clinical effectiveness and cost-effectiveness of tisagenlecleucel for treating paediatric and young adult patients (under the age of 25years) with relapsed or refractory (r/r) B-cell acute lymphoblastic leukaemia (ALL). This article presents a summary of the Evidence Review Group's (ERG's) independent review of the evidence submission, the committee's deliberations, and the subsequent development of NICE guidance for the use of tisagenlecleucel on the National Health Service (NHS) in England. Tisagenlecleucel is a chimeric antigen receptor-modified T-cell (CAR-T) product, the first of this emerging therapeutic class to be considered by NICE in this indication. The company's evidence submission was based upon three single-arm, phase II studies: ELIANA, ENSIGN, and B2101J. These trials demonstrated a beneficial effect of tisagenlecleucel, with significant extensions in event-free survival (EFS) and overall survival (OS) compared to historical control datasets on blinatumomab and salvage chemotherapy. Adverse events were common; 77% of patients suffered from cytokine release syndrome (CRS), 56% of whom required intensive care unit-level care. The ERG did not consider clofarabine monotherapy an appropriate proxy for salvage chemotherapy. The company presented a hybrid cost-effectiveness model, combining a decision tree and three-state partitioned survival model structure. The majority of quality-adjusted life-years (QALYs) gained were generated through additional life-years in the extrapolated 'long-term survival' phase of the model, where patients were assumed to be 'cured'. The ERG considered the results to be subject to substantial uncertainty, due in part to immature trial data, unresolved long-term treatment effects, and a lack of appropriate comparator data. The ERG implemented a number of changes to the company's model in an alternative base case, producing deterministic incremental cost-effectiveness ratios (ICERs) of £45,397 per QALY gained versus salvage chemotherapy, and £27,732 versus blinatumomab. The probabilistic model produced ICERs of £48,265 per QALY gained versus salvage chemotherapy, and £29,501 versus blinatumomab. The committee considered the ERG's analysis to be most closely aligned with their preferred assumptions, and did not consider tisagenlecleucel to meet both of the end-of-life (EoL) criteria. In recognition of the innovative nature of tisagenlecleucel, and the present immaturity of ongoing clinical trials, the committee considered further data collection would be valuable in resolving uncertainties around OS, the technology's novel mechanism of action, and the management of CRS and B-cell aplasia. The committee therefore recommended tisagenlecleucel for use in the Cancer Drugs Fund (CDF) until the conclusion of the ELIANA study (June 2023). This appraisal highlighted the difficulty of interpreting EoL criteria in the context of curative therapies and the valuation of cure versus extension of life. Further clarification of NICE's position in these situations may be necessary to ensure consistency and equity in their decision-making.

(Invited) Changes in Thermal Stability of Cyclic Aged Commercial Lithium-Ion Cells

Thermal stability is one of several factors affecting the safety properties of lithium-ion cells. The thermal stability for uncycled cells is well-documented, but the effect of cyclic ageing on thermal stability is far less studied and only for 18650 sized cells. In this paper, we describe how different temperature and current loads are affecting the thermal stability during cyclic aging. Three cylindrical lithium-ion power cells with different cathode, energy content and size were cyclic aged. Decrease in thermal stability was found in all three cyclic ageing test series as a function of relatively high current and low temperature. The decrease in thermal stability could be dangerous and should be an end of life criterion.

Introduction and Overview.

The overall aim of this book is to set out the main changes needed in the field of economic and regulatory conditions as a consequence of these rapid developments in oncology. The traditional approaches of health economics, like health economic evaluation, health technology assessment (HTA), modeling methods, assessing value, pricing techniques, are bound to be altered in the contributions to this book. It is understandable that with the life-threatening diagnosis of cancer the new treatment options need to be accompanied by the best available health economic tools. This pertains to well-implemented decision rules concerning willingness to pay, incremental cost-effectiveness ratio thresholds, equity, patient access, end of life criteria, etc. Their application differs with regard to the usual health economic analyzes implemented in other treatment areas. Overstating a bit one could ask whether we need a strongly modified concept of oncology economics?

