Anti-Vascular Endothelial Growth Factor Drugs Compared With Panretinal Photocoagulation for the Treatment of Proliferative Diabetic Retinopathy: A Cost-Effectiveness Analysis.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness of anti-vascular endothelial growth factor drugs (anti-VEGFs) compared with panretinal photocoagulation (PRP) for treating proliferative diabetic retinopathy (PDR) in the United Kingdom. METHODS: A discrete event simulation model was developed, informed by individual participant data meta-analysis. The model captures treatment effects on best corrected visual acuity in both eyes, and the occurrence of diabetic macular edema and vitreous hemorrhage. The model also estimates the value of undertaking further research to resolve decision uncertainty. RESULTS: Anti-VEGFs are unlikely to generate clinically meaningful benefits over PRP. The model predicted anti-VEGFs be more costly and similarly effective as PRP, generating 0.029 fewer quality-adjusted life-years at an additional cost of £3688, with a net health benefit of -0.214 at a £20 000 willingness-to-pay threshold. Scenario analysis results suggest that only under very select conditions may anti-VEGFs offer potential for cost-effective treatment of PDR. The consequences of loss to follow-up were an important driver of model outcomes. CONCLUSIONS: Anti-VEGFs are unlikely to be a cost-effective treatment for early PDR compared with PRP. Anti-VEGFs are generally associated with higher costs and similar health outcomes across various scenarios. Although anti-VEGFs were associated with lower diabetic macular edema rates, the number of cases avoided is insufficient to offset the additional treatment costs. Key uncertainties relate to the long-term comparative effectiveness of anti-VEGFs, particularly considering the real-world rates and consequences of treatment nonadherence. Further research on long-term visual acuity and rates of vision-threatening complications may be beneficial in resolving uncertainties.

Understanding the National Institute for Health and Care Excellence Severity Premium: Exploring Its Implementation and the Implications for Decision Making and Patient Access.

OBJECTIVES: This study aimed to evaluate the impact of the National Institute for Health and Care Excellence's (NICE) new severity modifier, which has replaced the end-of-life (EoL) premium, on future NICE recommendations, considering past decision-making patterns. METHODS: NICE technology appraisals (TAs) published between January 2020 and December 2022 were reviewed. Summary statistics were generated to assess how the new severity modifier might affect hypothetical decision making in historical TAs. RESULTS: A total of 138 data points were identified from 132 TAs. Although the EoL premium was applied in 46 appraisals (33%), 57 (39%) qualify for a severity-based quality-adjusted life-year (QALY) multiplier. Only 19 appraisals (14.6%) not receiving an EoL premium met the severity criteria, the majority (17) qualifying for a 1.2× multiplier. In appraisals predicted to meet the severity criteria, 45 (79%) were in oncology, making them 4.04 times (95% CI 1.91-9.02) more likely to qualify for a severity modifier than nononcology indications. Among historically EoL indications, 42 (91%) were predicted to meet the severity criteria, making them 14.8 times (95% CI 6.37-37.6) more likely to qualify for a severity modifier. CONCLUSIONS: The new severity modifier will predominantly benefit oncology indications, continuing their previous explicit prioritization under the EoL decision modifier. However, the new severity modifier is harder to achieve and less generous; only a fraction of appraisals qualify for the highest effective £51 000 per QALY threshold. The vast majority of indications previously approved at £50 000 per QALY would now need to meet a cost-effectiveness threshold of <£36 000. This may necessitate greater pricing flexibility from manufacturers and increase the likelihood of negative recommendations.

Ablative and non-surgical therapies for early and very early hepatocellular carcinoma: a systematic review and network meta-analysis.

