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.

Randomised trials comparing different healthcare settings: an exploratory review of the impact of pre-trial preferences on participation, and discussion of other methodological challenges.

BACKGROUND: We recently published a systematic review of different healthcare settings (such as outpatient, community or home) for administering intravenous chemotherapy, and concluded that performing conventionally designed randomised trials was difficult. The main problems were achieving adequate trial accrual rates and recruiting a study population which adequately represented the target population of interest. These issues stemmed from the fact that potential participants may have had pre-trial perceptions about the trial settings they may be allocated; such preferences will sometimes be strong enough for patients to decline an invitation to participate in a trial. A patient preference trial design (in which patients can choose, or be randomised to, an intervention) may have obviated these recruitment issues, although none of the trials used such a design. METHODS: In order to gain a better understanding of the broader prevalence and extent of these preference issues (and any other methodological challenges), we undertook an exploratory review of settings trials in any area of healthcare treatment research. We searched The Cochrane Library and Google Scholar and used snowballing methods to identify trials comparing different healthcare settings. RESULTS: Trial accrual was affected by patient preferences for a setting in 15 of the 16 identified studies; birth setting trials were the most markedly affected, with between 68 % and 85 % of eligible women declining to participate specifically because of preference for a particular healthcare setting. Recruitment into substance abuse and chemotherapy setting studies was also notably affected by preferences. Only four trials used a preference design: the proportion of eligible patients choosing to participate via a preference group ranged from between 33 % and 67 %. CONCLUSIONS: In trials of healthcare settings, accrual may be seriously affected by patient preferences. The use of trial designs which incorporate a preference component should therefore strongly be considered. When designing such trials, investigators should consider settings to be complex interventions, which are likely to have linked components which may be difficult to control for. Careful thought is also needed regarding the choice of comparator settings and the most appropriate outcome measures to be used.

Initial assessment and management of adults with suspected acute respiratory infection: a rapid evidence synthesis of reviews and cost-effectiveness studies.

Background: This work was undertaken to inform a National Institute for Health and Care Excellence guideline on the initial assessment of adults with suspected acute respiratory infection. Objective: To undertake a rapid evidence synthesis of systematic reviews and cost-effectiveness studies of signs, symptoms and early warning scores for the initial assessment of adults with suspected acute respiratory infection. Methods: MEDLINE, EMBASE and Cochrane Database of Systematic Reviews were searched for systematic reviews and MEDLINE, EMBASE, EconLit and National Health Service Economic Evaluation Database were searched for cost-effectiveness studies in May 2023. References of relevant studies were checked. Clinical outcomes of interest included escalation of care, antibiotic/antiviral use, time to resolution of symptoms, mortality and health-related quality of life. Risk of bias was assessed using the Risk of Bias in Systematic Reviews tool or the National Institute for Health and Care Excellence economic evaluations checklist. Results were summarised using narrative synthesis. Results: Nine systematic reviews and one cost-effectiveness study met eligibility criteria. Seven reviews assessed several early warning scores for patients with community- acquired pneumonia, one assessed early warning scores for nursing home-acquired pneumonia and one assessed individual signs/symptoms and the Centor score for patients with sore throat symptoms; all in face-to-face settings. Two good-quality reviews concluded that further research is needed to validate the CRB-65 in primary care/community settings. One also concluded that further research is needed on the Pneumonia Severity Index in community settings; however, the Pneumonia Severity Index requires data from tests not routinely conducted in community settings. One good-quality review concluded that National Early Warning Score appears to be useful in an emergency department/acute medical setting. One review (unclear quality) concluded that the Pneumonia Severity Index and CURB-65 appear useful in an emergency department setting. Two poor-quality reviews concluded that early warning scores can support clinical judgement and one poor-quality review found numerous problems with using early warning scores in a nursing home setting. A good-quality review concluded that individual signs and symptoms have a modest ability to diagnose streptococcal pharyngitis, and that the Centor score can enhance appropriate prescribing of antibiotics. The cost-effectiveness study assessed clinical scores and rapid antigen detection tests for sore throat, compared to delayed antibiotic prescribing. The study concluded that the clinical score is a cost-effective approach when compared to delayed prescribing and rapid antigen testing. Conclusions: Several early warning scores have been evaluated in adults with suspected acute respiratory infection, mainly the CRB-65, CURB-65 and Pneumonia Severity Index in patients with community-acquired pneumonia. The evidence was insufficient to determine what triage strategies avoid serious illness. Some early warning scores (CURB-65, Pneumonia Severity Index and National Early Warning Score) appear to be useful in an emergency department/acute medical setting; however, further research is required to validate the CRB-65 and Pneumonia Severity Index in primary care/community settings. The economic evidence indicated that clinical scores may be a cost-effective approach to triage patients compared with delayed prescribing. Future work and limitations: Only systematic reviews were eligible for inclusion in the synthesis of clinical evidence. There was a great deal of overlap in the primary studies included in the reviews, many of which had significant limitations. No studies were undertaken in remote settings (e.g. NHS 111). Only one cost-effectiveness study was identified, with limited applicability to the review question. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR159945.

