A Review of Meaningful Change Thresholds for EORTC QLQ-C30 and FACT-G Within Oncology.

OBJECTIVES: This literature review provides an overview of meaningful change thresholds for the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) and the Functional Assessment of Cancer Therapy - General (FACT-G) used across hematological cancers and solid tumors (melanoma, lung, bladder, and prostate). METHODS: Embase, MEDLINE, and PubMed were searched to identify relevant oncology publications from 2016 to 2021. Label claims from the US Food and Drug Administration and the European Medicines Agency for 7 recently approved drugs (pembrolizumab, atezolizumab, glasdegib, gilteritinib, tisagenlecleucel, axicabtagene ciloleucel, and daratumumab plus hyaluronidase-fihj) were reviewed. RESULTS: Publications providing guidance on meaningful change thresholds for the QLQ-C30 displayed a growing trend away from broad "legacy" thresholds of 10 points for all QLQ-C30 scales), toward deriving "contemporary" thresholds (eg, subscale specific, population specific). Contemporary publications generally provide guidance on selecting thresholds for specific scales that account for improved or worsening thresholds (eg, QLQ-C30 subscales). This trend was not clear for FACT-G, with less new guidance available. Most clinical trials used in regulatory label submissions have used thresholds of 10 points for the QLQ-C30 subscales and 3 to 7 points for the FACT-G total score. Despite the availability of more recent guidelines, contemporary meaningful change thresholds seem slow to emerge in the published literature and regulatory labels. CONCLUSIONS: Trialists should consider using contemporary thresholds, rather than legacy thresholds, for QLQ-C30 endpoints. Thresholds derived for a similar patient-population should be used where available. Further work is required to provide these across a broader range of cancer sites.

Optimizing the Use of High-Sensitivity Troponin Assays for the Early Rule-out of Myocardial Infarction in Patients Presenting with Chest Pain: A Systematic Review.

BACKGROUND: We assessed the accuracy and clinical effectiveness of high-sensitivity cardiac troponin (hs-cTn) assays for early rule-out of non-ST-segment elevation myocardial infarction (NSTEMI) in adults presenting with acute chest pain. METHODS: Sixteen databases were searched to September 2019. Review methods followed published guidelines. The bivariate model was used to estimate summary sensitivity and specificity with 95% confidence intervals for meta-analyses involving 4 or more studies, otherwise random-effects logistic regression was used. RESULTS: Thirty-seven studies (124 publications) were included in the review. The hs-cTn test strategies evaluated in the included studies were defined by the combination of 4 factors (assay, number of tests, timing of tests, and threshold concentration or change in concentration between tests). Clinical opinion indicated a minimum acceptable sensitivity of 97%. A single test at presentation using a threshold at or near the assay limit of detection could reliably rule-out NSTEMI for a range of hs-cTn assays. Serial testing strategies, which include an immediate rule-out step, increased the proportion ruled out without loss of sensitivity. Finally, serial testing strategies without an immediate rule-out step had excellent sensitivity and specificity, but at the expense of the option for immediate patient discharge. CONCLUSION: Test strategies that comprise an initial rule-out step, based on low hs-cTn concentrations at presentation and a minimum symptom duration, and a second step for those not ruled-out that incorporates a small absolute change in hs-cTn at 1, 2, or 3 hours, produce the highest rule-out rates with a very low risk of missed NSTEMI. PROSPERO REGISTRATION: CRD42019154716.

The relationship between Lp(a) and CVD outcomes: a systematic review.

Robust associations between lipoprotein(a) [Lp(a)] and CVD outcomes among general populations have been published in previous studies. However, associations in high risk primary prevention and secondary prevention populations are less well defined. In order to investigate this further, a systematic review was performed including prospective studies, which assessed the relationship between Lp(a) and CVD outcomes using multivariable analyses. Additional information was gathered on Lp(a) assays, multivariable modelling and population characteristics. Literature searches from inception up to December 2015 retrieved 2850 records. From these 60 studies were included. Across 39 primary prevention studies in the general population (hazard ratios ranged from 1.16 to 2.97) and seven high risk primary prevention studies (hazard ratios ranged from 1.01 to 3.7), there was evidence of a statistically significant relationship between increased Lp(a) and an increased risk of future CVD. Results in 14 studies of secondary prevention populations were also suggestive of a modest statistically significant relationship (hazard ratios ranged from 0.75 to 3.7).Therefore current evidence would suggest that increased Lp(a) levels are associated with modest increases in the risk of future CVD events in both general and higher risk populations. However, further studies are required to confirm these findings.

Systematic review and mixed treatment comparison of intravitreal aflibercept with other therapies for diabetic macular edema (DME).

BACKGROUND: This was an indirect comparison of the effectiveness of intravitreal aflibercept (IVT-AFL) 2 mg every 8 weeks after 5 initial monthly doses (or if different periods, after an initial monthly dosing period) (2q8) and other diabetic macular edema (DME) therapies at doses licensed outside the USA. METHODS: A comprehensive search was undertaken to source relevant studies. Feasibility networks were prepared to identify viable comparisons of 12-month outcomes between IVT-AFL 2q8 and therapies licensed outside the USA, which were assessed for clinical and statistical homogeneity. Pooled effect sizes (mean difference [MD] and relative risk/risk ratio [RR]) were calculated using fixed- and random-effects models. Indirect comparisons were performed using Bucher analysis. If at least one 'head-to-head' study was found then a mixed treatment comparison (MTC) was performed using Bayesian methods. Two 12-month comparisons could be undertaken based on indirect analyses: IVT-AFL 2q8 versus intravitreal ranibizumab (IVR) 0.5 mg as needed (PRN) (10 studies) and IVT-AFL 2q8 versus dexamethasone 0.7 mg implants (three studies). RESULTS: There was an increase in mean best-corrected visual acuity (BCVA) with IVT-AFL 2q8 over IVR 0.5 mg PRN by 4.67 letters [95% credible interval (CrI): 2.45-6.87] in the fixed-effect MTC model (10 studies) and by 4.82 letters [95% confidence interval (CI): 2.52-7.11] in the Bucher indirect analysis (four studies). IVT-AFL 2q8 doubled the proportion of patients gaining ≥ 10 Early Treatment Diabetic Retinopathy Study letters at 12 months compared with dexamethasone 0.7 mg implants (RR = 2.10 [95% CI: 1.29-3.40]) in the fixed-effect model. There were no significant differences in safety outcomes between IVT-AFL 2q8 and IVR 0.5 mg PRN or dexamethasone 0.7 mg implants. CONCLUSIONS: Studies of IVT-AFL 2q8 showed improved 12-month visual acuity measures compared with studies of IVR 0.5 mg PRN and dexamethasone 0.7 mg implants based on indirect comparisons. These analyses are subject to a number of limitations which are inherent in indirect data comparisons.

