Is the assumption of waning of treatment effect applied consistently across NICE technology appraisals? A case-study focusing on disease-modifying therapies for treatment of multiple sclerosis.

OBJECTIVES: Whether the effects of therapies may wane over time is a matter of debate, especially when considering their long-term cost-effectiveness. Here, we examined how the assumption of the waning of treatment effect was applied across the National Institute for Health and Care Excellence (NICE) appraisals for disease-modifying therapies (DMTs) used in multiple sclerosis. METHODS: We undertook a document analysis following a search of the NICE website. The inclusion criteria of the study were as follows: all publicly available documents related to completed appraisals for DMTs (period: January 2000 to July 2021). The exclusion criteria of the study were as follows: all documents that did not meet the inclusion criteria, especially pertaining to drugs used in other disease areas. We extracted information about the waning of treatment effect assumption as considered by companies, assessment groups, and appraisal committees, and we analyzed trends over time. RESULTS: We reviewed fifteen appraisals that reported guidance on sixteen DMTs. Irrespective of the drugs' mechanism of action or their pharmaceutical nature, there was substantial variation in the modalities when the assumption of waning was implemented. We noted the recent preference to use all-cause discontinuation as a proxy. This heterogeneity did not appear to affect acceptance of the DMTs (all but one were recommended for use across the National Health System (NHS)). CONCLUSIONS: Modeling the long-term effect of therapies is challenging, especially given the limited follow-up duration of related trials. This generates recurrent debates on the presence of waning of treatment efficacy and heterogeneity across appraisals. More refined recommendations obtained by consensus among stakeholders could help to achieve greater consistency in decision making.

Beating versus arrested heart isolated tricuspid valve surgery: An 11-year experience in the current era.

BACKGROUND AND AIM OF THE STUDY: Data about the beating heart (BH) technique for isolated tricuspid valve (TV) surgery compared to the arrested heart (AH) technique are sparse. We compared the outcomes of isolated TV surgery between BH and AH technique. METHODS: We performed an observational analysis of our database of isolated TV surgery. Patients were divided into two groups according to whether surgery was performed without (BH group) or with (AH group) aortic cross-clamping and cardioplegic arrest. The primary endpoint was survival to hospital discharge. Risk factors for in-hospital mortality were searched with multivariate analyses. We undertook further comparisons after propensity-score matching. RESULTS: From January 2007 to December 2017, we performed 82 isolated TV surgery (BH group, n = 47, 57.3%; AH group, n = 35, 42.7%). The mean age was 59.1 years, 56.1% were female. BH group patients were older (61.8 vs. 55.4 years; p = .035), had greater impaired renal function (glomerular filtration rate, 61.1 vs. 74.6 ml/min; p = .012), were more frequently operated for secondary TR (61.7 vs. 31.4%; p = .008), underwent more frequently a reoperation (53.2 vs. 28.6%; p = .042) and exhibited a higher surgical risk (EuroSCORE II, 3.92 vs. 2.50%; p = .013). In-hospital mortality was not different between both groups, either considering unmatched (BH = 10.6 vs. AH = 5.7%; OR = 1.96, 95% confidence interval [CI] = 0.36-10.77) or matched populations (BH = 10.6 vs. AH = 6.4%; OR = 1.89, 95% CI = 0.36-9.97). Age was the only predictor of in-hospital mortality. CONCLUSIONS: The BH technique showed comparable outcomes to the AH technique for isolated TV surgery despite a higher risk profile.

Comparative survival benefit of currently licensed second or third line treatments for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) negative advanced or metastatic non-small cell lung cancer: a systematic review and secondary analysis of trials.