Acute respiratory infections, such as cold and flu, are common and can be caused by viruses or bacteria. People with symptoms of acute respiratory infection often go to their general practitioner, who may advise them to stay at home (with or without antibiotics or antivirals) or might refer them to hospital if the infection is serious. Doctors assess the patient's symptoms or may use a tool called an 'early warning score' to judge whether the infection is serious. A systematic review is a research method where all relevant studies assessing a specific question are found and summarised. We aimed to summarise all systematic reviews and cost-effectiveness studies that assessed signs, symptoms and 'early warning scores' in adults with suspected acute respiratory infections in the community (i.e. not hospitalised patients). We found nine systematic reviews and one cost-effectiveness study. Several different early warning scores for acute respiratory infection have been assessed in systematic reviews. Seven of the reviews assessed early warning scores in patients with community-acquired pneumonia. Good-quality reviews concluded that further research is needed to see how useful the 'CRB-65' and 'Pneumonia Severity Index' early warning scores are for assessing pneumonia severity in the community. Another good-quality review concluded that the 'National Early Warning Score' early warning score appears to be useful in an emergency department setting. A good-quality review found that individual symptoms are not very reliable for diagnosing pharyngitis caused by streptococcal bacteria in patients with sore throat; the review also found that the 'Centor score' can help doctors decide whether to prescribe antibiotics for pharyngitis. The cost-effectiveness study assessed clinical scores and rapid antigen detection tests (which test for substances that increase in our blood when we have certain infections) in patients with sore throat, and found that clinical scores may be cost-effective compared to delaying prescribing antibiotics.

The effectiveness of ablative and non-surgical therapies for early hepatocellular carcinoma: Systematic review and network meta-analysis of randomised controlled trials.

BACKGROUND & AIMS: Non-surgical therapies are frequently used for patients with early or very early hepatocellular carcinoma (HCC). The aim of this systematic review and network meta-analysis (NMA) was to evaluate and compare the effectiveness of ablative and non-surgical therapies for patients with small HCC. METHODS: Nine databases were searched (March 2021) along with clinical trial registries. Randomised controlled trials (RCTs) of any ablative or non-surgical therapy versus any comparator in patients with HCC ≤3 cm were eligible. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. The effectiveness of therapies was compared using NMA. Threshold analysis was undertaken to identify which NMA results had less robust evidence. RESULTS: Thirty-seven eligible RCTs were included (including over 3700 patients). Most were from China (n = 17) or Japan (n = 7). Sample sizes ranged from 30 to 308 patients. The majority had a high RoB or some RoB concerns. No RCTs were identified for some therapies and no RCTs reported quality of life outcomes. The results of the NMA and treatment effectiveness rankings were very uncertain. However, the evidence demonstrated that percutaneous ethanol injection was worse than radiofrequency ablation for overall survival (hazard ratio [HR]: 1.45, 95% credible interval [CrI]: 1.16-1.82), progression-free survival (HR: 1.36, 95% CrI: 1.11-1.67), overall recurrence (relative risk [RR]: 1.19, 95% CrI: 1.02-1.39) and local recurrence (RR: 1.80, 95% CrI: 1.19-2.71). The threshold analysis suggested that robust evidence was lacking for some comparisons. CONCLUSIONS: It is unclear which treatment is most effective for patients with small HCC because of limitations in the evidence base. It is also not known how these treatments would impact on quality of life. Further high quality RCTs are needed to provide robust evidence but may be difficult to undertake.

