The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of mirabegron, having considered evidence on the nature of overactive bladder (OAB) and the value placed on the benefits of mirabegron by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee considered the treatment pathway for OAB and where mirabegron might be positioned. It understood that NICE's guideline CG40 on urinary incontinence in women (now replaced by NICE's guideline on urinary incontinence and pelvic organ prolapse in women) and NICE's guideline on lower urinary tract symptoms in men recommend that bladder training and lifestyle advice should be offered as first-line treatments for OAB, and that an antimuscarinic drug should be offered as a second-line treatment. The Committee heard from clinical specialists that there are currently no pharmacological treatments available other than antimuscarinic drugs, and if these failed the only options were invasive procedures (for example, botulinum toxin injections). The Committee heard from clinical specialists and patient experts that there was variation in service provision across the country both for the holistic care and support of people with OAB and incontinence, and the provision of botulinum toxin for OAB. The Committee concluded that mirabegron would be positioned in a complex treatment pathway that varied geographically but potentially offered an additional pharmacological treatment before invasive treatment options were considered.
The Committee discussed the effect of OAB on people. It heard from clinical specialists and patient experts that OAB is a broad spectrum condition, and some people develop individual coping strategies (for example, toilet mapping). It noted comments from patient experts about how debilitating the condition can be, with some people finding work and normal social activities difficult, or even becoming so anxious about their bladder symptoms that they do not leave home. The Committee was aware that individual circumstances mean that the effect of OAB is different for different people. The Committee noted comments from clinical specialists that, in frail older people, OAB was associated with increased risk of falls, fractures and urinary tract infections.
The Committee discussed the use of antimuscarinic drugs for OAB in clinical practice. The patient experts and clinical specialists discussed the need for pharmacological treatment of OAB within a holistic context, including bladder training, psychological support and lifestyle adjustment. They highlighted the importance of the need to explain treatments for OAB as part of a pathway, rather than pharmacological agents providing a 'quick fix'. The Committee noted that antimuscarinic drugs are known to have side effects, notably dry mouth and constipation. One patient expert explained that pharmacological agents do not necessarily lead to a satisfactory psychosocial outcome, particularly if the side effects are perceived as negative by the patient, but that if the side effects were explained as evidence that the treatment is working, they may be more acceptable and better tolerated. They also indicated that, although the average benefit of these agents seemed modest in clinical trials, some patients may gain significant benefit from them. The Committee heard from patient experts and clinical specialists that a disadvantage of immediate-release oxybutynin hydrochloride is the need for a 2 to 3-times-daily dosage, which may be inconvenient and which also left 6 hours in 24 when no effective drug may be circulating. It also heard from clinical specialists that oxybutynin hydrochloride is rarely prescribed in secondary care because most people will have tried 1 antimuscarinic before referral to a specialist. The Committee also noted that some antimuscarinic drugs may not be suitable for older people with comorbidities. The Committee concluded that an effective agent that was not an antimuscarinic could provide a valuable additional treatment option for people with OAB.
The Committee discussed the low persistence rates seen with antimuscarinic drugs. The patient experts indicated that people may stop treatment because of side effects and/or lack of clinical benefit, both of which contribute to the high discontinuation rates. However, the Committee heard from a clinical expert that some people stop treatment because they learn to manage their condition, or it improves. The Committee noted that the side-effect profile of mirabegron differed from that of the antimuscarinic drugs but it was not possible to predict whether this would have an effect on persistence rates. The Committee concluded that there was no clear evidence that persistence rates with mirabegron would differ from current pharmacological treatments.
The Committee discussed the available evidence from the manufacturer and the Evidence Review Group (ERG): the individual trial results, the manufacturer's pooled analysis of SCORPIO, ARIES and CAPRICORN, the ERG's meta-analysis comparing mirabegron with tolterodine tartrate based on results from SCORPIO, DRAGON and 178-CL-048, the manufacturer's mixed treatment comparison (MTC) and the ERG's revised MTC. The Committee noted that the safety trial TAURUS was not incorporated into the ERG's meta-analysis comparing mirabegron with tolterodine tartrate, and that there was a paucity of evidence comparing mirabegron directly with the NICE final scope comparators other than tolterodine tartrate modified release (MR). The Committee concluded that the evidence for a comparison of mirabegron with tolterodine tartrate using direct trial data was more robust than that from the 2 MTCs.
The Committee considered the generalisability of the trials to the UK population. It noted that there were no biologically plausible reasons for differences in OAB between different ethnic groups, and that SCORPIO and CAPRICORN were largely conducted in Europe, and ARIES was conducted in North America. There was some disagreement among the patient experts and clinical specialists on the average age of the population with OAB in the UK. The patient experts thought that there was a high incidence in people in their mid-40s and older, whereas the clinical specialists thought that the prevalence was higher in older populations, particularly above the age of 60. The Committee noted the differences of opinion, but concluded that this may reflect the differing demographics of those who accessed various services, such as self-referral continence services compared with secondary care. The Committee concluded that the trials were generalisable to the UK population.