BACKGROUND: A review of therapies for advanced cancers licenced by the EMA between 2009 and 2013 concluded that for more than half of these drugs there was little evidence of overall survival or quality of life benefit. Recent years have witnessed a growing number of licensed second-line pharmacotherapies for advanced/metastatic non-small cell lung cancer (NSCLC). With the aim of gauging patient survival benefit, we conducted a systematic review of randomised controlled trials (RCT) and compared survival outcomes from available licensed treatments for patients with advanced/metastatic NSCLC. METHODS: RCTs of second/third line treatments in participants with advanced/metastatic NSCLC and negative/low expression of Anaplastic Lymphoma Kinase (ALK) and of Epidermal Growth Factor Receptor (EGFR) were included. We searched electronic databases (MEDLINE; EMBASE; Web of Science) from January, 2000 up to July, 2017. Two or more independent reviewers screened bibliographic records, extracted data, and assessed risk of bias of studies. Published Kaplan Meier plots for OS and PFS along with restricted-mean-survival methods and parametric modelling were used to estimate the survival outcomes as mean number of months of survival. Network meta-analysis was undertaken to rank interventions and to make indirect comparisons. RESULTS: We included 11 RCTs with data for 7581 participants that compared nine different drugs. In studies of patients regardless of histology groups, targeted drugs (ramucirumab and nintedanib) yielded small overall survival gains of < 2.5 months over docetaxel, erlotinib provided no benefit, while immunotherapies (atezolizumab and pembrolizumab) delivered 5 to 6 months gain. Studies with patients stratified by histology confirmed the apparent superiority of immunotherapy (nivolumab and atezolizumab) over targeted treatments (ramucirumab, nintedanib, afatinib) providing between about 4 to 8 months OS gain over docetaxel. In network analysis immunotherapies consistently ranked higher than alternatives irrespective of population histology and outcome measure. CONCLUSION: Our review indicates that nivolumab, pembrolizumab and atezolizumab provide superior survival benefits compared to other licensed drugs for late stage NSCLC. Patient gains from these immunotherapies are substantial compared to the expected average survival with chemotherapy (docetaxel) of < 1 year for people with squamous histology and about 1.25 year for those with non-squamous histology.

Cost-effectiveness of tumor-treating fields added to maintenance temozolomide in patients with glioblastoma: an updated evaluation using a partitioned survival model.

PURPOSE: A first cost-effectiveness analysis has raised a strong concern regarding the cost of tumor treatment fields (TTF) added to maintenance temozolomide for patients with glioblastoma. This evaluation was based on effectiveness outcomes from an interim analysis of the pivotal trial, moreover it used a "standard" Markov model. Our objective was to update the cost-effectiveness evaluation using the more flexible potential of the "partitioned survival" model design and using the latest effectiveness data. METHODS: We developed the model with three mutually exclusive health states: stable disease, progressive disease, and dead. Good fit parametric models were developed for overall survival and progression free survival and these generated clinically plausible extrapolations beyond the observed data. We adopted the perspective of the French national health insurance and used a 20-year time horizon. Results were expressed as cost/life-years (LY) gained (LYG). RESULTS: The base case model generated incremental benefit of 0.604 LY at a cost of €453,848 which, after 4% annual discounting of benefits and costs, yielded an incremental cost effectiveness ratio (ICER) of €510,273/LYG. Using sensitivity analyses and bootstrapping methods results were found to be relatively robust and were only sensitive to TTF device costs and the modelling of overall survival. To achieve an ICER below €100,000/LYG would require a reduction in TTF device cost of approximately 85%. CONCLUSIONS: Using a different type of model and updated survival outcomes, our results show TTF remains an intervention that is not cost-effective, which greatly restrains its diffusion to potentially eligible patients.

How Do Pharmaceutical Companies Model Survival of Cancer Patients? A Review of NICE Single Technology Appraisals in 2017.

OBJECTIVES: Before an intervention is publicly funded within the United Kingdom, the cost-effectiveness is assessed by the National Institute of Health and Care Excellence (NICE). The efficacy of an intervention across the patients' lifetime is often influential of the cost-effectiveness analyses, but is associated with large uncertainties. We reviewed committee documents containing company submissions and evidence review group (ERG) reports to establish the methods used when extrapolating survival data, whether these adhered to NICE Technical Support Document (TSD) 14, and how uncertainty was addressed. METHODS: A systematic search was completed on the NHS Evidence Search webpage limited to single technology appraisals of cancer interventions published in 2017, with information obtained from the NICE Web site. RESULTS: Twenty-eight appraisals were identified, covering twenty-two interventions across eighteen diseases. Every economic model used parametric curves to model survival. All submissions used goodness-of-fit statistics and plausibility of extrapolations when selecting a parametric curve. Twenty-five submissions considered alternate parametric curves in scenario analyses. Six submissions reported including the parameters of the survival curves in the probabilistic sensitivity analysis. ERGs agreed with the company's choice of parametric curve in nine appraisals, and agreed with all major survival-related assumptions in two appraisals. CONCLUSIONS: TSD 14 on survival extrapolation was followed in all appraisals. Despite this, the choice of parametric curve remains subjective. Recent developments in Bayesian approaches to extrapolation are not implemented. More precise guidance on the selection of curves and modelling of uncertainty may reduce subjectivity, accelerating the appraisal process.

