Fesoterodine Is Cost-Effective Relative to Tolterodine and Javier Angulo,1 Jeffrey Trocio,2 Sonya Snedecor,3 Marion Kvasz,4 Javier Rejas5 Solifenacin for the Treatment of Overactive Bladder With 1Department of Urology, Hospital Universitario de Getafe, Madrid, Spain; 2Pfizer Inc, New York, New York, USA; 3Pharmerit North America LLC, Bethesda, Maryland, USA; Incontinence in Spain: Results of an Updated Economic Model 4Pfizer International Operations, Paris, France; 5Pfizer, España, Madrid, Spain

1 Introduction • Because treatment group was not a significant predictor of discontinuation, indicating that withdrawal rates were equal across drugs, the overall trial discontinuation rate was applied to all drugs in the model. • Overactive bladder (OAB) is defined as urinary urgency, with or without urgency urinary incontinence (UUI), usually with • Changes in health-related quality of life were assessed using data from the Overactive Bladder Questionnaire (OAB-q), increased daytime frequency and nocturia, in the absence of urinary tract infection or other obvious pathology.1,2 which was administered at baseline and week 12 in 2 of the fesoterodine trials.8,11 • OAB symptoms can be managed with nonpharmacologic measures (e.g., bladder training, changes in diet) and/or Using a published algorithm,13 OAB-q responses were transformed into preference-based utility values. pharmacologic therapy, with antimuscarinic drugs the first-line treatment option.3 • Using a regression analysis, only the number of micturitions and UUI episodes were statistically significant predictors of utility. • Fesoterodine, tolterodine extended release (ER), and solifenacin are among the antimuscarinics approved for the treatment • of OAB symptoms. ––The mean daily frequency of micturitions and UUI episodes at baseline and week 12 for each drug was obtained from clinical trial data and entered into the regression model to obtain utility estimates based on patient’s treatment status • OAB symptoms are chronic and require long-term treatment, thereby making the cost-effectiveness of treatment an (responder or nonresponder); utility estimates were used to calculate quality-adjusted life-years (QALYs) at various time important consideration. points based on a patient’s treatment status. • Previous cost-effectiveness studies have used varying data sources and methods to compare the cost-effectiveness of • Medical resource use costs examined in the model included those for antimuscarinic drugs, incontinence pads, physician different antimuscarinic drugs.4-7 visits, laboratory tests, and costs of OAB- or incontinence-related comorbidities (i.e., fracture, skin infection, urinary tract • Studies on the cost-effectiveness of tolterodine ER compared with oxybutynin and of solifenacin compared with infection, depression). oxybutynin, propiverine, tolterodine, and fesoterodine have been reported.4-6 • Cost-effectiveness of fesoterodine vs tolterodine ER and solifenacin was summarized using the incremental cost- • To date, only one study has evaluated the relative cost-effectiveness of fesoterodine.5 effectiveness ratio (ICER; the ratio of incremental cost to incremental QALYs). • In Spain, treatments are generally considered cost-effective if the ICER is less than approximately €30,000. 2 Objectives • Estimated outcomes are the percentage of patients remaining on each treatment (i.e., responders) at the end of the model • To calculate the cost-effectiveness of fesoterodine versus tolterodine ER and solifenacin in the treatment of patients with duration and the expected costs and QALYs associated with each treatment. OAB and UUI in Spain • Probabilistic sensitivity analysis was used to determine the effect of parameter uncertainty on model outcomes. • In probabilistic sensitivity analysis, cost-effectiveness vs no treatment is summarized using the net monetary benefit 3 Methods (NMB; monetary valuation of 1 QALY × QALYs gained by using the intervention). • If the value of the QALY gained is greater than the additional cost of treatment, NMB is positive and the intervention is • A 1-year decision-tree economic model (Figure 1) was developed using data from 4 randomized, double-blind, placebo- cost-effective. controlled, 12-week trials of fesoterodine (2 of fesoterodine alone and 2 compared with tolterodine ER)8-11 and from a published clinical trial of solifenacin.12 4 Results • Inclusion criteria for the fesoterodine and tolterodine ER studies included patients aged ≥18 years with ≥8 micturitions per day, ≥1 UUI episodes per day, and/or ≥2 urgency episodes per day. • The predicted percentage of patients remaining on treatment and continent at week 52 was higher with fesoterodine (20%) • Inclusion criteria for the solifenacin study included patients aged ≥18 years with ≥8 micturitions per day, ≥1 urgency than with tolterodine ER (18%) or solifenacin (16%) (Table 1). episodes per day, and/or ≥1 UUI episodes per day. • The model predicted that fesoterodine would be the most effective drug with the highest QALYs and be associated with the lowest cost (Table 1). Figure 1. Decision Tree Model • After 1 year of treatment, total QALYs were higher with fesoterodine than with tolterodine ER or solifenacin. • Predicted total costs for fesoterodine were lower than those for solifenacin but higher than those for tolterodine ER. Week 4 Week 12 Week 24 Week 52 Table 1. Model Outcomes and Incremental Cost-Effectiveness Ratios (ICERs) at Week 52 Responder Responder Feso 4 mg Fesoterodine Tolterodine ER Solifenacin Responder Feso 4 mg Discontinue Responders, % 19.5 18.0 16.3 Discontinue Total QALYs 0.762 0.756 0.752 Responder Feso 4 mg Discontinue Total cost €2745 €2695 €2841 Responder Discontinue Responder Feso 8 mg Antimuscarinic €450 €337 €412 Discontinue Responder Feso 8 mg Medical €145 €146 €148 Discontinue Incontinence pads €362 €380 €401 Feso 4 mg Nonresponder Feso 8 mg Nonresponder Discontinue Comorbidities €1788 €1831 €1880

