GSK Clinical Study Register

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1 In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register. The following guiding principles have been applied to the disclosure: Information will be excluded in order to protect the privacy of patients and all named persons associated with the study Patient data listings will be completely removed* to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register. Aggregate data will be included; with any direct reference to individual patients excluded *Complete removal of patient data listings may mean that page numbers are no longer consecutively numbered

2 Costs to Men at Increased Risk for Prostate Cancer When Taking Dutasteride and Placebo: Economic Analyses of the REDUCE Clinical Trial Final Report February 7, 2011 Prepared for Dr. Senior HE&OR Manager Global Health Outcomes, NA GlaxoSmithKline MAI C 4646 Research Triangle Park, NC Prepared by RTI Health Solutions 200 Park Offices Research Triangle Park, NC RTI-HS Project No

3 TABLE OF CONTENTS 1. INTRODUCTION OBJECTIVE METHODS Analysis Populations Types of Analyses Performed Description of the Resource Use and Costs Data Unit Costs Cost Calculations Calculation of Quality-Adjusted Life-year Resource Use and Cost Outliers STATISTICAL METHODS Statistical Methodology for Resource Use Analyses Statistical Methodology for Cost Analyses Statistical Methodology for Cost-effectiveness Analysis DEVIATIONS FROM THE ANALYSIS PLAN RESULTS Results of Resource Use Analyses Results of Cost Analyses Results of Cost-effectiveness Analysis DISCUSSION AND LIMITATIONS REFERENCES APPENDIX A: LIST OF ASSUMPTIONS... 1 APPENDIX B: ALGORITHMS FOR INCLUSION OF RESOURCES AND CALCULATION OF DURATIONS... 1 Algorithm Algorithm Algorithm APPENDIX C: LIST OF DETERMINING THE CONCOMITANT MEDICATIONS... 1 List 2 MedDRA SOC... 2 APPENDIX D: UNIT COSTS... 1 APPENDIX E: QUALITY-ADJUSTED LIFE-YEAR ALGORITHM... 1 APPENDIX F: CONSTRUCTING THE COST-EFFECTIVENESS ACCEPTABILITY CURVE... 1 APPENDIX G: DEVIATIONS FROM ANALYSIS PLAN... 1 Deviations... 2 APPENDIX H: ANALYSIS TABLES... 1 ii

4 List of Appendix H Tables... 2 iii

5 LIST OF TABLES Table 1. Analysis Populations...2 Table 2. Summary of Utility Values Used to Calculate Quality-Adjusted Life-years...8 Table 3. Summary of Data From the REDUCE Trial Used to Calculate Quality-Adjusted Lifeyears Table 4. Cost-effectiveness Analyses Perspectives Table 5. Populations, by Treatment Table 6. Summary of Resource Utilization Costs for Main Categories: Global Population Table 7. Mean Total Cost, by Treatment and Follow-up Time Table 8. Summary of Resource Utilization Costs for Main Categories: Adjusted Global Population Table 9. Baseline Cost-effectiveness Results Table 10. Bootstrap Runs of Cost-effectiveness Results Table D-1. Concomitant Medications: Unit Costs...2 Table D-2. Resources: Unit Costs...2 Table H-1a. Summary of Inpatient Resource Utilization Responses (Biopsy Population, Region = All Countries)...4 Table H-1b. Summary of Inpatient Resource Utilization Responses (Biopsy Population, Region = US, Canada, and Puerto Rico)...5 Table H-1c. Summary of Inpatient Resource Utilization Responses (Biopsy Population, Baseline PSA < 4.9)...6 Table H-1d. Summary of Inpatient Resource Utilization Responses (Biopsy Population, Baseline PSA Between 4.9 and < 6.8)...7 Table H-1e. Summary of Inpatient Resource Utilization Responses (Biopsy Population, Baseline PSA 6.8)...8 Table H-2a. Summary of Inpatient Resource Utilization Responses (Biopsy Population, Region = All Countries), Patients With at Least One Inpatient Hospitalization...9 Table H-2b. Summary of Inpatient Resource Utilization Responses (Biopsy Population, Region = US, Canada, and Puerto Rico), Patients With at Least One Inpatient Hospitalization Table H-2c. Summary of Inpatient Resource Utilization Responses (Biopsy Population, Baseline PSA < 4.9), Patients With at Least One Inpatient Hospitalization Table H-2d. Summary of Inpatient Resource Utilization Responses (Biopsy Population, Baseline PSA Between 4.9 and < 6.8), Patients With at Least One Inpatient Hospitalization Table H-2e. Summary of Inpatient Resource Utilization Responses (Biopsy Population, Baseline PSA 6.8), Patients with at least one Inpatient Hospitalization Table H-3a. Summary of Alpha-Blocker Use (Biopsy Population, Region = All Countries) Table H-3b. Summary of Alpha-Blocker Use (Biopsy Population, Region = US, Canada, and Puerto Rico) Table H-3c. Summary of Alpha-Blocker Use (Biopsy Population, Baseline PSA < 4.9) iv

