TA959 · STA
Not recommended for routine commissioning. Not eligible for Cancer Drugs Fund due to lack of plausible potential for cost-effectiveness at the proposed price.
Source documents
Intervention
Conditions
Comparators
| Name | Type | Established | Committee preferred |
|---|---|---|---|
| bortezomib in combination | active drug | Yes | Yes |
| standard care (bortezomib in combination) | standard of care | Yes | — |
| standard care | standard of care | Yes | — |
Clinical trials
| Trial | Design | Phase | Pivotal |
|---|---|---|---|
| ANDROMEDA | RCT | phase 3 | Yes |
Economic model
ICER
Methodological decisions (24)
Choice between ALchemy and EMN23-UK observational datasets to model standard care outcomes and population characteristics
Company: EMN23-UK preferred due to access to patient-level data
ERG: ALchemy better represents NHS clinical practice due to higher proportion of bortezomib-based regimens and UK-based methodology
Committee: Both ALchemy and EMN23-UK may be representative of UK clinical practice, but uncertainty remains with EMN23-UK due to high levels of missing data from re-categorisation
ICER impact: increases
Administration cost for bortezomib plus daratumumab infusion
Company: £99 per cycle based on specialist nursing costs, aligned with other NICE daratumumab appraisal
ERG: £99 underestimates true cost; should be £332 based on HRG codes
Committee: £99 underestimated; should be £1,127 per cycle (HRG 12Z at £161 day 1 plus HRG 15Z at £322 for days 8, 15, 22 in cycles 1-2 and 3-6; £161 only for maintenance from cycle 7)
ICER impact: decreases
Administration cost for bortezomib plus daratumumab. Company used £99 based on specialist nursing costs, but ERG noted HRG codes ranged from £241-£2,110. Cancer Drugs Fund lead considered £99 underestimated true cost.
Company: £99 administration cost (based on specialist nursing costs), with scenario analyses at £123 and £332
Committee: For cycles 1-6: £1,127 per cycle (HRG 12Z £161 day 1 + HRG 15Z £322 for days 8,15,22). For cycles 7+: £161 per cycle for monotherapy. Same costs apply to both daratumumab and standard care arms for cycles 1-6.
ICER impact: increases
Whether chemotherapy administration costs should differ between daratumumab in combination and standard care arms.
Committee: Same administration cost (£1,127 per cycle) for both arms in cycles 1-6; lower cost (£161) for daratumumab monotherapy from cycle 7 onwards to reflect subcutaneous administration.
ICER impact: increases
Whether partial response and no response should be combined or separated in the Markov model
Company: Initial model combined partial and no response into one category
ERG: Not explicitly stated, but clinical experts noted different management in practice
Committee: Separate response categories for partial and no response to reflect clinical practice
ICER impact: uncertain_direction
Decision tree for treatment response categorisation followed by Markov model for long-term outcomes
Company: Original model combined partial and no response into a single category
Committee: Separate partial and no response groups to reflect clinical practice differences in management
ICER impact: uncertain_direction
Whether ANDROMEDA population, excluding those with cardiac stage 3b disease and on dialysis, is generalisable to NHS practice
Company: Trial exclusions were ethically justified and based on recruitment issues; excluded people cannot tolerate standard-dose bortezomib
Committee: Population is broadly generalisable to NHS despite exclusions, and committee willing to consider daratumumab across full licensed indication
ICER impact: uncertain_direction
Assessment timepoint for haematological response: 3 months vs 6 months
Company: 6-month assessment reflects better proxy for overall survival
ERG: 3-month assessment reflects NHS clinical practice
Committee: 3-month timepoint should be used in base case but choice of dataset (EMN23-UK or ALchemy) is uncertain
ICER impact: uncertain_direction
Whether to include people with end-stage cardiac and renal disease in the population. Company presented no trial evidence for people with severe complications.
Committee: Should include people with end-stage cardiac and renal disease in population
ICER impact: uncertain_direction
Maximum treatment duration for daratumumab in combination plus maintenance therapy
Company: 24 cycles maximum in line with ANDROMEDA trial and product characteristics
Committee: Acceptable to model maximum of 24 cycles; NHS England would commission in line with marketing authorisation
ICER impact: negligible
Maximum duration of daratumumab treatment capped at 24 cycles (6 cycles in combination + 18 cycles monotherapy maintenance), based on clinical trial protocol despite clinical experts noting that clinicians would likely prefer to continue treatment beyond 24 cycles for responders.