Is monitoring of plasma 5-fluorouracil levels in metastatic / advanced colorectal cancer clinically effective? A systematic review.

BACKGROUND: Pharmacokinetic guided dosing of 5-fluorouracil chemotherapies to bring plasma 5-fluorouracil into a desired therapeutic range may lead to fewer side effects and better patient outcomes. High performance liquid chromatography and a high throughput nanoparticle immunoassay (My5-FU) have been used in conjunction with treatment algorithms to guide dosing. The objective of this study was to assess accuracy, clinical effectiveness and safety of plasma 5-fluorouracil guided dose regimen(s) versus standard regimens based on body surface area in colorectal cancer. METHODS: We undertook a systematic review. MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations; EMBASE; Cochrane Library; Science Citation Index and Conference Proceedings (Web of Science); and NIHR Health Technology Assessment Programme were searched from inception to January 2014. We reviewed evidence on accuracy of My5-FU for estimating plasma 5-fluorouracil and on the clinical effectiveness of pharmacokinetic dosing compared to body surface area dosing. Estimates of individual patient data for overall survival and progression-free survival were reconstructed from published studies. Survival and adverse events data were synthesised and examined for consistency across studies. RESULTS: My5-FU assays were found to be consistent with reference liquid chromatography tandem mass spectrometry. Comparative studies pointed to gains in overall survival and in progression-free survival with pharmacokinetic dosing, and were consistent across multiple studies. CONCLUSIONS: Although our analyses are encouraging, uncertainties remain because evidence is mainly from outmoded 5-fluorouracil regimens; a randomised controlled trial is urgently needed to investigate new dose adjustment methods in modern treatment regimens.

Cost-effectiveness of left atrial appendage occlusion during cardiac surgery in France: An economic evaluation based on the LAAOS III study.

OBJECTIVES: Left atrial appendage occlusion during cardiac surgery is a therapeutic option for stroke prevention in patients with atrial fibrillation. The effectiveness and safety of left atrial appendage occlusion have been evaluated in several studies, including the LAAOS-III trial. While these studies have demonstrated efficacy and safety, the long-term economic impact of this surgical technique has not yet been assessed. Here, we aimed to evaluate the cost-effectiveness and cost-utility of left atrial appendage occlusion during cardiac surgery over a long-term time horizon. METHODS: Our study was based on a model representing an hypothetical cohort with the same characteristics as LAAOS-III trial patients. We modelled the incidence of ischemic strokes and systemic embolisms in each intervention arm: "occlusion" and "no-occlusion," using a one-month cycle length with a 20-year time horizon. Regarding occlusion devices, sutures, staples, or an approved surgical occlusion device (AtriClip™-AtriCure, Ohio, USA) could be used. RESULTS: Our model generated an average cost savings of 607 euros per patient and an incremental gain of 0.062 quality-adjusted life years (QALYs), resulting an incremental cost-utility ratio (ICUR) of €-9,775/QALY. The scenario analysis in which occlusion was systematically performed using the AtriClip™ device generated an ICUR of €3,952/QALY gained. CONCLUSIONS: In the base-case analysis, the strategy proved to be more effective and less costly, confirming left atrial appendage occlusion during cardiac surgery as an economically dominant strategy. The scenario analysis also appeared cost-effective, although it did not result in cost savings. This study provides a new perspective on the assessment of the cost-effectiveness of these techniques.

Impact of updated trial data on the cost-effectiveness of percutaneous mitral repair.