Aortic remodelling following the treatment and regression of hypertensive left ventricular hypertrophy: a cardiovascular magnetic resonance study.

BACKGROUND: Increased arterial stiffness independently predicts adverse prognosis. While different antihypertensive strategies produce different magnitudes of left ventricular hypertrophy (LVH) regression, there are no comparative data on how these strategies affect arterial stiffness. The aim was to determine the longitudinal change in aortic stiffness following the treatment of essential hypertension with two mechanistically different antihypertensive treatment strategies. METHODS AND RESULTS: Forty-two patients with essential hypertension and CMR confirmed with LVH were randomly assigned to antihypertensive regimes for 6 months. Treatment strategies were designed either to inhibit the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS) (valsartan and moxonidine, group VM) or to have neutral effect on these systems (bendroflumethiazide and amlodipine, group BA). Both treatment groups underwent identical baseline and a 6-month follow-up CMR and were compared with a healthy age-matched control group. Baseline aortic distensibility (AD) was lower in both hypertensive groups compared with controls (2.8 × 10(-3 )mmHg(-1) in group VM (p = 0.001) and 3.3 × 10(-3 )mmHg(-1) group BA (p = 0.039) compared with 4.5 × 10(-3 )mmHg(-1) in the control group). AD increased after antihypertensive therapy (VM: 2.8 × 10(-3 )mmHg(-1)-4.2 × 10(-3 )mmHg(-1) (p = 0.001); BA 3.3 × 10(-3 )mmHg(-1)-4.6 × 10(-3 )mmHg(-1) (p < 0.01)). In both treatment groups AD returned to a level comparable with the normal control group (p = 0.81) after 6 months. CONCLUSIONS: In patients with essential hypertension and LVH, AD was lower than in matched normal controls. Despite the opposing pharmacological mechanisms utilised across the treatment groups, the improvement in AD was similar, suggesting that blood pressure reduction per se may be more important than RAAS and SNS inhibition for the improvement of aortic remodelling.

Fenfluramine for Treating Dravet Syndrome: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Fenfluramine, tradename Fintepla®, was appraised within the National Institute for Health and Care Excellence (NICE) single technology appraisal (STA) process as Technology Appraisal 808. Within the STA process, the company (Zogenix International) provided NICE with a written submission and a mathematical health economic model, summarising the company's estimates of the clinical effectiveness and cost-effectiveness of fenfluramine for patients with Dravet syndrome (DS). This company submission (CS) was reviewed by an evidence review group (ERG) independent of NICE. The ERG, Kleijnen Systematic Reviews in collaboration with Maastricht University Medical Centre, produced an ERG report. This paper presents a summary of the ERG report and the development of the NICE guidance. The CS included a systematic review of the evidence for fenfluramine. From this review the company identified and presented evidence from two randomised trials (Study 1 and Study 1504), an open-label extension study (Study 1503) and 'real world evidence' from a prospective and retrospective study. Both randomised trials were conducted in patients up to 18 years of age with DS, whose seizures were incompletely controlled with previous anti-epileptic drugs. A Bayesian network meta-analysis was performed to compare fenfluramine with cannabidiol plus clobazam. There was no evidence of a difference between any doses of fenfluramine and cannabidiol in the mean convulsive seizure frequency (CSF) rate during treatment. However, fenfluramine increased the number of patients achieving ≥ 50% reduction in CSF frequency from baseline compared to cannabidiol. The company used an individual-patient state-transition model (R version 3.5.2) to model cost-effectiveness of fenfluramine. The CSF and convulsive seizure-free days were estimated using patient-level data from the placebo arm of the fenfluramine registration studies. Subsequently, a treatment effect of either fenfluramine or cannabidiol was applied. Utility values for the economic model were obtained by mapping Pediatric Quality of Life Inventory data from the registration studies to EuroQol-5D-3L Youth (EQ-5D-Y-3L). The company included caregiver utilities in their base-case, as the severe needs of patients with DS have a major impact on parents and caregivers. There were several key issues. First, the company included caregiver utilities in the model in a way that when patients in the economic model died, the corresponding caregiver utility was also set to zero. Second, the model was built in R statistical software, resulting in transparency issues. Third, the company assumed the same percentage reduction for convulsive seizure days as was estimated for CSF. Fourth, during the final appraisal committee meeting, influential changes were made to the model that were not in line with the ERG's preferences (but were accepted by the appraisal committee). The company's revised and final incremental cost effectiveness ratio (ICER) in line with committee preferences resulted in fenfluramine dominating cannabidiol. Fenfluramine was recommended as an add-on to other antiepileptic medicines for treating seizures associated with DS in people aged 2 years and older in the National Health Service (NHS).

Relationship between FEV1 change and patient-reported outcomes in randomised trials of inhaled bronchodilators for stable COPD: a systematic review.

