TA873 · STA
Cannabidiol is recommended as an add-on treatment for seizures caused by tuberous sclerosis complex in people aged 2 years and over, only if seizures are not controlled by 2 or more antiseizure medications (used alone or in combination) or these treatments were not tolerated; seizure frequency is checked every 6 months and cannabidiol is stopped if seizure frequency has not fallen by at least 30% compared with the 6 months before starting treatment; and the company provides cannabidiol according to the commercial arrangement.
Source documents
Intervention
Conditions
Comparators
| Name | Type | Established | Committee preferred |
|---|---|---|---|
| usual care including antiseizure medications with or without surgery or vagus nerve stimulation | standard of care | Yes | — |
| usual care with antiseizure medications | standard of care | Yes | — |
| usual care | standard of care | — | — |
Clinical trials
| Trial | Design | Phase | Pivotal |
|---|---|---|---|
| GWPCARE6 | RCT | not_stated_in_chunk | Yes |
Economic model
ICER
Methodological decisions (18)
Number of carers and inclusion of carer utility decrements in model
Company: Assumed 2 cumulative carers (1 primary plus others) based on Dravet syndrome data; included utility decrements for carers
ERG: not_stated_in_chunk
Committee: Appropriate to include carer quality of life effects; 1.8 carers appropriate for modelling (concluded at end of section 3.14, not fully shown in chunk)
ICER impact: decreases
ERG highlighted that everolimus may form part of usual care, but committee noted everolimus has different indication and requires restrictive monitoring, so population receiving everolimus at same pathway point would be very small. Committee agreed usual care including antiseizure medications with or without surgery or vagus nerve stimulation was appropriate comparator.
ERG: Questioned whether everolimus should be considered as part of usual care in the population where antiseizure medications are not tolerated
Committee: Usual care including antiseizure medications with or without surgery or vagus nerve stimulation
ICER impact: uncertain_direction
Average dose of cannabidiol for cost modelling
Company: 12 mg/kg/day based on clinical expert advice and German dispensing data
ERG: Concerned that 12 mg/kg/day was not verified by clinical trial data
Committee: 15 mg/kg/day for decision making to account for loss of benefit compared to GWPCARE6 (which used up to 25 mg/kg/day or 50 mg/kg/day)
ICER impact: increases
Healthcare resource use estimates, particularly hospitalisation rates
Company: Used Delphi panel estimates; higher hospitalisation rates reflecting spectrum of severity in tuberous sclerosis complex
ERG: Modelled 50% reduction in hospitalisation rates to align with other cannabidiol appraisals (Dravet and Lennox-Gastaut syndromes)
Committee: 50% reduction from Delphi panel hospitalisation rates should be used for decision making
ICER impact: decreases
Modelling of costs and utility benefits associated with TAND (tuberous sclerosis complex-associated neuropsychiatric disorder) aspects
Company: Included TAND costs and modelled utility benefit and cost reduction for responders (≥50% seizure reduction); conservative estimates at technical engagement using lowest utility benefit and ages 2-6 years only
ERG: Concerned that prevalence rates, costs and utility benefits not from clinical trials; Delphi consensus on response definition incomplete; responder proportion from full trial applied only to 2-6 year-olds
Committee: Appropriate to include TAND costs and benefits despite uncertainties, using company's technical engagement estimates
ICER impact: decreases
Hospital admission rates; whether baseline rates from Delphi panel should be adjusted downward
Company: Used baseline hospitalisation rates from Delphi panel consensus
ERG: Reduced hospitalisation rates by 50% in base case
Committee: Agreed preferred assumptions aligned with ERG base case including 50% reduction in hospitalisation rates
ICER impact: increases
Average dose of cannabidiol to use in cost-effectiveness model
Company: Used 12 mg/kg/day
ERG: Used 15 mg/kg/day in base case
Committee: Preferred assumptions aligned with ERG base case using 15 mg/kg/day. Acknowledged that changing average dose significantly increased cost-effectiveness estimates.
ICER impact: increases
How to model the proportion of people seizure-free over a 7-day cycle using regression model predictions
Company: Used 6.5-day cut-off based on negative binomial regression model limitations; later provided scenario with 6.61-day cut-off
ERG: Highlighted that 6.5-day cut-off overestimates seizure-freedom; provided scenario using 7-day cut-off
Committee: 6.61-day cut-off is most appropriate for decision making
ICER impact: uncertain_direction
Committee noted that uncaptured benefits in the company's model included quality-of-life benefits from reducing seizure severity, reduction in hospitalisation rates, physical and mental benefits to the wider family, and mortality benefit from reducing SUDEP related to tuberous sclerosis complex.
