TA894 · STA
Source documents
Intervention
Condition
Comparators
| Name | Type | Established | Committee preferred |
|---|---|---|---|
| rituximab with cyclophosphamide, doxorubicin, vincristine and prednisolone (chop) | active drug | — | — |
| rituximab with cyclophosphamide, vincristine and prednisolone (cvp) | active drug | — | — |
| rituximab with bendamustine | active drug | — | — |
| rituximab with lenalidomide | active drug | — | — |
| obinutuzumab with bendamustine | active drug | — | — |
| standard care (blended comparator after 3 or more treatments) | standard of care | — | — |
| standard care | standard of care | Yes | — |
Clinical trials
| Trial | Design | Phase | Pivotal |
|---|---|---|---|
| ZUMA-5 | single_arm | phase 2 | Yes |
| SCHOLAR-5 | observational | — | — |
| DELTA | single_arm | phase 2 | — |
| ZUMA-22 | RCT | 3 | Yes |
Economic model
ICER
Methodological decisions (17)
Company used blended comparator approach reflecting multiple treatment options after 3 or more systemic treatments, excluding rituximab monotherapy and best supportive care
Company: Blended comparator of rituximab combinations, rituximab with lenalidomide, and obinutuzumab with bendamustine is appropriate; rituximab monotherapy and BSC excluded as would be used in less fit patients
Committee: Company's blended comparator approach and treatments included were suitable for decision making; reflects clinical practice in NHS
ICER impact: uncertain_direction
Selection and composition of blended comparator for standard care after 3 or more treatments
Company: Used SCHOLAR-5 data to inform comparator effectiveness; restricted cohorts to people with follicular lymphoma after at least 3 prior treatments in line with anticipated marketing authorisation; excluded idelalisib, radioimmunotherapy, CVP and experimental treatments as not representative of NHS treatments
ERG: Concerned that comparative effectiveness from single-arm studies prone to bias due to lack of randomised comparators; noted ERG's concerns about SCHOLAR-5 data quality and generalisability
Committee: Noted ERG's concerns about lack of randomised comparators; concluded using SCHOLAR-5 data acceptable to inform comparative effectiveness despite concerns
ICER impact: uncertain_direction
Infusion, monitoring and hospitalisation costs for axicabtagene ciloleucel treatment
Company: Applied daily hospitalisation costs of £903 to mean duration of hospitalisation observed in ZUMA-5; aligned with previous CAR T-cell therapy appraisals in inpatient monitoring setting
ERG: Noted time-on-treatment curves not consistent with derived PFS and OS curves; highlighted company capped time on treatment at overall survival; noted time on comparator treatments remains uncertain due to limited data
Committee: Noted company's calculated costs lower than NHS England Cancer Drugs Fund tariff of £96,016 (2022-23) for CAR T-cell therapy delivery in people aged 19+ years; noted clinical experts expected intravenous immunoglobulin for longer than company's 12-month estimate; noted at first meeting that tariff was best available source for current NHS costs; noted lack of full transparency on tariff derivation; recognised need to explore potential issues of double counting or undercounting costs
ICER impact: increases
CAR T-cell therapy delivery costs including infusion, monitoring, hospitalisation, leukapheresis, conditioning chemotherapy, and bridging therapy
Company: Company used bottom-up costing approach with individual cost categories; estimated cost lower than NHS tariff; disagreed that NHS tariff (£96,016 for 2022-23) should be used, citing lack of transparency and potential double-counting
ERG: ERG agreed company's approach was underestimate but raised concerns about NHS tariff derivation methodology; agreed transparency would be beneficial
Committee: Committee agreed that company's revised cost of £41,101 was most appropriate, as it accounted for increased staffing needs while representing a reasonable projection avoiding the high infrastructure costs in the tariff
ICER impact: decreases
Long-term survivor assumptions in economic model; both company and ERG assumed proportion of people could be considered long-term survivors from future time point with zero risk of progression; long-term survivors assumed to have 9% higher probability of death than general population from year 5 onwards
Company: Base-case assumption was 25% of people receiving axicabtagene ciloleucel were long-term survivors; extrapolation applied from 5 years; non-long-term survivors followed Weibull distribution fitted to full ZUMA-5 dataset; based on clinical opinion and clinical validation; long-term survivors assumed to have utility equal to general population (revised to agree with ERG after consultation)
