TA226 · STA
Source documents
Intervention
Conditions
Comparators
| Name | Type | Established | Committee preferred |
|---|---|---|---|
| observation (no treatment) | no treatment | Yes | — |
| ibritumomab tiuxetan | active drug | — | — |
| observation | no treatment | Yes | — |
| watchful waiting | no treatment | Yes | — |
Clinical trials
| Trial | Design | Phase | Pivotal |
|---|---|---|---|
| PRIMA trial (Primary Rituximab and Maintenance) | RCT | III | Yes |
| EORTC 20981 study | not stated | not stated | — |
| ECOG 1496 study | RCT | — | — |
| SAKK 35/98 study | RCT | — | — |
| PRIMA trial | RCT | phase III | Yes |
| PRIMA | RCT | — | Yes |
| ECOG 1496 | RCT | — | — |
| SAKK 35/98 | RCT | — | — |
Economic model
ICER
Methodological decisions (29)
Ibritumomab tiuxetan was listed as a comparator in the decision problem but was excluded from the economic model
Company: Ibritumomab tiuxetan not considered appropriate because of limited evidence of benefits and limited UK prescribing
ICER impact: uncertain_direction
Economic model did not include disutility values for grade 3 and 4 adverse events or for receiving chemotherapy
Company: Costs associated with grade 3 and 4 adverse events were included but disutility values were not included
ICER impact: uncertain_direction
Inclusion and costing of adverse events
Company: Did not include disutilities for grade 3 and 4 adverse events; assumed equivalent costs
ERG: Noted omission would favour rituximab maintenance because rituximab arm experiences more adverse events; concerned about underestimation of PF2 costs
ICER impact: decreases
Model structure and flexibility for sensitivity analyses
Company: Used three-state Markov model
ERG: Noted model structure did not allow sufficient flexibility for requested sensitivity analyses; had to adjust outcomes/costs post-hoc rather than adjust parameters
ICER impact: uncertain_direction
Conversion rate from progression-free survival to overall survival
Company: 89.2% conversion rate in revised base-case
ERG: Not explicitly stated but implied concern about high conversion rate
Committee: Sensitivity analyses with 70%, 80%, 90% conversion rates plausible; clinical specialists indicated expectation of at least 70%
ICER impact: uncertain_direction
Early stopping bias adjustment: ERG proposed adjusting hazard ratio from 0.55 to 0.719 to account for PRIMA trial stopping earlier than planned
Company: Not explicitly stated
ERG: Evidence suggests studies that stop earlier often overestimate clinical benefit; hazard ratio should be adjusted for early reporting bias
Committee: Adjusting for early reporting bias is not routinely included in technology appraisals and is not a current requirement in NICE methods guide
ICER impact: increases
Applicability of EORTC 20981 study data for economic modelling
Company: Used EORTC 20981 data to inform adverse event costs
ERG: Questioned reliability because EORTC 20981 participants received different induction treatments; only half received rituximab-containing induction
ICER impact: uncertain_direction
Age adjustment: median age in PRIMA trial was 57 years but UK clinical practice typically sees mean age 60-65 years at start of first-line treatment
Company: Revised base case using mean age of 62.5 years appropriately reflects UK clinical practice
ERG: Manufacturer's age adjustment method did not reflect prognostic importance of incident age; proposed adjusting hazard ratios for specific age groups
Committee: Satisfied that manufacturer's base-case analysis appropriately adjusted for age; ERG's hazard ratio adjustment for different age groups not needed
ICER impact: decreases
Age of trial population versus NHS practice
Company: Median age 57 years at randomisation in PRIMA trial
ERG: Added uncertainty regarding applicability to UK practice where mean age typically 60-65 years
Committee: Manufacturer's revised base-case with mean age 62.5 years at induction appropriately adjusted
ICER impact: decreases
Early reporting bias adjustment for progression-free survival hazard ratio
Company: Used unadjusted progression-free survival HR of 0.55 from PRIMA trial
ERG: Adjusted HR to 0.719 (30.7% increase) to account for early reporting bias based on Bassler et al. 2010 metaregression
ICER impact: increases
Hazard ratio adjustment for early trial closure bias in PRIMA trial
Company: Hazard ratio of 0.55 for PFS without adjustment
ERG: Early closure may overestimate benefit; hazard ratio should be increased to adjust for bias
Committee: Adjustment for early reporting bias not routinely included in NICE appraisals and not current requirement in NICE methods guide; manufacturer's hazard ratio of 0.55 appropriate
ICER impact: increases
Manufacturer used Gompertz function to extrapolate progression-free survival data beyond the end of PRIMA trial (which ended at 25 months median follow-up) to estimate median progression-free survival
Company: Gompertz function provided better fit than alternative functions
ICER impact: uncertain_direction
Choice of parametric function for extrapolating progression-free survival beyond trial follow-up (4 years)
Company: Used Gompertz parametric function as base case, which generated highest overall estimate compared with exponential function
ERG: Expressed concerns about use of Gompertz function and noted that if other functions were used, conversion rates would need to be higher for ICER below £30,000
ICER impact: increases
Conversion of progression-free survival gain to overall survival gain
Company: Base case assumed 89.2% conversion rate; questioned plausibility of lower rates
ERG: Predicted at least 50% conversion rate needed for ICER below £30,000; explored 70%, 80%, 90% rates in sensitivity analyses
ICER impact: increases
Maturity of overall survival data