Background: A wide range of ablative and non-surgical therapies are available for treating small hepatocellular carcinoma in patients with very early or early-stage disease and preserved liver function. Objective: To review and compare the effectiveness of all current ablative and non-surgical therapies for patients with small hepatocellular carcinoma (≤ 3 cm). Design: Systematic review and network meta-analysis. Data sources: Nine databases (March 2021), two trial registries (April 2021) and reference lists of relevant systematic reviews. Review methods: Eligible studies were randomised controlled trials of ablative and non-surgical therapies, versus any comparator, for small hepatocellular carcinoma. Randomised controlled trials were quality assessed using the Cochrane Risk of Bias 2 tool and mapped. The comparative effectiveness of therapies was assessed using network meta-analysis. A threshold analysis was used to identify which comparisons were sensitive to potential changes in the evidence. Where comparisons based on randomised controlled trial evidence were not robust or no randomised controlled trials were identified, a targeted systematic review of non-randomised, prospective comparative studies provided additional data for repeat network meta-analysis and threshold analysis. The feasibility of undertaking economic modelling was explored. A workshop with patients and clinicians was held to discuss the findings and identify key priorities for future research. Results: Thirty-seven randomised controlled trials (with over 3700 relevant patients) were included in the review. The majority were conducted in China or Japan and most had a high risk of bias or some risk of bias concerns. The results of the network meta-analysis were uncertain for most comparisons. There was evidence that percutaneous ethanol injection is inferior to radiofrequency ablation for overall survival (hazard ratio 1.45, 95% credible interval 1.16 to 1.82), progression-free survival (hazard ratio 1.36, 95% credible interval 1.11 to 1.67), overall recurrence (relative risk 1.19, 95% credible interval 1.02 to 1.39) and local recurrence (relative risk 1.80, 95% credible interval 1.19 to 2.71). Percutaneous acid injection was also inferior to radiofrequency ablation for progression-free survival (hazard ratio 1.63, 95% credible interval 1.05 to 2.51). Threshold analysis showed that further evidence could plausibly change the result for some comparisons. Fourteen eligible non-randomised studies were identified (n ≥ 2316); twelve had a high risk of bias so were not included in updated network meta-analyses. Additional non-randomised data, made available by a clinical advisor, were also included (n = 303). There remained a high level of uncertainty in treatment rankings after the network meta-analyses were updated. However, the updated analyses suggested that microwave ablation and resection are superior to percutaneous ethanol injection and percutaneous acid injection for some outcomes. Further research on stereotactic ablative radiotherapy was recommended at the workshop, although it is only appropriate for certain patient subgroups, limiting opportunities for adequately powered trials. Limitations: Many studies were small and of poor quality. No comparative studies were found for some therapies. Conclusions: The existing evidence base has limitations; the uptake of specific ablative therapies in the United Kingdom appears to be based more on technological advancements and ease of use than strong evidence of clinical effectiveness. However, there is evidence that percutaneous ethanol injection and percutaneous acid injection are inferior to radiofrequency ablation, microwave ablation and resection. Study registration: PROSPERO CRD42020221357. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme (NIHR award ref: NIHR131224) and is published in full in Health Technology Assessment; Vol. 27, No. 29. See the NIHR Funding and Awards website for further award information.

Hepatocellular carcinoma is the most common type of primary liver cancer. There are a range of different treatments available for patients with early hepatocellular carcinoma. We looked for clinical trials in patients with small tumours (up to 3 cm) that compared different treatments. We brought together and analysed the results of these trials to see which treatments were most effective in terms of survival, progression, side effects and quality of life. Overall, the evidence has limitations; many trials had few patients and were of poor quality. Most were from China or Japan, where the common causes of liver disease and treatments available differ from those in the United Kingdom. The results of our analyses were very uncertain so we cannot be sure which treatment is the best overall. We did find that three treatments ­ radiofrequency ablation, microwave ablation and surgery ­ were generally more effective than percutaneous ethanol injection and percutaneous acid injection. There was not enough evidence to be certain which treatment was better when radiofrequency ablation was compared with laser ablation, microwave ablation, proton beam therapy or surgery. We found only poor-quality, non-randomised trials on high-intensity focused ultrasound, cryoablation and irreversible electroporation. There was very little evidence on treatments that combined radiofrequency ablation with other therapies. We found no studies that compared electrochemotherapy, histotripsy, stereotactic ablative radiotherapy or wider radiotherapy techniques with other treatments. Only two studies reported data on quality of life or patient satisfaction. We discussed the findings with patients and clinical experts. Stereotactic ablative radiotherapy was highlighted as a treatment that requires further research; however, it is only appropriate for certain subgroups of patients. Feasibility studies could inform future clinical trials by exploring issues such as whether patients are willing to take part in a trial or find the treatments acceptable.

Developing a novel device, Eggcell, to improve temperature stability during oocyte collection for IVF.

RESEARCH QUESTION: What temperature fluctuations are oocytes exposed to during oocyte retrieval? Can an alternative method of oocyte retrieval be designed to minimize these fluctuations? DESIGN: Mock oocyte retrieval procedures were performed to investigate the change in temperature when the follicular fluid is drained into collection tubes and when the fluid is subsequently poured into dishes to allow identification of the cumulus-oocyte complex (COC). A new device, the Eggcell, has been designed that addresses the problem of these temperature fluctuations. To confirm its safety and demonstrate the clinical applicability of Eggcell, laboratory validation was performed prior to use with human participants (n = 15). RESULTS: Eggcell meets its design specification to provide temperature stability within the physiological range for aspirated follicular fluid. The COC can be successfully retained within the chamber (n = 180) without evidence of loss or damage to the oocytes or compromise of fertilization rate, blastocyst development or clinical outcome. CONCLUSIONS: This study has demonstrated the successful first stages of development of a new medical device. Further studies are needed for comparative evaluation of clinical outcome with standard technology.

Intensive behavioural interventions based on applied behaviour analysis (ABA) for young children with autism: A cost-effectiveness analysis.

