TA891 · STA
Only if the companies provide both drugs according to the commercial arrangements (simple discount patient access scheme for both ibrutinib and venetoclax, with confidential discounts)
Source documents
Intervention
Condition
Comparators
| Name | Type | Established | Committee preferred |
|---|---|---|---|
| fludarabine, cyclophosphamide and rituximab (fcr) | active drug | Yes | — |
| bendamustine and rituximab (br) | active drug | Yes | — |
| acalabrutinib and venetoclax | active drug | — | — |
| obinutuzumab plus chlorambucil | active drug | Yes | Yes |
| venetoclax plus obinutuzumab | active drug | Yes | Yes |
| acalabrutinib | active drug | Yes | Yes |
| ibrutinib | active drug | Yes | Yes |
Clinical trials
| Trial | Design | Phase | Pivotal |
|---|---|---|---|
| GLOW | RCT | Phase III | Yes |
| E1912 | RCT | — | — |
| CAPTIVATE | RCT | — | Yes |
| RESONATE | observational | — | — |
| ELEVATE-TN | RCT | — | — |
| CLL14 | RCT | — | — |
Economic model
Methodological decisions (9)
Committee noted implementing 'FCR or BR suitability' criterion challenging for NHS clinicians; placed greater weight on unsuitable group results where comparators (acalabrutinib, obinutuzumab+chlorambucil, venetoclax+obinutuzumab) more relevant than FCR.
Company: Presented modelling for multiple populations
ERG: Appropriate to focus on FCR/BR unsuitable comparisons
Committee: Greater weight on FCR/BR unsuitable and high-risk group results; comparators more relevant for NHS England
ICER impact: uncertain_direction
Model implied cure of CLL for ibrutinib plus venetoclax and acalabrutinib arms when progression risk fell to 0% due to background mortality exceeding disease hazards.
Company: Age at cap consistent; standard methodology for modelling
ERG: CLL is not curable; treatments aim to maintain remissions; inconsistent across groups
Committee: Acknowledged limitations; scenarios addressing inconsistency acceptable; model outcomes appropriate
ICER impact: negligible
For FCR or BR unsuitable group: use of anchored MAICs to compare ibrutinib plus venetoclax against acalabrutinib and venetoclax plus obinutuzumab. EAG noted inconsistency between ATT and ATC results and non-proportional hazards.
Company: Presented scenario analysis with time-varying hazard ratios and anchored MAICs acceptable; clinical equivalence of acalabrutinib to ibrutinib
ERG: Cautious about applying GLOW follow-up (immature) to 30-40 year horizon; concerns about proportional hazards assumption; requested acalabrutinib vs ibrutinib clinical equivalence validation
Committee: ATC approach suitable; anchored MAICs acceptable in absence of direct evidence and more mature data; clinical equivalence between acalabrutinib and ibrutinib plausible and acceptable
ICER impact: uncertain_direction
Semi-Markov model limited to exponential distributions for transitions from second-line and post-progression states. Tunnel states used only for cost tracking, not health state occupancy.
Company: Semi-Markov model structure appropriate; exponential distribution good fit to RESONATE data
ERG: Appropriate model structure but limitations prevent exploration of alternative survival distributions
Committee: Model structure adequate despite limitations
ICER impact: negligible
Company estimated first-line progression hazard by subtracting general population mortality from overall hazards, resulting in 0% progression risk after certain age. In FCR/BR unsuitable group earlier than suitable group due to higher background mortality.
Company: Age at progression-free survival cap (~85 years) consistent across groups
ERG: Method created inconsistencies; FCR/BR unsuitable group reached 0% risk much earlier, implying cure; data does not support differential progression risk between groups
Committee: Model structure and outcomes remain appropriate despite limitations; company's scenario with capped progression probability in unsuitable group acceptable
ICER impact: negligible
High-risk CLL group: ELEVATE-TN included high-risk patients but GLOW excluded them. Company assumed efficacy results from non-high-risk could apply to high-risk population.
Company: FCR or BR unsuitable indirect comparison results applicable to high-risk; acalabrutinib clinically equivalent to ibrutinib; referred to previous NICE acceptance of ibrutinib efficacy assumption
ERG: Cautious about applying non-high-risk efficacy to high-risk population; clinical outcomes optimistic
Committee: Clinical equivalence between acalabrutinib and ibrutinib plausible in high-risk CLL population; acceptable for decision making
ICER impact: increases
Company assumed treatment effect of ibrutinib plus venetoclax maintained for lifetime (30-40 years). EAG cited immature clinical data and requested waning scenarios.
Company: Treatment effect maintained for lifetime horizon
ERG: Concern about immature data supporting lifetime assumption; requested treatment effect waning scenarios
Committee: Acknowledged waning scenarios; 5-year waning conservative; considered all waning scenarios in decision making
ICER impact: decreases
Progression-free first-line utility: company mapped EQ-5D-5L from GLOW to EQ-5D-3L.
Company: Value consistent with CLL14 and ELEVATE-TN; ran capping scenario
ERG: Value higher than UK population age-sex matched utility; therefore overestimate
Committee: Prefer capped UK utility values; agreed with clinical experts that quality of life post-CLL treatment lower than general population
ICER impact: increases
Progression-free second-line and progressed state utilities: company used 0.6 from Holzner et al. 2004 for both states.
Company: Used 0.6 from Holzner, age-adjusted to trial populations
ERG: Only 0.6 appropriate for progressed state; for second-line, preferred utility multiplier approach using GLOW EQ-5D ratios to adjust first-line value
Committee: Agreed 0.6 underestimate; EAG multiplier approach appropriate; acknowledged limited impact on final outcomes
ICER impact: increases
Evidence gaps
Commercial arrangement
Special considerations