Lifetime prediction of 20 kV field-aged silicone rubber insulators via condition assessment

Field investigations of silicone rubber (SiR) insulators provide useful information about their performance. The field performance of SiR insulators depends on many factors, including electrical stress, and environmental and service conditions experienced. This paper provides a condition assessment of the housing material of five different types of 20 kV field-aged SiR insulators from the same manufacturer with different operating years and states. The assessment was performed through mechanical, electrical, and material techniques. The main objective of this paper is to investigate the aging behavior of SiR insulators, in order to predict their lifetimes. Thermogravimetric analysis (TGA) and Fourier transform infrared spectroscopy (FTIR) were utilized to quantify the degree of degradation. The mechanisms of the variations in mechanical properties for aged samples were also discussed. In a tensile test, the reduction of strain-to-break to 50% and in other tests the failure of insulators in salt fog chamber were used as the end of life criterion. Finally, the lifetime of the tested insulators was predicted based on the various aforementioned tests.

Revised sealed tube test procedure for thermal verification of liquid-immersed transformer insulation systems

Over the last few years, there have been numerous claims that the thermal performance of cellulose can be improved by the presence of ester liquids. However, solid verification of this phenomenon by a recognized, standardized test procedure is still missing. The article will present a summary of different historical studies that suggest some improvement of cellulose when immersed in ester liquids. Inaccuracies of these studies and a shortage of some important data will also be discussed. The recent industry discussion on the actual thermal performance of cellulose in natural or synthetic ester liquids resulted in a need for performing thorough studies on this subject. It was agreed within IEC Technical Committee 14 “Power Transformers”, that comprehensive studies shall be made. It is likely that the sealed tube test methodology discussed in this article could be used for developing more systematic conclusions on cellulose-ester thermal performance.A number of standardized test procedures were proposed in the past for new insulation system thermal evaluation. They included the Lockie Test, sealed tube testing and other laboratory testing methods. The Lockie Test was one method used to verify the higher thermal capability claimed for this new insulation system. However, the method uses complete transformers in the procedure and as such is specific to the individual manufacturer’s design. More recently, the dual temperature test has been proposed and has been shown to be a useful procedure, although the equipment necessary is very specialized and complicated. However, this procedure only tests the wire insulation, although it is still the best procedure for testing a system with widely differing thermal capability between the liquid and the solid insulations.The latest revision of IEEE Std C57.100 defines the Lockie Test procedure along with the dual temperature test and the sealed tube test. The sealed tube test was originally developed only as a means of determining equivalent material substitution and has been maligned in the past as an inadequate laboratory test. As with all simulated accelerated testing, this procedure certainly has its weaknesses. However, the 2011 revision of IEEE Std C57.100 now uses a relative thermal index technique rather than the original absolute method, mitigating one of the most problematic issues with the procedure. This new version also addresses many of the other weaknesses of the original method. The end of life criteria is based on either degree of polymerization (DP) or retained tensile as the determining factor. However, since DP is specific to cellulose products, tensile retention is suggested as the end of life criteria which works universally for almost all solid materials for both power and distribution transformers.An example of a new insulation system based on aramid enhanced cellulose paper immersed in mineral oil will be presented in detail, in order to clarify the procedure of full thermal evaluation following the IEEE Std C57.100-2011 sealed tube test procedure.

Plug-in hybrid electric vehicle LiFePO4 battery life implications of thermal management, driving conditions, and regional climate

Battery degradation strongly depends on temperature, and many plug-in electric vehicle applications employ thermal management strategies to extend battery life. The effectiveness of thermal management depends on the design of the thermal management system as well as the battery chemistry, cell and pack design, vehicle system characteristics, and operating conditions. We model a plug-in hybrid electric vehicle with an air-cooled battery pack composed of cylindrical LiFePO4/graphite cells and simulate the effect of thermal management, driving conditions, regional climate, and vehicle system design on battery life. We estimate that in the absence of thermal management, aggressive driving can cut battery life by two thirds; a blended gas/electric-operation control strategy can quadruple battery life relative to an all-electric control strategy; larger battery packs can extend life by an order of magnitude relative to small packs used for all-electric operation; and batteries last 73–94% longer in mild-weather San Francisco than in hot Phoenix. Air cooling can increase battery life by a factor of 1.5–6, depending on regional climate and driving patterns. End of life criteria has a substantial effect on battery life estimates.

PHP198 - DEFINING END-OF-LIFE: IS THE SHORT LIFE EXPECTANCY CRITERION BIASED AGAINST YOUNG PEOPLE AND CHILDREN?