BACKGROUND: Interactions between spirometry and patient-reported outcomes in COPD are not well understood. This systematic review and study-level analysis investigated the relationship between changes in FEV1 and changes in health status with bronchodilator therapy. METHODS: Six databases (to October 2009) were searched to identify studies with long-acting bronchodilator therapy reporting FEV1 and health status, dyspnoea or exacerbations. Mean and standard deviations of treatment effects were extracted for each arm of each study. Relationships between changes in trough FEV1 and outcomes were assessed using correlations and random-effects regression modelling. The primary outcome was St George's Respiratory Questionnaire (SGRQ) total score. RESULTS: Thirty-six studies (≥ 3 months) were included. Twenty-two studies (23,654 patients) with 49 treatment arms each contributing one data point provided SGRQ data. Change in trough FEV1 and change in SGRQ total score were negatively correlated (r = -0.46, p < 0.001); greater increases in FEV1 were associated with greater reductions (improvements) in SGRQ. The correlation strengthened with increasing study duration from 3 to 12 months. Regression modelling indicated that 100 mL increase in FEV1 (change at which patients are more likely to report improvement) was associated with a statistically significant reduction in SGRQ of 2.5 (95% CI 1.9, 3.1), while a clinically relevant SGRQ change (4.0) was associated with 160.6 (95% CI 129.0, 211.6) mL increase in FEV1. The association between change in FEV1 and other patient-reported outcomes was generally weak. CONCLUSIONS: Our analyses indicate, at a study level, that improvement in mean trough FEV1 is associated with proportional improvements in health status.

High-sensitivity troponin assays for early rule-out of acute myocardial infarction in people with acute chest pain: a systematic review and economic evaluation.

BACKGROUND: Early diagnosis of acute myocardial infarction is important, but only 20% of emergency admissions for chest pain will actually have an acute myocardial infarction. High-sensitivity cardiac troponin assays may allow rapid rule out of myocardial infarction and avoid unnecessary hospital admissions. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of high-sensitivity cardiac troponin assays for the management of adults presenting with acute chest pain, in particular for the early rule-out of acute myocardial infarction. METHODS: Sixteen databases were searched up to September 2019. Review methods followed published guidelines. Studies were assessed for quality using appropriate risk-of-bias tools. The bivariate model was used to estimate summary sensitivity and specificity for meta-analyses involving four or more studies; otherwise, random-effects logistic regression was used. The health economic analysis considered the long-term costs and quality-adjusted life-years associated with different troponin testing methods. The de novo model consisted of a decision tree and a state-transition cohort model. A lifetime time horizon (of 60 years) was used. RESULTS: Thirty-seven studies (123 publications) were included in the review. The high-sensitivity cardiac troponin test strategies evaluated are defined by the combination of four factors (i.e. assay, number and timing of tests, and threshold concentration), resulting in a large number of possible combinations. Clinical opinion indicated a minimum clinically acceptable sensitivity of 97%. When considering single test strategies, only those using a threshold at or near to the limit of detection for the assay, in a sample taken at presentation, met the minimum clinically acceptable sensitivity criterion. The majority of the multiple test strategies that met this criterion comprised an initial rule-out step, based on high-sensitivity cardiac troponin levels in a sample taken on presentation and a minimum symptom duration, and a second stage for patients not meeting the initial rule-out criteria, based on presentation levels of high-sensitivity cardiac troponin and absolute change after 1, 2 or 3 hours. Two large cluster randomised controlled trials found that implementation of an early rule-out pathway for myocardial infarction reduced length of stay and rate of hospital admission without increasing cardiac events. In the base-case analysis, standard troponin testing was both the most effective and the most costly. Other testing strategies with a sensitivity of 100% (subject to uncertainty) were almost equally effective, resulting in the same life-year and quality-adjusted life-year gain at up to four decimal places. Comparisons based on the next best alternative showed that for willingness-to-pay values below £8455 per quality-adjusted life-year, the Access High Sensitivity Troponin I (Beckman Coulter, Brea, CA, USA) [(symptoms > 3 hours AND < 4 ng/l at 0 hours) OR (< 5 ng/l AND Δ < 5 ng/l at 0 to 2 hours)] would be cost-effective. For thresholds between £8455 and £20,190 per quality-adjusted life-year, the Elecsys® Troponin-T high sensitive (Roche, Basel, Switzerland) (< 12 ng/l at 0 hours AND Δ < 3 ng/l at 0 to 1 hours) would be cost-effective. For a threshold > £20,190 per quality-adjusted life-year, the Dimension Vista® High-Sensitivity Troponin I (Siemens Healthcare, Erlangen, Germany) (< 5 ng/l at 0 hours AND Δ < 2 ng/l at 0 to 1 hours) would be cost-effective. CONCLUSIONS: High-sensitivity cardiac troponin testing may be cost-effective compared with standard troponin testing. STUDY REGISTRATION: This study is registered as PROSPERO CRD42019154716. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 25, No. 33. See the NIHR Journals Library website for further project information.

Heart disease is a leading cause of death in the UK, with myocardial infarction (heart attack) accounting for approximately 4% of all deaths recorded in 2018. Many people attend hospital with chest pain and suspected myocardial infarction, and chest pain has been reported as the most common cause of hospital admissions in the UK, accounting for approximately 5% of all emergency admissions in 2017­18. It is important to diagnose people who are suspected of having a myocardial infarction as early as possible to ensure quick and effective treatment. However, only around 20% of emergency admissions for chest pain will actually have an myocardial infarction and there are many other possible causes of chest pain (e.g. gastro-oesophageal disorders, muscle pain, anxiety or stable ischaemic heart disease). Current practice for ruling out myocardial infarction includes blood tests taken when the patient is first seen in the emergency department and repeated after 3­6 hours or 10­12 hours, depending on the test used. Tests that can quickly tell which patients do not have myocardial infarction could therefore avoid unnecessary hospital admissions and anxiety for many people. We aimed to assess the clinical effectiveness and cost-effectiveness of high-sensitivity troponin tests, used as single tests or repeated over a short time, for the early rule out of myocardial infarction in people who present to hospital with chest pain. We found that high-sensitivity troponin tests can safely rule out myocardial infarction within the 4-hour NHS emergency department target. Health economic analyses indicated that high-sensitivity tests may be considered value for money compared with standard troponin tests, which require repeat testing at 10­12 hours.

Avatrombopag and lusutrombopag for thrombocytopenia in people with chronic liver disease needing an elective procedure: a systematic review and cost-effectiveness analysis.