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.

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.

The Clinical and Cost Effectiveness of Inotuzumab Ozogamicin for the Treatment of Adult Relapsed or Refractory B-Cell Acute Lymphoblastic Leukaemia: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited Pfizer, the manufacturer of inotuzumab ozogamicin (henceforth inotuzumab), to submit clinical- and cost-effectiveness evidence for inotuzumab as part of NICE's single technology appraisal process. The Centre for Reviews and Dissemination and the Centre for Health Economics, both at the University of York, were commissioned as the independent evidence review group (ERG). The clinical-effectiveness data were from a multicentre randomised controlled trial that compared inotuzumab with standard of care (SoC), where SoC was the investigator's choice of chemotherapy. Inotuzumab demonstrated statistically significant improvements in response rates or in the proportion of patients progressing to haematopoietic stem cell transplant (HSCT) but failed to meet the second primary objective of longer overall survival. Treatment-emergent adverse events were more frequent in the SoC arm, except veno-occlusive disease, which was more frequent in the inotuzumab arm. The company's economic model split patients into three post-hoc subgroups and used a partitioned survival approach within each group, with a cure assumption 3 years after receiving HSCT. In contrast with the trial results, the economic model estimated substantial improvement in survival with inotuzumab compared with SoC, providing an additional 5.2 life-years and 2.2 quality-adjusted life-years (QALYs) using a discount rate of 1.5% per annum. The ERG's critique highlighted a number of concerns, including the use of a post-hoc post-randomisation patient subset for extrapolation, the choice of a 1.5% discount rate, the complexity of the parametric modelling, the assumption of further treatment benefit post-HSCT, the nature of the cure assumption, and the length of inpatient stay while receiving treatment. The combination of the ERG's adjustments resulted in an incremental cost-effectiveness ratio (ICER) of £122,174 per QALY gained using Kaplan-Meier survival estimates and £114,078 per QALY gained with parametric survival models fit to the trial data. The final determination of the appraisal followed four NICE Appraisal Committee meetings, an appeal by the company and other stakeholders, two patient access schemes, and a company response to each appraisal consultation. The final ICER post-consultation was between £33,749 and £37,497 per QALY gained compared with SoC (excluding the confidential discount for blinatumomab received as subsequent therapy). The Appraisal Committee concluded that the ICER for inotuzumab was within the range usually considered cost effective for end-of-life care and recommended inotuzumab within its licensed indication.

Psychosocial interventions for non-professional carers of people with Parkinson's disease: a systematic scoping review.

AIM: This paper is a report of a scoping review to systematically identify and collate the evidence on psychosocial interventions for non-professional carers of people with Parkinson's disease. BACKGROUND: Carers are critical to people with Parkinson's disease maintaining independent living and quality of life. Parkinson's disease imposes a challenging constellation of symptoms and no summary of effective interventions for carers and their unique support needs exists. DATA SOURCES: Thirty electronic databases were searched from their inception to July 2006, and bibliographies and specific internet sites were scanned. METHODS: Eligible studies were categorized according to design, type of economic evaluation where applicable, number of participants, country of evaluation, intervention, orientation, provider, setting, method of delivery, carer population, patient population, carer outcomes, patient outcomes and authors' conclusions. Data were extracted by one reviewer and checked by another reviewer; discrepancies were resolved through discussion or arbitration by a third reviewer. FINDINGS: Thirty studies met the inclusion criteria. Most investigated relatively unique interventions involving multiple elements; the majority were not aimed primarily at carers but were embedded in patient treatment programmes. Many were pilot studies, employing weak research designs and involving very small numbers of participants and most were not designed to assess the clinical or cost effectiveness of the intervention for the carers. CONCLUSION: Several interventions merit further investigation but there is currently little evidence to show which approaches are effective and cost effective in supporting carers. Future studies need to employ appropriate and rigorous research designs with adequate samples and outcome measures, and with more focus on the carer.

Deconstructing media coverage of trastuzumab (Herceptin): an analysis of national newspaper coverage.

