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As part of its Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (GlaxoSmithKline [GSK]) of Benlysta (belimumab) to submit evidence regarding its clinical and cost effectiveness, for the review and possible extension of a previously conditionally approved intravenous formulation of belimumab for the treatment of active autoantibody-positive systemic lupus erythematosus (SLE). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review of the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the NICE Appraisal Committee. This appraisal is different to the previous appraisal in three ways: (1). This appraisal expands its definition of 'high disease activity'. (2). In TA397, belimumab was approved, with a managed access arrangement (MAA), for adults only. This appraisal includes subjects aged 5 years or older. (3). The original appraisal included an intravenous formulation only, but the current appraisal also includes a new subcutaneous formulation in the form of a prefilled pen. The company was required to collect real-world data from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR), including data on the efficacy, safety, and effect on health-related quality of life of belimumab versus rituximab. This appraisal considers these data as well as additional clinical trial evidence presented in the company's updated submission to address uncertainties identified during the original appraisal. The ERG identified three major concerns with the evidence presented on the clinical effectiveness in the current submission; namely, short follow-up in the main comparative trials (BLISS-SC, BLISS-52 and BLISS-76); using the propensity score-matching (PSM) analysis in calibrating the cost-effectiveness model can severely bias the results in favour of belimumab; and BILAG-BR data are not suitable for a comparison of belimumab with rituximab. The main issue in the economic analysis was the uncertainty about long-term disease activity progression and resulting organ damage. The company's approach of calibrating modelled organ damage to longer-term data analysed using the PSM analysis was methodologically inappropriate. The final analysis comparing belimumab with standard treatment for the intravenous formulation resulted in an incremental cost-effectiveness ratio of 12,335 pound per quality-adjusted life-year (QALY) gained and 30,278 pound per QALY gained in the company's and ERG's base-case analyses, respectively. For the subcutaneous formulation, the final analysis resulted in 8480 pound per QALY gained and 29,313 pound per QALY gained in the company's and ERG's base-case analyses, respectively. NICE recommended belimumab in both intravenous and subcutaneous formulations as an add-on treatment option for active autoantibody-positive SLE in the HDA-2 subgroup.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Gilead) of filgotinib (Jyseleca(TM)), as part of the single technology appraisal process, to submit evidence for its clinical and cost effectiveness for the treatment of patients with moderate to severe rheumatoid arthritis (RA). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review of the clinical- and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the NICE Appraisal Committee. The evidence for filgotinib was based on two good-quality international randomised controlled trials. In FINCH 1, filgotinib was compared with placebo, and in FINCH 2, filgotinib was compared with adalimumab and placebo. As there was no head-to-head evidence with most active comparators, the company performed two separate network meta-analyses (NMAs), one for the conventional disease-modifying antirheumatic drugs-inadequate response population and one for the biological disease-modifying antirheumatic drugs-inadequate response population. The outcomes analysed were American College of Rheumatology response criteria at weeks 12 and 24, and European League Against Rheumatism response criteria at 24 weeks. The statistical methods used to perform the NMAs were valid and were in line with previous NICE appraisals. Results of the NMAs are confidential and cannot be reported here, but they were uncertain due to heterogeneity of the included studies. The economic analysis of the patient population with moderate RA suffered from limited evidence on the progression from moderate to severe health states. For the moderate RA population, the final analyses comparing filgotinib, with or without methotrexate, against standard of care resulted in incremental cost-effectiveness ratios of around 20,000 pound per quality-adjusted life-year gained in the company's and ERG's base-case and scenario analyses. NICE recommended filgotinib in combination with methotrexate or as monotherapy when methotrexate is contraindicated, or if people cannot tolerate it, for patients with moderate RA whose disease had responded inadequately to two or more conventional disease-modifying antirheumatic drugs (DMARDs). For the severe RA population, in view of the higher or similar net health benefits that filgotinib provided versus its comparators, NICE recommended filgotinib with or without methotrexate for patients whose disease had responded inadequately to two or more conventional DMARDs, who had been treated with one or more biological DMARDs, if rituximab was not an option, or after treatment with rituximab.