BACKGROUND: There have been no licensed treatment options in the UK for treating thrombocytopenia in people with chronic liver disease requiring surgery. Established management largely involves platelet transfusion prior to the procedure or as rescue therapy for bleeding due to the procedure. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of two thrombopoietin receptor agonists, avatrombopag (Doptelet®; Dova Pharmaceuticals, Durham, NC, USA) and lusutrombopag (Mulpleta®; Shionogi Inc., London, UK), in addition to established clinical management compared with established clinical management (no thrombopoietin receptor agonist) in the licensed populations. DESIGN: Systematic review and cost-effectiveness analysis. SETTING: Secondary care. PARTICIPANTS: Severe thrombocytopenia (platelet count of < 50,000/µl) in people with chronic liver disease requiring surgery. INTERVENTIONS: Lusutrombopag 3 mg and avatrombopag (60 mg if the baseline platelet count is < 40,000/µl and 40 mg if it is 40,000-< 50,000/µl). MAIN OUTCOME MEASURES: Risk of platelet transfusion and rescue therapy or risk of rescue therapy only. REVIEW METHODS: Systematic review including meta-analysis. English-language and non-English-language articles were obtained from several databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials, all searched from inception to 29 May 2019. ECONOMIC EVALUATION: Model-based cost-effectiveness analysis. RESULTS: From a comprehensive search retrieving 11,305 records, six studies were included. Analysis showed that avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy or rescue therapy only, and mostly with a statistically significant difference (i.e. 95% confidence intervals not overlapping the point of no difference). However, only avatrombopag seemed to be superior to no thrombopoietin receptor agonist in reducing the risk of rescue therapy, although far fewer patients in the lusutrombopag trials than in the avatrombopag trials received rescue therapy. When assessing the cost-effectiveness of lusutrombopag and avatrombopag, it was found that, despite the success of these in avoiding platelet transfusions prior to surgery, the additional long-term gain in quality-adjusted life-years was very small. No thrombopoietin receptor agonist was clearly cheaper than both lusutrombopag and avatrombopag, as the cost savings from avoiding platelet transfusions were more than offset by the drug cost. The probabilistic sensitivity analysis showed that, for all thresholds below £100,000, no thrombopoietin receptor agonist had 100% probability of being cost-effective. LIMITATIONS: Some of the rescue therapy data for lusutrombopag were not available. There were inconsistencies in the avatrombopag data. From the cost-effectiveness point of view, there were several additional important gaps in the evidence required, including the lack of a price for avatrombopag. CONCLUSIONS: Avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy, but they were not cost-effective given the lack of benefit and increase in cost. FUTURE WORK: A head-to-head trial is warranted. STUDY REGISTRATION: This study is registered as PROSPERO CRD42019125311. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 51. See the NIHR Journals Library website for further project information.

Thrombocytopenia, which is a reduction in platelet numbers in the blood, is a common complication of chronic liver disease. It increases the risk of bleeding during procedures including liver biopsy and transplantation. It can delay or prevent procedures, leading to illness and death. Established treatment largely involves platelet transfusion before the procedure or as rescue therapy for bleeding. This report aims to systematically review the clinical effectiveness and estimate the cost-effectiveness of the first two recently licensed treatments, thrombopoietin receptor agonists avatrombopag (Doptelet^®; Dova Pharmaceuticals, Durham, NC, USA) (60 mg if platelet count is < 40,000/µl and 40 mg if platelet count is 40,000­< 50,000/µl) and lusutrombopag (Mulpleta^®; Shionogi Inc., London, UK) (3 mg if platelet count is < 50,000/µl), compared with established treatment. From a comprehensive search, six studies were included. Clinical effectiveness analysis showed that avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy. Only avatrombopag seemed superior to no thrombopoietin receptor agonist in reducing rescue therapy alone. Cost-effectiveness analysis found that lusutrombopag and avatrombopag were more expensive than no thrombopoietin receptor agonist over a lifetime, as the savings from avoiding platelet transfusions were exceeded by the drug cost, and without long-term health benefits. The probabilistic sensitivity analysis, which examined the effect of uncertainty, showed that no thrombopoietin receptor agonist had 100% probability of being cost-effective. Uncertainty about the price of avatrombopag and the content and costs of platelet transfusions and the potential under-reporting of use to estimate platelet transfusion-specific mortality had the greatest impact on results. If the price of avatrombopag was (confidential information has been removed) below the price of lusutrombopag, avatrombopag would become cost saving in the 40,000­< 50,000/µl subgroup. However, although in some scenarios avatrombopag costs could decrease in the 40,000­< 50,000/µl subgroup to around 10% more than the cost of no thrombopoietin receptor agonist, there would be negligible health benefits and the incremental cost-effectiveness ratios would remain very high, meaning that lusutrombopag and avatrombopag would still not be considered cost-effective.

Cannabidiol for Adjuvant Treatment of Seizures Associated with Lennox-Gastaut Syndrome and Dravet Syndrome: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

GW Research Ltd. provided two separate, but similar, submissions to the National Institute for Health and Care Excellence (NICE) on the clinical and cost-effectiveness of cannabidiol (CBD) 10 mg/kg/day, trade name Epidyolex®, for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS). This paper highlights important methodological issues related to the company submissions, the Evidence Review Group (ERG) reports, and the subsequent development of the NICE guidance by the Appraisal Committee (AC) for the use of CBD. The company identified four randomised controlled trials (RCTs) of CBD (GWPCARE1 and GWPCARE2 for DS, and GWPCARE3 and GWPCARE4 for LGS) and an ongoing open-label extension study (GWPCARE5) as relevant to both submissions. In these RCTs, CBD in addition to current clinical management (CCM) was compared to CCM without CBD (i.e. CCM plus placebo). GWPCARE2 and GWPCARE3 were three-arm studies and compared two dosages of CBD (10 mg/kg/day and 20 mg/kg/day) in addition to CCM and CCM plus placebo. GWPCARE1 and GWPCARE4 compared CBD (20 mg/kg/day) in addition to CCM and CCM plus placebo. Both DS patients in GWPCARE2 and LGS patients in GWPCARE3 who received 10 mg/kg/day CBD in addition to CCM achieved better seizure frequency outcomes than those who received CCM plus placebo. In the company's base case, use of CBD for LGS patients resulted in an incremental cost-effectiveness ratio (ICER) of £31,107 per quality-adjusted life year (QALY) gained and, for DS patients, £36,046 per QALY gained versus CCM. The ERG considered that these ICERs were extremely uncertain and suffered from validity issues concerning model structure (e.g. patients receiving CCM moved back to baseline drop seizure frequency), input (e.g. inclusion of caregivers' QALYs), and transparency issues (e.g. hidden worksheets and coding in Visual Basic for Applications), and hence incorporated adjustments to the original base case which increased the ICERs. During the process, the European Medicines Agency (EMA) licence granted marketing authorisation for CBD only in conjunction with clobazam. Hence, the company provided evidence from this subgroup in an additional submission, which resulted in an ICER of £33,721 per QALY gained for LGS and an ICER of £32,471 per QALY gained for DS. In this submission and clarifications, the ERG was able to verify and validate most of the company's responses to the ERG's concerns. However, some issues remained regarding the face validity of model assumptions on patient pathways after treatment discontinuation. Finally, the AC recommended CBD with clobazam as an option for treating seizures associated with LGS and DS in patients aged 2 years and older only if (1) the frequency of drop seizures is checked every 6 months and CBD is stopped if the frequency has not fallen by at least 30% compared with 6 months before starting treatment and (2) the company provides CBD according to the commercial arrangement.

