RESULTS

3RESULTS

3.1. Manufacturer’s Base Case

The manufacturer’s base-case analysis in the submission was an analysis of Ona A versus BSC in OAB patients under a reference scenario; patients who do not achieve adequate response (response to therapy defined as ≥ 50% reduction in UI episodes from baseline) after their first injection discontinue therapy and receive BSC. Under the reference scenario, patients receiving Ona A experienced 565 fewer UI episodes per year compared with a BSC patient. Clinical improvement in UI episodes translated to 3.778 QALYs gained with Ona A versus 3.642 QALYs gained with BSC over five years. Thus, there is an incremental gain of 0.136 QALYs achieved with Ona A therapy. This resulted in an incremental cost per QALY of $34,029 (Table 5). Other key results of the base-case analysis are summarized in Table 6.

Table 5

Summary of Results of the Manufacturer’S Base Case.

Table 6

Key Results from Base-Case Analysis.

3.1.1. Scenario Analysis

The manufacturer also undertook a scenario analysis in which Ona A patients are offered a second injection prior to deciding on treatment discontinuation. In this analysis, Ona A resulted in an incremental cost per QALY of $38,387 versus BSC (Table 7).

Table 7

Summary of Results of the Manufacturer’s Scenario Analysis.

3.2. Summary of the Manufacturer’s Sensitivity Analyses

3.2.1. One-Way Sensitivity Analyses

The manufacturer conducted several one-way sensitivity analyses, based on either standard errors or a sensible range of values, as well as alterations to the model assumptions. The manufacturer reported that the results were robust to changes in model assumptions, with the ICURs of all scenarios falling under the $50,000 per QALY willingness-to-pay threshold. Using utilities directly elicited from individuals results in the lowest estimated ICUR ($11,104); assuming a re-treatment interval of 5.45 months results in the highest estimated ICUR ($49,071). The manufacturer identified the source of utility estimates, average time to Ona A re-treatment and scenario of Ona A re-treatment as the sources of highest uncertainty.

Probabilistic Sensitivity Analyses

A probabilistic sensitivity analysis was performed using 1,000 iterations. The manufacturer reported that more than 60% of iterations fell below a willingness-to-pay threshold of $50,000 per QALY.

3.3. CADTH Common Drug Review Analyses

3.3.1. Health States Utility Values

The manufacturer’s rationale for differential utility per health state across treatment groups was to capture additional benefits in terms of micturition and nocturia associated with Ona A therapy, based on trial data indicating Ona A patients in any health state had better I-QOL scores and greater self-reported treatment benefit compared with placebo patients in the same health state.² This approach introduces the impact of treatment benefits of Ona A that were not the outcomes of interest in the submitted economic evaluation (health states were defined based on relative reduction and absolute number of daily UIEs), and may result in double-counting of Ona A benefits. CDR sensitivity analyses using uniform utility values across the model’s health states produced ICURs ranging from $43,914 per QALY (using utility values from Ona A at the end of cycle 1) to $91,536 per QALY (using utility values from Ona A at cycle 2 of the base case; i.e., non-responders who do not receive additional doses of Ona A).

3.3.2. Proportion of Patients Receiving Sacral Nerve Stimulation and Time to Sacral Nerve Stimulation Treatment

The manufacturer acknowledged a wide variability in the results of the physician surveys conducted; although most urologists in Canada do not perform SNS, those who do reported high estimates.² The clinical expert on this review confirmed that issues with the availability and accessibility to urologists who specialize in performing SNS leads to increased waiting time for getting the treatment and, consequently, reduced the proportion of OAB patients receiving SNS. CDR sensitivity analyses on the proportion of patients receiving SNS and the time to SNS treatment were performed using estimates based on clinical expert opinion. The CDR reanalyses produced an ICUR range of $56,728 to $60,144 per QALY (Table 8).

Table 8

Results of CDR Reanalyses on SNS and Anticholinergics (ICUR, $/QALY, Ona A Versus BSC).

3.3.3. Use of Anticholinergics in the Best Supportive Care Group

The manufacturer acknowledged that approximately 40% of patients will likely continue anticholinergics in real life (which was also consistent with the clinical expert’s opinion), but considered that the efficacy of anticholinergics would not be superior to placebo, and did not include costs or efficacy related to use of anticholinergics.² Results of the SCORPIO study (which aimed to evaluate the efficacy and safety of the beta-3 agonist mirabegron in OAB patients) showed that patients having failed previous anticholinergic therapy and receiving tolterodine had a greater reduction in daily UIE versus those receiving only placebo.³ In a sensitivity analysis in which CDR assumed 40% of patients on anticholinergics (and using the average monthly cost as per manufacturer’s report, $46.80), but varying the response rate in the BSC group at the end of cycle 1 by 10% as per the SCORPIO study, the ICUR increased to $57,986.

a. Most Likely Scenario

A CDR reanalysis was conducted wherein the health state utility values for BSC were applied throughout the model for both treatment groups (Table 4). This revised model will allow Ona A patients who are not responding to receive re-treatment for a second dose before determining treatment efficacy. This is based on clinical expert opinion indicating that variability in response could be due to Ona A not being injected properly or not being absorbed; therefore, if no improvement is detected after three months, a second administration of Ona A would be needed. The scenario will also assume that 10% of patients will receive SNS after a median duration of eight months; this reflects real-life practice and the limited availability of and accessibility to SNS in Canada.⁹^,¹⁰ Finally, the scenario will assume that 40% of BSC patients will continue using anticholinergics and will show a response rate of 10%. The ICUR for Ona A under the most likely scenario increased from $34,029 to $59,388 per QALY gained.