Health technology assessment (HTA) agencies use end-of-life (EoL) criteria to justify higher incremental cost-effectiveness thresholds to improve access to treatments that may not otherwise demonstrate adequate value for money. We argue that, as currently defined, EoL criteria are biased against young people and children and consider some possible alternative approaches. A key component of HTA EoL criteria is short life expectancy. For instance, the National Institute for Health and Care Excellence and the Scottish Medicines Consortium EoL criteria include a life expectancy requirement of less than 24 and 36 months, respectively. The short life expectancy criterion reflects the notion that the patient has a terminal illness, and death from that disease is imminent. However, a recent HTA assessment involving a pediatric cancer drug raises questions about the adequacy of the short life expectancy criterion. In this case, life expectancy of the indicated population was greater than 3 years, with median overall survival of approximately 4 years. However, in a pediatric population, this significantly reduced life expectancy satisfies our intuitive sense of being at the EoL, but it does not meet the HTA short life expectancy criterion. On this basis we argue that current HTA EoL criteria are biased against young people and children. We consider potential alternatives to the short life expectancy criterion, including: eliminating the criterion; utilizing a separate threshold for non-elderly patients; and redefining the criterion in terms of the proportion of a life cut short. We argue for use of the latter concept and that equity considerations help to justify the use of a higher cost-effectiveness threshold in non-elderly patient populations. As currently defined the short life expectancy criterion is biased against non-elderly patients with a limited life expectancy. Redefining EoL criteria using the concept of a life cut short may help to address this problem.

PSY81 - How much is nice really prepared to pay for Orphan and end-of-life Drugs?

New health technologies are required to demonstrate clinical and cost-effectiveness before recommendation by the National Institute for Health and Care Excellence (NICE) for reimbursement in England; however, higher cost-effectiveness thresholds may be considered for orphan and end-of-life (EOL) therapies. To help inform future submissions, the incremental cost-effectiveness ratios (ICERs) of – and rationale behind – accepted NICE submissions for orphan and EOL therapies were assessed. All NICE single technology appraisals from January 2009 to December 2014 were included in the analysis. The decision, rationale, and manufacturer’s ICER (including patient access scheme where applicable) for each submission were extracted. Appraisals were then assessed for meeting NICE EOL or European orphan drug criteria. Multiple technology appraisals, resubmissions, vaccination programmes, requests for advice, and submissions where an ICER could not be determined were excluded. Of 111 relevant NICE submissions, 12 met orphan drug criteria, 16 met EOL criteria and 4 met both. For orphan drugs, 8/12 (67%) were accepted, with a mean ICER of £33,725 for accepted submissions (range: £24,544 - 56,693). For EOL drugs, 12/16 (75%) were accepted, with a mean ICER of £40,906 for accepted submissions (range: £14,795-£62,829). This compared with an overall acceptance rate for non-orphan/EOL NICE submissions of 71/87 (82%), with a mean ICER of £15,303 for accepted submissions (range: £1,537-£35,208). Rationale for acceptance of orphan and EOL drug submissions included unmet therapeutic need, lack of alternative treatment options, and innovation. Based on the evidence, NICE’s decision threshold was significantly higher for orphan/EOL drugs than for others (p<0.001). However, the overall acceptance rate was lower, and restrictions to patient sub-populations as well as patient access schemes were often applied. Nevertheless, the incorporation of elements such as unmet need into the decision-making process makes high ICERs appropriate where there is strong evidence of demonstrable clinical benefit.

PCN268 - The Life and Death of the End of Life Treatment Appraisal Criteria in Nice Technology Appraisals?

