Introduction
Overactive bladder (OAB) is defined by the International Continence Society as urinary urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia, in the absence of other causes of similar symptoms [
1,
2]. OnabotulinumtoxinA (BOTOX
®, Allergan, Irvine, CA) is a purified neurotoxin complex for the treatment of OAB with symptoms of urinary incontinence (UI), urgency and frequency in adults. It is recommended in many clinical guidelines, including those of the European Association of Urology [
3], the American Urological Association [
4] and the UK National Institute for Health and Care Excellence (NICE) [
5], for patients whose UI symptoms are not managed adequately through behavioural changes or the use of anticholinergic medication. More than half of patients stop taking anticholinergic agents because of ineffectiveness, adverse events (AEs), or cost [
6]. In the absence of onabotulinumtoxinA, patients may use best supportive care (BSC), including incontinence pads and, for some individuals, continuation of pharmacological therapies and occasional use of clean intermittent catheterisation (CIC), to manage their symptoms, or they may be candidates for more invasive therapies to manage OAB such as sacral nerve stimulation (SNS) or surgery [
3].
The safety and efficacy of onabotulinumtoxinA in the management of idiopathic OAB in patients inadequately managed with anticholinergic medications was assessed in two double-blind, phase 3 trials (
https://clinicaltrials.gov/, NCT00910520 and NCT00910845) with identical study designs [
7,
8]. In brief, both primary endpoints were met in the two pivotal trials. At week 12, patients treated with onabotulinumtoxinA experienced a significantly greater reduction in UI episodes than those who received a placebo saline injection (−2.95 vs −1.03 and −2.65 vs −0.87, respectively; both
P < 0.001), and a significantly greater proportion reported perceiving an improvement in symptoms since receipt of treatment (62.8 vs 26.8 % and 60.8 vs 29.2 %, respectively; both
P < 0.001). OnabotulinumtoxinA also provided a statistically significant benefit across secondary endpoints at week 12 compared with placebo, including urological and health-related quality of life outcomes. After 12 weeks, all individuals could request retreatment with onabotulinumtoxinA, and after 24 weeks patients became eligible to roll over directly into a long-term extension study (NCT00915525) [
9], which will be completed in 2015.
To support these clinical data, we developed a model to estimate the cost-effectiveness of onabotulinumtoxinA compared with BSC, as cost-effectiveness data were not available in this population. A cost-effectiveness model was developed using pooled data from the phase 3 trials and the long-term extension trial to estimate the costs and outcomes of the use of onabotulinumtoxinA + BSC (hereafter, onabotulinumtoxinA) compared with BSC alone for the management of idiopathic OAB with symptoms of urge UI, urgency and frequency in adults who have an inadequate response to, or are intolerant of, an anticholinergic medication, over a 10-year period. The perspective is that of the NHS.
Discussion
The cost-effectiveness model showed that, in the base-case deterministic analysis, onabotulinumtoxinA 100 U was economically dominant over BSC for the management of OAB with symptoms of urge UI, urgency and frequency in adults who have an inadequate response to, or are intolerant of, an anticholinergic medication. Economic dominance was achieved through the higher probability of experiencing a reduction in the number of UI episodes with onabotulinumtoxinA than with BSC. Reduction in the frequency of UI episodes was associated with decreased healthcare resource utilisation, particularly the use of incontinence pads, and with lower overall costs and increased quality of life. When uncertainty was taken into account via a probabilistic sensitivity analysis, there was an 89 % probability that the ICER was below £20,000—a commonly accepted threshold for cost-effectiveness in the UK for non-cancer treatments [
31]. The relatively flat curve for the probabilistic analysis around the £20,000 willingness-to-pay threshold indicates a consistent probability of therapy being cost-effective around this threshold. Although there is a previously published economic evaluation of onabotulinumtoxinA 100 U for the treatment of idiopathic OAB [
32], this is the first study that incorporates phase 3 data in line with the newly approved indication [
33].
The model was based on the pivotal trials of onabotulinumtoxinA in OAB [
7,
8]. Although the model followed the clinical trials as closely as possible, some modifications were made to incorporate practical aspects of treating patients with OAB that were not part of the trial design, including the use of anticholinergic medication. In the trials, patients were not able to use anticholinergic medications, but in clinical practice patients often continue using anticholinergics as part of BSC, despite the symptoms of OAB being inadequately managed with these drugs. The reduction in OAB symptoms experienced among individuals randomised to placebo saline injections was included in the model as a proxy for any potential efficacy for anticholinergics. This was modelled conservatively as the effect at MC 1 was assumed to last for the duration of the model (with no further transition probabilities applied in the BSC group).