ERG: Agreed mixture-cure model not possible due to immature ZUMA-5 data; expected proportion of long-term survivors due to unique mechanism of action but proportion cannot be validated; used Weibull distribution with hazard of death adjusted to 1.2 times higher than general population matched for age and sex; explored scenarios with 1.5x and 2x adjustment and pessimistic generalised gamma scenario; believed long-term survivors unlikely to attain general population utility while experiencing elevated mortality risk; preferred utility decrement for long-term survivors
Committee: At first meeting, concluded it was uncertain if company's long-term survival assumptions appropriate given immature ZUMA-5 data and uncertainties in SCHOLAR-5; noted long-term survivor proportion assumption had little effect on cost-effectiveness results; noted company did not clearly present model predictions for long-term vs non-long-term survivors separately; after company provided stratified survival graph in response to consultation, took both company and ERG approaches into account but noted analyses did not resolve issues with long-term and non-long-term survivor assumptions; concluded ERG's approach of using utility decrement for long-term survivors more appropriate
ICER impact: decreases
Long-term survivor proportion and how survivors are modelled after treatment
Company: Company made assumptions about long-term survivor proportions in the model
ERG: ERG had concerns about survivor proportion assumptions
Committee: Committee considered long-term survivor proportion assumptions as a key source of uncertainty
ICER impact: uncertain_direction
Company used propensity-score-weighted indirect comparison with SMR weighting to adjust baseline imbalances between ZUMA-5 and SCHOLAR-5 studies
Company: Propensity-score weighting with SMR weighting improved comparability between studies and reduced bias in comparative effectiveness
ERG: SMR weighting application was not transparent; stronger assumptions needed for unanchored comparison; some key covariates (e.g. follicular lymphoma subtype/grade) excluded from weighting despite large standardised mean differences
ICER impact: uncertain_direction
Company used propensity-score-weighted indirect comparison (SMR weighting) to address baseline imbalances between ZUMA-5 and SCHOLAR-5; company applied unanchored indirect comparison using propensity-score weighting and matching methods
Company: Propensity-score-weighting approach based on NICE DSU Technical Support Document 18 and recent literature; focused on covariates strongly correlated with outcomes; excluded covariates with limited effect on sample size
ERG: Propensity-score weighting should adjust for all treatment effect modifiers and prognostic variables; failure to adjust for follicular lymphoma subtypes and other lower grade subtypes in SCHOLAR-5 may have biased results in favour of current fourth line care; generating comparative effectiveness from real-world data is challenging with limited sample sizes
Committee: Committee noted the company's approach and use of propensity-score-weighting method was highly uncertain at first meeting; acknowledged ERG concerns about excluded covariates (particularly follicular lymphoma subtype); recognised trade-off between adjusting for all variables and maintaining adequate sample size; noted company explored alternative methods including G-estimation and E-value with consistent results; concluded the adjustment method used is highly complex
ICER impact: uncertain_direction
Use of single-arm trial data with external control comparator data rather than randomised comparison
ERG: ERG noted that comparative effectiveness results from single-arm studies were prone to bias due to lack of randomised comparators
Committee: Using SCHOLAR-5 data to inform comparative effectiveness was acceptable in context of lack of data for this specific population
ICER impact: increases
Company used partitioned survival model with 3 health states (pre-progression, progressed, death) to estimate cost-effectiveness; committee questioned whether mixture-cure modelling approach should be used
Company: Mixture-cure model or spline model not possible due to immaturity of ZUMA-5 data
ERG: Model structure appropriate; partitioned survival model captured all relevant health states; some uncertainties noted in model assumptions such as long-term survivor assumptions
Committee: Committee concluded that the company's model structure was appropriate for decision making
ICER impact: negligible
Time on treatment for comparator treatments in the model
Company: Originally used median number of treatment cycles from product characteristics and fitted exponential distribution; assumed equal subsequent treatment costs in both arms; originally allowed treatment to continue beyond progression; after technical engagement, agreed to cap time on treatment at point of progression