When updated clinical trial data becomes available reassessing the cost-effectiveness of technologies may modify estimates and influence decision-making. We investigated the impact of updated trial outcomes on the cost-effectiveness of percutaneous mitral repair (PR) for secondary mitral regurgitation. We updated our previous three-state time-varying Markov model to assess the cost-effectiveness of PR + guideline directed medical treatment (GDMT) versus GDMT alone. Key clinical inputs (overall survival (OS) and heart failure hospitalisations (HFH)) were obtained using the 3-year trial findings from the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy) RCT. We calculated incremental cost-effectiveness ratios (ICER) and report how these differ between analyses based on early (2-year) and updated (3-year) evidence. Updated trial data showed an increase in mortality in the intervention arm between two and three years follow-up that was not seen in the control arm. Deterministic and multivariate cost-effectiveness modelling yielded incremental cost effectiveness ratios ICERs of €38,123 and €31,227 /QALY. Compared to our 2-year based estimate (€21,918 / QALY) these results imply an approximate 1.5-fold increase in ICER. The availability of updated survival analyses from the COAPT pivotal trial suggests previous estimates based on 2-year trial findings were over optimistic for the intervention.

Potential impact on cost-effectiveness estimates of using immature survival data: a case study based on transcatheter edge-to-edge repair (TEER) used for patients with severe mitral regurgitation at high surgical risk.

OBJECTIVE: To review the survival modelling used in cost-effectiveness studies evaluating an interventional procedure and to discuss implications for decision-makers. DESIGN: A case study of three economic evaluations that each used immature data from the EVEREST II High Surgical Risk (HSR) Study of transcatheter edge-to-edge repair (TEER) for patients with severe mitral regurgitation (MR) who were at high risk of surgery. SETTING: Estimation of patient survival in cost-effectiveness studies. PARTICIPANTS: The EVEREST II HSR Study included 78 patients who had TEER of the mitral valve using the MitraClip device and a retrospectively identified control group of 36 patients who received medical management and were followed up for 12 months. Observed survival (TEER arm only) was updated at 5 years. RESULTS: Two studies used 12-month observed mortality from EVEREST II HSR to model survival over lifetime horizons. Observed and modelled survival were associated with considerable uncertainty due to short follow-up and small numbers of participants. Modelling control patients' survival required an approximate 10-fold extrapolation based on 12-month observation of only 38 patients. Observed 5-year survival in the TEER group differed from that less mature follow-up suggesting that survival modelling based on shorter follow-up was unsatisfactory. No public domain data for the control group are available beyond 12-month follow-up so meaningful estimates using mature data for both arms are currently not possible. A third study developed survival models using incompletely reported transitions between MR grades in EVEREST II HSR and mortality rates observed for different MR grades derived from a study in an unrelated population. CONCLUSIONS: Modelling survival in such small samples followed up for only 12 months is associated with great uncertainty, and cost-effectiveness results based on these analyses should be viewed as premature and used cautiously in reimbursement decisions.

A comparison of published time invariant Markov models with Partitioned Survival models for cost effectiveness estimation; three case studies of treatments for glioblastoma multiforme.

BACKGROUND: Cost-effectiveness analyses of treatments for glioblastoma multiforme (GBM) have mostly used state transition Markov models with time invariant transition probabilities (TIMMs). In three case studies of GBM treatments, we compared Partitioned Survival model (PSM) results with published outputs from TIMMs. METHODS: PSMs used the same RCT data sources, utility values, time horizons, cycle times and annual discounting used in published TIMMs. Reported overall survival and progression-free survival plots were digitised and fitted with a range of parametric models. Economic model outputs were generated in the same form as reported for the TIMMs. PSM output uncertainty was explored in univariate and in multivariate sensitivity analyses. RESULTS: PSMs generated incremental cost-effectiveness ratios that were different to the published TIMMs. The magnitude of difference was substantial in two cases. The PSMs were reasonably robust and in sensitivity analyses were sensitive to variations in the same model inputs as were the TIMMs. When compared to the RCT data, the TIMMs tended to generate underestimates of the likely overall survival gain. TIMM estimates for depletion of individuals from the stable disease state and for accumulation in the dead state had relatively poor resemblance to the source RCT data. CONCLUSION: TIMMs delivered different cost-effectiveness estimates to PSMs; in two cases, TIMMs produced substantially lower ICER values than PSMs. Model output differences appear attributable to less realistic cost-and-benefit estimates generated in TIMMs due to rapid depletion from the stable disease state and/or accumulation in the dead state.

Ocrelizumab not recommended in France for patients with primary progressive multiple sclerosis while recommended in England: a review comparing the assessment by HAS and NICE.