Systematic review and network meta-analysis of the efficacy and safety of lidocaine 700 mg medicated plaster vs. pregabalin.

Objective: Neuropathic pain prevalence is estimated between 7% and 10% of the population. International guidelines recommend a variety of drugs at different therapy lines for pain relief. However, side effect profiles, for example, prompted the UK government recently to classify pregabalin and gabapentin as class C drugs. Lidocaine 700 mg medicated plaster (LMP) might be a safer alternative. A systematic review assessed how LMP and pregabalin compared in terms of efficacy and safety. The review focused on pain reduction, quality of life and adverse events in peripheral neuropathic pain (PNP) i.e. post-herpetic neuralgia, diabetic peripheral neuropathy, post-surgical/trauma, or other PNP conditions.Methods: Electronic databases were searched as well as a number of other sources up to November 2018. Sensitive strategies were used, with no restriction by language or publication status. Two independent reviewers screened records and extracted data with consensus determining final decisions. Risk of bias was assessed using the Cochrane Collaboration 2011 checklist for RCTs. Full network meta-analysis was conducted to compare LMP to pregabalin 300/600 mg in terms of pain reduction, quality of life, as well as serious adverse events and selected adverse events. Trials with enriched enrolment design were excluded.Results: Searches retrieved 7,104 records. In total 111 references pertaining to 43 RCTs were included for data extraction. Bayesian network meta-analysis of several pain outcomes showed no clear difference in efficacy between treatments However, LMP was clearly advantageous in terms of dizziness and any adverse event vs. pregabalin 600 mg/day and discontinuations vs. pregabalin 300 mg/day or 600 mg/day, as well as being associated with improved quality of life (albeit in this case based on weak evidence).Conclusions: LMP was found to be similar to pregabalin in reducing pain in all populations but had a better adverse events profile.

Durvalumab for the Treatment of Locally Advanced, Unresectable, Stage III Non-Small Cell Lung Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (AstraZeneca) of durvalumab (IMFINZITM) to submit evidence for the clinical and cost effectiveness of durvalumab for the treatment of patients with locally advanced, unresectable, stage III non-small cell lung cancer whose tumours express programmed death-ligand 1 (PD-L1) on ≥ 1% of tumour cells and whose disease has not progressed after platinum-based chemoradiation therapy. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review on the clinical- and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the Appraisal Committee. The CS included a systematic review that identified one randomised controlled trial, comparing durvalumab with SoC. Participants with tumours expressing PD-L1 on ≥ 1% of tumour cells accounted for approximately 40% of the total participants. In this subgroup, a benefit in progression-free survival (PFS) [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.31-0.63] and overall survival (HR 0.54, 95% CI 0.35-0.81) was reported. Adverse events were comparable between both treatments, but more serious adverse events were reported for durvalumab (64/213 [30%] vs. 18/90 [20%]). The ERG's concerns regarding the economic analysis included a likely overestimation of PFS for the durvalumab arm, the choice of timepoint for treatment waning, as well as the way treatment waning was incorporated in the model, and potential overestimation of utility values without applying an age- or treatment-related decrement. The revised ERG base-case resulted in a deterministic incremental cost-effectiveness ratio of £50,238 per quality-adjusted life-year gained, with substantial remaining uncertainty. NICE recommended durvalumab as an option for use within the Cancer Drugs Fund only in a subpopulation (concurrent platinum-based chemoradiation therapy) with a commercially managed access agreement in place.

Fluocinolone Acetonide Intravitreal Implant for Treating Recurrent Non-infectious Uveitis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited Alimera Sciences, the company manufacturing fluocinolone acetonide intravitreal implant (FAc) 0.19 mg (tradename ILUVIEN®), to submit evidence on the clinical and cost-effectiveness of FAc for treating recurrent non-infectious uveitis. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre + , was commissioned to act as the independent Evidence Review Group (ERG). This paper contains a summary of the clinical and cost-effectiveness evidence submitted by the company, the ERG's critique on the submitted evidence, and the guidance issued by the NICE Appraisal Committee (AC). The company submission (CS) was mainly informed by the PSV-FAI-001 trial in which FAc was compared with (limited) current practice [(L)CP], which was not considered to be representative of UK clinical practice by the ERG. There was no comparison of FAc to any treatment listed in the final scope, and especially to the dexamethasone intravitreal implant (dexamethasone), which was considered to be a relevant comparator by the AC. The primary outcome of the PSV-FAI-001 was recurrence of uveitis in the treated eye. Most of the events for the primary outcome were imputed during the PSV-FAI-001 trial, which probably led to an overestimation of the number of recurrences of disease, and a biased estimate of the relative effectiveness of FAc versus (L)CP. Finally, the place of FAc in the treatment pathway was not clearly defined by the company. Substantial uncertainty surrounded the cost-effectiveness results due to the shortcomings of the clinical evidence. Additionally, the quality of life of patients was not measured during the PSV-FAI-001 trial and long-term effectiveness data of FAc were lacking. The ERG adjusted several issues identified in the CS and added dexamethasone as a comparator in the decision analytic model. The ERG presented multiple analyses as base-cases because several elements of the assessment remained uncertain. The fully incremental ERG results ranged from dexamethasone (extendedly) dominating FAc (when assuming a hazard ratio of 1 or 0.7 for dexamethasone versus FAc) to an incremental cost-effectiveness ratio (ICER) of £30,153 per quality-adjusted life-year (QALY) gained for FAc versus (L)CP [when assuming a hazard ratio of 0.456 for dexamethasone versus (L)CP]. The ICER of FAc versus (L)CP ranged from £12,325 to £30,153 per QALY gained. After a second AC meeting where alternative company scenarios comparing FAc with dexamethasone were considered by the AC, the AC concluded that "the results of the company's analyses ranged from the fluocinolone acetonide implant being dominant (that is, it was more effective and costs less), to an ICER of £29,461 per QALY gained, and most of the ICERs were below £20,000 per QALY gained". Therefore, the AC recommended FAc as a cost-effective use of National Health Service (NHS) resources for treating recurrent non-infectious uveitis affecting the posterior segment of the eye in the final TA590 guidance (published July 2019).