BACKGROUND: The economic and social costs of autism are significant. This study evaluates the cost-effectiveness of early intensive Applied Behaviour Analysis (ABA)-based interventions for autistic pre-school children in the UK. METHODS: A de novo economic analysis was developed in Microsoft Excel comparing early intensive ABA-based interventions compared with treatment as usual (TAU). The analysis used 15.5-year time horizon, with costs and benefits discounted a 3.5%. The model structure was based on cohort structure to capture changes in adaptive behaviour and cognitive ability over time. The analysis was informed by an individual patient data (IPD) meta-analysis of available evidence. RESULTS: Adopting a public sector perspective, early intensive ABA-based therapies were associated with greater incremental costs and greater benefits. When pessimistic assumptions were made regarding the long-term effects of treatment incremental costs were £46,103 and incremental quality-adjusted life years (QALYs) were 0.24, resulting in an incremental cost-effectiveness ratio (ICER) of £189,122 per quality-adjusted life year (QALY). When optimistic assumptions were made about long-term effects, incremental costs were £39,233 with incremental benefits of 0.84 QALYs. The resulting ICER was £46,768 per QALY. Scenario analyses emphasised the importance of assumptions made regarding adult outcomes and type of school attended, both of which significantly affect the results of the analysis. CONCLUSIONS: The results of this economic analysis suggest that early intensive ABA-based interventions are unlikely to represent value for money, based on a £20,000 to £30,000 per QALY threshold typically adopted to inform UK healthcare funding decisions. However, important gaps in the available evidence, limit the strength of the conclusions that can be drawn from the presented analysis. Further research, focusing on the trajectory of autistic children following intervention is likely to be highly beneficial to resolving some of these uncertainties.

Appraising the Costs of Genomic Testing for Histology-Independent Technologies: An Illustrative Example for NTRK Fusions.

OBJECTIVES: Histology-independent (HI) technologies are authorized for patients with advanced or metastatic cancer if they express a particular biomarker regardless of its position in the body. Although this represents an important advancement in cancer treatment, genomic testing to identify eligible individuals for HI technologies will require substantial investment and impact their cost-effectiveness. Estimating these costs is complicated by several issues, which affect not only the overall cost of testing but also the distribution of testing costs across tumor types. METHODS: Key issues that should be considered when evaluating the cost of genomic testing to identify those eligible for HI technologies are discussed. These issues are explored in illustrative analyses where costs of genomic testing for NTRK fusions in England for recently approved HI technologies are estimated. RESULTS: The prevalence of mutation, testing strategy adopted, and current testing provision affect the cost of identifying eligible patients. The illustrative analysis estimated the cost of RNA-based next-generation sequencing to identify 1 individual with an NTRK fusion ranged between £377 and £282 258. To improve cost-effectiveness, testing costs could be shared across multiple technologies. An estimated additional ∼4000 patients would need to be treated with other HI therapies for testing in patients with advanced or metastatic cancer to be cost-effective. CONCLUSIONS: The cost of testing to identify individuals eligible for HI technologies affect the drug's cost-effectiveness. The cost of testing across tumor types varies owing to heterogeneity in the mutation's prevalence and current testing provision. The cost-effectiveness of HI technologies may be improved if testing costs could be shared across multiple agents.

The Cost-Effectiveness of Selective Internal Radiation Therapies Compared With Sorafenib for Treating Advanced Unresectable Hepatocellular Carcinoma in the United Kingdom.

OBJECTIVES: To assess the cost-effectiveness of selective internal radiation therapy (SIRT) compared with sorafenib for the treatment of patients with advanced hepatocellular carcinoma in the United Kingdom, including a selected subgroup of patients who have been identified as benefiting from treatment with SIRT. METHODS: A de novo economic model was developed comparing SIRT with sorafenib using data from two large randomized controlled trials. The model structure comprised a decision tree representing the outcome of the work-up procedure, transitioning into a 3-state partitioned survival model to project long-term survival outcomes. Cost-effectiveness in a post hoc defined subgroup with low tumor burden and good liver function was explored. RESULTS: At list price, SIRT was predicted to be less costly but less effective than sorafenib with an estimated saving of £156 089 per quality-adjusted life-year forgone, with cost savings of £4589 and 0.029 fewer quality-adjusted life-years than sorafenib. Accounting for existing confidential discounts for sorafenib, two SIRTs were cost-effective at a £30 000 willingness-to-pay threshold compared with sorafenib when a discount for the technologies was introduced. In the subgroup with low tumor burden and good liver function, SIRT may be associated with greater survival benefits and cost savings. CONCLUSIONS: Accounting for confidential discounts, on average, SIRT technologies represent value for money in the whole advanced hepatocellular carcinoma population, being less effective but less costly than sorafenib. Results from a subgroup with low tumor burden and good liver function suggest that the cost-effectiveness of SIRTs may be maximized in this group, but further research is required to demonstrate the validity of effectiveness benefits.

Management of patients presenting to the emergency department with sudden onset severe headache: systematic review of diagnostic accuracy studies.

OBJECTIVE: Advances in imaging technologies have precipitated uncertainty and inconsistency in the management of neurologically intact patients presenting to the Emergency Department (ED) with non-traumatic sudden onset severe headache with a clinical suspicion of subarachnoid haemorrhage (SAH). The objective of this systematic review was to evaluate diagnostic strategies in these patients. METHODS: Studies assessing any decision rule or diagnostic test for evaluating neurologically intact adults with a severe headache, reaching maximum intensity within 1 hour, were eligible. Eighteen databases (including MEDLINE and Embase) were searched. Quality was assessed using QUADAS-2. Where appropriate, hierarchical bivariate meta-analysis was used to synthesise diagnostic accuracy results. RESULTS: Thirty-seven studies were included. Eight studies assessing the Ottawa SAH clinical decision rule were pooled; sensitivity 99.5% (95% CI 90.8 to 100), specificity 24% (95% CI 15.5 to 34.4). Four studies assessing CT within 6 hours of headache onset were pooled; sensitivity 98.7% (95% CI 96.5 to 100), specificity 100% (95% CI 99.7 to 100). The sensitivity of CT beyond 6 hours was considerably lower (≤90%; 2 studies). Three studies assessing lumbar puncture (LP; spectrophotometric analysis) following negative CT were pooled; sensitivity 100% (95% CI 100 to 100), specificity 95% (95% CI 86.0 to 98.5). CONCLUSION: The Ottawa SAH Rule rules out further investigation in only a small proportion of patients. CT undertaken within 6 hours (with expertise of a neuroradiologist or radiologist who routinely interprets brain images) is highly accurate and likely to be sufficient to rule out SAH; CT beyond 6 hours is much less sensitive. The CT-LP pathway is highly sensitive for detecting SAH and some alternative diagnoses, although LP results in some false positive results.