INTRODUCTION: Ocrelizumab is the first approved drug for primary progressive multiple sclerosis. Following appraisal by health technology assessment (HTA) bodies, this medicine has not been widely covered across European countries. We have compared the HTA process in England and France. AREA COVERED: We undertook an analysis of relevant documents that were published by the two HTA bodies. We analyzed patients' availability of Ocrelizumab at the different stages of the process. EXPERT OPINION: We identified differences in the assessment, one being the use of a different population of the pivotal trial, which has resulted in the consideration of distinct clinical effectiveness estimates. Ocrelizumab became available earlier in France as part of an early access program. However, rapid access was discontinued for newly eligible patients following an opinion concluding that Ocrelizumab yielded no additional benefit over placebo. This opinion was not compatible with the criteria allowing reimbursement in France.In England, there was no early access program and following an appraisal that included cost-effectiveness evaluation combined with pricing agreements, medicine was finally recommended. In conclusion, differences in the HTA process may result in appreciable differences in timing and outcome from marketing authorization to the adoption of newly licensed drugs.

Newborn Screening for Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase and Mitochondrial Trifunctional Protein Deficiencies Using Acylcarnitines Measurement in Dried Blood Spots-A Systematic Review of Test Accuracy.

Background: Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiencies are rare autosomal recessive fatty acid ß-oxidation disorders. Their clinical presentations are variable, and premature death is common. They are included in newborn blood spot screening programs in many countries around the world. The current process of screening, through the measurement of acylcarnitines (a metabolic by-product) in dried blood spots with tandem mass spectrometry, is subject to uncertainty regarding test accuracy. Methods: We conducted a systematic review of literature published up to 19th June 2018. We included studies that investigated newborn screening for LCHAD or MTP deficiencies by tandem mass spectrometry of acylcarnitines in dried blood spots. The reference standards were urine organic acids, blood acylcarnitine profiles, enzyme analysis in cultured fibroblasts or lymphocytes, mutation analysis, or at least 10-year follow-up. The outcomes of interest were sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Assessment of titles, abstracts, and full-text papers and quality appraisal were carried out independently by two reviewers. One reviewer extracted study data. This was checked by a second reviewer. Results: Ten studies provided data on test accuracy. LCHAD or MTP deficiencies were identified in 23 babies. No cases of LCHAD/MTP deficiencies were identified in four studies. PPV ranged from 0% (zero true positives and 28 false positives from 276,565 babies screened) to 100% (13 true positives and zero false positives from 2,037,824 babies screened). Sensitivity, specificity, and NPV could not be calculated as there was no systematic follow-up of babies who screened negative. Conclusions: Test accuracy estimates of screening for LCHAD and MTP deficiencies with tandem mass spectrometry measurement of acylcarnitines in dried blood were variable in terms of PPVs. Screening methods (including markers and thresholds) varied between studies, and sensitivity, specificity, and NPVs are unknown.

Conflicting findings between the Mitra-Fr and the Coapt trials: Implications regarding the cost-effectiveness of percutaneous repair for heart failure patients with severe secondary mitral regurgitation.

PURPOSE: Two randomized controlled trials (RCTs), Mitra-Fr and Coapt, evaluating the benefit of percutaneous repair (PR) for heart failure (HF) patients with severe mitral regurgitation, have led to conflicting results. We aimed to evaluate the impact of these trial results on the cost-effectiveness of PR using effectiveness inputs from the two RCTs. METHODS: We developed a time varying Markov type model with three mutually exclusive health states: alive without HF hospitalisation, alive with HF hospitalisation, and dead. Clinically plausible extrapolations beyond observed data were obtained by developing parametric modelling for overall survival and HF hospitalisations using published data from each trial. We adopted the perspective of the French Health System and used a 30-year time horizon. Results were expressed as € / quality-adjusted life year (QALY) gained using utility inputs from literature. FINDINGS: Results are presented using treatment efficacy measures from Mitra-F and Coapt trials respectively. With the Mitra-Fr data, after annual discounting, the base case model generated an incremental 0.00387 QALY at a cost of €25,010, yielding an incremental cost effectiveness ratio (ICER) of €6,467,032 / QALY. The model was sensitive to changes made to model inputs. There was no potential of PR being cost-effective. With the Coapt data, the model generated 1.19 QALY gain at a cost of €26,130 yielding an ICER of €21,918 / QALY and at a threshold of >€50,000/QALY PR had a probability of 1 of being cost-effective. IMPLICATIONS: Cost effectiveness results were conflicting; reconciling differences between trials is a priority and could promote optimal cost effectiveness analyses and resource allocation.