Protocol for the ProFHER (PROximal Fracture of the Humerus: Evaluation by Randomisation) trial: a pragmatic multi-centre randomised controlled trial of surgical versus non-surgical treatment for proximal fracture of the humerus in adults.

BACKGROUND: Proximal humeral fractures, which occur mainly in older adults, account for approximately 4 to 5% of all fractures. Approximately 40% of these fractures are displaced fractures involving the surgical neck. Management of this group of fractures is often challenging and the outcome is frequently unsatisfactory. In particular it is not clear whether surgery gives better outcomes than non-surgical management. Currently there is much variation in the use of surgery and a lack of good quality evidence to inform this decision. METHODS/DESIGN: We aim to undertake a pragmatic UK-based multi-centre randomised controlled trial evaluating the effectiveness and cost-effectiveness of surgical versus standard non-surgical treatment for adults with an acute closed displaced fracture of the proximal humerus with involvement of the surgical neck. The choice of surgical intervention is left to the surgeon, who must use techniques that they are fully experienced with. This will avoid 'learning curve' problems. We will promote good standards of non-surgical care, similarly insisting on care-provider competence, and emphasize the need for comparable provision of rehabilitation for both groups of patients.We aim to recruit 250 patients from a minimum of 18 NHS trauma centres throughout the UK. These patients will be followed-up for 2 years. The primary outcome is the Oxford Shoulder Score, which will be collected via questionnaires completed by the trial participants at 6, 12 and 24 months. This is a 12-item condition-specific questionnaire providing a total score based on the person's subjective assessment of pain and activities of daily living impairment. We will also collect data for other outcomes, including general health measures and complications, and for an economic evaluation. Additionally, we plan a systematic collection of reasons for non-inclusion of eligible patients who were not recruited into the trial, and their baseline characteristics, treatment preferences and intended treatment. DISCUSSION: This article presents the protocol for a multi-centre randomised controlled trial. It gives extensive details of, and the basis for, the chosen methods, and describes the key measures taken to avoid bias and to ensure validity. TRIAL REGISTRATION: Current Controlled Trials ISRCTN50850043.

Arsenic Trioxide for Treating Acute Promyelocytic Leukaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited Teva, the company manufacturing arsenic trioxide (ATO; tradename Trisenox®), to submit evidence for the clinical and cost effectiveness of ATO for untreated and relapsed or refractory acute promyelocytic leukaemia (APL). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the independent Evidence Review Group (ERG). This paper presents a summary of the company submission (CS), the ERG's critical review of the clinical and cost effectiveness evidence in the CS, key methodological considerations and the development of the NICE guidance by the Appraisal Committee (AC). The CS presented three randomized controlled trials (RCTs). Two of these were trials in newly diagnosed APL (APL0406 and AML17) and the third trial was in patients with relapsed APL. Results from APL0406 showed that more people having AATO [ATO plus all-trans retinoic acid (ATRA)] were alive at 50 months compared with people having AIDA (ATRA in combination with idarubicin) (99% vs. 93%; p = 0.007). There was also a statistically significant lower cumulative incidence of relapse with AATO compared with AIDA at 50 months (2% vs. 14%; p = 0.001). At 4 years, results from AML17 showed a significant difference in event-free survival (91% vs. 70%; p = 0.002) favouring AATO but not in overall survival (93% vs. 89%; p = 0.250). The only trial presented for relapsed/refractory patients compared AATO with ATO, which was not a relevant comparison according to the NICE scope. The AC concluded that AATO was effective for untreated APL while for relapsed or refractory APL the effectiveness of ATO was considered uncertain and the long-term safety remains unexplored. In the CS base-case, AATO was less expensive (£31,088 saved) and more effective (2.546 quality-adjusted life-years (QALYs) gained) than AIDA and thus the dominating strategy for newly diagnosed low- to intermediate-risk APL. However, the ERG's critical assessment highlighted a number of concerns, including deviations from the NICE reference case and a lack of detailed description and justification of parameters and assumptions related to (the extrapolation of) treatment effectiveness. However, it was reassuring that AATO for untreated APL remained dominant in the ERG base-case, and that the worst-case scenario produced by the ERG resulted in an incremental cost-effectiveness ratio (ICER) of £21,622. The AC concluded that although there was uncertainty in the model, it could recommend ATO for both untreated and relapsed or refractory APL.

