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Relevant comparators
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| The 2 pivotal trials – the CARE 3 and CARE 4 trials – evaluated the efficacy and safety of cannabidiol and usual care versus usual care. From the comparator table, lamotrigine was missing. Lamotrigine is listed as 1 of 2 medications approved for seizure management in patients with LGS, with the other being rufinamide. Of note, the cost of lamotrigine is significantly less than the cost of rufinamide. | Comment from the drug programs to inform CDEC deliberations. The CADTH review team notes that lamotrigine is specifically indicated for LGS and is reimbursed by at least 1 Canadian jurisdiction, thereby meeting CADTH’s criteria as a comparator. The current CADTH review of cannabidiol includes lamotrigine in the economic evaluation. Of note, in the CADTH review of rufinamide for LGS, lamotrigine was considered a relevant comparator. |
Rufinamide is an ASM indicated for adjunctive treatment of seizures associated with LGS. CDEC recommends the following criteria for public drug coverage:under the care of a physician experienced in treating LGS-associated seizures currently receiving 2 or more antiepileptic drugs in whom less costly antiepileptic drugs are ineffective or not approved.
Health Canada is currently reviewing a generic submission for rufinamide.In the CARE 3 and CARE 4 trials, patients were required to have experienced treatment failure with more than 1 ASM. Patients were required to be stable on 1 or more ASMs. A task force of the International League Against Epilepsy recommended replacing the term “intractable” epilepsy with “drug-resistant” epilepsy and proposed that “drug-resistant” be defined as the failure of adequate trials of 2 tolerated, appropriately chosen and administered antiseizure medications (whether as monotherapy or in combination) to achieve seizure freedom. | Comment from the drug programs to inform CDEC deliberations. |
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Considerations for initiation of therapy
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LGS diagnosis:is based on signs and symptoms; genetic testing is not required requires the presentation of a triad of the following characteristics: presence of multiple seizure types (i.e., tonic, atonic, and tonic-clonic); abnormal EEG patterns of slow-spike wave complexes; and moderate to severe cognitive impairment in the CARE 3 and CARE 4 trials, required at least 8 drop seizures per 28-day period.
Should all 3 of these characteristics be present to confirm a diagnosis of LGS? Should a minimum number of drop seizures per month be applied to diagnose LGS? | The clinical experts noted that the alignment of the diagnosis of LGS with the clinical presentations of the presence of multiple seizure types, abnormal EEG patterns of slow-spike wave complexes and paroxysmal fast activity, and moderate-to-severe cognitive impairment is reasonable. The clinical experts consulted by CADTH believed that the diagnosis of LGS should not be contingent on a minimum number of drop seizures per 28-day period. CDEC noted that the benefit of treatment with cannabidiol for patients with fewer than 8 LGS-associated seizures per 28 days remains unknown. |
| In the CARE 3 and CARE 4 trials, patients were required to have documented treatment failure with more than 1 ASM, and currently be stable on 1 or more ASM. To be eligible for cannabidiol, should patients be required to meet the definition of treatment-resistant epilepsy (failure of 2 or more ASMs), similar to rufinamide? | The clinical experts consulted by CADTH agreed that the definition of treatment-resistant epilepsy involves the failure of 2 or more ASMs, which aligns with the definition used in the CARE 3 and CARE 4 trials (i.e., treatment failure with more than 1 ASM). This is the also the threshold used to refer patients with LGS for epilepsy surgery. However, the threshold for defining treatment-resistant epilepsy may be set higher or lower depending on the circumstances. As noted by the clinical experts, some special conditions that prevent clinicians from prescribing traditional antiseizure medications, such as the presence of mitochondrial disorders or previous documented allergy to sodium channel blockers, should be carefully assessed for the possibility of prescribing cannabidiol in the setting of failure of 1 antiseizure drug. |
| Consider alignment with the reimbursement criteria for rufinamide, if appropriate. | Comment from the drug programs to inform CDEC deliberations. |
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Considerations for continuation or renewal of therapy
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| What objective measures are used to assess and monitor therapeutic response in clinical practice? | Patient and/or caregiver feedback and clinical assessment are used to assess and monitor therapeutic response to treatment for seizures associated with LGS in the clinical practice setting. In some special circumstances, an EEG should also be considered as part of therapeutic response for patients with LGS, as per the clinician judgment. |
| In most jurisdictions, rufinamide receives indefinite coverage once approved. No renewal criteria were provided in the submission. | Comment from the drug programs to inform CDEC deliberations. |
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Considerations for discontinuation of therapy
