TA243 · STA
Recommended in combination with CVP, CHOP, MCP, CHVPi, or chlorambucil for symptomatic stage III-IV follicular lymphoma in previously untreated patients
Source documents
Interventions
Conditions
Comparators
| Name | Type | Established | Committee preferred |
|---|---|---|---|
| cvp alone | active drug | Yes | — |
| chop alone | active drug | Yes | — |
| mcp alone | active drug | Yes | — |
| chvpi alone | active drug | Yes | — |
| chlorambucil alone | active drug | Yes | — |
| cvp | active drug | Yes | — |
| chop | active drug | Yes | — |
| mcp | active drug | Yes | — |
| chvpi | active drug | Yes | — |
| chlorambucil | active drug | Yes | — |
| cvp (cyclophosphamide, vincristine and prednisolone) | active drug | Yes | — |
| chop (cyclophosphamide, doxorubicin, vincristine and prednisolone) | active drug | Yes | — |
| mcp (mitoxantrone, chlorambucil and prednisolone) | active drug | Yes | — |
| chvpi (cyclophosphamide, doxorubicin, etoposide, prednisolone and interferon-α) | active drug | Yes | — |
Clinical trials
| Trial | Design | Phase | Pivotal |
|---|---|---|---|
| M39021 | RCT | III | Yes |
| GLSG-2000 | RCT | III | Yes |
| OSHO-39 | RCT | III | Yes |
| FL2000 | RCT | III | Yes |
| EORTC 20981 | — | — | — |
| Four randomised controlled trials comparing rituximab plus chemotherapy vs chemotherapy alone | RCT | — | Yes |
| Four good-quality RCTs | RCT | III | Yes |
Economic model
ICER
Methodological decisions (15)
Whether to recommend rituximab with any chemotherapy regimen or to restrict to those with clinical and economic evidence
Committee: Recommending rituximab with any chemotherapy is not appropriate despite likely clinical effectiveness, as it would result in recommending unappraisal combinations and cost-effectiveness cannot be assumed without evidence. However, rituximab plus chlorambucil recommended based on informal cost-effectiveness advice and likely patient benefit
ICER impact: uncertain_direction
Inclusion of rituximab plus chlorambucil despite limited clinical data and no formal cost-effectiveness analysis
Company: Not addressed separately
ERG: Provided informal cost-effectiveness advice that ICER for rituximab plus chlorambucil would remain cost-effective if QALY gain was half that of rituximab plus CHOP
Committee: Committee concluded rituximab plus chlorambucil was appropriate use of NHS resources for older patients or those with lower performance status
ICER impact: uncertain_direction
Assessment Group developed individual patient model simulating 100,000 patients with separation of responders and non-responders, differing from manufacturer's Markov approach.
Company: Used Markov model estimating costs and benefits from first-line treatment over lifetime
ERG: Developed individual patient model simulating 100,000 patients with responder/non-responder separation
ICER impact: uncertain_direction
Whether trial populations are representative of UK advanced follicular lymphoma patients
Committee: Trial population was younger than median age of UK patients, but results could be considered broadly representative of UK clinical practice outcomes because some rituximab combinations (e.g. rituximab plus CHOP) are given to younger patients and subgroup analysis by age showed benefit regardless of age
ICER impact: negligible
Uncertain relative effect and absolute response rates of rituximab added to chemotherapy regimens other than those studied in clinical trials (CHVPi and chlorambucil)
Company: Submitted cost-effectiveness for rituximab plus CHVPi
ERG: Did not include rituximab plus CHVPi due to trial design issues and limited UK use
Committee: Committee was persuaded that rituximab would provide additional clinical benefit when added to chemotherapy despite limited evidence for some regimens; accepted rituximab plus chlorambucil based on clinical specialist advice despite absence of formal cost-effectiveness analysis
ICER impact: uncertain_direction
Assessment Group highlighted inconsistencies in manufacturer's model including derivation of transition probability, calculation of post-progression survival, and potential over-estimation of rituximab effect through use of time-to-event data confounded by subsequent treatments.
Company: Used time-to-event data from clinical trials with responders receiving subsequent treatments
ERG: Noted this may have over-estimated the effect of rituximab
ICER impact: decreases
For CHOP and MCP comparisons, Assessment Group used M39021 trial data as proxy for progression-free survival curves rather than first-line induction trial data, to avoid confounding by stem-cell transplantation or interferon maintenance therapy.
Company: Not explicitly stated
ERG: Used M39021 trial data as proxy for first-line progression-free survival curves for CHOP and MCP comparisons
ICER impact: uncertain_direction
Assessment Group tested assumption of 25% reduction in efficacy of rituximab when used as second-line treatment in patients previously treated with rituximab.
Company: Not explicitly stated
ERG: Explored scenario assuming 25% reduction in rituximab efficacy in second-line for previously-treated patients
ICER impact: increases
Manufacturer and Assessment Group did not include first-line rituximab maintenance treatment in base-case analyses
Company: Not included in base case
ERG: Not included in base case
Committee: Committee concluded these factors needed to be considered when making cost-effectiveness decision, and noted that ICERs increased when first-line maintenance was assumed
ICER impact: increases
Whether rituximab efficacy is maintained when patients are re-treated with rituximab after relapse
Company: No loss of efficacy on re-treatment
ERG: Uncertainty regarding whether loss of efficacy occurs on re-treatment; sensitivity analysis showed that 25% reduction in re-treatment efficacy would increase ICERs from £7720–£10,800 to £14,900–£26,900
Committee: Efficacy of rituximab after re-treatment is a key uncertainty in the economic modelling but uncertainty was not such that it increased ICERs above the threshold range
ICER impact: increases
Whether efficacy of rituximab is maintained when used again as second-line induction treatment after first-line rituximab
Company: Assumed efficacy maintained
ERG: Assumed efficacy maintained
Committee: Committee noted this assumption and concluded ICERs increased if there was a reduction in efficacy on re-treatment
ICER impact: increases
Assessment Group considered manufacturer's assumption that patients receive either CHOP or rituximab plus CHOP as second-line treatment did not reflect the range of treatments used in clinical practice.
Company: Assumed patients receive either CHOP or rituximab plus CHOP as second-line treatment
ERG: Did not consider this reflected range of treatments in clinical practice
ICER impact: increases
Whether to include rituximab first-line maintenance treatment in the treatment pathway
ERG: Recommended inclusion in scenario analysis; inclusion increased ICERs to £15,000–£21,600
Committee: Appropriate to consider ICERs from scenario analysis including first-line maintenance treatment in light of NICE TA226 recommendations; both guidances should be considered for review together
ICER impact: increases
Appropriate subsequent treatment pathways after first-line therapy
Company: Assumed CHOP or CHOP alone after first-line treatment
ERG: Developed model to include CHOP, fludarabine-cyclophosphamide, and stem-cell transplant based on clinical adviser input
Committee: Treatment pathways in Assessment Group's model are appropriate and reflect clinical practice in the UK
ICER impact: uncertain_direction
Disagreement over utility values: manufacturer used disaggregated values based on degree of response to therapy, Assessment Group used aggregated health-state utilities based on number of lines of treatment.
Company: Used disaggregated utility values from main analysis of Pettengell et al. 2006: PF1 = 0.88; PF2 = 0.79; progressive disease = 0.62, with different values for first-line and second-line progression-free survival
ERG: Used aggregated health-state utilities from additional analysis with unified values for first-line and second-line progression-free survival = 0.805; progressive disease = 0.7363, considered more appropriate as utilities not based on degree of response
ICER impact: uncertain_direction
Evidence gaps
Commercial arrangement
Special considerations
Cross-references