Obinutuzumab in Combination with Chemotherapy for the First-Line Treatment of Patients with Advanced Follicular Lymphoma : An Evidence Review Group Evaluation of the NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE), as part of the institute's single technology appraisal (STA) process, invited the company that makes obinutuzumab (Roche Products Limited) to submit evidence of the clinical and cost effectiveness of the drug in combination with chemotherapy, with or without obinutuzumab as maintenance therapy for adult patients with untreated, advanced follicular lymphoma (FL) in the UK. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company's submission, the ERG review, and NICE's subsequent decisions. The clinical evidence was derived from two phase III, company-sponsored, randomised, open-label studies. Most evidence on obinutuzumab was based on the GALLIUM trial that compared obinutuzumab in combination with chemotherapy as induction followed by obinutuzumab maintenance monotherapy with rituximab in combination with chemotherapy as induction followed by rituximab maintenance monotherapy in previously untreated patients with FL (grades 1-3a). Long-term clinical evidence was based on the PRIMA trial, studying the benefit of two years of rituximab maintenance after first-line treatment in patients with FL. The cost-effectiveness evidence submitted by the company relied on a partitioned survival cost-utility model, implemented in Microsoft® Excel. The base-case incremental cost-effectiveness ratio (ICER) presented in the company submission was <£20,000 per quality-adjusted life-year (QALY) gained. Although the ERG concluded that the economic model met the NICE reference case to a reasonable extent, some errors were identified and several assumptions made by the company were challenged. A new base-case scenario produced by the ERG suggested an ICER that was higher than the company base case, but still below £30,000 per QALY gained. However, some ERG scenario analyses were close to or even above the threshold. This was the case in particular for assuming a treatment effect that did not extend beyond trial follow-up. These results led to an initial negative recommendation by the appraisal committee. Subsequently, the company submitted a revised base case focusing on patients at intermediate or high risk of premature mortality. Simultaneously, a further price discount for obinutuzumab was granted. In addition to the company's revised base case, the ERG suggested a restriction of the treatment effect to 5 years and implemented biosimilar uptake and cheaper prices for rituximab. All of these adjustments did not exceed £30,000 per QALY gained and therefore the use of obinutuzumab for patients with advanced FL and a Follicular Lymphoma International Predictive Index (FLIPI) score of two or more could be recommended.

The harvest plot: a method for synthesising evidence about the differential effects of interventions.

BACKGROUND: One attraction of meta-analysis is the forest plot, a compact overview of the essential data included in a systematic review and the overall 'result'. However, meta-analysis is not always suitable for synthesising evidence about the effects of interventions which may influence the wider determinants of health. As part of a systematic review of the effects of population-level tobacco control interventions on social inequalities in smoking, we designed a novel approach to synthesis intended to bring aspects of the graphical directness of a forest plot to bear on the problem of synthesising evidence from a complex and diverse group of studies. METHODS: We coded the included studies (n = 85) on two methodological dimensions (suitability of study design and quality of execution) and extracted data on effects stratified by up to six different dimensions of inequality (income, occupation, education, gender, race or ethnicity, and age), distinguishing between 'hard' (behavioural) and 'intermediate' (process or attitudinal) outcomes. Adopting a hypothesis-testing approach, we then assessed which of three competing hypotheses (positive social gradient, negative social gradient, or no gradient) was best supported by each study for each dimension of inequality. RESULTS: We plotted the results on a matrix ('harvest plot') for each category of intervention, weighting studies by the methodological criteria and distributing them between the competing hypotheses. These matrices formed part of the analytical process and helped to encapsulate the output, for example by drawing attention to the finding that increasing the price of tobacco products may be more effective in discouraging smoking among people with lower incomes and in lower occupational groups. CONCLUSION: The harvest plot is a novel and useful method for synthesising evidence about the differential effects of population-level interventions. It contributes to the challenge of making best use of all available evidence by incorporating all relevant data. The visual display assists both the process of synthesis and the assimilation of the findings. The method is suitable for adaptation to a variety of questions in evidence synthesis and may be particularly useful for systematic reviews addressing the broader type of research question which may be most relevant to policymakers.

Ixekizumab for Treating Moderate-to-Severe Plaque Psoriasis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence invited Eli Lilly and Company Ltd, the company manufacturing ixekizumab (tradename Taltz®), to submit evidence for the clinical and cost effectiveness of ixekizumab. Ixekizumab was compared with tumour necrosis factor-α inhibitors (etanercept, infliximab, adalimumab), ustekinumab, secukinumab, best supportive care and, if non-biological treatment or phototherapy is suitable, also compared with systemic non-biological therapies and phototherapy with ultraviolet B radiation for adults with moderate-to-severe plaque psoriasis. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Center, was commissioned as the independent Evidence Review Group. This article presents a summary of the company submission, the Evidence Review Group report and the development of the National Institute for Health and Care Excellence guidance for the use of this drug in England and Wales by the Appraisal Committee. The Evidence Review Group produced a critical review of the clinical and cost effectiveness of ixekizumab based on the company submission. The company submission presented three randomised controlled trials identified in a systematic review. All randomised controlled trials were phase III, multicentre placebo-controlled trials including 3866 participants with moderate-to-severe psoriasis. Two trials also included an active comparator (etanercept). All randomised controlled trials showed statistically significant increases in two primary outcomes, static Physician Global Assessment (0,1) and improvement of 75% from baseline in the Psoriasis Area and Severity Index. Ixekizumab was generally well tolerated in the randomised controlled trials, with similar discontinuation rates because of adverse events as placebo or etanercept. The most frequent adverse events of special interest were infections and injection-site reactions. The company submission also included a network meta-analysis of relevant comparators. The Evidence Review Group highlighted some issues regarding the systematic review process and an issue with the generalisability of the findings in that the trials failed to include patients with moderate psoriasis according to a widely used definition. This issue was considered by the Appraisal Committee and the population was deemed generalisable to patients in England and Wales. Based on the network meta-analysis, the Appraisal Committee concluded that ixekizumab was more clinically effective than adalimumab and ustekinumab, and agreed it was likely that ixekizumab was similarly effective compared with secukinumab and infliximab while tolerability was similar to other biological treatments approved for treating psoriasis. The Evidence Review Group's critical assessment of the company's economic evaluation highlighted a number of concerns, including (1) the use of relative outcomes such as Psoriasis Area and Severity Index response to model the cost effectiveness; (2) the exclusion of the consequences of adverse events; (3) the assumption of no utility gain in the induction phase; (4) equal annual discontinuation rates for all treatments; (5) the selection of treatment sequences for consideration in the analyses and; (6) the transparency of the Visual Basic for Applications code used to develop the model. Although some of these issues were adjusted in the Evidence Review Group base case, the Evidence Review Group could not estimate the impact of all of these issues, and thus acknowledges that there are still uncertainties concerning the cost-effectiveness evidence. In the Evidence Review Group base-case incremental analysis, the treatment sequence incorporating ixekizumab in the second line has an incremental cost-effectiveness ratio of £25,532 per quality-adjusted life-year gained vs. the etanercept sequence. Ixekizumab in the first-line sequence has an incremental cost-effectiveness ratio of £39,129 per quality-adjusted life-year gained compared with the treatment sequence incorporating ixekizumab in the second line. Consistent with its conclusion regarding clinical effectiveness, the Appraisal Committee concluded that the cost effectiveness of ixekizumab for treating moderate-to-severe plaque psoriasis was similar to that of other biological treatments, already recommended in previous National Institute for Health and Care Excellence guidance. The committee concluded that the incremental cost-effectiveness ratio was within the range that could be considered a cost-effective use of National Health Service resources.