Exploring Heterogeneity in Histology-Independent Technologies and the Implications for Cost-Effectiveness.

BACKGROUND: The National Institute for Health and Care Excellence and a number of international health technology assessment agencies have recently undertaken appraisals of histology-independent technologies (HITs). A strong and untested assumption inherent in the submissions included identical clinical response across all tumour histologies, including new histologies unrepresented in the trial. Challenging this assumption and exploring the potential for heterogeneity has the potential to impact upon cost-effectiveness. METHOD: Using published response data for a HIT, a Bayesian hierarchical model (BHM) was used to identify heterogeneity in response and to estimate the probability of response for each histology included in single-arm studies, which informed the submission for the HIT, larotrectinib. The probability of response for a new histology was estimated. Results were inputted into a simplified response-based economic model using hypothetical parameters. Histology-independent and histology-specific incremental cost-effectiveness ratios accounting for heterogeneity were generated. RESULTS: The results of the BHM show considerable heterogeneity in response rates across histologies. The predicted probability of response estimated by the BHM is 60.9% (95% credible interval 16.0; 91.8%), lower than the naively pooled probability of 74.5%. A mean response probability of 56.9% (0.2; 99.9%) is predicted for an unrepresented histology. Based on the economic analysis, the probability of the hypothetical HIT being cost-effective under the assumption of identical response is 78%. Allowing for heterogeneity, the probability of various approval decisions being cost-effective ranges from 93% to 11%. CONCLUSIONS: Central to the challenge of reimbursement of HITs is the potential for heterogeneity. This study illustrates how heterogeneity in clinical effectiveness can result in highly variable and uncertain estimates of cost-effectiveness. This analysis can help improve understanding of the consequences of histology-independent versus histology-specific decisions.

Intensive behavioural interventions based on applied behaviour analysis for young children with autism: An international collaborative individual participant data meta-analysis.

LAY ABSTRACT: Early intensive applied behaviour analysis-based interventions are designed to support young autistic children's learning and development. Unfortunately, the available evidence about the effectiveness of these interventions remains unclear. Several reviews have focused on the published findings rather than contacting the authors to collect and analyse data about the individual participants in the original studies. Also, most of the studies were carried out by groups involved in delivering the interventions leading to the potential bias in interpreting the results. Our research team (supported by an international advisory group) carried out an independent individual patient data review by collecting the original participant data from the authors of the studies, to examine the effectiveness of these interventions. The results suggested that early intensive applied behaviour analysis-based interventions might lead to some changes in children's cognitive ability (intelligence quotient) and everyday life skills after 2 years, compared with standard treatments. However, all the studies had problems with the way they were designed. Also, few of the studies looked at outcomes that have been described as most important to autistic people or followed children beyond 2 years. We think that further systematic reviews of the existing evidence are unlikely to add to the findings of our review. Furthermore, we recommend that future research should investigate which types of supports and interventions are most effective for children and families, prioritising outcomes measures that are meaningful for the autism community and include, wherever possible, longer-term follow-up.

Modelling approaches for histology-independent cancer drugs to inform NICE appraisals: a systematic review and decision-framework.