OBJECTIVE: To explore and critically describe the content and main narratives of UK national daily newspaper coverage of trastuzumab (Herceptin). DESIGN: We used the NewsBank database to search eight national daily newspapers, and their Sunday equivalents, retrospectively from 19 February 2006 back to the earliest mention of trastuzumab or Herceptin (19 May 1998). Setting UK national newspapers. MAIN OUTCOME MEASURES: To be eligible for inclusion, articles had to contain at least three sentences about trastuzumab. Articles that focused on the financial performance of companies associated with the drug were excluded from the analysis. For each included article, we extracted bibliographic details and data, and independently rated the reporting slant towards trastuzumab and, where relevant, the reporting slant towards access to treatment. RESULTS: We identified 361 articles that met the study inclusion criteria. The proprietary name of Herceptin was always used, with only eight articles mentioning the generic alternative. 294/361 included articles (81.5%) were rated as being positive towards trastuzumab, the remainder rated as neutral. Access to trastuzumab treatment was the main narrative running across included articles and reports of individual patients seeking treatment featured prominently throughout. In 208/361 of included articles (57%) the reporting slant towards access to trastuzumab treatment was rated as negative. 178/361 of included articles (49.3%) mentioned licensing, but rarely mentioned that licensing processes can only occur when the manufacturer applies for a licence. Only a minority of articles mentioned that the drug had to be licensed before it could be subject to the NICE approval process. CONCLUSIONS: Newspaper coverage of trastuzumab has been characterized by uncritical reporting. Journalists (and consumers) should be more questioning when confronted with information about new drugs and of the motives of those who seek to set the news agenda.

Integrated Care to Address the Physical Health Needs of People with Severe Mental Illness: A Mapping Review of the Recent Evidence on Barriers, Facilitators and Evaluations.

People with mental health conditions have a lower life expectancy and poorer physical health outcomes than the general population. Evidence suggests this is due to a combination of clinical risk factors, socioeconomic factors, and health system factors, notably a lack of integration when care is required across service settings. Several recent reports have looked at ways to better integrate physical and mental health care for people with severe mental illness (SMI). We built on these by conducting a mapping review that looked for the most recent evidence and service models in this area. This involved searching the published literature and speaking to people involved in providing or using current services. Few of the identified service models were described adequately and fewer still were evaluated, raising questions about the replicability and generalisability of much of the existing evidence. However, some common themes did emerge. Efforts to improve the physical health care of people with SMI should empower staff and service users and help remove everyday barriers to delivering and accessing integrated care. In particular, there is a need for improved communication among professionals and better information technology to support them, greater clarity about who is responsible and accountable for physical health care, and greater awareness of the effects of stigmatisation on the wider culture and environment in which services are delivered.

Updated meta-review of evidence on support for carers.

Objective To update a 2010 meta-review of systematic reviews of effective interventions to support carers of ill, disabled, or older adults. In this article, we report the most promising interventions based on the best available evidence. Methods Rapid meta-review of systematic reviews published from January 2009 to 2016. Results Sixty-one systematic reviews were included (27 high quality, 25 medium quality, and nine low quality). The quality of reviews has improved since the original review, but primary studies remain limited in quality and quantity. Fourteen high quality reviews focused on carers of people with dementia, four on carers of those with cancer, four on carers of people with stroke, three on carers of those at the end of life with various conditions, and two on carers of people with mental health problems. Multicomponent interventions featured prominently, emphasizing psychosocial or psychoeducational content, education and training. Improved outcomes for carers were reported for mental health, burden and stress, and wellbeing or quality of life. Negative effects were reported in reviews of respite care. As with earlier work, we found little robust evidence on the cost-effectiveness of reviewed interventions. Conclusions There is no 'one size fits all' intervention to support carers. There is potential for effective support in specific groups of carers, such as shared learning, cognitive reframing, meditation, and computer-delivered psychosocial support for carers of people with dementia. For carers of people with cancer, effective support may include psychosocial interventions, art therapy, and counselling. Carers of people with stroke may also benefit from counselling. More good quality, theory-based, primary research is needed.

A systematic review highlights threats to validity in studies of barriers to cancer trial participation.

