The key limitations of the manufacturer’s submitted economic evaluation pertains to the use of different utility values between treatment groups within the same health state, which does not respect good modelling practices and might have introduced double-counting of potential benefits of Ona A compared with BSC. The decision to use different utility values was based on clinical trial results showing improved quality of life in Ona A patients versus BSC patients. The manufacturer attributed these findings to Ona A treatment, conferring additional benefits to patients in terms of micturition and nocturia. The same utility value should be applied to both treatment groups in a given health state. Further, it is important to note that for some health states, the difference in utility value between the two treatment groups was very small; thus, differences observed in the clinical trial might be due to the small number of patients in these health states. For the health state “< 50% reduction and ≤ 1 UIE,” patients in the BSC group showed a higher utility value than patients in the Ona A group (0.852 versus 0.828), which is inconsistent with the manufacturer’s justification. CDR reanalyses therefore assigned health state–specific utility values, regardless of treatment group or model cycle.
In defining the model health states, the manufacturer utilized both the absolute number of UIE and the relative reduction of UIE from baseline. The manufacturer states that integrating the absolute number of UIE as a component of the health states allows for a more straightforward association of resource use parameters with the number of UI episodes from cross-sectional studies and provides information about disease severity as defined by number of UIE. However, within the same health state, a lower number of UIEs are applied to patients on Ona A compared with patients on standard of care, thus pre-emptively overestimating the benefits of Ona A. The impact of this approach (of combining absolute and relative UIE per health state) was not relevant to this analysis, as the number of UIEs is used only in calculating the costs associated with use of incontinence pads — costs that are not normally reimbursed by Canadian drug plans.
The manufacturer acknowledged that in real life, a proportion of patients would likely continue to receive anticholinergics. The manufacturer’s report indicates that the placebo effects (BSC group) from the phase 3 trials were assumed to be reflective of the treatment effects of anticholinergic medications in this patient population (i.e., patients not adequately managed with anticholinergic medications); therefore, in a conservative approach, no costs were assigned to anticholinergic medication use. However, there is evidence showing that in patients who have failed previous anticholinergic therapies, re-treatment with another anticholinergic might result in a better response than placebo only over 12 weeks.3
Finally, the manufacturer’s sensitivity analyses showed the model results to be sensitive to variations in re-treatment frequency. The eight-month interval used by the manufacturer, based on data from the ongoing extension trial (study 096), was deemed realistic by the clinical expert despite being different from the 24-week (six-month) median interval reported in the clinical trials.
provides a further summary of other limitations identified with the manufacturer’s submission.
Other Limitations of the Manufacturer’s Economic Submission.
4.1. Issues for Consideration
4.1.1. Clinical Practice
The manufacturer’s requested listing for Ona A is for the treatment of refractory UI due to overactive bladder; Canadian clinical guidelines suggest that patients may be considered refractory if they have tried and failed at least two adequate trials of anticholinergic medications.11 Myrbetriq (mirabegron), a drug from a different class of treatments (i.e., selective beta 3-adrenoceptor agonist), received approval by Health Canada for the treatment of OAB with symptoms of urgency, urgency incontinence, and urinary frequency, and is currently under review by CDR. The impact of mirabegron’s introduction on the place of Ona A in the treatment of OAB in Canada and the consequent utilization of SNS is unclear. The cost-effectiveness of Ona A compared with mirabegron is also unclear at this time.
Other Health Technology Assessment Findings
Ona A has received positive recommendation from the Scottish Medicines Consortium and the Australian Pharmaceutical Benefits Advisory Committee for this indication. Further information pertaining to these recommendations is located in Appendix 4.
4.2. Off-label or Expanded Use
Clinical expert opinion defined response to Ona A therapy as a 50% improvement in OAB symptoms, not exclusive to UI; improvement in urgency episodes, reduction in frequency, or improvement in nocturia (i.e., being able to defer two hours before micturition versus hourly). The expanded definition of treatment response suggests a possible increase in Ona A utilization in patients who may be showing less than 50% reduction in their daily incontinence episodes but are considered positive responders due to improvements in other symptoms.
4.3. Patient Input
Patient input was received from The Canadian Continence Foundation (TCCF), which compiled information through a cross-sectional survey of a random cohort of Canadian patients with OAB currently receiving treatment, who were initially identified from the Foundation’s database. The patient group stated that patients with OAB experience:
Negative effects on social life through the inability to leave home as often as desired, avoiding going out on holidays, avoiding public transportation, fear of odour, reduction in sexual activity, and avoidance of new intimate relationships
Reduced ability to work or loss of productivity
Financial burden from purchasing incontinence supplies, which are not subsidized.
The economic evaluation submitted by the manufacturer takes into account the costs and outcomes associated with UIEs due to OAB. The manufacturer’s submission also includes an economic analysis from the societal perspective as part of the sensitivity analyses. The societal perspective considers the productivity loss associated with OAB.
4.4. Conclusions
A key limitation was the manufacturer’s modelling of health state utilities. Other limitations include the stopping rule for Ona A, proportion of patients receiving SNS, time to initiation of SNS, and efficacy of anticholinergics in the BSC group compared with real-life clinical practice. When accounting for these limitations, CDR found that the ICUR of Ona A plus BSC compared with BSC alone ranged from $56,932 to $60,451 per QALY gained, with a most likely ICUR estimate of $59,388 per QALY gained. The place in therapy and cost-effectiveness of Ona A compared with mirabegron is unclear at this time.