BACKGROUND: The first histology-independent marketing authorisation in Europe was granted in 2019. This was the first time that a cancer treatment was approved based on a common biomarker rather than the location in the body at which the tumour originated. This research aims to explore the implications for National Institute for Health and Care Excellence appraisals. METHODS: Targeted reviews were undertaken to determine the type of evidence that is likely to be available at the point of marketing authorisation and the analyses required to support National Institute for Health and Care Excellence appraisals. Several challenges were identified concerning the design and conduct of trials for histology-independent products, the greater levels of heterogeneity within the licensed population and the use of surrogate end points. We identified approaches to address these challenges by reviewing key statistical literature that focuses on the design and analysis of histology-independent trials and by undertaking a systematic review to evaluate the use of response end points as surrogate outcomes for survival end points. We developed a decision framework to help to inform approval and research policies for histology-independent products. The framework explored the uncertainties and risks associated with different approval policies, including the role of further data collection, pricing schemes and stratified decision-making. RESULTS: We found that the potential for heterogeneity in treatment effects, across tumour types or other characteristics, is likely to be a central issue for National Institute for Health and Care Excellence appraisals. Bayesian hierarchical methods may serve as a useful vehicle to assess the level of heterogeneity across tumours and to estimate the pooled treatment effects for each tumour, which can inform whether or not the assumption of homogeneity is reasonable. Our review suggests that response end points may not be reliable surrogates for survival end points. However, a surrogate-based modelling approach, which captures all relevant uncertainty, may be preferable to the use of immature survival data. Several additional sources of heterogeneity were identified as presenting potential challenges to National Institute for Health and Care Excellence appraisal, including the cost of testing, baseline risk, quality of life and routine management costs. We concluded that a range of alternative approaches will be required to address different sources of heterogeneity to support National Institute for Health and Care Excellence appraisals. An exemplar case study was developed to illustrate the nature of the assessments that may be required. CONCLUSIONS: Adequately designed and analysed basket studies that assess the homogeneity of outcomes and allow borrowing of information across baskets, where appropriate, are recommended. Where there is evidence of heterogeneity in treatment effects and estimates of cost-effectiveness, consideration should be given to optimised recommendations. Routine presentation of the scale of the consequences of heterogeneity and decision uncertainty may provide an important additional approach to the assessments specified in the current National Institute for Health and Care Excellence methods guide. FURTHER RESEARCH: Further exploration of Bayesian hierarchical methods could help to inform decision-makers on whether or not there is sufficient evidence of homogeneity to support pooled analyses. Further research is also required to determine the appropriate basis for apportioning genomic testing costs where there are multiple targets and to address the challenges of uncontrolled Phase II studies, including the role and use of surrogate end points. 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. 76. See the NIHR Journals Library website for further project information.

In May 2017, the US Food and Drug Administration granted the first approval for a cancer treatment based on a common biomarker rather than the location in the body at which the tumour originated (the tumour site); that is, a site-agnostic or 'histology-independent' indication was granted. Research from the National Institute for Health and Care Excellence suggests that there are approximately 20 technologies currently in development for histology-independent indications. The first marketing authorisation was granted in Europe in 2019. Histology-independent treatments have the potential to have important effects in patient populations for whom there are currently limited or no available treatment options. However, it is also important to ensure that the use of these treatments in the NHS is supported by systematic and robust assessments of clinical evidence (i.e. how well the medicine or treatment works) and economic evidence (i.e. the medicine's value for money). These assessments are undertaken by the National Institute for Health and Care Excellence, usually for treatments targeting specific tumours sites. However, a histology-independent marketing authorisation would probably include many tumour sites and it is not possible for the National Institute for Health and Care Excellence to conduct a separate assessment for each tumour site for which the treatment could be beneficial. As a result, the National Institute for Health and Care Excellence needs to consider how these products can be appropriately assessed without creating unnecessary delays in patient access. This research explores the extent to which the National Institute for Health and Care Excellence's existing approaches for assessing clinical and economic value can be applied to histology-independent indications, and any changes that might be required. We explore the nature and amount of evidence that is typically available at the point of initial marketing authorisation and develop recommendations to establish the evidence and analyses required to help inform the National Institute for Health and Care Excellence's decisions. We use case studies to highlight possible challenges and to explore ways that these challenges might be addressed. This research will help to inform future National Institute for Health and Care Excellence policy on how to appraise cancer drugs with histology-independent indications. It will also inform the development of guidance for those developing these treatments to help their understanding of the clinical effectiveness and cost-effectiveness assessments that will be required to inform the National Institute for Health and Care Excellence's appraisals.

Selective internal radiation therapies for unresectable early-, intermediate- or advanced-stage hepatocellular carcinoma: systematic review, network meta-analysis and economic evaluation.

