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Cannabidiol for Adjuvant Treatment of Seizures Associated with Lennox–Gastaut Syndrome and Dravet Syndrome: An Evidence Review Group Perspective of a NICE Single Technology Appraisal


  • Ben Wijnen

    (Maastricht University Medical Centre+ (MUMC+)
    Trimbos Institute (Netherlands Institute of Mental Health and Addiction))

  • Nigel Armstrong

    (Kleijnen Systematic Reviews Ltd)

  • Bram Ramaekers

    (Maastricht University Medical Centre+ (MUMC+))

  • Willem Witlox

    (Maastricht University Medical Centre+ (MUMC+))

  • Marie Westwood

    (Kleijnen Systematic Reviews Ltd)

  • Debra Fayter

    (Kleijnen Systematic Reviews Ltd)

  • Steve Ryder

    (Kleijnen Systematic Reviews Ltd)

  • Titas Buksnys

    (Kleijnen Systematic Reviews Ltd)

  • Gill Worthy

    (Kleijnen Systematic Reviews Ltd)

  • Kate Misso

    (Kleijnen Systematic Reviews Ltd)

  • Sabine Grimm

    (Maastricht University Medical Centre+ (MUMC+))

  • Jos Kleijnen

    (Kleijnen Systematic Reviews Ltd)

  • Manuela Joore

    (Maastricht University Medical Centre+ (MUMC+)
    Maastricht University)


GW Research Ltd. provided two separate, but similar, submissions to the National Institute for Health and Care Excellence (NICE) on the clinical and cost-effectiveness of cannabidiol (CBD) 10 mg/kg/day, trade name Epidyolex®, for the adjunctive treatment of seizures associated with Lennox–Gastaut syndrome (LGS) and Dravet syndrome (DS). This paper highlights important methodological issues related to the company submissions, the Evidence Review Group (ERG) reports, and the subsequent development of the NICE guidance by the Appraisal Committee (AC) for the use of CBD. The company identified four randomised controlled trials (RCTs) of CBD (GWPCARE1 and GWPCARE2 for DS, and GWPCARE3 and GWPCARE4 for LGS) and an ongoing open-label extension study (GWPCARE5) as relevant to both submissions. In these RCTs, CBD in addition to current clinical management (CCM) was compared to CCM without CBD (i.e. CCM plus placebo). GWPCARE2 and GWPCARE3 were three-arm studies and compared two dosages of CBD (10 mg/kg/day and 20 mg/kg/day) in addition to CCM and CCM plus placebo. GWPCARE1 and GWPCARE4 compared CBD (20 mg/kg/day) in addition to CCM and CCM plus placebo. Both DS patients in GWPCARE2 and LGS patients in GWPCARE3 who received 10 mg/kg/day CBD in addition to CCM achieved better seizure frequency outcomes than those who received CCM plus placebo. In the company’s base case, use of CBD for LGS patients resulted in an incremental cost-effectiveness ratio (ICER) of £31,107 per quality-adjusted life year (QALY) gained and, for DS patients, £36,046 per QALY gained versus CCM. The ERG considered that these ICERs were extremely uncertain and suffered from validity issues concerning model structure (e.g. patients receiving CCM moved back to baseline drop seizure frequency), input (e.g. inclusion of caregivers’ QALYs), and transparency issues (e.g. hidden worksheets and coding in Visual Basic for Applications), and hence incorporated adjustments to the original base case which increased the ICERs. During the process, the European Medicines Agency (EMA) licence granted marketing authorisation for CBD only in conjunction with clobazam. Hence, the company provided evidence from this subgroup in an additional submission, which resulted in an ICER of £33,721 per QALY gained for LGS and an ICER of £32,471 per QALY gained for DS. In this submission and clarifications, the ERG was able to verify and validate most of the company’s responses to the ERG’s concerns. However, some issues remained regarding the face validity of model assumptions on patient pathways after treatment discontinuation. Finally, the AC recommended CBD with clobazam as an option for treating seizures associated with LGS and DS in patients aged 2 years and older only if (1) the frequency of drop seizures is checked every 6 months and CBD is stopped if the frequency has not fallen by at least 30% compared with 6 months before starting treatment and (2) the company provides CBD according to the commercial arrangement.

Suggested Citation

  • Ben Wijnen & Nigel Armstrong & Bram Ramaekers & Willem Witlox & Marie Westwood & Debra Fayter & Steve Ryder & Titas Buksnys & Gill Worthy & Kate Misso & Sabine Grimm & Jos Kleijnen & Manuela Joore, 2020. "Cannabidiol for Adjuvant Treatment of Seizures Associated with Lennox–Gastaut Syndrome and Dravet Syndrome: An Evidence Review Group Perspective of a NICE Single Technology Appraisal," PharmacoEconomics, Springer, vol. 38(10), pages 1043-1053, October.
  • Handle: RePEc:spr:pharme:v:38:y:2020:i:10:d:10.1007_s40273-020-00932-4
    DOI: 10.1007/s40273-020-00932-4

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    Blog mentions

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    1. Chris Sampson’s journal round-up for 12th October 2020
      by Chris Sampson in The Academic Health Economists' Blog on 2020-10-12 11:00:03

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