A key area of uncertainty in cost-utility models is the source of utility estimates. Valuing states of health for economic evaluation has often been accomplished using generic preference-based instruments such as the EQ-5D, SF-6D and others. However, these instruments may produce substantially different values for the same health states, and their ability to discriminate between individuals whose health states are known to differ and to detect a known change in an individual’s health state may be limited [
34‐
38]. Deriving a condition-specific preference index de novo or from an existing condition-specific health measure is one approach to address these limitations. Because of this uncertainty, three different utility sources were used to test the robustness of results in the model. EQ-5D index values were used in the base case [
38]. The estimated EQ-5D utility difference of 0.15 (0.92–0.77) between the dry health state and the ≥5 UI episodes per day health state is consistent with previous evidence, including the NICE guideline for UI in women [utility difference of 0.11 (0.85–0.74)] [
5] as well as with earlier economic evaluations in OAB [
15,
32]. Utilities were also estimated directly from the condition-specific I-QOL [
39] as well as from the SF-12v2 (IUI and SF-6D utilities) [
13,
14], and evaluated in scenario analysis. Utilities directly elicited from the I-QOL tool gave the largest QALY differential in favour of onabotulinumtoxinA (0.57), with utilities from the generic SF-12 giving the smallest difference (0.13). The QALY differential with the EQ-5D utilities (0.21) was closer to the SF-12v2 estimate than to the I-QOL estimate. Despite the variability seen across utility sources, cost-effectiveness results remained consistent and across each utility source tested, onabotulinumtoxinA remained dominant over BSC.
Scenario analysis was used to assess the cost-effectiveness of onabotulinumtoxinA when compared directly with SNS. This scenario was included as it is potentially relevant in some referral centres in England, in which a decision is made between treatment with SNS and onabotulinumtoxinA. In the current analysis, onabotulinumtoxinA was dominant over SNS. This broadly agrees with the recent NICE analysis, in which the strategy of providing onabotulinumtoxinA to eligible women was more likely to be cost-effective, at the £20,000 threshold, than the strategy of providing SNS first [
20].
For two scenario analyses, onabotulinumtoxinA was no longer dominant over BSC. The first was when SNS was not included as a downstream treatment. In the base case, a larger proportion of patients treated with BSC than those treated with onabotulinumtoxinA did not achieve an adequate response to therapy and were therefore eligible to receive SNS therapy. Removal of SNS from the treatment pathway eliminated the associated downstream costs, which resulted in greater savings in the BSC group. This led to a non-dominant but still cost-effective ICER in favour of onabotulinumtoxinA. Although this analysis shows that the inclusion of SNS makes no qualitative difference to the finding that onabotulinumtoxinA is a cost-effective therapy in this indication, SNS is a viable treatment option after failure of initial therapies and it is therefore warranted to include it somewhere in the treatment pathway.
The second non-dominant scenario resulted when the administration cost of onabotulintoxinA was increased (doubled) from £219 to £449 to account for any variation in tariff used in the NHS [
20]. However, the ICER remained cost-effective even after this increase in cost. The tornado diagram showed that the model was also sensitive to the incidence of UTI in the onabotulinumtoxinA arm, and to the number of UI episodes.
One limitation of the model is that costs and health outcomes arising from the long-term consequences of poorly managed OAB and UI were not included. These might include damage to the skin from prolonged contact with urine [
40,
41], possible fractures and injuries from falls [
42,
43], and increased mortality associated with OAB in elderly patients [
44]. If these data become available, they could be incorporated into an updated model. A second limitation is that the results from some investigator-led onabotulinumtoxinA studies, with follow-up of up to 8 years, could not be included in the analysis [
17]. Although discontinuation rates were modelled using a retrospective analysis with a median follow-up of 38 months [
10], other studies were not included because of differences in study design (e.g. different dose of onabotulinumtoxinA, non-randomised study design and a different patient population) that would prevent meaningful comparison with the clinical trial data. The current model used long-term data from the second interim analysis of the ongoing long-term extension study (cut-off date 15 May 2012). A third limitation is that the model does not include treatment with the new oral pharmacological agent mirabegron. This was not included as mirabegron was unlicensed when the model was being developed and did not have an established clinical profile. A fourth limitation is that, as with any RCT, the pivotal trials from which the model data were derived were designed to have the internal validity required to establish efficacy and safety, but may not have the external validity needed to demonstrate “real world” effectiveness. In order to mitigate this limitation, we used interim efficacy data from the open-label, long-term extension study in our model [
9]. In addition, real-world studies have corroborated the efficacy and safety results observed in the pivotal trials [
45].
This economic evaluation is expected to be generalisable to other healthcare systems. Although this economic evaluation used costs and resource use specific to England and Wales, and costs differ substantially across countries, the overall model structure is in accordance with international OAB treatment guidelines [
3,
4,
20].
In summary, this study has demonstrated that onabotulinumtoxinA is cost-effective compared with both BSC and SNS for the treatment of OAB in patients who were not managed adequately with anticholinergic medication.