Committee: Maximum of 24 cycles is acceptable to model
ICER impact: decreases
Company submitted end-of-life case for cardiac stage 3b disease subgroup but had not proposed limiting treatment to this population or presented cost-effectiveness evidence for this subgroup.
Committee: End-of-life criteria not met; no separate recommendation for cardiac stage 3b subgroup
ICER impact: negligible
Whether haematological response is appropriate as a surrogate for overall survival in cost-effectiveness model
Company: Haematological response is appropriate as a surrogate because factors associated with haematological response (cardiac involvement, renal disease) are associated with overall survival risk
Committee: Haematological response measured at 3 or 6 months reflects a clinically important outcome, but overall survival benefit has not been demonstrated in trial data
ICER impact: increases
Use of haematological response as surrogate endpoint for overall survival when ANDROMEDA has not demonstrated survival benefit
Company: Haematological response is appropriate surrogate for survival benefit
ERG: Insufficient evidence for surrogate validity
Committee: Potential confounding between haematological response and overall survival is not appropriately explored
ICER impact: increases
Use of haematological response as surrogate for overall survival prediction. Company did not adequately address possibility of confounding. Overall survival data from ANDROMEDA are immature with no difference seen at latest interim cut.
Company: Used haematological response to model overall survival without adequately addressing confounding
Committee: Should assess haematological response at 3 months but explore scenario using 6 months; consider confounding factors in haematological response-to-OS relationship
ICER impact: increases
Extrapolation of long-term overall survival beyond trial follow-up using haematological response strata
Company: EMN23-UK dataset appropriate for extrapolation beyond 3-6 cycles
ERG: ALchemy dataset preferred; concerns about missing data in re-categorised EMN23-UK
Committee: High uncertainty in extrapolations for overall survival in longer term using either dataset
ICER impact: uncertain_direction
Modelling approach for overall survival. Committee uncertain about extrapolation methodology and confounding factors in relationship between haematological response and overall survival.
ERG: Noted observational studies used standard care regimens, not daratumumab
Committee: Extrapolated overall survival in longer term may lie between ALchemy data and censored/re-categorised EMN23-UK data; explore confounding factors
ICER impact: uncertain_direction
Duration of maintenance daratumumab monotherapy after induction
Company: Daratumumab monotherapy continued until disease progression or maximum 18 cycles (24 cycles total)
Committee: Some people, particularly those at low risk of progression, may not need maintenance depending on haematological response
ICER impact: increases
Modelling sustained survival benefit from daratumumab maintenance monotherapy after cycle 6
Company: Applied 4.4% survival uplift to all response categories from cycle 7 onwards based on 12-month landmark analysis
ERG: Uplift inappropriately applied independent of response category
Committee: Company's approach to modelling sustained benefit not appropriate; considerable uncertainty in calculation method and appropriateness of benefit continuing after daratumumab stopped
ICER impact: decreases
Application of expected increased survival benefit for daratumumab maintenance monotherapy from cycle 7 onwards. Committee found this approach uncertain for decision making.
Company: Applied expected survival benefit for daratumumab maintenance from cycle 7 onwards
Committee: Company's approach of applying expected increased survival benefit for maintenance monotherapy is not appropriate for decision making
ICER impact: increases
Validation of utility values derived from ANDROMEDA EQ-5D-5L against alternative data source
Company: EQ-5D-5L data from ANDROMEDA are appropriate; ALchemy SF36v2 data not yet published
ERG: Should use SF36v2 data from ALchemy to validate ANDROMEDA utilities
Committee: Should have validated with ALchemy data but acknowledged non-availability at time of appraisal
ICER impact: uncertain_direction
Utility values derived from ANDROMEDA rather than ALchemy. Company unable to use SF36v2 data from ALchemy due to lack of published patient-level data.
Company: Used utilities from ANDROMEDA as ALchemy data not published
Committee: Should have validated ANDROMEDA-derived utilities against ALchemy SF36v2 data if available
ICER impact: uncertain_direction
Face validity of utility values for very good partial response and end-stage organ failure
Company: Values from ANDROMEDA EQ-5D-5L are appropriate
ERG: Values for very good partial response counterintuitively lower than partial/no response; disutility for end-stage organ failure likely higher
Committee: Values plausible but likely not maintainable throughout second-line treatment and end-stage organ failure
ICER impact: uncertain_direction
Some utility values lack face validity, particularly for second-line treatment and end-stage organ failure states, which are unlikely to be maintained throughout these disease phases.
Committee: Review utility values for clinical plausibility in advanced disease states
ICER impact: increases
Evidence gaps
Commercial arrangement
Special considerations