Correction to: Venetoclax for Treating Chronic Lymphocytic Leukaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

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Pembrolizumab for Previously Treated Advanced or Metastatic Urothelial Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Pembrolizumab is an intravenously administered monoclonal antibody licensed for locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy. This summary presents the perspective of Warwick Evidence, the Evidence Review Group (ERG) appointed by the National Institute of Health and Care Excellence (NICE) for the single technology appraisal of pembrolizumab for this indication. Pembrolizumab is manufactured by Merck, Sharp and Dohme (MSD). The major source of clinical effectiveness was the KEYNOTE-045 trial, where 542 patients received either pembrolizumab or clinician's choice of docetaxel, paclitaxel or vinflunine as a second-line treatment. No indirect treatment comparison was performed. The clinical effectiveness was assessed using hazard ratios for overall survival (OS) and progression-free survival (PFS) of the intention-to-treat (ITT) population, together with the subpopulations positive for programmed cell death 1 ligand 1 (PD-L1) expression (combined positive score [CPS] ≥ 1%) and strongly positive for PD-L1 expression (CPS ≥ 10%). In the ITT population, OS improved with pembrolizumab (HR 0.73, 95% CI 0.59-0.91) while PFS outcomes showed no difference (HR 0.98, 95% CI 0.81-1.19). Pembrolizumab demonstrated a better safety profile than its combined comparators, with fewer patients experiencing adverse events (60.9 vs 90.2%). Similar results were observed in populations expressing PD-L1. MSD estimated the cost effectiveness of pembrolizumab using a de novo partitioned survival model. The model had three health states: pre-progression, post-progression and death, where OS and PFS estimates excluded patients who received vinflunine. The largest uncertainty was over the selection of the parametric models used to extrapolate OS and PFS and the time point for when to begin their extrapolation. The company preferences for extrapolation were not well supported and the ERG disagreed with their selection for OS. Utility values were also contentious, with the company preferring to use pooled time-to-death-based utilities pooled across treatment arms, whilst the ERG preferred pooled progression-based utilities. The company preferred to use data from patients receiving vinflunine when calculating the utility values, which the ERG disagreed with as this is not recommended treatment within the UK. The company assumed a lifetime treatment effect for their model; however, the lack of evidence made it difficult to confidently provide a realistic estimate of treatment effect duration. Various durations were explored (3, 5 and 10 years). The first appraisal committee meeting concluded that pembrolizumab was not cost effective, largely due to uncertainty in the OS and PFS extrapolations. The company's second submission included an additional 4 months follow-up to survival data. The company in this new submission maintained their original assumptions in their base-case analysis, changing only the choice of parametric curve for PFS. This change resulted in the OS and PFS curves intersecting at 6 years in the pembrolizumab arm, at which point PFS identically followed OS. This resulted in no patients in the post-progression health state beyond this time point, and therefore, the majority of pembrolizumab's benefit came from pre-progression survival. Given the unclear PFS benefit, the ERG found this implausible and maintained their original base-case model assumptions. Considerable uncertainty remained over the specification of the extrapolations and the duration of treatment effect. Based on a new-value proposition submitted by the company, the appraisal committee concluded that pembrolizumab had plausible potential to be cost effective. Pembrolizumab was referred for funding through the Cancer Drugs Fund, so that further data could be collected with the aim of diminishing the outstanding uncertainties pertaining to its clinical effectiveness.