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| How would you define treatment failure? | The clinical experts indicated that the following events could be indictive of treatment failure in patients with LGS: |
| There are no discontinuation criteria identified in the CDR recommendations for rufinamide. | Comment from the drug programs to inform CDEC deliberations. |
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Considerations for prescribing of therapy
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| The dosing schedule for cannabidiol as per the sponsor is:How frequently do patients require the maximum recommended dose of 20 mg/kg/day? | The clinical experts stated that, in clinical practice, the maximum dose of any ASMs will always be attempted; however, many patients are unable to tolerate the maximum dose. As clinical experience with cannabidiol in patients with LGS is limited, the clinical experts were unable to comment how frequently the maximum dose of 20 mg/kg/day may be required or tolerated. |
| Cannabidiol is available as an amber liquid with 100 mg/mL of cannabidiol in a 100 mL bottle. Patients are titrated to effective therapeutic dose during the first 2 weeks of therapy. The patient or caregiver is required to measure the dose. Frequency of administration and volume of liquid (small quantities) has the potential to result in wastage. | Comment from the drug programs to inform CDEC deliberations. |
| There may be limited access to neurologists in some regions. | Comment from the drug programs to inform CDEC deliberations. |
| Patients were excluded from the CARE 3 and CARE 4 trials if they were taking more than 4 concurrent ASMs. As cannabidiol is intended to be used as adjunctive therapy, more information about drug interactions would be beneficial. Cannabidiol is a potent CYP3A4 and CYP2C19 inhibitor and is known to increase drug levels of clobazam, rufinamide, and topiramate. | Comment from the drug programs to inform CDEC deliberations. |
| Consider aligning prescribing criteria with rufinamide, if appropriate. | Comment from the drug programs to inform CDEC deliberations. The clinical experts consulted by CADTH for the purpose of this review agreed with this comment. |
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Generalizability
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Refractory epilepsy is a medical condition that is challenging to treat. Medical cannabis is used in this space. There will be interest in patients with refractory or drug-resistant epilepsy switching to a pharmaceutical-grade alternative for many reasons, including:pharmacist involvement and medication review barriers to access to medical cannabis, such as only being available by mail order or requirement of a credit card for purchase physical labelling of product coverage by public and/or private insurersa consistent product availability greater potency of cannabidiol compared to medical grade cannabis products, which typically have a maximum concentration of 50 mg/mL.
In clinical practice, do you have challenges related to using the medical cannabis pathway supported by Health Canada? Do you foresee other patients with drug-resistant epilepsy pursuing access to cannabidiol? | The clinical experts noted that there are several challenges in navigating the medical cannabis pathway supported by Health Canada, including a lack of physician comfort with the paperwork involved with authorizing medical cannabis. The clinical experts believed it would be fair to assume that patients with other types of treatment-resistant epilepsy would pursue access to cannabidiol. |
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Care provision issues
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| The indication population often presents with intellectual and physical disabilities. Communicating and reporting of side effects may be challenging in this population. Patients in the CARE 3 and CARE 4 trials were taking on average 3 ASMs concomitantly with cannabidiol, which can create uncertainty in the root cause of side effects. | Comment from the drug programs to inform CDEC deliberations. |
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System and economic issues
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The submitted list price for cannabidiol is $1,424.54 per 100 mL bottle. Cannabidiol is dosed according to weight; as such, there is a substantial cost increase with increased body weight and/or age. The price of cannabidiol by weight is as follows:20 kg (44 lb) 40 kg (88 lb) 80 kg (176 lb)
The price for the comparator drugs:lamotrigine (adult) 400 mg/day is $6.60 per day or $2,409 annually rufinamideb (adult maximum dose) 800 mg/day is $7.98 per day or $2,912 annually.
| Comment from the drug programs to inform CDEC deliberations. |
| Cannabidiol is an adjunctive therapy, and therefore the cost of other ASMs needs to be considered. | Comment from the drug programs to inform CDEC deliberations. |
| The cost of cannabidiol submitted by the sponsor is considerably higher than the medical cannabis (cannabidiol predominant) products. Patients who cannot afford upfront costs of this medication may resort to alternative pathways. Cannabidiol could have potential equity implications. | Comment from the drug programs to inform CDEC deliberations. The clinical experts consulted by CADTH for the purpose of this review agreed with this comment. |