Committee: Committee acknowledged these uncaptured benefits were important for improving quality of life and would take them into account in decision making despite cost-effectiveness uncertainties
Number of carers to include in model; whether carer disutilities should be applied additively
Company: Initially 2 carers (1 primary + others) based on Lagae 2019 data from Dravet syndrome; updated to 1.8 carers at committee direction
ERG: Used 1.8 carers in base case, aligning with Dravet and Lennox-Gastaut guidance; concerned about additive application of disutilities
Committee: Agreed that carer disutilities should not be purely additive; 1.8 carers appropriate to align with previous cannabidiol appraisals. While 2 carers have greater total burden than 1, it would not be 2 times greater.
ICER impact: decreases
Impact of institutionalisation on carer utility; whether and how much institutionalisation reduces carer disutility
Company: Initially did not model impact on carer utility during institutionalisation. Updated to use ERG approach after committee direction.
ERG: Assumed 50% reduction in carer disutility for institutionalised individuals
Committee: Appropriate to include reduction in carer disutility for institutionalisation, with ERG approach preferable given lack of data supporting specific size of reduction
ICER impact: increases
Proportion of people achieving seizure-freedom; use of 6.61-day cut-off for proportion seizure-free over 7 days
Company: Not explicitly detailed in these pages
ERG: Not explicitly detailed in these pages
Committee: Preferred to use 6.61-day cut-off for proportion seizure-free over 7 days
ICER impact: uncertain_direction
Committee noted differences between arms in GWPCARE6 regarding clobazam use, which can increase cannabidiol effectiveness when taken adjunctively. However, clinical expert confirmed clobazam is used in NHS practice similarly to GWPCARE6 and use would not be expected to increase if cannabidiol was recommended.
Committee: GWPCARE6 is broadly generalisable to NHS clinical practice
ICER impact: negligible
Company proposed stopping cannabidiol if seizure frequency does not reduce by 30% from baseline, assessed every 6 months. Committee concluded this was appropriate.
Committee: Stop if seizure frequency has not fallen by at least 30% compared with the 6 months before starting treatment, assessed every 6 months
ICER impact: uncertain_direction
Health state utility values for the model
Company: Used vignette study with general public using time trade-off method; values kept confidential
ERG: not_explicitly_stated_in_chunk
Committee: Acknowledged uncertainty and differences from other cannabidiol appraisals but considered analyses using company's utility values acceptable
ICER impact: uncertain_direction
Health state utilities derived from vignette study using time trade-off method by general public rather than from literature or clinical trials
Company: Vignettes from general public appropriate given lack of literature values; utilities considered confidential
ERG: Not explicitly stated, but accepted methodology while noting uncertainty
Committee: Company's health state utilities are uncertain and differ from utilities in other cannabidiol appraisals. The committee would have liked to see data supporting plausibility of vignette values, especially for seizure-free and most severe health states. However, acknowledging high uncertainty, considered analyses using company's utility values in decision making.
ICER impact: uncertain_direction
Discrepancy in health state utilities between tuberous sclerosis complex and Lennox-Gastaut/Dravet syndromes; difficulty comparing seizure severity across conditions due to differences in seizure types and TSC being a multi-organ disease
Company: Differences partly due to different seizure severity categories; TSC multi-organ complications make comparison difficult
ERG: Not explicitly differentiated
Committee: Utility values uncertain due to multi-organ nature of TSC and differences from other cannabidiol appraisals. Committee concerned company model did not adequately capture impact of non-seizure aspects of TSC on quality of life.
ICER impact: uncertain_direction
Seizure-free health state utility for carers; whether to use average 45-year-old utility or adjust for carer ageing
Company: Updated to use utility value for average 45-year-old based on typical parent age of 13-year-old child
ERG: Concerned this overestimated impact of seizure freedom; provided scenarios with lower values; maintained 0.881 value in preferred assumption after consultation
Committee: Value of 0.881 for seizure-free health state for carers is uncertain but appropriate for decision making. Absolute utility decrement unchanged regardless of value used.
ICER impact: negligible
Evidence gaps
Commercial arrangement
Special considerations
Cross-references