3.3.4. Pricing Analysis

Given the level of uncertainty in the results, a price analysis was undertaken to determine the price reduction required to achieve certain lower ICURs (Table 9).

Table 9

Price Analyses for OnabotulinumtoxinA.

Publication Details

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Publisher

Canadian Agency for Drugs and Technologies in Health, Ottawa (ON)

NLM Citation

OnabotulinumtoxinA for Injection (Botox): For the Treatment of Overactive Bladder [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2015 Jul. 3, RESULTS.

Table 5Summary of Results of the Manufacturer’S Base Case

	Costs ($)	Incremental Costs ($)	QALYs	Incremental QALYs	ICUR ($/QALY)
Ona A	$6,484	$4,633	3.778	0.136	$34,029
BSC	$1,851	NA	3.642	NA	reference

: BSC = best supportive care; ICUR = incremental cost-utility ratio; NA = not applicable; Ona A = onabotulinumtoxinA; QALY = quality-adjusted life-year.

: Source: Manufacturer’s Pharmacoeconomic Report, Table 25, page 72.²

Table 6Key Results from Base-Case Analysis

	Ona A	BSC	Difference
Number of events per patient per year
Number of UIE	907	1,471	−565
Number of UTI	1	0.3	0.6
Number of follow-up physician visits	4.08	4.54	−0.47
Incontinence pad use	907	1,471	−565
CIC use	8	0.6	7.4
Costs (5 years, discounted)
Total direct costs	$6,484	$1,851	$4,633
Total intervention costs	$5,823	$0	$5,823
Intervention drug costs	$1,929	$0	$1,929
Intervention administration costs	$3,809	$0	$3,809
Urodynamic tests	$85
BSC costs
Downstream SNS costs	$159	$1,341	−$1,165
Follow-up physician visit costs	$480	$520	−$40
Adverse event costs
UTI costs	$21	$7	$14

: BSC = best supportive care; CIC = clean intermittent catheterization; ICUR = incremental cost-utility ratio; Ona A = onabotulinumtoxinA; QALY = quality-adjusted life-year; SNS = sacral nerve stimulation; UIE = urinary-incontinence episode; UTI = urinary tract infection.

: Source: Manufacturer’s Pharmacoeconomic Report, Table 25, page 72.²

Table 7Summary of Results of the Manufacturer’s Scenario Analysis

	Costs ($)	Incremental costs ($)	QALYs	Incremental QALYs	ICUR ($/QALY)
Ona A	$7,286	$5,434	3.784	0.142	$38,387
BSC	$1,851	NA	3.642	NA	reference

: BSC = best supportive care; ICUR = incremental cost-utility ratio; NA = not applicable; Ona A = onabotulinumtoxinA; QALY = quality-adjusted life-year.

Table 8Results of CDR Reanalyses on SNS and Anticholinergics (ICUR, $/QALY, Ona A Versus BSC)

% SNS	Efficacy of Anticholinergics = Placebo, No Cost^a				Average monthly cost for anticholinergics: $46.80				Average monthly cost for anticholinergics: $46.80
	Efficacy of Anticholinergics = Placebo, No Cost^a				Efficacy of Anticholinergics = Placebo^a				Efficacy of Anticholinergics = 10% > Placebo^a
	Time to SNS Procedure (Mo)				Time to SNS Procedure (Mo)				Time to SNS Procedure (Mo)
	2 mo	6 mo	8 mo	12 mo	2 mo	6 mo	8 mo	12 mo	2 mo	6 mo	8 mo	12 mo
5%	$60,144	$60,047	$59,950	$59,964	$51,541	$51,458	$51,372	$51,395	$60,451	$60,343	$60,235	$60,246
10%	$59,513	$59,317	$59,120	$59,151	$50,728	$50,562	$50,387	$50,438	$59,828	$59,608	$59,388^b	$59,414
15%	$58,839	$58,541	$58,243	$58,294	$49,860	$49,609	$49,346	$49,431	$59,160	$58,825	$58,490	$58,535
20%	$58,119	$57,716	$57,313	$57,391	$48,932	$48,596	$48,243	$48,367	$58,443	$57,988	$57,535	$57,604
23%	$57,662	$57,195	$56,728	$56,824	$48,343	$47,957	$47,550	$47,701	$57,986	$57,459	$56,932	$57,020

: BSC = best supportive care; CDR = CADTH Common Drug Review; ICUR = incremental cost-utility ratio; mo = months; Ona A = onabotulinumtoxinA; QALY = quality-adjusted life-year; SNS = sacral nerve stimulation.

a: All the CDR reanalyses described in Table 8 are based on the scenario in which patients are offered a second injection prior to deciding on treatment discontinuation

b: CDR most likely scenario.

Table 9Price Analyses for OnabotulinumtoxinA

Scenario	ICUR Based on Manufacturer’s Analysis	Revised ICUR Based on CDR “Most Likely Scenario”
Manufacturer’s base case	$34,029^a	$59,388^a
10% price reduction	$32,632	$56,918
20% price reduction	$31,234	$54,447
30% price reduction	$29,836	$51,977
40% price reduction	$28,439	$49,507
50% price reduction	$27,041	$47,036
60% price reduction	$25,644	$44,566
70% price reduction	$24,246	$42,096
80% price reduction	$22,848	$39,625
90% price reduction	$21,451	$37,155

: CDR = CADTH Common Drug Review; ICUR = incremental cost-utility ratio.

a: Manufacturer’s submitted price of $357.00 per 100 U vial.