OBJECTIVE: To investigate the barriers, modifiers, and benefits involved in participating in randomized controlled trials of cancer therapies as perceived by health care providers and patients. STUDY DESIGN AND SETTING: We conducted a systematic review of the literature to identify published and unpublished studies in any language using electronic databases searched from 1996 to 2004, contact with experts, and reference lists. All study designs were acceptable provided relevant data were reported. Two reviewers were involved in the selection of studies, data extraction, and quality assessment processes. Studies were combined in a narrative synthesis. RESULTS: Fifty-six studies met the inclusion criteria and represented the perspective of the patient or the health care provider or both. Although a range of barriers to trial participation were identified, a number of threats to the internal and external validity of the included studies limited interpretation of the evidence. CONCLUSION: The limitations within the evidence base do not permit a clear interpretation of the barriers, moderators, and benefits involved in participation in cancer trials. We recommend that trialists prospectively identify the issues relevant to a particular trial using the current research as a starting point. We report checklists to guide this process.

Service user engagement in health service reconfiguration: a rapid evidence synthesis.

OBJECTIVE: To assess what is known about effective patient and public engagement in health service reconfiguration processes and identify implications for further research and health care practice. METHODS: Rapid systematic review of published and grey literature to identify methods or approaches to engagement in decisions about health service reconfiguration; and to examine how engagement has worked or not worked in specific examples of system change. Following a search for literature published in English from 2000 to March 2014, eight systematic reviews, seven primary studies and 24 case studies (of which 6 were exemplars) were included. We undertook a narrative synthesis to consider five aspects of engagement with health service reconfiguration. RESULTS: Engagement varied in nature and intensity, and efforts generally involved multiple methods. There was no evidence on the isolated impact of any particular engagement method or collection of methods. In general, engagement was most likely to be successful when started early, when led and supported by clinicians, and when it offered opportunities for genuine interaction. The impact of engagement was variably measured and demonstrated, and frequently defined as process measures rather than the outcomes of proposals for service reconfiguration. Little was reported on the potential negative impact of service user engagement. CONCLUSIONS: Patients and the public can be engaged through various methods. Problems often arise because decision-makers paid insufficient attention to issues considered important by patients and the public. Guidance setting out the stages of reconfiguration and opportunities for service user input could be a helpful practical framework for future engagement activity. Future evaluation and explicit reporting of engagement and impact is needed.

The Clinical and Cost Effectiveness of Vortioxetine for the Treatment of a Major Depressive Episode in Patients With Failed Prior Antidepressant Therapy: A Critique of the Evidence.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of vortioxetine (Lundbeck) to submit clinical and cost-effectiveness evidence for vortioxetine for the treatment of major depressive episodes (MDEs), as part of the Institute's Single Technology Appraisal (STA) process. The Centre for Reviews and Dissemination and Centre for Health Economics at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and the resulting NICE guidance TA367 issued in November 2015. The ERG critically reviewed the evidence presented in the manufacturer's submission and identified areas requiring clarification, for which the manufacturer provided additional evidence. Two phase III randomised controlled trials for a second-line population involving vortioxetine were identified-REVIVE and TAK318. These two trials represent only 972 of over 7000 patients included in trials of vortioxetine. In REVIVE, there was a statistically significant difference in depression scores favouring vortioxetine compared with agomelatine [mean Montgomery-Åsberg Depression Rating Scale (MADRS) score difference of 2.16 points; 95 % confidence interval 0.81-3.51]. The ERG concluded that, based on all the evidence, rather than the substantially restricted subset of evidence originally considered by the manufacturer, vortioxetine is likely to be similar in efficacy to other analysed antidepressants [citalopram, sertraline, escitalopram and venlafaxine extended release (XR)], and may be more efficacious than agomelatine and inferior to duloxetine. The ERG concluded that vortioxetine may be more tolerable than other analysed antidepressants (sertraline, venlafaxine XR and bupropion), although the limited data prevent firm conclusions. The base-case incremental cost-effectiveness ratio (ICER) of vortioxetine reported by the manufacturer was £378 per quality-adjusted life-year (QALY) compared with venlafaxine. Given considerable concerns about the indirect treatment comparison undertaken by the manufacturer, the use of only a restrictive subset of the available evidence, and concerns regarding comparators and structural model assumptions, the ERG believes that this is not a valid estimate of the cost effectiveness of vortioxetine. Following corrections made to the model made by the ERG, the estimated cost effectiveness of vortioxetine was sensitive to the source of evidence used, in addition to whether certain comparators were excluded. The NICE thus asked the manufacturer to provide a revised economic model, which incorporated the broader evidence base and considered the cost effectiveness of vortioxetine as a third-line treatment. Assuming equal efficacy, vortioxetine was shown to be less costly and generate a higher QALY gain than relevant comparators at the third-line of treatment owing to its tolerability and adverse event profile. The NICE Appraisal Committee recommended vortioxetine as an option for treating MDEs in adults whose condition has responded inadequately to two antidepressants within the current episode.