† Discontinue Responder Fesoterodine ICER relative to comparator – €7900 Dominant* Discontinue Responder Tol 4 mg QALY=quality-adjusted life-year. Responder Tol 4 mg Discontinue *Fesoterodine is considered dominant if it is more effective and less costly than the comparator drug. †In Spain, treatments are generally considered cost-effective if the ICER is less than approximately €30,000. Discontinue • The percentage of simulations (n=5000) for which each drug had the greatest NMB across a range of QALY valuations is Responder Tol 4 mg Nonresponder Discontinue plotted in Figure 2. Discontinue Figure 2. Proportion of Sensitivity Analysis Samples for Which Fesoterodine, Tolterodine ER, or Responder Responder Tol 4 mg Solifenacin Had the Highest NMB at Various Willingness-to-Pay Thresholds Responder Tol 4 mg Discontinue Discontinue 1.2 Fesoterodine Tolterodine ER OAB Tol 4 mg Nonresponder Tol 4 mg Nonresponder Discontinue Patient 1.0 Solifenacin Discontinue Discontinue Responder Responder Soli 5 mg 0.8 Responder Soli 5 mg Discontinue Discontinue 0.6 Responder Soli 5 mg Nonresponder Discontinue

Discontinue Responder Probability Responder Soli 10 mg 0.4 Responder Soli 10 mg Discontinue Discontinue 0.2 Soli 5 mg Nonresponder Soli 10 mg Nonresponder Discontinue

Discontinue 0 Discontinue 0 7500 15000 22500 30000 37500 45000 52500 60000 67500 75000 Willingness-to-Pay Threshold (€/QALY gained) No treatment • Sensitivity analysis confirmed that fesoterodine is cost-effective relative to tolterodine ER in 79% of the analysis simulations and economically superior to solifenacin in 81% of the simulations. • The principal limitations of the model are: All patients begin treatment at the lowest dose of each modeled drug. At week 4, responders continue current treatment dose and nonresponders in the fesoterodine and solifenacin groups titrate to a higher dose; tolterodine ER nonresponders remain on current treatment dose. At week 12, • The fesoterodine 4-mg dose was used in only 2 of the 4 fesoterodine trials included in the analyses. all nonresponders discontinue treatment. At weeks 24 and 52, response is assumed to be maintained unless patients discontinue treatment. Feso=fesoterodine; Soli=solifenacin; Tol=tolterodine ER. • Use of published solifenacin data required assumptions to extract data for the estimation of solifenacin efficacy.

• The model was designed to reflect typical clinical treatment patterns for patients with OAB symptoms who were starting 5 Conclusions treatment with fesoterodine 4 mg, tolterodine ER 4 mg, or solifenacin 5 mg, each given once daily. • Overall, this economic analysis suggests that fesoterodine is cost-effective compared with • The model included the option for fesoterodine and solifenacin doses to increase to 8 mg and 10 mg, respectively, at week tolterodine ER and cost saving compared with solifenacin for the treatment of OAB and UUI 4 if a response of <1 UUI episode per day was not met; the results presented here were calculated based on the assumption in Spain. that all nonresponders increased their dose. • The recommended dosage of tolterodine ER is 4 mg once daily; unless they discontinued treatment, all patients in the tolterodine ER group remained on that dosage regardless of treatment response. 6 References • Data were pooled across trials for fesoterodine and for tolterodine ER, and the proportion of responders from (1) baseline 1. Abrams P, et al. Neurourol Urodyn. 2002;21:167-178. to week 4; (2) week 4 to week 12 after nonresponse at week 4; and (3) week 4 to week 12 after response at week 4 was 2. Haylen BT, et al. Neurourol Urodyn. 2010;29:4-20. calculated. 3. Andersson KE, et al. Curr Opin Urol. 2009;19:380-394. 4. Varadharajan S, et al. Am J Manag Care. 2005;11(4 suppl):S140-S149. • The proportions of responders were calculated using logistic regression models designed to evaluate the relative efficacy of 5. Cardozo L, et al. BJU Int. 2010;106:506-514. fesoterodine 4 mg and 8 mg, tolterodine ER, and placebo across all 4 trials. 6. Milsom I, et al. Acta Obstet Gynecol Scand. 2009;88:693-699. • To obtain solifenacin data suitable for use in the model, the following analytical steps were performed: 7. Hughes DA and Dubois D. Pharmacoeconomics. 2004;22:1047-1059. 8. Kaplan SA, et al. BJU Int. 2011;107:1432-1440. • The reported percentage decrease from baseline to week 12 in daily UUI episodes and micturitions with solifenacin was 9. Chapple C, et al. Eur Urol. 2007;52:1204-1212. applied to the baseline values from the fesoterodine trials. 10. Nitti VW, et al. J Urol. 2007;178:2488-2494. • The estimated mean number of UUI episodes at week 12 was simulated using a negative binomial distribution that 11. Herschorn S, et al. BJU Int. 2010;105:58-66. accounts for discrete data (i.e., number of recorded UUI episodes) and best approximates the observed symptom 12. Chapple CR, et al. BJU Int. 2004;93:303-310. 13. Yang Y, et al. Value Health. 2009;12:159-166. distribution in the fesoterodine trials. This allowed us to calculate the expected proportion of UUI responders. • The ratio of estimated solifenacin to placebo efficacy at week 12 was calculated and applied to the estimated week 4 and This study was sponsored by Pfizer Inc. Editorial support was provided by Karen Zimmermann at Complete Healthcare Communications, Inc., and was funded by Pfizer Inc. week 12 conditional placebo response proportions. • Discontinuation rates for fesoterodine and tolterodine ER were estimated from pooled trial data using a Weibull survival 41st Meeting of the International Continence Society model and extrapolated to 52 weeks. August 29–September 2, 2011 Glasgow, UK