The Committee discussed which outcomes are important and relevant when treating OAB. The patient experts and clinical specialists discussed the range of attitudes of people towards their OAB, from it being a mild inconvenience to very debilitating. The patient experts and clinical specialists also commented that the definition of satisfactory treatment outcomes was broad and varied from person to person, with some people feeling that being completely 'dry' was the only important outcome, whereas others felt that being in control of the symptoms or having fewer micturition episodes was a satisfactory response to treatment. The Committee considered the primary and secondary outcomes reported in the trials. The Committee noted that in the draft update to that NICE's guideline CG40 on urinary incontinence in women, only wet OAB was addressed, and treatment efficacy was assessed using a binary continent/incontinent outcome. However, this guideline was still in development and could be subject to change. The Committee noted that frequency of micturition and incontinence episodes were used as the primary outcomes in this appraisal. It agreed that these outcomes captured the main benefits for people with OAB, and included the benefits both for those who had incontinence and those who did not. The Committee concluded that frequency of micturitions and incontinence episodes were the most relevant outcomes for this appraisal.
The Committee discussed the results for micturition frequency and incontinence for mirabegron. It noted that there were modest changes in frequency compared with placebo (see section 3.11). It noted the results of the manufacturer's pooled analysis showing a statistically significant improvement in mean difference from baseline in incontinence and frequency of micturition compared with placebo. It noted comments from a patient expert that the people on placebo could have experienced benefits because they changed their lifestyle as part of the treatment, which they considered showed that medication was more effective when embedded in a holistic programme. The Committee concluded that mirabegron was clinically effective compared with placebo.
The Committee explored the evidence of mirabegron compared with tolterodine tartrate. The manufacturer explained that it did not provide a direct analysis of mirabegron against tolterodine tartrate despite it being a comparator arm in SCORPIO because tolterodine tartrate was designated an active control and the trial was not powered to make such comparisons. The Committee was not convinced that this was a good reason for not presenting a comparison, and noted that the manufacturer provided an indirect analysis for mirabegron compared with tolterodine tartrate through its MTC (see section 3.18). Additionally, it was aware that the ERG had performed a meta-analysis of mirabegron compared with tolterodine tartrate, using data from the 3 trials that had tolterodine tartrate as an active comparator (SCORPIO, DRAGON and 178-CL-048; see section 3.25). The Committee noted that the results of the ERG's meta-analysis showed that mirabegron was statistically significantly more effective at reducing frequency of micturition and reducing incontinence than tolterodine tartrate. The Committee also noted that in TAURUS, a safety trial, there were no statistically significant differences between mirabegron and tolterodine tartrate for number of micturition episodes per day, but that tolterodine tartrate was statistically significantly more effective at reducing incontinence. The Committee noted the ERG's comments that the participants in TAURUS were recruited from SCORPIO and ARIES and so may be a selected rather than representative OAB population. On balance, despite some concerns about the data from TAURUS, the Committee concluded that the evidence for a comparison between mirabegron and tolterodine tartrate was satisfactory, and that mirabegron was likely to be as clinically effective as tolterodine tartrate.
The Committee discussed the manufacturer's MTC comparing mirabegron with the other drugs listed in the scope. The Committee noted that, in the manufacturer's MTC, which included 40 trials, there were very small gains or differences in the primary clinical outcomes for all the agents (see section 3.18). The Committee noted the ERG's comments that the manufacturer's MTC contained heterogeneous trials in terms of trial quality and populations. The Committee considered the ERG's MTC using fewer, more homogeneous trials. The Committee noted the ERG's MTC produced similar results to the manufacturer's MTC with the exception of solifenacin succinate 5 mg and 10 mg, which were statistically significantly more effective at reducing incontinence episodes than mirabegron. The ERG, like the manufacturer, generally found very small differences in effect between the comparators. The Committee heard different opinions from the clinical specialists as to whether, in clinical practice, the efficacy of all antimuscarinic drugs was similar to that of tolterodine tartrate. One clinical specialist indicated that solifenacin succinate was regarded as being more effective than other antimuscarinic drugs by some clinicians, particularly tolterodine tartrate. Another clinical specialist disagreed, indicating that solifenacin succinate may be perceived to be more effective, but this is because it is frequently used at a higher dose than is available for the other antimuscarinic agents. The Committee concluded that the MTCs indicated that mirabegron, like antimuscarinic drugs, offers modest improvements compared with placebo, but it was more uncertain whether it had equivalent efficacy to all antimuscarinics.