Will the US$5 million onasemnogene abeparvosec treatment for spinal muscular atrophy represent 'value for money' for the NHS? A rapid inquiry into suggestions that it may be cost-effective.

OBJECTIVES: Nusinersen (Spinraza®, Biogen) and onasemnogene abeparvosec (Zolgensma®, Novartis) are novel gene-based therapies for the orphan disease Spinal Muscular Atrophy. Onasemnogene abeparvosec has been allocated an acquisition cost of up to US$5 million per patient. We undertook a rapid inquiry to evaluate if onasemnogene abeparvosec is likely to be cost-effective for the UK NHS. METHODS: We used publicly available cost-effectiveness data and recommended methodology to perform cost-utility evaluation of onasemnogene abeparvosec versus best supportive care and nusinersen. RESULTS: Our evaluations highlight wide variations in cost and benefit estimates of nusinersen and indicate that onasemnogene abeparvosec is unlikely to represent value for money according to current standards of reimbursement. Results are discussed in the context of reimbursement decisions for orphan diseases. CONCLUSION: Commonly implemented commercial confidentiality practices combined with uncertain data obscure scrutiny and justification of past and present reimbursement decisions for orphan drugs. Future cutting edge expensive therapies will be numerous, they will entail very substantial economic strains. We conclude that there is an urgent and increasing need for the development of improved procedures that can lead to equitable, consistent, and transparent decision-making.

Ocrelizumab for Treating Patients with Primary Progressive Multiple Sclerosis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Ocrelizumab is indicated for relapsing remitting and primary progressive multiple sclerosis (RRMS and PPMS, respectively). In an appraisal undertaken by the National Institute for Health and Care Excellence (NICE), the company Roche presented the evidence for ocrelizumab used in patients with PPMS, which came from one single randomised controlled trial (RCT) comparing ocrelizumab versus placebo. Based on results from this trial, the licensed indication was restricted to patients with early PPMS in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity. Overall, the Evidence Review Group (ERG) found that the RCT had a low risk of bias. In the post-hoc defined magnetic resonance imaging (MRI) active subgroup, matching the label indication, the risk of confirmed disability progression sustained for 12 weeks (CDP-12) was significantly delayed in the ocrelizumab group compared to placebo. However, considering the same risk with progression sustained for 24 weeks (CDP-24), which was deemed the most clinically relevant, the benefit from ocrelizumab did not reach statistical significance. In the same MRI active subgroup, benefits from ocrelizumab on functional outcomes and on health-related quality of life were not clearly demonstrated. A de novo Markov model was used to estimate the cost-effectiveness of ocrelizumab versus best supportive care (BSC) for treating patients with PPMS. Health states were defined by the Expanded Disability Status Scale (EDSS), ranging from 0 to 9. Disability progression was based on the MSBase natural history cohort that exhibited disease progression in the absence of disease-modifying therapy. Treatment with ocrelizumab delayed disability progression, with evidence of its clinical effectiveness obtained from the RCT. The economic analysis was undertaken from the National Health Service and Personal Social Services perspective, and the outcomes were reported in terms of life years gained and quality-adjusted life years (QALYs), with the overall results reported in terms of an incremental cost-effectiveness ratio (ICER), expressed as cost per QALY gained over a 50-year time horizon. Both costs and effects were discounted at 3.5% per annum. The company undertook deterministic one-way sensitivity analyses and scenario analyses, including probabilistic sensitivity analysis (PSA). The ERG raised several concerns, which were discussed at the appraisal committee meetings, resulting in the committee's preferences being applied and a revised economic analysis from the company. Under an approved patient access scheme with appraisal committee preferences applied, analyses yielded an ICER of approximately £78,300 per QALY. Sensitivity analysis results indicated that the treatment effect on CDP-12 had the greatest impact. Results for the PSA showed that at a willingness-to-pay threshold of £30,000 per QALY gained, ocrelizumab versus BSC had a zero probability of being cost-effective. Following new analyses submitted by the company, with a revised confidential patient access scheme, NICE recommended ocrelizumab in the treatment of early PPMS in adults with imaging features characteristic of inflammatory activity.

Assessing the outcomes of prolonged cessation-induction and aid-to-cessation trials: floating prolonged abstinence.