BACKGROUND: Hepatocellular carcinoma is the most common type of primary liver cancer. Treatment choice is dependent on underlying liver dysfunction and cancer stage. Treatment options include conventional transarterial therapies for patients with intermediate-stage disease and systemic therapy [e.g. sorafenib (Nexavar®; Bayer plc, Leverkusen, Germany)] for patients with advanced-stage disease. Selective internal radiation therapies deliver radiation to liver tumours via microspheres that are injected into the hepatic artery. There are three selective internal radiation therapies: TheraSphere™ [BTG Ltd, London, UK (now Boston Scientific, Marlborough, MA, USA)], SIR-Spheres® (Sirtex Medical Ltd, Woburn, MA, USA) and QuiremSpheres® (Quirem Medical BV, Deventer, the Netherlands). OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of selective internal radiation therapies for treating patients with unresectable early-, intermediate- or advanced-stage hepatocellular carcinoma. METHODS: A search was undertaken to identify clinical effectiveness literature relating to selective internal radiation therapies and relevant comparators for the treatment of hepatocellular carcinoma. Studies were critically appraised and summarised. The network of evidence was mapped to estimate the relative effectiveness of the different selective internal radiation therapies and comparator treatments. An economic analysis evaluated the cost-effectiveness. RESULTS: Twenty studies were included in the clinical effectiveness review. Two large randomised controlled trials rated as having a low risk of bias [SARAH: Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux GP, et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled Phase 3 trial. Lancet Oncol 2017;18:1624-36; and SIRveNIB: Chow PKH, Gandhi M, Tan SB, Khin MW, Khasbazar A, Ong J, et al. SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol 2018;36:1913-21] found no significant difference in overall survival or progression-free survival between SIR-Spheres and sorafenib (systemic therapy) in an advanced population, despite greater tumour response in the SIR-Spheres arm of both trials. There were some concerns regarding generalisability of the SARAH and SIRveNIB trials to UK practice. All other studies of SIR-Spheres, TheraSphere or QuiremSpheres were either rated as being at a high risk of bias or caused some concerns regarding bias. A network meta-analysis was conducted in adults with unresectable hepatocellular carcinoma who had Child-Pugh class A liver cirrhosis and were ineligible for conventional transarterial therapies. The analysis included the SARAH and SIRveNIB trials as well as a trial comparing lenvatinib (Kisplyx®; Eisai Ltd, Tokyo, Japan) (systemic therapy) with sorafenib. There were no meaningful differences in overall survival between any of the treatments. The base-case economic analysis suggested that TheraSphere may be cost-saving relative to both SIR-Spheres and QuiremSpheres. However, incremental cost differences between TheraSphere and SIR-Spheres were small. In a fully incremental analysis, which included confidential Patient Access Scheme discounts, lenvatinib was the most cost-effective treatment and dominated all selective internal radiation therapies. In pairwise comparisons of sorafenib with each selective internal radiation therapy, sorafenib also dominated all selective internal radiation therapies. LIMITATIONS: The existing evidence cannot provide decision-makers with clear guidance on the comparative effectiveness of treatments in early- and intermediate-stage hepatocellular carcinoma or on the efficacy of TheraSphere or QuiremSpheres. CONCLUSIONS: In the advanced-stage hepatocellular carcinoma population, two large randomised trials have shown that SIR-Spheres have similar clinical effectiveness to sorafenib. None of the selective internal radiation therapies was cost-effective, being more costly and less effective than lenvatinib, both at list price and with Patient Access Scheme discounts. FUTURE WORK: Future studies may wish to include early- and intermediate-stage hepatocellular carcinoma patients and the low tumour burden/albumin-bilirubin 1 subgroup of advanced-stage patients. Future high-quality studies evaluating alternative selective internal radiation therapies would be beneficial. STUDY REGISTRATION: This study is registered as PROSPERO CRD42019128383. 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. 48. See the NIHR Journals Library website for further project information.

Hepatocellular carcinoma is the most common type of liver cancer. The choice of treatment depends on the extent of the cancer and liver function. Selective internal radiation therapies deliver radiation directly to liver tumours via tiny beads injected into the main blood vessel into the liver. There are three selective internal radiation therapies: TheraSphere™ [BTG Ltd, London, UK (now Boston Scientific, Marlborough, MA, USA)], SIR-Spheres^® (Sirtex Medical Ltd, Woburn, MA, USA) and QuiremSpheres^® (Quirem Medical BV, Deventer, the Netherlands). Our aim was to assess the clinical effectiveness of selective internal radiation therapies for patients with hepatocellular carcinoma that is not treatable by surgery, and to assess whether or not these therapies represent good value for money. There was no meaningful difference between SIR-Spheres and sorafenib (Nexavar^®; Bayer plc, Leverkusen, Germany), which is a cancer drug for advanced hepatocellular carcinoma. Studies of other selective internal radiation therapies and studies in patients with less advanced disease were generally of poor quality, so their results may not be reliable. We could not assess whether or not selective internal radiation therapies are beneficial to patients with early- or intermediate-stage hepatocellular carcinoma, or whether or not TheraSphere and QuiremSpheres are beneficial. Compared with sorafenib or lenvatinib (Kisplyx^®; Eisai Ltd, Tokyo, Japan) (another systemic cancer drug), none of the selective internal radiation therapies were good value for money for treating patients with advanced hepatocellular carcinoma. We found that TheraSphere might be cheaper than SIR-Spheres and QuiremSpheres, but differences between TheraSphere and SIR-Spheres were small. There was not enough evidence for patients with early or intermediate disease to say whether or not selective internal radiation therapy is good value for treating these patients. Future studies in these populations, alongside any studies comparing the selective internal radiation therapies against each other, would be helpful.

Methods for selecting the best evidence to inform a NICE technology appraisal on selective internal radiation therapies for hepatocellular carcinoma.

BACKGROUND: Systematic reviews of medical devices are particularly challenging as the quality of evidence tends to be more limited than evidence on pharmaceutical products. This article describes the methods used to identify, select and critically appraise the best available evidence on selective internal radiation therapy devices for treating hepatocellular carcinoma, to inform a technology appraisal for the National Institute for Health and Care Excellence. METHODS: A comprehensive search of ten medical databases and six grey literature sources was undertaken to identify studies of three devices (TheraSphere®, SIR-Spheres® and QuiremSpheres®) for treating hepatocellular carcinoma. The large evidence base was scoped before deciding what level of evidence to include for data extraction and critical appraisal. The methodological quality of the included studies was assessed using criteria relevant to each study design. RESULTS: Electronic searches identified 4755 records; over 1000 met eligibility criteria after screening titles and abstracts. A hierarchical process was used to scope these records, prioritising comparative studies over non-comparative studies, where available. One hundred ninety-four full papers were ordered; 64 met the eligibility criteria. For each intervention, studies were prioritised by study design and applicability to current UK practice, resulting in 20 studies subjected to critical appraisal and data extraction. Only two trials had a low overall risk of bias. In view of the poor quality of the research evidence, our technology appraisal focused on the two higher quality trials, including a thorough critique of their reliability and generalisability to current UK practice. The 18 poorer quality studies were briefly summarised; many were very small and results were often contradictory. No definitive conclusions could be drawn from the poorer quality research evidence available. CONCLUSIONS: A systematic, pragmatic process was used to select and critically appraise the vast quantity of research evidence available in order to present the most reliable evidence on which to develop recommendations. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019128383.