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

The National Institute for Health and Care Excellence (NICE), as part of the institute’s single technology appraisal (STA) process, invited the company that makes obinutuzumab (Roche Products Limited) to submit evidence of the clinical and cost effectiveness of the drug in combination with chemotherapy, with or without obinutuzumab as maintenance therapy for adult patients with untreated, advanced follicular lymphoma (FL) in the UK. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company’s submission, the ERG review, and NICE’s subsequent decisions. The clinical evidence was derived from two phase III, company-sponsored, randomised, open-label studies. Most evidence on obinutuzumab was based on the GALLIUM trial that compared obinutuzumab in combination with chemotherapy as induction followed by obinutuzumab maintenance monotherapy with rituximab in combination with chemotherapy as induction followed by rituximab maintenance monotherapy in previously untreated patients with FL (grades 1–3a). Long-term clinical evidence was based on the PRIMA trial, studying the benefit of two years of rituximab maintenance after first-line treatment in patients with FL. The cost-effectiveness evidence submitted by the company relied on a partitioned survival cost-utility model, implemented in Microsoft® Excel. The base-case incremental cost-effectiveness ratio (ICER) presented in the company submission was

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

The National Institute for Health and Care Excellence, as part of the institute's single technology appraisal process, invited the manufacturer of ribociclib (Kisqali((R)), Novartis) to submit evidence regarding the clinical and cost effectiveness of the drug in combination with an aromatase inhibitor for the treatment of previously untreated, hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer. Kleijnen Systematic Reviews Ltd and Erasmus University Rotterdam were commissioned as the Evidence Review Group for this submission. The Evidence Review Group reviewed the evidence submitted by the manufacturer, corrected and validated the manufacturer's decision analytic model, and conducted exploratory analyses to assess the robustness and validity of the presented clinical and cost-effectiveness results. This article describes the company submission, the Evidence Review Group assessment and National Institute for Health and Care Excellence subsequent decisions. The main clinical effectiveness evidence was obtained from the MONALEESA-2 trial, a randomised controlled trial comparing ribociclib plus letrozole with placebo plus letrozole. Progression-free survival was significantly longer in the ribociclib group (95% confidence interval, 19.3-not reached) vs. 14.7 months (95% confidence interval 13.0-16.5) in the placebo group. To assess the cost effectiveness of ribociclib in combination with an aromatase inhibitor, the company developed an individual patient-level model using a discrete-event simulation approach in Microsoft((R)) Excel. In the model, simulated patients move through a series of three health states until death, i.e. first-line progression-free survival, second-line progression-free survival and progressive disease. The length of progression-free survival during the first line was informed by the MONALEESA-2 trial. The benefit in progression-free survival in the first line was transferred to a benefit in overall survival assuming full progression-free survival to overall survival surrogacy (because of the immaturity of overall survival data from the MONALEESA-2 trial). Patient-level data from the BOLERO-2 trial, evaluating the addition of everolimus to exemestane in the second-line treatment of postmenopausal HR-positive advanced breast cancer, were used to inform the length of progression-free survival during the second line. Costs included in the model were treatment costs (e.g. technology acquisition costs of first, second, third and/or later line treatments), drug administration costs, monitoring costs and health state costs (including terminal care). Additionally, the costs of adverse events associated with the first-line treatment were incorporated. The Evidence Review Group recalculated the incremental cost-effectiveness ratio using data from a different data cut-off date from the MONALEESA-2 trial and by changing some assumptions (e.g. progression-free survival to overall survival surrogacy approach and post-progression third and/or later line treatment-related costs). After two appraisal committee meetings and a revised base case submitted by the company (including a second enhanced patient access scheme discount), the committee concluded that taking into account the uncertainties in the calculation of the cost effectiveness, there were plausible cost-effectiveness estimates broadly in the range that could be considered as a cost-effective use of National Health Service resources. Therefore, ribociclib was recommended as a treatment option for the first-line treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, contingent on the company providing ribociclib with the discount agreed in the second enhanced patient access scheme.