INTRODUCTION: A Society for Research on Nicotine and Tobacco working group recommended outcome measures for cessation-induction trials and aid-to-cessation trials. Cessation-induction trials aim to motivate unwilling quitters to make a quit attempt. Aid-to-cessation trials give either medication or behavioral interventions to increase the rate at which willing quitters succeed in their attempts. Nicotine-assisted reduction programs combine features of both types of interventions by giving nicotine replacement to unwilling quitters. Treatment can be prolonged more than a year, quit attempts can occur and succeed early or late in the program, and renewed quit attempts are an inherent part of the program. Conventional outcome measures are tied to a fixed but arbitrary point in follow-up and cannot capture the true outcome: Prolonged cessation anchored to the point at which a person makes a successful quit attempt. DISCUSSION: We propose that the outcome should be counted from the successful quit attempt that began during the treatment period and continues for a defined period, ideally 6 months. In particular, if a trial compared a short reduction program with a long reduction program, it would not be possible to obtain an unbiased assessment of the outcome of such a trial using a measure tied to a fixed point in follow-up. Floating prolonged abstinence could provide such an assessment and is suitable for either prolonged cessation-induction trial or combined cessation-induction and aid-to-cessation trials.

Clinical effectiveness and cost-effectiveness of pegvisomant for the treatment of acromegaly: a systematic review and economic evaluation.

BACKGROUND: Acromegaly, an orphan disease usually caused by a benign pituitary tumour, is characterised by hyper-secretion of growth hormone (GH) and insulin-like growth factor I (IGF-1). It is associated with reduced life expectancy, cardiovascular problems, a variety of insidiously progressing detrimental symptoms and metabolic malfunction. Treatments include surgery, radiotherapy and pharmacotherapy. Pegvisomant (PEG) is a genetically engineered GH analogue licensed as a third or fourth line option when other treatments have failed to normalise IGF-1 levels. METHODS: Evidence about effectiveness and cost-effectiveness of PEG was systematically reviewed. Data were extracted from published studies and used for a narrative synthesis of evidence. A decision analytical economic model was identified and modified to assess the cost-effectiveness of PEG. RESULTS: One RCT and 17 non-randomised studies were reviewed for effectiveness. PEG substantially reduced and rapidly normalised IGF-1 levels in the majority of patients, approximately doubled GH levels, and improved some of the signs and symptoms of the disease. Tumour size was unaffected at least in the short term. PEG had a generally safe adverse event profile but a few patients were withdrawn from treatment because of raised liver enzymes. An economic model was identified and adapted to estimate the lower limit for the cost-effectiveness of PEG treatment versus standard care. Over a 20 year time horizon the incremental cost-effectiveness ratio was pound81,000/QALY and pound212,000/LYG. To reduce this to pound30K/QALY would require a reduction in drug cost by about one third. CONCLUSION: PEG is highly effective for improving patients' IGF-1 level. Signs and symptoms of disease improve but evidence is lacking about long term effects on improved signs and symptoms of disease, quality of life, patient compliance and safety. Economic evaluation indicated that if current standards (UK) for determining cost-effectiveness of therapies were to be applied to PEG it would be considered not to represent good value for money.

Comparison of health technology assessment for new medicines in France and England: an example based on ixazomib for patients with relapsed or refractory multiple myeloma.

Introduction: The appraisal of medicines is often a complex and iterative process. We compared the health technology assessment (HTA) process in England and France taking as a case study the example of ixazomib for multiple myeloma. Methods: We undertook an analysis of eight relevant published documents identifed from the websites of the French and English HTA bodies (HAS and NICE, respectively). We analyse patients' availability of ixazomib resulting in the different stages of the appraisal process. Results: We identified differences in the assessment, one of these being the use of an appraisal scope in England allowing the differentiation of populations and comparators according to previously approved treatments. Ixazomib became available earlier in France as part of an early access programme, but the availability was soon discontinued for newly eligible patients following an HAS determination that Ixazomib yielded no additional benefit. This opinion resulted in long pricing discussions. In England, despite the absence of an early access programme and following a process that included cost-effectiveness evaluation combined with pricing discussions, the medicine was fairly rapidly recommended for use. Conclusions: Differences in the HTA process may result in appreciable differences in time from marketing authorisation to health service adoption of newly licensed drugs.