Interventions based on early intensive applied behaviour analysis for autistic children: a systematic review and cost-effectiveness analysis.

BACKGROUND: Early intensive applied behaviour analysis-based interventions are intensive interventions for autistic children that are often delivered on a one-to-one basis for 20-50 hours per week. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of early intensive applied behaviour analysis-based interventions for autistic children, based on current evidence. METHODS: A systematic review and individual participant data meta-analysis were conducted to evaluate the clinical effectiveness of an early intensive applied behaviour analysis-based intervention for autistic children. An economic analysis included a review of existing analyses and the development of a new model. RESULTS: Twenty studies were included in the clinical review. Individual participant data were retrieved from 15 of these studies. Results favoured the interventions when assessing adaptive behaviour after 2 years compared with treatment as usual/eclectic interventions (mean difference 7.00, 95% confidence interval 1.95 to 12.06). In analyses of cognitive ability (intelligence quotient), results favoured the interventions by approximately 10 points after 1 year (mean difference 9.16, 95% confidence interval 4.38 to 13.93) and 2 years (mean difference 14.13, 95% confidence interval 9.16 to 19.10). Evidence for other outcomes was limited and meta-analyses were generally inconclusive. There was no evidence that the effect of the interventions varied with characteristics of the children, but data were limited. Adopting a £30,000 per quality-adjusted life-year threshold, the results of the cost-effectiveness analysis indicate that early intensive applied behaviour analysis-based interventions would need to generate larger benefits or cost savings to be cost-effective. Adopting a public sector perspective and making pessimistic assumptions about long-term effects, the incremental cost-effectiveness ratio for early intensive applied behaviour analysis-based therapy compared with treatment as usual is £189,122 per quality-adjusted life-year. When optimistic assumptions are made, the incremental cost-effectiveness ratio is £46,768 per quality-adjusted life-year. Scenario analyses indicated that these interventions can potentially be cost-effective if long-term improvements persist into adulthood, or if they have significant impact on educational placement. Care should be taken when interpreting these scenarios owing to the limited data. LIMITATIONS: All included studies were at risk of bias, there was substantial heterogeneity and effects varied considerably across studies. The effect of intervention on autism symptom severity, language development and school placement remains uncertain because of the limited data. The long-term effects are unclear owing to a lack of follow-up data. CONCLUSIONS: This review found limited evidence that early intensive applied behaviour analysis-based interventions may improve cognitive ability and adaptive behaviour, but the long-term impact of the interventions remains unknown. The economic analysis is constrained by the limited effectiveness evidence, but suggests that these interventions are unlikely to be cost-effective unless clear long-term benefits, or a substantial change in which schools children attend, can be identified. FUTURE WORK: Further studies into the effectiveness of early intensive applied behaviour analysis-based interventions may be warranted if they include well-defined, alternative interventions as comparators and collect relevant outcomes. Consideration should be given to future studies that not only address whether or not early intensive applied behaviour analysis-based interventions are clinically effective, but also aim to identify which components of early intensive applied behaviour analysis-based interventions might drive effectiveness. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017068303. 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. 35. See the NIHR Journals Library website for further project information.

Autism is a lifelong condition that affects how people understand the world and interact with others. Early intensive applied behaviour analysis-based interventions are an approach designed to help young (preschool) autistic children. This approach is often delivered on a one-to-one basis, for 20­50 hours per week, over a period of several years. This project obtained and analysed the original data from studies of early intensive applied behaviour analysis-based interventions, to determine whether or not these interventions are beneficial. It also investigated whether or not the interventions represent good value for money. The results suggest that early intensive applied behaviour analysis-based interventions may improve children's intelligence, communication, social and life skills more than standard approaches. However, some results could be inaccurate or incorrect, and there was no evidence about other important outcomes, such as the severity of autism and where children went to school. Most studies lasted for around 2 years, which means that it is not known if early intensive applied behaviour analysis-based interventions have meaningful long-term benefits. It was not possible to fully assess whether or not these interventions provided value for money, as the benefits of early intensive applied behaviour analysis-based interventions were unclear, although the available evidence suggested that they did not. Early intensive applied behaviour analysis-based interventions may, however, provide value for money if their effects were to last into adulthood, or if receiving early intensive applied behaviour analysis had a large impact on the type of school children attended. Future studies of early interventions may be helpful, but should consider looking at which components of early applied behaviour analysis-based interventions are the most important, rather than at whether or not they work better than other interventions. Future studies should also follow best current research practice and evaluate outcomes that matter to autistic people and their families.

Aging: therapeutics for a healthy future.