Trifluridine-Tipiracil for Previously Treated Metastatic Colorectal Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited Servier, the company manufacturing trifluridine and tipiracil (T/T; trade name: Lonsurf®), to submit evidence for the clinical and cost effectiveness of T/T compared with best supportive care (BSC) for metastatic colorectal cancer (third-line or later). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the Evidence Review Group (ERG). This paper presents a summary of the company's submission (CS), the ERG report and the development of the NICE guidance for the use of this drug in England and Wales by the appraisal committee (AC). The ERG produced a critical review of the clinical and cost effectiveness of T/T based upon the CS. In the CS, pooled evidence of two trials (a phase II trial and RECOURSE) showed that T/T resulted in a significant increase in overall survival [OS; hazard ratio (HR) 0.67, 95% CI 0.58-0.78] and progression-free survival (PFS; HR 0.46, 95% CI 0.40-0.53). The AC considered the survival benefit of T/T clinically meaningful although relatively small. The ERG highlighted that none of the participants in the phase II trial and approximately half of the RECOURSE participants (394 of 800) were from Europe, which might limit the applicability of the study findings to the NHS. Moreover, the ERG's critical assessment of the company's economic evaluation highlighted a number of concerns that resulted in 11 adjustments to the company's base-case analysis. The ERG adjustments that had the largest impact were using the RECOURSE trial data only (instead of the pooled evidence), fixing errors and violations and using the utilities from the CORRECT trial (identified in the literature review) only. The ERG preferred to use the RECOURSE trial data only given the suboptimal methodology used by the company to pool the evidence. However, since there were no fundamental arguments to prevent the two trials from being pooled, the ERG also presented its base-case analysis based on the pooled effectiveness estimates. The company base-case resulted in an incremental cost effectiveness ratio (ICER) of £44,032 per QALY gained while the ERG base-case resulted in ICERs of £52,695 and £49,392 per QALY gained based on the RECOURSE trial only and pooled evidence, respectively. Since the AC concluded that the most plausible ICER was £49,392 per QALY gained, and that T/T meets end-of-life criteria, T/T was recommended as a cost effective use of NHS resources.

Pomalidomide with Dexamethasone for Treating Relapsed and Refractory Multiple Myeloma Previously Treated with Lenalidomide and Bortezomib: An Evidence Review Group Perspective of an NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE), as part of the institute's single technology appraisal (STA) process, invited the manufacturer of pomalidomide (POM; Imnovid®, Celgene) to submit evidence regarding the clinical and cost effectiveness of the drug in combination with dexamethasone (POM + LoDEX) for the treatment of relapsed and refractory multiple myeloma (RRMM) after at least two regimens including lenalidomide (LEN) and bortezomib (BOR). Kleijnen Systematic Reviews Ltd (KSR) and Erasmus University Rotterdam were commissioned as the Evidence Review Group (ERG) for this submission. The ERG reviewed the evidence submitted by the manufacturer, validated the manufacturer's decision analytic model, and conducted exploratory analyses in order to assess the robustness and validity of the presented clinical and cost-effectiveness results. This paper describes the company submission, the ERG assessment, and NICE's subsequent decisions. The company conducted a systematic review to identify studies comparing POM with comparators outlined in the NICE scope: panobinostat with bortezomib and dexamethasone (PANO + BOR + DEX), bendamustine with thalidomide and dexamethasone (BTD) and conventional chemotherapy (CC). The main clinical effectiveness evidence was obtained from MM-003, a randomized controlled trial (RCT) comparing POM + LoDEX with high-dose dexamethasone (HiDEX; used as a proxy for CC). Additional data from other studies were also used as nonrandomized observational data sources for the indirect treatment comparison of POM + LoDEX with BTD and PANO + BOR + DEX. Covariate or treatment switching adjustment methods were used for each comparison. The model developed in Microsoft® Excel 2010 using a semi-Markov partitioned survival structure, submitted in the original submission to NICE for TA338, was adapted for the present assessment of the cost effectiveness of POM + LoDEX. Updated evidence from the clinical-effectiveness part was used for the survival modelling of progression-free survival and overall survival. For POM + LoDEX, the patient access scheme (PAS) discount was applied to the POM price. Three separate comparisons were conducted for each comparator, each comparison using a different dataset and adjustment methods. The ERG identified and corrected some errors, and the corrected incremental cost-effectiveness ratios (ICERs) for POM + LoDEX versus each comparator were presented: approximately £45,000 per quality-adjusted life-year (QALY) gained versus BTD, savings of approximately £143,000 per QALY lost versus PANO + BOR + DEX, and approximately £49,000 per QALY gained versus CC. The ERG also conducted full incremental analyses, which revealed that CC, POM + LoDEX and PANO + BOR + DEX were on the cost-effectiveness frontier. The committee's decision on the technology under analysis deemed that POM + LoDEX should be recommended as an option for treating multiple myeloma in adults at third or subsequent relapse of treatments including both LEN and BOR, contingent on the company providing POM with the discount agreed in the PAS.