Evaluation of earlier versus later dietary management in long-chain 3-hydroxyacyl-CoA dehydrogenase or mitochondrial trifunctional protein deficiency: a systematic review.

BACKGROUND: Mitochondrial trifunctional protein (MTP) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiencies are rare fatty acid ß-oxidation disorders. Without dietary management the conditions are life-threatening. We conducted a systematic review to investigate whether pre-symptomatic dietary management following newborn screening provides better outcomes than treatment following symptomatic detection. METHODS: We searched Web of Science, Medline, Pre-Medline, Embase and the Cochrane Library up to 23rd April 2018. Two reviewers independently screened titles, abstracts and full texts for eligibility and quality appraised the studies. Data extraction was performed by one reviewer and checked by another. RESULTS: We included 13 articles out of 7483 unique records. The 13 articles reported on 11 patient groups, including 174 people with LCHAD deficiency, 18 people with MTP deficiency and 12 people with undifferentiated LCHAD/MTP deficiency. Study quality was moderate to weak in all studies. Included studies suggested fewer heart and liver problems in screen-detected patients, but inconsistent results for mortality. Follow up analyses compared long-term outcomes of (1) pre-symptomatically versus symptomatically treated patients, (2) screened versus unscreened patients, and (3) asymptomatic screen-detected, symptomatic screen-detected, and clinically diagnosed patients in each study. For follow up analyses 1 and 2, we found few statistically significant differences in the long-term outcomes. For follow up analysis 3 we found a significant difference for only one comparison, in the incidence of cardiomyopathy between the three groups. CONCLUSIONS: There is some evidence that dietary management following screen-detection might be associated with a lower incidence of some LCHAD and MTP deficiency-related complications. However, the evidence base is limited by small study sizes, quality issues and risk of confounding. An internationally collaborative research effort is needed to fully examine the risks and the benefits to pre-emptive dietary management with particular attention paid to disease severity and treatment group.

Autologous Chondrocyte Implantation with Chondrosphere for Treating Articular Cartilage Defects in the Knee: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Chondrosphere (Spherox) is a form of autologous chondrocyte implantation (ACI). It is licensed for repair of symptomatic articular cartilage defects of the femoral condyle and the patella of the knee with defect sizes up to 10 cm2 in adults. In a single technology appraisal (STA) [TA508] undertaken by the National Institute of Health and Care Excellence (NICE), Warwick Evidence was the Evidence Review Group (ERG) invited to independently review the evidence submitted by the manufacturer, Co.Don. The clinical effectiveness data came from their COWISI randomised controlled trial (RCT), which compared Chondrosphere with microfracture (MF). The timing of this appraisal was unfortunate given that MF was no longer the most relevant comparator because NICE had contemporaneously published guidance approving ACI in place of MF. Moreover, the COWISI RCT enrolled mostly patients with small defect sizes. Evidence of clinical effectiveness for Chondrosphere used in people with larger defect size came from another RCT, which compared three doses of Chondrosphere and that by design could not provide evidence comparing Chondrosphere to any other forms of ACI. To estimate the relative clinical performance of Chondrosphere versus other ACI, Co.Don conducted an indirect treatment comparison by network meta-analyses (NMA). The NMA was flawed in that the distribution of population characteristics that are effect modifiers greatly differed across the treatment comparisons of the network. The ERG questioned both the appropriateness of the NMA and the validity of the resulting estimates. Co.Don estimated the cost-effectiveness of Chondrosphere using a lifetime Markov model with all patients receiving the first repair during the first cycle of the model then moving into one of three health states: success, no further repair (NFR), or a second repair, if necessary. Subsequent to the first cycle, those who were a success either remained a success or moved to second repair. All those in NFR remained in NFR. The cost-effectiveness of Chondrosphere compared to other ACI forms relied on the clinical effectiveness estimates of success and failure rates obtained from the company's indirect comparisons, the validity of which the ERG questioned. The company revised cost-effectiveness estimates for Chondrosphere versus MF and for Chondrosphere versus matrix-applied characterised autologous cultured chondrocyte implant (MACI) were £4360 and around £18,000 per quality-adjusted life year gained, respectively. NICE recommended ACI using Chondrosphere for treating symptomatic articular cartilage defects of the femoral condyle and patella of the knee in adults only if certain requirements were met.