ERG: Noted time-on-treatment curves not consistent with PFS and OS curves; highlighted that allowing treatment beyond progression while applying subsequent treatment costs may overestimate comparator arm costs; broadly satisfied with company's updated base case; noted time on comparator treatments remains uncertain due to limited data
Committee: Clinical experts explained treatment unlikely to continue beyond progression; noted time on comparator treatments had large impact on cost-effectiveness results; despite uncertainty, concluded would accept the approach for decision making in context of this appraisal
ICER impact: decreases
Time on treatment for comparator treatments in relation to disease progression
Company: Original model capped time on treatment at overall survival, allowing treatment to continue beyond progression
ERG: ERG noted time-on-treatment curves were not consistent with progression-free survival and overall-survival curves; highlighted clinical implausibility of treatment beyond progression
Committee: Committee agreed with ERG that treatment should be capped at point of progression rather than continuing beyond
ICER impact: decreases
Committee preference for parametric survival distributions for extrapolating progression-free and overall survival for standard care using SCHOLAR-5 data
Company: Company used gamma extrapolation in line with its original base case; did not clearly justify the choice of gamma distribution
ERG: ERG considered generalised gamma, log-logistic and log-normal distributions to provide the best statistical fits; noted estimates of survival extrapolation were highly uncertain
Committee: Committee preferred exponential distribution for progression-free survival and gamma distribution for overall survival; noted company did not justify gamma choice; noted removing DELTA cohort from SCHOLAR-5 had large effect on cost-effectiveness results
ICER impact: increases
Choice of parametric distributions for extrapolating overall survival and progression-free survival beyond trial data
Company: Company used exponential and other distributions in original model
ERG: ERG had concerns about curve selection
Committee: Committee preferred Weibull distribution for overall survival and generalised gamma distribution for progression-free survival in axicabtagene ciloleucel arm; gamma distribution for overall survival and exponential distribution for progression-free survival in standard care arm
ICER impact: uncertain_direction
Uncertainty about long-term treatment effect of axicabtagene ciloleucel due to immature survival data and lack of plateau in Kaplan-Meier curves
Company: Post-hoc analysis censoring allogeneic stem cell transplants at 24 months showed plateau and no positive impact of subsequent transplant on overall survival
ERG: Kaplan-Meier curves from 36-month data cut showed alignment with 5-year extrapolation but with heavy censoring from 3 years onwards; 24 months too early to determine impact of subsequent treatment; longer follow-up needed
Committee: While data indicates sustained benefit, long-term treatment effect is uncertain
ICER impact: increases
Source of health-state utility values for economic model; no health-related quality-of-life data collected in ZUMA-5 and SCHOLAR-5
Company: Originally used utility values from NICE technology appraisal on lenalidomide with rituximab for previously treated follicular lymphoma based on AUGMENT study; after technical engagement, agreed with ERG and updated base case to use Wild et al. (2006) utility values; assumed long-term survivors have utility equal to general population; clarified assumptions based on previous NICE CAR T-cell technology appraisal guidance
ERG: Concerned most people in AUGMENT study were at earlier disease stage and would have higher quality of life than people after 3+ treatments; preferred Wild et al. (2006) with EQ-5D data from relapsed or refractory follicular lymphoma patients; highlighted study limitations but considered it better reflected quality of life after 3 treatments; preferred utility decrement for long-term survivors; broadly agreed with company's updated base case but considered it unlikely long-term survivors would attain general population utility while experiencing elevated mortality risk
Committee: Concluded ERG's approach of using utility decrement for long-term survivors was more appropriate; noted source of utility values had small effect on cost-effectiveness results; recognised uncertainties; noted company's assumption of rebound to general-population utility for long-term survivors favoured axicabtagene ciloleucel
ICER impact: decreases
Whether to apply a utility decrement for long-term survivors after axicabtagene ciloleucel treatment
Company: Not explicitly stated but company's base case choices implied
ERG: Not explicitly stated
Committee: Committee preferred including a utility decrement for long-term survivors after axicabtagene ciloleucel treatment
ICER impact: increases
Evidence gaps
Commercial arrangement
Special considerations
Cross-references