Background The liver is affected by two of the most common groups of malignant tumours: primary liver tumours and liver metastases from colorectal carcinoma or other extrahepatic primary cancers. Liver metastases are significantly more common than primary liver cancer, and the reported long-term survival rate after radical surgical treatment is approximately 50%. However, R0 resection (resection for cure) is not feasible in the majority of patients; therefore, other treatments have to be considered. One of these is percutaneous ethanol injection (PEI), which causes dehydration and necrosis of tumour cells, accompanied by small-vessel thrombosis, leading to tumour ischaemia and destruction of the tumour. Objectives To assess the beneficial and harmful effects of percutaneous ethanol injection (PEI) compared with no intervention, other ablation methods, or systemic treatments in people with liver metastases. Search methods We searched the following databases up to 10 September 2019: the Cochrane Hepato-Biliary Group Controlled Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; MEDLINE Ovid; Embase Ovid; Science Citation Index Expanded; Conference Proceedings Citation Index - Science; Latin American Caribbean Health Sciences Literature (LILACS); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We also searched clinical trials registers such as ClinicalTrials.gov, the International Clinical Trials Registry Platform (ICTRP), and the US Food and Drug Administration (FDA) (17 September 2019). Selection criteria Randomised clinical trials assessing beneficial and harmful effects of percutaneous ethanol injection and its comparators (no intervention, other ablation methods, systemic treatments) for liver metastases. Data collection and analysis We followed standard methodological procedures as outlined by Cochrane. We extracted information on participant characteristics, interventions, study outcomes, study design, and trial methods. Two review authors performed data extraction and assessed risk of bias independently. We assessed the certainty of evidence by using GRADE. We resolved disagreements by discussion. Main results We identified only one randomised clinical trial comparing percutaneous intratumour ethanol injection (PEI) in addition to transcatheter arterial chemoembolisation (TACE) versus TACE alone. The trial was conducted in China and included 48 trial participants with liver metastases: 25 received PEI plus TACE, and 23 received TACE alone. The trial included 37 male and 11 female participants. Mean participant age was 49.3 years. Sites of primary tumours included colon (27 cases), stomach (12 cases), pancreas (3 cases), lung (3 cases), breast (2 cases), and ovary (1 case). Seven participants had a single tumour, 15 had two tumours, and 26 had three or more tumours in the liver. The bulk diameter of the tumour on average was 3.9 cm, ranging from 1.2 cm to 7.6 cm. Participants were followed for 10 months to 43 months. The trial reported survival data after one, two, and three years. In the PEI + TACE group, 92%, 80%, and 64% of participants survived after one year, two years, and three years; in the TACE alone group, these percentages were 78.3%, 65.2%, and 47.8%, respectively. Upon conversion of these data to mortality rates, the calculated risk ratio (RR) for mortality at last follow-up when PEI plus TACE was compared with TACE alone was 0.69 (95% confidence interval (CI) 0.36 to 1.33; very low-certainty evidence) after three years of follow-up. Local recurrence was 16% in the PEI plus TACE group and 39.1% in the TACE group, resulting in an RR of 0.41 (95% CI 0.15 to 1.15; very low-certainty evidence). Forty-five out of a total of 68 tumours (66.2%) shrunk by at least 25% in the PEI plus TACE group versus 31 out of a total of 64 tumours (48.4%) in the TACE group. Trial authors reported some adverse events but provided very few details. We did not find data on time to mortality, failure to clear liver metastases, recurrence of liver metastases, health-related quality of life, or time to progression of liver metastases. The single included trial did not provide information on funding nor on conflict of interest. Authors' conclusions Evidence for the effectiveness of PEI plus TACE versus TACE in people with liver metastases is of very low certainty and is based on one small randomised clinical trial at high risk of bias. Currently, it cannot be determined whether adding PEI to TACE makes a difference in comparison to using TACE alone. Evidence for benefits or harms of PEI compared with no intervention, other ablation methods, or systemic treatments is lacking.