Ipilimumab for Previously Untreated Unresectable Malignant Melanoma: A Critique of the Evidence.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of ipilimumab (Bristol-Myers Squibb Pharmaceuticals Limited) to submit clinical and cost-effectiveness evidence for previously untreated advanced (unresectable or metastatic) melanoma as part of the Institute's Single Technology Appraisal process. The Centre for Reviews and Dissemination and Centre for Health Economics at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This article presents a summary of the manufacturer's submission of ipilimumab, the ERG review and the resulting NICE guidance TA319, issued in July 2014. Ipilimumab at a recommended dose of 3 mg/kg monotherapy was previously granted marketing authorisation by the European Medicines Agency in adult patients who had received prior therapy and was recommended by NICE in guidance TA268. In October 2013, the EMA approved the extension of this indication to previously untreated advanced melanoma patients. NICE decisions are bound by the marketing authorisation; therefore, the decision problem faced by the NICE Appraisal Committee was whether ipilimumab at a recommended dose of 3 mg/kg monotherapy was effective and cost effective compared with first-line standard of care involving dacarbazine (DTIC) and vemurafenib (for BRAF V600 mutation-positive patients). The CA184-024 trial was the primary source of clinical evidence for ipilimumab. However, this was based on a dose of 10 mg/kg with concomitant DTIC. The results over a 5-year period indicated that ipilimumab 10 mg/kg plus DTIC demonstrated a significant increase in median overall survival (OS) of 2.1 months compared with DTIC plus placebo (11.2 vs. 9.1 months). The BRIM-3 trial, which was an open-label randomised controlled trial (RCT) in BRAF V600 mutation-positive patients, was the primary source of evidence for an indirect comparison with vemurafenib. The results showed that vemurafenib increased median OS by 3.6 months compared with DTIC (13.2 vs. 9.6 months). The economic evaluation compared the costs and outcomes of ipilimumab by assuming that the 3 mg/kg dosing regimen was clinically equivalent in efficacy to an ipilimumab 10 mg/kg dosing regimen plus DTIC and by using a treatment sequencing approach that incorporated second-line active therapy and third-line best supportive care (BSC). In the first appraisal meeting, the committee recommended ipilimumab only in the context of research as part of a clinical study. This was primarily based on the lack of robust evidence to support the assumption of clinical equivalence between dosages and the absence of evidence available to inform the sequential use of treatments. Following the consultation, the manufacturer submitted additional analyses and evidence to support the cost effectiveness of ipilimumab at first line. The manufacturer's response was based on concerns relating to uncertainty surrounding the relative efficacy of ipilimumab 3 mg/kg monotherapy compared with DTIC and vemurafenib, comparability of the patient populations at first and second line, and the effects of concomitant DTIC. These additional analyses indicated that the incremental cost-effectiveness ratio (ICER) was £ 47,900 per quality-adjusted life-year (QALY) gained for ipilimumab compared with DTIC and £ 28,600 per QALY gained for ipilimumab compared with vemurafenib. Following consideration of the additional evidence and the responses from a large number of consultees and commentators, the committee recommended ipilimumab as an option for adults with previously untreated advanced melanoma.

Palliative thoracic radiotherapy for non-small-cell lung cancer: a systematic review.