Increased healthcare and pharmaceutical understanding has led to the eradication of many childhood, infectious and preventable diseases; however, we are now experiencing the impact of aging disorders as the lifespan increases. These disorders have already become a major burden on society and threaten to become a defining challenge of our generation. Indications such as Alzheimer's disease gain headlines and have focused the thinking of many towards dementia and cognitive decline in aging. Indications related to neurological function and related behaviors are thus an extremely important starting point in the consideration of therapeutics.However, the reality is that pathological aging covers a spectrum of significant neurological and peripheral indications. Development of therapeutics to treat aging and age-related disorders is therefore a huge need, but represents a largely unexplored path. Fundamental scientific questions need to be considered as we embark towards a goal of improving health in old age, including how we 1) define aging as a therapeutic target, 2) model aging preclinically and 3) effectively translate from preclinical models to man. Furthermore, the challenges associated with identifying novel therapeutics in a financial, regulatory and clinical sense need to be contemplated carefully to ensure we address the unmet need in our increasingly elderly population. The complexity of the challenge requires different perspectives, cross-functional partnerships and diverse concepts. We seek to raise issues to guide the field, considering the current state of thinking to aid in identifying roadblocks and important challenges early. The need for therapeutics that address aging and age-related disorders is acute, but the promise of effective treatments provides huge opportunities that, as a community, we all seek to enable effectively as soon as possible.

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

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

Correction to: Ceritinib for Untreated Anaplastic Lymphoma Kinase-Positive Advanced Non-Small-Cell Lung: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal.

The title of the article should read.

Ceritinib for Untreated Anaplastic Lymphoma Kinase-Positive Advanced Non-Small-Cell Lung Cancer: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the company that manufactures ceritinib (Zykadia®, Novartis) to submit evidence on the clinical and cost effectiveness of the drug, as a first-line treatment for adults with anaplastic lymphoma kinase (ALK)-positive (+) advanced non-small-cell lung cancer (NSCLC), as part of the Institute's single technology appraisal (STA) process. The CRD (Centre for Reviews and Dissemination) and CHE (Centre for Health Economics) Technology Assessment Group at the University of York was commissioned to act as the Evidence Review Group (ERG). This paper describes the Company's submission (CS), the ERG review and NICE's subsequent decisions. The evidence submitted in support of ceritinib, as the first-line treatment in ALK+ advanced NSCLC, was a phase III, international, multicentre, open-label randomised controlled trial (RCT) comparing ceritinib with pemetrexed/cisplatin plus pemetrexed maintenance therapy (chemotherapy [CT] group). The results indicated that ceritinib prolonged progression-free survival (PFS) compared with CT. The only comparator considered in the CS was crizotinib. The evidence selected in support of crizotinib was PROFILE 1014, an open-label RCT of crizotinib, compared with pemetrexed/cisplatin CT (without maintenance therapy), in previously untreated advanced or metastatic ALK+ NSCLC. The design and population of PROFILE 1014 was similar to that of ASCEND-4, though there were some differences between the trials. The Company considered it not possible to perform an 'anchor-based' analysis of first-line ceritinib and crizotinib, and presented a Matching-Adjusted Indirect Comparison (MAIC) of ceritinib and crizotinib using only the ALK inhibitor arm of ASCEND-4 and PROFILE 1014. The indirect comparison suggests that ceritinib may be more effective in prolonging PFS than crizotinib. The ERG agreed that an indirect comparison using only the ALK inhibitor arm of the trials was the only option available in the present assessment; however, a number of limitations and potential bias were identified in this analysis. The Company's model estimated that ceritinib was cost effective when compared with crizotinib. However, the ERG highlighted several concerns with the Company's analysis; the ERG's preferred base case estimated an incremental cost-effectiveness ratio of £69,255 per quality-adjusted life-year (no patient access scheme [PAS] included). The ERG considered the economic analysis to be sensitive to changes in assumption used, partly due to the due to the immaturity of the overall survival data from trials, which leads to uncertainty around the extrapolation used. The NICE Appraisal Committee concluded that ceritinib is recommended, within its marketing authorisation, as an option for untreated ALK+ advanced NSCLC in adults, if the Company provides it with the discount agreed in the PAS.

Synthetic cannabinoid use in an acute psychiatric inpatient unit.

In the present study, we explored the prevalence of new psychoactive substance use by people admitted into an Australian acute public mental health facility specializing in comorbid mental health and substance use. These substances have since been banned from retail outlets, but the pattern of uptake and reasons people use them is informative in terms of motivations and the management of substance use more generally. A cross-sectional study to explore the use of synthetic cannabis by people admitted to an acute adult mental health unit was undertaken. Associations with diagnostic, service use, and demographic profiles were explored. Fifty-six percent of people reported having used at least one type of new psychoactive substance, including 53.5% who reported using synthetic cannabis alone, and 18.8% who reported using both synthetic cannabis and other new psychoactive substances. Synthetic cannabis use was not associated with any demographic or diagnostic groups. Legality and availability (43% combined) were common reasons for use, along with the feeling of intoxication (20%). The high prevalence of new psychoactive substance use adds weight to the recommendation that clinicians should routinely screen for substances from the time of admission. Accurate information about these substances is required in order to provide accurate guidance and appropriate interventions to people in their care.