The Committee was aware that the rate of adverse events was no different between the mirabegron and tolterodine tartrate 4 mg arms in TAURUS (see section 3.16), but that the nature of the adverse events experienced differed. In TAURUS and SCORPIO, dry mouth was more common in the tolterodine tartrate arm than in the mirabegron arm, in which the incidence was similar to that in the placebo arm. The Committee understood from the patient experts that dry mouth was the most bothersome side effect of antimuscarinic drugs and contributed to discontinuation with treatment. The Committee acknowledged that the rate of dry mouth was statistically significantly lower for mirabegron than for tolterodine tartrate, and the other antimuscarinic drugs (2.8% versus 8.6% in TAURUS, and for all antimuscarinic drugs in the MTC [see sections 3.16 and 3.19]). The Committee concluded that the different side effects of mirabegron compared with antimuscarinic drugs could be of benefit for those who cannot tolerate the specific side effects of antimuscarinic drugs, particularly dry mouth. The Committee concluded that, for people who cannot tolerate antimuscarinic drugs, mirabegron may be a suitable alternative treatment.
The Committee discussed whether there were any differences in the clinical effectiveness of mirabegron in men and women. It noted that sex was a pre-specified subgroup in the pooled analysis of the SCORPIO, ARIES and CAPRICORN trials. Additionally, it noted that, in the manufacturer's pooled analysis, mirabegron 50 mg was numerically more effective in women than men for micturition frequency and incontinence. However, the Committee noted that the trials contained a minority (approximately 30%) of male participants. Additionally, it was aware that the rate of incontinence was lower in male than in female trial participants, so the number of men with incontinence symptoms was low. The Committee also heard from 1 clinical specialist that, in older men, incontinence may be related to bladder outflow obstruction rather than OAB and that bladder outflow obstruction may have been present in some of the male participants in the trials. The clinical specialists explained that incontinence secondary to bladder outflow obstruction would not be expected to respond to either antimuscarinic drugs or mirabegron, and could therefore confound the results. The clinical specialists indicated that they knew of no biologically plausible reasons why mirabegron would be less effective in men than in women. The Committee concluded that the lower efficacy in men demonstrated in the trials might be explained by the trial design and recruitment, and it did not pursue this further.
The Committee discussed the subgroup analyses comparing the clinical effectiveness of mirabegron in treatment-naive and pre-treated populations. The Committee noted there were no statistically significant differences between the effects of mirabegron in these 2 subgroups, and concluded there was no pharmacological reason why the effects of mirabegron would differ between these groups. In addition, the Committee heard from the manufacturer that trials using mirabegron in combination with antimuscarinic drugs were ongoing because it is thought that the different mechanisms of action may enhance the effects of the individual drugs.
The Committee considered the need for alternatives to current treatments for OAB. It heard from clinical specialists that, for those who had contraindications to antimuscarinic drugs, had not gained clinical benefit, or who had unacceptable side effects, there was an unmet need for alternative pharmacological treatments. This could avoid invasive treatments such as botulinum toxin, which may have significant side effects (for example, urinary retention needing catheterisation). The Committee heard that, in line with existing NICE guidelines, antimuscarinic drugs are routinely used as the first pharmacological treatment for OAB, and there is long-term evidence that people benefit from them. There is also considerable clinical experience in the use of antimuscarinic drugs and the management of their side effects. However, the Committee concluded that there was a need for pharmacological alternatives to antimuscarinic drugs for people in whom these are contraindicated, or for whom they are ineffective or associated with unacceptable side effects.
The Committee considered the available cost-effectiveness evidence. It discussed the manufacturer's base-case incremental cost-effectiveness ratio ICER of £4,400 per quality-adjusted life years (QALY) gained for mirabegron 50 mg compared with tolterodine tartrate MR 4 mg. The Committee noted the ERG's comment that the manufacturer's model was accurate and transparent but also its concerns related to some of the costs in the model and assumptions of discontinuation (see section 3.52). The Committee noted the small QALY gains seen in both the manufacturer's and ERG's analyses (see section 3.41). The Committee acknowledged that the ERG's cumulative sensitivity analyses resulted in a similar ICER to the manufacturer's (£4,400 per QALY gained in the manufacturer's base case, and £5,272 per QALY gained in the ERG's cumulative sensitivity analyses). The Committee concluded that the base-case analyses were similar for the manufacturer and the ERG, and were likely to be robust. The Committee concluded that mirabegron was therefore likely to be cost effective when compared with tolterodine tartrate MR 4 mg.
