Allergan's Botox, UCB Pharma's Neupro receive "do not list" recommendations from CADTH

The Canadian Drug Expert Committee (CDEC), operating under the Canadian Agency for Drugs and Technologies in Health (CADTH), has issued "do not list" recommendations for Allergan (US)'s Botox (onabotulinumtoxinA), for the treatment of chronic migraines, and UCB (Belgium)'s Neupro (rotigotine), for idiopathic Parkinson's disease.

Botox for the treatment of chronic migraines

The committee has issued a negative recommendation for Botox in the prophylaxis management of chronic migraines mainly because of the "limitations" of the two randomised controlled trials (RCTs; PREEMPT-1 and PREEMPT-2). Patients with medication-overuse headaches were included in the trials, which prevented an accurate evaluation of the clinical benefits of the treatment, according to the CDEC. Furthermore, although the treatment demonstrated statistical efficacy over placebo, the magnitude of the effect was "relatively small" – ranging from -1.4 to -2.3 headache days per 28-day period.

Concerning the cost-utility analysis, the manufacturer-submitted incremental cost-utility ratio (ICUR) for Botox compared with best supportive care (BSC) was CAD25,470 (USD23,441) per quality-adjusted life year (QALY) in patients that had failed at least three other prophylactic medications. The ICUR for the entire population eligible under the indication was CAD28,940 per QALY. However, the committee has noted certain limitations within the manufacturer-submitted assessment, which notably failed to capture physician visits and drug administration costs. Factoring in the added costs, the ICUR rose to CAD42,000 per QALY for the sub-population and CAD47,000 for the entire Health Canada-approved population. The CDEC notes that the annual cost of treatment at the submitted price of CAD3.57 per unit would range between CAD2,856 and CAD3,570.

The final recommendation can be found here.

Neupro for the treatment of idiopathic Parkinson's disease

The CDEC has also issued a negative listing recommendation for Neupro, in the treatment of Parkinson's disease (PD), mainly owing to issues with two clinical RCTs (SP513 and SP515) that "failed to consistently demonstrate" that the treatment is non-inferior to ropinirole and pramipexole, respectively. Consequently, the efficacy of the treatment compared with "less costly non-ergolinic dopamine agonists is uncertain". The Common Drug Review (CDR) submission was for the treatment of early idiopathic PD (EPD), with rotigotine as a monotherapy, as well as the treatment of advanced idiopathic PD (APD), with rotigotine in combination with levodopa.

Regarding cost-effectiveness, the CDEC has found limitations within the manufacturer-submitted cost-minimisation analysis comparing Neupro to generic pramipexole and ropinirole. According to the agency, UCB assumed similar clinical efficacy among the three treatments based on a meta-analysis assessment and failed to comparatively assess safety profiles. At the recommended doses, the agency estimated that daily treatment with Neupro for EPD (CAD3.54–7.27) and APD (CAD6.50–14.54) would cost more than generic pramipexole (CAD0.79–2.37), generic ropinirole (CAD0.85–4.37), levodopa-decarboxylase inhibitor combinations (CAD0.84–8.00), entacapone (CAD0.40–3.21), and monoamine-oxidase B inhibitors (CAD1.00–7.00).

The full recommendation can be found here.

Outlook and implications

Allergan's Botox has realised significant success in therapeutic indications – including blepharospasm, strabismus, cervical dystonia, focal spasticity, equinus foot, bladder dysfunction, and primary hyperhidrosis of the axillae. However, the CADTH has decided not to issue a listing recommendation for chronic migraines at this time, noting certain limitations within the trials as well as the relatively small – albeit significant – effect of treatment. According to the CADTH, patients with medication-overuse headaches should not have been included in the two RCTs as their condition is distinct from chronic migraines. Furthermore, based on patient group feedback, a 50% reduction in headache days is considered a "marker of efficacy" – this was "far below", therefore the modest reduction in headache days with Botox, according to the agency.

UCB's transdermal patch is indicated for the symptomatic treatment of moderate to severe idiopathic restless legs syndrome in adults, in addition to the treatment of the signs and symptoms of idiopathic PD as a single-agent therapy or in combination with levodopa for advanced PD. The CDEC was not satisfied that Neupro demonstrated non-inferiority to other genericised treatments available in the market, but the agency notes that in the SP513 trial, a higher dosage of comparator ropinirole was used (24mg/day) than routinely administered in clinical practice (10–15mg/day), which "may have biased the efficacy results in favour of ropinirole and the safety results in favour of rotigotine in that trial". Furthermore, concerning its mode of administration, the agency has noted that there were inadequate data to suggest an added benefit of a transdermal patch over oral medication through patient adherence and clinical outcomes. However, that could be an area where additional post-marketing data could support a more favourable listing.

All Canadian provinces and territories, except for Québec, utilise CDEC recommendations for the listing of medicines on drug plan formularies. However, individual jurisdictions have the authority to make the final decision regarding reimbursement of these drugs. Furthermore, all brand-name drugs processed through the two national health technology assessment agencies – the CDR and the Pan-Canadian Oncology Drug Review – will now be considered for negotiation through the recently instated Pan-Canadian Pricing Alliance.