Since January 2009, NICE in the UK allows end of life (EOL) treatments to exceed the upper end (£30,000/QALY) of the threshold range for incremental cost-effectiveness ratios (ICERs) by using higher weights for EOL life-years. With discussions surrounding the concept and implementation, and the introduction of the value based assessment framework, the aim of this study was to review NICE technology appraisals (TAs) in oncology to assess the interpretation, implementation and implications of the criteria. All completed TAs in oncology since 2009 were searched. When multiple submissions of the same TA were made, the latest were selected. Data were extracted to capture details of the appraisal (e. g. treatment, indication and decision), the consideration of the five different EOL criteria (applicability, interpretation, effect on the decision) and the method of implementation (weighting, threshold). 61 TAs, including six multiple technology appraisals, assessing 71 technologies were reviewed. EOL criteria were considered in 40 TAs covering 44 technologies. EOL weighting was considered appropriate for 36% of technologies. Most technologies fulfilled the criterion of <24 month life expectancy (rejected in 14%), extension of life by ≥3 months or robustness of its calculation was the most common cause of rejection (32%/25% respectively). These criteria were inconsistently applied, using different methods (e. g. medians, restricted means from extrapolation, means from trial or model). The criterion of small population favoured technologies with limited indication (rejection 20%). Earlier TAs presented weight calculations, while later TAs only presented ICERs. Although aiming for greater transparency, the criteria left a large scope for interpretation in the decision making. Also, with the emphasis from applying higher weights to EOL life-years shifting to a differential threshold for certain indications, the original idea of considering wider societal preferences seem to have been neglected, that the new guidance should remedy.

High thresholds may alter end-of-life behavior in a dual chamber pacemaker.

We noted a series of 12 consecutive patients with a DDD Genisis pacemaker that showed an unexpected and a relatively rapid fall in battery voltage and output as these devices approached end-of-life (EOL). Twenty-one of 24 leads were Vitatron Helifix leads and there was a relatively high mean threshold (atrial 2.5 +/- 0.94 V; ventricular 2.9 +/- 0.65 V). These devices were replaced after 65 +/- 12 months. During the 9.3 +/- 3.5 months before replacement, a striking fall in voltage from 2.7 +/- 0.04 V to 2.49 +/- 0.05 V was seen. Battery impedance rose from 3 +/- 1.2 K omega to 10.2 +/- 4.3 K omega during this same period. We unexpectedly observed a marked difference between programmed and telemetered output for both atrial (50%) and ventricular leads (30%). A discrepancy between measured and telemetered magnet rate was also seen. Despite this relatively rapid fall in battery voltage, several of these devices did not meet the manufacturer's recommended replacement time (RRT) criteria by magnet rate or according to the projected RRT determined by the relationship of battery impedance to current drain. These data have implications for the selection of RRT and EOL criteria for this device. Magnet rate measured by surface ECG was the safest indicator for RRT. Follow-up for this pulse generator should be increased to every 2 months when battery impedance is > 2 KOhms or if there is a difference between programmed and measured output amplitude of more than 15%. The data also highlight the effect of combining high threshold leads with modern pacemakers with relatively "small" batteries as well as certain problems with telemetered data.

Influence de la qualité de l’interface fibre de verre / matrice sur le comportement mécanique monoaxial et biaxial de plaques et de tubes en matériaux composites

Composites, bi-phasic materials made up of a fibre reinforced organic matrix, have very attractive mechanical and physical assets. Although their properties mainly depend on those of each phase (fibre and matrix), the quality of the fibre/matrix interface also plays an essential role in the definition of their characteristics. In order to reveal this role, The Department of Polymers and Composites Technology of the Ecole des Mines de Douai has investigated the behaviour of composite samples, differing only by the interface quality, under the laws of loading, which are used most in industrial fields:– monoaxial tension with monitoring of acoustic emission spectra,–interlaminar shear,–crack initiation and crack growth in mode I,–viscoelasticity in bending,–biaxial monotonic tension, cyclic loading with increasing amplitude and dynamic fatigue.Biaxial tests were carried out on industrial tubing systems under internal pressure, the other tests on standard flat test pieces. In tension and interlaminar shear, fibre/matrix adhesion has only little influence on the behaviour of the material. In return, the incidence of this parameter appears to be more pronounced through mode I fracture mechanics and viscoelasticity studies. Initiation and growth energies thus can be influenced by the interface quality by up to 50%. In the same way, variations of 45% on the modulus loss and of 70% on the damping at glass transition temperature are noticed. Concerning the study of tubing system, the level of sensitivity to the interface quality is dependent on the type of load applied and the end of life criteria which have been chosen, weeping or threshold of non-linearity. Under monotonic loading one can observe maximum divergences of 17% on the values of weeping pressures; these gaps increase considerably if first damage pressures are considered, and can reach 30%. In terms of circumferential stresses, these differences are still more pronounced and can go as high as 45%. The fatigue lifetime is also very strongly affected by the nature of the fibre/matrix interface, which can make it possible to multiply the lifetime by 30.