The Committee explored the results from the manufacturer's secondary base case and incremental analysis comparing mirabegron with the other antimuscarinic drugs defined in the scope. It observed that this analysis relied on the effectiveness results from the manufacturer's MTC and that, for technical reasons, it had not been possible for the results from the ERG's MTC to be incorporated into the ERG's economic analyses, leading to some uncertainty about the results. The Committee noted that most of the ERG's sensitivity analyses had a small effect on the resulting ICERs for mirabegron compared with comparators, except for solifenacin succinate 5 mg. In this case, when the assumption of persistence of treatment was set to 28% (as opposed to equal to that of the comparator, 35%) the ICER compared with solifenacin succinate 5 mg rose from £12,500 to £32,700 per QALY gained. The Committee acknowledged there were no data on persistence with mirabegron other than from the clinical trials, and that data from the trials were unlikely to be representative of the persistence rates in clinical practice because, in the trials, patients were actively encouraged to continue taking the drug for the entire trial duration. The Committee concluded that the ERG's analysis using a lower persistence rate for mirabegron than solifenacin succinate resulted in mirabegron being cost ineffective compared with solifenacin succinate 5 mg, and that, if the ERG's MTC had been incorporated into the model, the ICER could have been higher. However, because of the small differences in QALY gains, and the lack of evidence on persistence rates in practice for mirabegron, this was subject to significant uncertainty.
The Committee discussed the incorporation of adverse events in the economic analyses. It noted that the only adverse events incorporated into the modelling were dry mouth and constipation, and that dry mouth was a particular side effect of antimuscarinic drugs (see section 3.30). The Committee expressed concern that no side effects that may be more common with mirabegron were included in the model. It questioned whether this might be favourable to mirabegron because it took no account of the similar rate of withdrawal due to adverse events in the mirabegron and tolterodine tartrate arms of TAURUS (5.9% for mirabegron and 5.7% for tolterodine tartrate). As a result, the ICER for mirabegron compared with tolterodine tartrate could be underestimated. The Committee concluded that the specific adverse events incorporated in the model were likely to favour mirabegron over all the antimuscarinic drugs.
The Committee discussed the most plausible ICERs for mirabegron. It remained concerned about the fact that it had not been possible to assess the impact of incorporating the ERG's MTC into the economic analysis, which might have given different ICERs. However, the Committee noted that it had more robust evidence comparing mirabegron with tolterodine tartrate 4 mg and was satisfied that it was no less clinically effective than tolterodine tartrate 4 mg. The Committee questioned whether tolterodine tartrate was likely to be representative of the effectiveness of antimuscarinic drugs as a class, or whether the results from the manufacturer's MTC against the other agents were robust. The Committee noted that the ICERs were relatively unstable, and varied with small fluctuations in the QALY calculations. However, the differences between the QALYs calculated were consistently small in both the manufacturer's and ERG's analyses. The Committee accepted that mirabegron has a different mechanism of action than that of antimuscarinic drugs. It also has a different side-effect profile, but the same rate of discontinuation due to adverse events as tolterodine tartrate. It took into consideration that the calculated ICERs were based on small and uncertain differences of clinical efficacy between mirabegron and a range of available antimuscarinic drugs, which may or may not have similar efficacy as a class. Therefore the cost effectiveness compared with antimuscarinic drugs as a class was uncertain. However, the Committee concluded that mirabegron was likely to be a cost-effective treatment for people with OAB for whom antimuscarinic drugs are contraindicated, not effective, or produce unacceptable side effects.
The Committee considered a comment the manufacturer submitted in response to the appraisal consultation document, in which the manufacturer requested that the Committee consider how the guidance should be interpreted for more vulnerable groups of patients, for example, older patients or those who already have a high anticholinergic burden due to other prescribed medications. The Committee noted that withdrawal rates due to adverse events did not differ in the mirabegron and tolterodine tartrate arms of the TAURUS trial and the manufacturer did not provide additional evidence of mirabegron having a lower rate of adverse events in older patients. The Committee concluded that there was no evidence to support a different recommendation for older people. With respect to people who had a high anticholinergic burden from other medications, the Committee concluded that normal prescribing practice would involve an assessment of existing medications and potential drug interactions, and it was not necessary to specify this in the guidance.
The Committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations. The only potential equality issue identified was whether incontinence disproportionately affects people on a low income, due to the need to purchase incontinence pads and other auxiliary goods. However, the Committee noted that this was not a group protected under equalities legislation, and that the use of mirabegron would be unlikely to affect this group disproportionately.
The Committee discussed whether mirabegron should be considered an innovative technology, or if there were any significant and substantial health benefits that were not included in the economic model. The Committee considered the potentially innovative nature of mirabegron in that it targeted different receptors from those targeted by antimuscarinic drugs. The Committee accepted mirabegron's different and innovative mechanism of action, but concluded that all the benefits would be adequately captured in the QALY calculation.