TA615 · STA
Frequency of drop seizures checked every 6 months and cannabidiol stopped if the frequency has not fallen by at least 30% compared with the 6 months before starting treatment. Company to provide cannabidiol according to commercial arrangement.
Source documents
Intervention
Condition
Comparators
| Name | Type | Established | Committee preferred |
|---|---|---|---|
| placebo | placebo | — | — |
| usual care | standard of care | Yes | — |
Clinical trials
| Trial | Design | Phase | Pivotal |
|---|---|---|---|
| GWPCARE3 | RCT | Phase 3 | Yes |
| GWPCARE4 | RCT | Phase 3 | Yes |
| GWPCARE5 | open_label | — | — |
Economic model
Methodological decisions (16)
Model validity concern with QALYs for patients stopping cannabidiol
ERG: Identified that model generates more favourable results for patients stopping cannabidiol than expected; when all clinical inputs equal, model estimated higher QALYs for cannabidiol than expected
ICER impact: increases
Company used median body weight from trials to calculate weight-based dose. Committee preferred mean weight, noting median was lower than mean and good practice recommends mean values.
Company: Median weight appropriate due to significant outliers in trial data
Committee: Mean body weight should be used; committee agreed outlier patients would receive treatment in NHS
ICER impact: decreases
Company assumed maintenance dose of 10 mg/kg/day for all patients despite 10-20 mg/kg/day range in summary of product characteristics. Company provided scenario with 12 mg/kg/day average (20% at 20 mg/kg/day).
Company: Base case 10 mg/kg/day appropriate; scenario with 12 mg/kg/day average and another with 9 mg/kg/day provided
Committee: Scenario with 12 mg/kg/day average dose preferred as it captures dose increases
ICER impact: increases
Company assumed 2 carers per patient based on clinical expert opinion. Provided scenarios with 1.8 carers (literature-based, Lagae et al. 2017) and 3 carers. Linear multiplication of disutility by number of carers.
Company: 2 carers base case; scenarios with 1.8 and 3 provided; vignette study accounted for care-sharing
Committee: 1.8 carers scenario preferable; linear multiplication approach inappropriate but limited impact with 1.8 value
ICER impact: increases
Definition of health states by seizure frequency ranges
Company: Initially used health states with very wide seizure ranges (e.g. 45-110 seizures) divided by overall trial population
Committee: Health states defined by narrower ranges of seizures based on clinical rationale, with most patients experiencing 50% seizure change moving to different health state
ICER impact: decreases
Health state definition based on seizure frequency ranges. Company initially used wide ranges (e.g. 45-110 seizures), committee was concerned these lacked clinical rationale. Company revised to narrower ranges based on 50% seizure change being clinically meaningful.
Company: Wide seizure ranges initially, then revised to narrower ranges ensuring 50% change moves patients to different health state
Committee: Narrower ranges of seizures appropriate for decision making
ICER impact: negligible
Company divided each of 3 drop seizure health states into substates based on seizure-free days (exploratory endpoint). Committee noted other approaches like discrete event simulation may be more appropriate but accepted this method.
Company: Substates based on seizure-free days to capture both seizure frequency and days without seizures benefits
Committee: Approach acceptable, though other methods like discrete event simulation may be more appropriate
ICER impact: negligible
Model reassignment of patients who stopped cannabidiol. Company assumed those stopping return to health states in same proportions as usual care patients, but most stopping were in highest seizure frequency state initially. This could result in some being reassigned to lower seizure states than baseline.
Company: Patients who stop cannabidiol should be reassigned to health states in same proportions as usual care; justified by lack of clinical data on stopping outcomes
Committee: Patients should be split into quantiles and redistributed to corresponding quantiles in usual care arm to limit inappropriate transitions
ICER impact: increases
Company assumed people without drop seizures have lower epilepsy-related mortality risk (58% reduction per Trinka et al. 2013), later halved to 29%. Committee concerned observational evidence was confounded and not supported by trial evidence.
Company: Reasonable to assume 29% mortality reduction for seizure-free patients based on observational data
Committee: Insufficient evidence to prove cannabidiol prolongs life; prefer scenario without mortality benefit assumption
ICER impact: decreases
Whether to apply stopping rule at 3 months or 6 months
Company: Stopping at 3 months inappropriate because titration to therapeutic dose takes longer than 3 months
Committee: Stopping rule should be assessed every 6 months, based on reduction in drop seizures compared with 6 months before starting cannabidiol
ICER impact: uncertain_direction
Company assumed cannabidiol effect maintained in same health state beyond 27 months based on 36-month open-label extension data. Clinical experts expected efficacy to diminish over time as with other antiepileptic drugs.
Company: Effect maintained as long as patient takes cannabidiol; captured diminishment only through increased stopping rates in scenario
Committee: Effect likely to diminish over time; scenario analysis capturing stopping captures some but not all effects of efficacy waning
ICER impact: increases
Company model originally assumed usual care patients returned to baseline health states. Revised to assume patients remained in same health states from cycle 2 onward to address lack of comparator data in open-label extension.
Company: Patients remain in same health states from 6 months onward; assumption disadvantages cannabidiol by overestimating usual care effectiveness
Committee: New base-case assumption in line with preferences and appropriate for lack of comparator data
ICER impact: negligible
Capturing benefits of reducing non-drop seizures
Company: Applied additional disutility value from de Kinderen et al. 2016 epilepsy preference study, assuming patients with fewer drop seizures benefit from fewer non-drop seizures
ERG: Concerned about double counting of benefits and unable to reproduce company's utility estimates; clinical trial data on non-drop seizure reduction not used directly in model
Committee: Company's approach may not be valid and may double-count benefits; however, benefit of reducing non-drop seizures should be considered in decision-making
ICER impact: uncertain_direction
Company included non-drop seizure benefits via disutility adjustment from public preference study (de Kinderen et al. 2016). ERG concerned about double counting and could not reproduce utility estimates. Clinical trial data on non-drop seizure reduction not directly used.
Company: Applied additional disutility value from literature for non-drop seizure reduction
ERG: Approach may have led to double counting; unable to reproduce estimates
Committee: Approach may not be valid, but acknowledged importance of reducing non-drop seizures and would consider in decision-making
ICER impact: uncertain_direction
Company used vignette study values from patients and carers instead of literature data. Vignette study asked patients/carers to rate health states; lowest value was 0 (death) vs EQ-5D allowing negative values. Committee noted limitations but found values appropriate.
Company: Vignette study necessary due to lack of literature data matching model structure; company considered values confidential
Committee: Vignette approach justified but has limitations; values from Verdian et al. 2018 general population study better aligned with NICE preference, but vignette values acceptable given model structure constraints
ICER impact: uncertain_direction
Company included carer quality-of-life decrements based on vignette study, applied to only 2 highest seizure frequency health states. Committee concerned about limited scope and preference for public preference study values.
Company: Vignette study values appropriate for captured health states; other family members may benefit from improved seizure control
Committee: Appropriate to include carers' quality of life; vignette study best available source despite limitations
ICER impact: negligible
Evidence gaps
Commercial arrangement
Special considerations