Company: Used available PRIMA trial data with follow-up to 4 years
ERG: Noted follow-up data not available beyond 4 years and median time to progression/death could not be estimated by group; cautioned data immature with few events
ICER impact: increases
Extrapolation of progression-free survival benefit beyond PRIMA trial period; manufacturer assumed proportional increase in survival over time
Company: Proportional increase in survival is appropriate for extrapolation
ERG: Manufacturer's extrapolation assuming proportional increase may not reflect true effect
Committee: Not explicitly stated; deferred to clinical opinion on plausibility of duration assumptions
ICER impact: uncertain_direction
Extrapolation method for clinical benefit beyond observed PRIMA trial period
Company: Proportional increase in survival with time assumed in base case
ERG: Method may not reflect true effect
Committee: Acknowledged uncertainty but accepted manufacturer's sensitivity analyses
ICER impact: uncertain_direction
Duration of clinical benefit from rituximab maintenance treatment assumed to be sustained over 6 years (4 years beyond the end of treatment in PRIMA trial). After 6 years, risk of disease progression assumed equal in both arms
Company: Assumed 6-year duration based on PRIMA trial results, EORTC 20981 study and expert opinion
Committee: The model was sensitive to assumptions regarding duration of treatment effect; when treatment effect stopped after 47 months instead of 72 months, ICER increased to £21,151 per QALY
ICER impact: increases
Duration of clinical benefit of rituximab maintenance treatment: manufacturer assumed 6 years (2 years treatment + 4 years sustained benefit), ERG suggested 28 months based on patient-level data, clinical specialists suggested 3-4 years (1-2 years beyond treatment)
Company: 6 years duration of benefit is plausible, supported by EORTC 20981 study for second-line treatment and clinical opinion
ERG: 28 months based on patient-level data from PRIMA trial after which progression rate no better than observation
Committee: Satisfied that manufacturer's sensitivity analyses (28, 36, and 48 months) presented most plausible range in line with clinical opinion and available data
ICER impact: increases
Duration of clinical benefit of rituximab maintenance treatment
Company: 6 years (2 years of treatment and 4 years of sustained benefit)
ERG: 28 months based on patient-level data from PRIMA trial
Committee: Sensitivity analyses with 28, 36 and 48 months considered plausible; clinical specialists indicated 3-4 years (1-2 years beyond treatment) likely, with up to 6 years plausible
ICER impact: increases
Duration of clinical benefit from rituximab maintenance treatment
Company: Not explicitly stated in this chunk
Committee: 36 to 48 months, in line with clinical opinion
ICER impact: decreases
Duration of clinical benefit from rituximab maintenance therapy
Company: Base case assumed clinical benefit sustained for 72 months (6 years); also presented sensitivity analyses with 28, 36, and 48 months
ERG: Cautioned that if gain in progression-free survival progressively declines, ICER could substantially increase; suggested benefit may last only 28 months based on cumulative hazard plots
ICER impact: increases
Modelling of post-progression treatments
Company: Used post-progression treatments from PRIMA trial
ERG: Stated that treatments were in line with UK practice but unsure whether timing in trial reflected routine practice
ICER impact: uncertain_direction
Health-related quality-of-life utilities derived from Pettengel et al. 2008 study (UK-based, 215 patients with follicular lymphoma) rather than EQ-5D questionnaires from PRIMA trial itself
Company: PRIMA trial participants did not routinely complete EQ-5D questionnaires; used Pettengel study instead with values: 0.88 (disease free/PF1), 0.79 (complete response/PF2), 0.62 (active disease/PD)
ICER impact: uncertain_direction
Health utility values for progression-free health states
Company: Used 0.88 for PF1 (disease free) and 0.79 for PF2 (complete response to therapy) from Pettengel et al. 2008
ERG: Considered same utility value should be used in both states because both represent remission/full response; conducted sensitivity analysis using 0.79 for both
ICER impact: increases
Health-related quality of life differences between treatment arms
Company: Model includes utility values 0.88 and 0.79 for PF1 and PF2 health states
ERG: Sensitivity analyses on utility values
Committee: Changes to utility gains had marginal effect on ICER; ICER largely driven by overall survival gains
ICER impact: negligible
Inclusion of utility associated with delaying chemotherapy in the model
Company: Model did not include utility of delaying chemotherapy
Committee: Committee acknowledged that inclusion of utility from delaying chemotherapy would decrease the ICER
ICER impact: decreases
Conversion rate from progression-free survival to overall survival benefit: manufacturer assumed 89.2% conversion in revised base case
Company: 89.2% conversion rate is appropriate; conversion rate was not a direct model input but required artificial modification of parameters for sensitivity analysis
ERG: Should have sought patient registry or observational data to validate conversion rate; rate of 89.2% may be overestimated
Committee: Satisfied that sensitivity analyses with 70%, 80%, and 90% conversion rates provided plausible range
ICER impact: decreases
Utility gain from delaying chemotherapy not included in model
Company: Unable to incorporate because of limitations in model structure
ERG: Not stated
Committee: Acknowledged omission would decrease ICER if included (improve cost effectiveness)
ICER impact: increases
Evidence gaps
Commercial arrangement
Special considerations
Cross-references