Venetoclax for Treating Chronic Lymphocytic Leukaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Venetoclax is licensed to treat relapsed or refractory (R/R) chronic lymphocytic leukaemia (CLL). As part of the Single Technology Appraisal (STA) ID944, the National Institute for Health and Care Excellence (NICE) invited AbbVie, the manufacturer, to submit evidence on the use of venetoclax, within its licensed indication. The Evidence Review Group (ERG), Warwick Evidence, was asked to provide an independent and critical review of the submitted evidence. Evidence came from three single-arm trials in CLL patients with or without 17p deletion [del(17p])/TP53 chromosomal abnormalities. The anticipated licensed indication specified that venetoclax-eligible del(17p)/TP53 patients should have not responded to, or be deemed unsuitable for, B-cell receptor inhibitor (BCRi) therapy, and that non-del(17p)/TP53 patients should have not responded to both chemoimmunotherapy and BCRi therapy. The three trials were heterogeneous in terms of both del(17p)/TP53 status and previous exposure to BCRi therapy. The M13-982 study investigated 158 R/R CLL patients with the 17p deletion, but only a small number had received previous BCRi therapy; the M12-175 study investigated 67 patients with CLL or small lymphocytic lymphoma, some with the 17p deletion, but very few previously treated with BCRi therapy; and the M14-032 study included 105 patients previously treated with BCRi therapy (either idelalisib or ibrutinib), some of whom had unknown mutation status. The ERG concluded that the study populations did not directly conform to those specified in the licensed indication or in the NICE scope. Outcomes reported included overall response rate (ORR), duration of response, progression-free survival (PFS) and overall survival (OS); adverse events were reported for the pooled population of all three studies, as well as separately for each study. The median PFS was 41.4 and 27.2 months among patients in the M12-175 and M13-982 trials, respectively, whereas the median PFS was not reached in the M14-032 trial. Some results were designated academic in confidence and cannot be reported here. The submission provided a de novo partitioned survival cost-effectiveness model with three health states: pre-progression, post-progression and dead. Transition probabilities between health states were estimated using Weibull models for PFS and OS. The ERG judged the model structure to be appropriate. Venetoclax was compared with best supportive care (BSC) in patients with or without del(17p)/TP53 mutation status, and with palliative care (PC). To populate the del(17p)/TP53 venetoclax arm, the submission pooled del(17p)/TP53 patients from all three studies and fitted Weibull models for PFS and OS. PFS and OS models for non-del(17p)/TP53 venetoclax patients were obtained by applying hazard ratios (HRs) to the del(17p)/TP53 OS and PFS models, derived using Cox's regression analysis comparing del(17p)/TP53 and non-del(17p)/TP53 patients pooled from the M14-032 and M12-175 studies. The ERG expressed reservations about the company's pooling procedure, but acknowledged its expedience given the small evidence base. For the BSC comparator arm, the submission used the rituximab + placebo arm from a randomised controlled trial comparing idelalisib + rituximab versus placebo + rituximab ('study 116'). Weibull regression data for OS and PFS were taken from the idelalisib STA (ID764) submitted by Gilead to NICE. The ERG considered the use of the study 116 rituximab arm to be inconsistent with the licensed indication for venetoclax because these patients had neither not responded to nor were inappropriate for BCRi therapy, being eligible to be randomised to idelalisib. Another difficulty was the requirement for a technical correction in survival analysis because of considerable switching from rituximab to idelalisib. The ERG considered that post-progression survival of patients from the idelalisib arm of study 116 provided a more appropriate representation of BSC since these patients had not responded to BCRi therapy, consistent with venetoclax's licensed indication. For PC, the company submission used data from the UK CLL Forum. The company's base-case analysis indicated that venetoclax was clinically effective, but the resulting incremental cost-effectiveness ratios (ICERs) for del(17p)/TP53 (£39,940/quality-adjusted life-year [QALY] gained) and non-del(17p)/TP53 (£47,370/QALY gained) patients were well above the NICE threshold of £20,000-30,000/QALY. The ERG identified two errors in the implementation of the company's parametric models-one related to the implementation of HRs, and the other to the derivation of the Weibull shape parameters obtained from the Gilead idelalisib submission. The ERG made plausible adjustments to the company's base-case and corrected errors, resulting in a reduced estimate of the cost effectiveness of venetoclax in non-del(17p)/TP53 and del(17p)/TP53 indications; in the ERG's preferred base case, using post-progression survival of patients in the idelalisib arm of study 116 as the BSC comparator, deterministic ICERs were higher than the company's base-case for both indications: £57,476/QALY gained for del(17p)/TP53 and £77,779/QALY gained for non-del(17p)/TP53. The NICE Appraisal Committee's preliminary recommendation was that venetoclax used within its licensed indication should not be recommended for use in the National Health Service (NHS). In response to the preliminary recommendation, the company submitted new analyses; however, at a subsequent appraisal committee meeting, the original recommendation was upheld and the committee concluded there were large uncertainties around the clinical effectiveness of venetoclax and BSC, and that under the committee's preferred assumptions, the ICERs were higher than those generally considered cost effective, even when end-of-life criteria were taken into account. The company submitted further evidence, and the final guidance recommended venetoclax for use with the Cancer Drugs Fund for the two populations in this technology appraisal.

Choice of statistical model for cost-effectiveness analysis and covariate adjustment: empirical application of prominent models and assessment of their results.

CONTEXT: Statistical models employed in analysing patient-level cost and effectiveness data need to be flexible enough to adjust for any imbalanced covariates, account for correlations between key parameters, and accommodate potential skewed distributions of costs and/or effects. We compare prominent statistical models for cost-effectiveness analysis alongside randomised controlled trials (RCTs) and covariate adjustment to assess their performance and accuracy using data from a large RCT. METHOD: Seemingly unrelated regressions, linear regression of net monetary benefits, and Bayesian generalized linear models with various distributional assumptions were used to analyse data from the TASMINH2 trial. Each model adjusted for covariates prognostic of costs and outcomes. RESULTS: Cost-effectiveness results were notably sensitive to model choice. Models assuming normally distributed costs and effects provided a poor fit to the data, and potentially misleading inference. Allowing for a beta distribution captured the true incremental difference in effects and changed the decision as to which treatment is preferable. CONCLUSIONS: Our findings suggest that Bayesian generalized linear models which allow for non-normality in estimation offer an attractive tool for researchers undertaking cost-effectiveness analyses. The flexibility provided by such methods allows the researcher to analyse patient-level data which are not necessarily normally distributed, while at the same time it enables assessing the effect of various baseline covariates on cost-effectiveness results.