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

BACKGROUND: The liver is affected by two of the most common groups of malignant tumours: primary liver tumours and liver metastases from colorectal carcinoma or other extrahepatic primary cancers. Liver metastases are significantly more common than primary liver cancer, and long‐term survival rate after radical surgical treatment is approximately 50%. However, R0 resection (resection for cure) is not feasible in the majority of people; therefore, other treatments have to be considered. One possible option is based on the concept that the blood supply to hepatic tumours originates predominantly from the hepatic artery. Transarterial chemoembolisation (TACE) of the hepatic artery can be achieved by administering a chemotherapeutic drug followed by vascular occlusive agents, and can lead to selective necrosis of the liver tumour while it may leave normal parenchyma virtually unaffected. This can also be performed without chemotherapy, which is called bland transarterial embolisation (TAE). OBJECTIVES: To assess the beneficial and harmful effects of TAE or TACE compared with no intervention or placebo in people with liver metastases. SEARCH METHODS: We searched the Cochrane Hepato‐Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, and four more databases (December 2019). We also searched two trials registers and the US Food and Drug Administration database (September 2019). SELECTION CRITERIA: Randomised clinical trials assessing beneficial and harmful effects of TAE or TACE compared with no intervention or placebo for liver metastases. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodological procedures. We extracted information on participant characteristics, interventions, study outcomes, study design, and trial methods. Two review authors independently extracted data and assessed risk of bias. We assessed the certainty of evidence with GRADE. We resolved disagreements by discussion. MAIN RESULTS: We included one randomised clinical trial with 61 participants (43 male and 18 female) with colorectal cancer with liver metastases: 22 received transarterial embolisation (TAE; hepatic artery embolisation), 19 received transarterial chemoembolisation (TACE; 5‐fluorouracil hepatic artery infusion chemotherapy with degradable microspheres), and 20 received 'no active therapeutic intervention' as a control. Most tumours were synchronous, unresectable metastases involving up to 75% of the liver. Participants were followed for a minimum of seven months. The trial was at high risk of bias. Very‐low‐certainty evidence found inconclusive results for mortality at 44 months between the TAE and TACE versus no intervention groups (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.74 to 1.06; 61 participants). Local recurrence was reported in 10 participants without any details about the group allocation. Very‐low‐certainty evidence found little or no difference in mortality between the TAE and no intervention groups (RR 0.91, 95% CI 0.75 to 1.10; 42 participants). Median survival was 7 months from trial entry (range 2 to 44 months) in the TAE group and 7.9 months (range 1 to 26 months) in the control group, and 8.7 months after diagnosis (range 2 to 49 months) in the TAE group and 9.6 months (range 1 to 27 months) in the control group. The trial authors reported the differences were not statistically significant. There were no reported side effects in the control group. In the TAE group, 18 participants experienced short‐term symptoms of 'post‐embolisation syndrome', which were relieved with symptomatic treatment; one participant also had a local puncture site haematoma. Very‐low‐certainty evidence found little or no difference in mortality between the TACE and no intervention groups (RR 0.83, 95% CI 0.65 to 1.07; 39 participants). Median survival in the TACE group was 10.7 months (range 3 to 38 months) from trial entry, and 13.0 months (range 3 to 38 months) after diagnosis. The trial authors reported that differences between groups were not statistically significant. All participants experienced short‐term nausea, with or without vomiting, immediately after treatment; one participant developed a wound infection, and one developed deep vein thrombosis. The trial did not measure failure to clear liver metastases, time to progression of liver metastases, tumour response measures, or health‐related quality of life. Cancer Research Campaign, a non‐profit organisation, provided a grant for the trial; Pharmacia Ltd. delivered the Port‐a‐Cath arterial delivery systems and degradable starch microspheres. We identified one ongoing trial comparing TACE plus chemotherapy versus chemotherapy alone in people with unresectable colorectal liver metastases who failed with first‐line chemotherapy (NCT03783559). AUTHORS' CONCLUSIONS: Based on one, small randomised trial at high risk of bias, the evidence is very uncertain about the effect of TAE or TACE versus no active therapeutic intervention on mortality for people with liver metastases as the true effect may be substantially different. The trial did not measure failure to clear liver metastases, time to progression of liver metastases, tumour response measures, or health‐related quality of life. Short‐term, minor adverse events were recorded in the intervention groups only. Large trials, following current standards of conduct and reporting, are required to explore the benefits and harms of TAE or TACE compared with no intervention or placebo in people with resectable and unresectable liver metastasis.