Non-small-cell lung cancer is one of the most common malignant tumors worldwide. The majority of patients are not treatable with curative intent because of the extent of disease or patient comorbidity. Radiotherapy to the primary intrathoracic tumor is used with the aim of palliating troublesome local symptoms in approximately 25% of patients. The dose/fractionation regimens used evolved empirically, and surveys have shown widespread variation. It has not yet been clearly established which regimens give the most benefit and least toxicity. This systematic review identified 12 randomized controlled trials comparing palliative external beam radiotherapy regimens. Narrative synthesis has been performed. Palliative radiotherapy is effective in controlling symptoms. There is no strong evidence that better palliation is obtained with higher radiation doses but good evidence that toxicity is greater. There is evidence of a modest survival benefit with higher dose schedules in patients with good performance status. The majority of patients should receive short courses (one or two fractions) of hypofractionated radiotherapy, Selected patients with good performance status should be considered for higher dose regimens if the chance of modest improvement in survival and palliation is considered worth the additional inconvenience and toxicity.

An overview and methodological assessment of systematic reviews and meta-analyses of enhanced recovery programmes in colorectal surgery.

OBJECTIVES: To identify and critically assess the extent to which systematic reviews of enhanced recovery programmes for patients undergoing colorectal surgery differ in their methodology and reported estimates of effect. DESIGN: Review of published systematic reviews. We searched the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA) Database from 1990 to March 2013. Systematic reviews of enhanced recovery programmes for patients undergoing colorectal surgery were eligible for inclusion. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was length of hospital stay. We assessed changes in pooled estimates of treatment effect over time and how these might have been influenced by decisions taken by researchers as well as by the availability of new trials. The quality of systematic reviews was assessed using the Centre for Reviews and Dissemination (CRD) DARE critical appraisal process. RESULTS: 10 systematic reviews were included. Systematic reviews of randomised controlled trials have consistently shown a reduction in length of hospital stay with enhanced recovery compared with traditional care. The estimated effect tended to increase from 2006 to 2010 as more trials were published but has not altered significantly in the most recent review, despite the inclusion of several unique trials. The best estimate appears to be an average reduction of around 2.5 days in primary postoperative length of stay. Differences between reviews reflected differences in interpretation of inclusion criteria, searching and analytical methods or software. CONCLUSIONS: Systematic reviews of enhanced recovery programmes show a high level of research waste, with multiple reviews covering identical or very similar groups of trials. Where multiple reviews exist on a topic, interpretation may require careful attention to apparently minor differences between reviews. Researchers can help readers by acknowledging existing reviews and through clear reporting of key decisions, especially on inclusion/exclusion and on statistical pooling.

Effectiveness and implementation of enhanced recovery after surgery programmes: a rapid evidence synthesis.

OBJECTIVES: To assess the evidence on the impact of enhanced recovery programmes for patients undergoing elective surgery in acute hospital settings in the UK. DESIGN: Rapid evidence synthesis. Eight databases were searched from 1990 to March 2013 without language restrictions. Relevant reports and guidelines, websites and reference lists of retrieved articles were scanned to identify additional studies. Systematic reviews, RCTs not included in the systematic reviews, economic evaluations and UK NHS cost analysis, implementation case studies and surveys of patient experience in a UK setting were eligible for inclusion. PRIMARY AND SECONDARY OUTCOME MEASURES: We assessed the impact of enhanced recovery programmes on health or cost-related outcomes, and assessed implementation case studies and patient experience in UK settings. Studies were quality assessed where appropriate using the Centre for Reviews and Dissemination Database of Abstracts of Reviews of Effects critical appraisal process. RESULTS: 17 systematic reviews and 12 additional RCTs were included. Ten relevant economic evaluations were included. No cost analysis studies were identified. Most of the evidence focused on colorectal surgery. 14 innovation case studies and 15 implementation case studies undertaken in National Health Service settings described factors critical to the success of an enhanced recovery programme. Evidence for colorectal surgery suggests that enhanced recovery programmes may reduce hospital stays by 0.5-3.5 days compared with conventional care. There were no significant differences in reported readmission rates. Other surgical specialties showed greater variation in reductions in length of stay reflecting the limited evidence identified. Findings relating to other outcomes were hampered by a lack of robust evidence and poor reporting. CONCLUSIONS: There is consistent, albeit limited, evidence that enhanced recovery programmes can reduce length of patient hospital stay without increasing readmission rates. The extent to which managers and clinicians considering implementing enhanced recovery programmes in UK settings can realise savings will depend on length of stay achieved under their existing care pathway.