The National Institute for Health and Care Excellence (NICE), as part of the institute’s single technology appraisal (STA) process, invited the company that makes obinutuzumab (Roche Products Limited) to submit evidence of the clinical and cost effectiveness of the drug in combination with chemotherapy, with or without obinutuzumab as maintenance therapy for adult patients with untreated, advanced follicular lymphoma (FL) in the UK. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company’s submission, the ERG review, and NICE’s subsequent decisions. The clinical evidence was derived from two phase III, company-sponsored, randomised, open-label studies. Most evidence on obinutuzumab was based on the GALLIUM trial that compared obinutuzumab in combination with chemotherapy as induction followed by obinutuzumab maintenance monotherapy with rituximab in combination with chemotherapy as induction followed by rituximab maintenance monotherapy in previously untreated patients with FL (grades 1–3a). Long-term clinical evidence was based on the PRIMA trial, studying the benefit of two years of rituximab maintenance after first-line treatment in patients with FL. The cost-effectiveness evidence submitted by the company relied on a partitioned survival cost-utility model, implemented in Microsoft® Excel. The base-case incremental cost-effectiveness ratio (ICER) presented in the company submission was

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Bristol-Myers Squibb) of nivolumab (Opdivo (R)) to submit evidence of its clinical and cost effectiveness for metastatic or unresectable urothelial cancer. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG), which produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company's submission to NICE. Nivolumab was compared with docetaxel, paclitaxel, best supportive care and retreatment with platinum-based chemotherapy (cisplatin plus gemcitabine, but only for patients whose disease has had an adequate response in first-line treatment). Two ongoing, phase I/II, single-arm studies for nivolumab were identified, but no studies directly compared nivolumab with any specified comparator. Evidence from directly examining the single arms of the trial data indicated little difference between the outcomes measured from the nivolumab and comparator studies. A simulated treatment comparison (STC) analysis was used in an attempt to reduce the bias induced by naive comparison, but there was no clear evidence that risk of bias was reduced. Multiple limitations in the STC were identified and remained. The effect of an analysis based on different combinations of covariates in the prediction model remains unknown. The ERG's concerns regarding the economic analysis included the use of a non-established response-based survival analysis method, which introduced additional uncertainty. The use of time-dependent hazard ratios produced overfitting and was not represented in the probabilistic sensitivity analysis. The use of a treatment stopping rule to cap treatment cost left treatment effectiveness unaltered. A relevant comparator was excluded from the base-case analysis. The revised ERG deterministic base-case incremental cost-effectiveness ratios based on the company's Appraisal Consultation Document response were 58,791 pound, 78,869 pound and 62,352 pound per quality-adjusted life-year gained versus paclitaxel, docetaxel and best supportive care, respectively. Nivolumab was dominated by cisplatin plus gemcitabine in the ERG base case. Substantial uncertainties about the relative treatment effectiveness comparing nivolumab against all comparators remained. NICE did not recommend nivolumab, within its marketing authorisation, as an option for treating locally advanced, unresectable or metastatic urothelial carcinoma in adults who have had platinum-containing therapy, and considered that nivolumab was not suitable for use within the Cancer Drugs Fund.

The Evidence Review Group members that contributed to this editorial are funded by the UK NIHR HTA Programme. The views and opinions expressed are those of the authors and do not necessarily reflect those of the UK Department of Health and the NIHR.