6 Table H-3d. Summary of Alpha-Blocker Use (Biopsy Population, Baseline PSA Between 4.9 and < 6.8) Table H-3e. Summary of Alpha-Blocker Use (Biopsy Population, Baseline PSA 6.8) Table H-4a. Summary of Alpha-Blocker Use (Biopsy Population, Region = All Countries), Patients With at Least One Alpha-Blocker Use Table H-4b. Summary of Alpha-Blocker Use (Biopsy Population, Region = US, Canada, and Puerto Rico), Patients With at Least One Alpha-Blocker Use Table H-4c. Summary of Alpha-Blocker Use (Biopsy Population, Baseline PSA < 4.9), Patients With at Least One Alpha-Blocker Use Table H-4d. Summary of Alpha-Blocker Use (Biopsy Population, Baseline PSA Between 4.9 and < 6.8), Patients With at Least One Alpha-Blocker Use Table H-4e. Summary of Alpha-Blocker Use (Biopsy Population, Baseline PSA 6.8), Patients With at Least One Alpha-Blocker Use Table H-5a. Summary of Patient Numbers by Resource Utilization Responses (Biopsy Population, Region = All Countries) Table H-5b. Summary of Patient Numbers by Resource Utilization Responses (Biopsy Population, Region = US, Canada, and Puerto Rico) Table H-5c. Summary of Patient Numbers by Resource Utilization Responses (Biopsy Population, Baseline PSA < 4.9) Table H-5d. Summary of Patient Numbers by Resource Utilization Responses (Biopsy Population, Baseline PSA Between 4.9 and < 6.8) Table H-5e. Summary of Patient Numbers by Resource Utilization Responses (Biopsy Population, Baseline PSA 6.8) Table H-6a. Summary of Resource Utilization Costs (Biopsy Population, Region = All Countries) 34 Table H-6b. Summary of Resource Utilization Costs (Biopsy Population, Region = US, Canada, and Puerto Rico) Table H-6c. Summary of Resource Utilization Costs (Biopsy Population, Baseline PSA < 4.9) Table H-6d. Summary of Resource Utilization Costs (Biopsy Population, Baseline PSA Between 4.9 and < 6.8) Table H-6e. Summary of Resource Utilization Costs (Biopsy Population, Baseline PSA 6.8) Table H-7a. Summary of Resource Utilization Costs (Biopsy Population, Region = All Countries), Adjusted for Patients With Post-Cancer Follow-up of Less Than 1 Year Table H-7b. Summary of Resource Utilization Costs (Biopsy Population, Region = US, Canada, and Puerto Rico), Adjusted for Patients With Post-Cancer Follow-up of Less Than 1 Year 52 Table H-7c. Summary of Resource Utilization Costs (Biopsy Population, Baseline PSA < 4.9), Adjusted for Patients With Post-Cancer Follow-up of Less Than 1 Year Table H-7d. Summary of Resource Utilization Costs (Biopsy Population, Baseline PSA Between 4.9 and < 6.8), Adjusted for Patients With Post-Cancer Follow-up of Less Than 1 Year Table H-7e. Summary of Resource Utilization Costs (Biopsy Population, Baseline PSA 6.8), Adjusted for Patients With Post-Cancer Follow-up of Less Than 1 Year v

7 LIST OF FIGURES Figure 1. Scatter Plot of Bootstrap Runs for Global Analysis Figure 2. Cost-effectiveness Acceptability Curve of Bootstrap Runs for Global Analysis Figure F-1. Cost-effectiveness Plane... F-2 Figure F-2. Cost-effectiveness Acceptability Curve... F-4 vi

8 ABBREVIATIONS 5ARI ASAP AUR BPH CI CRF GSK HGPIN ICER n/a PCa PSA QALY REDUCE SD TURP US UTI 5-alpha reductase inhibitor atypical small acinar proliferation acute urinary retention benign prostatic hyperplasia confidence interval case report form GlaxoSmithKline high-grade prostatic intraepithelial neoplasia incremental cost-effectiveness ratio not applicable prostate cancer prostate-specific antigen quality-adjusted life-year Reduction by Dutasteride of Prostate Cancer Events standard deviation transurethral resection of the prostate United States urinary tract infection vii

9 1. INTRODUCTION The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) clinical trial was a 4-year, Phase III, international, multicenter, randomized, double-blind, placebocontrolled, parallel group study. Its goal was to evaluate the efficacy and safety of oral, once-daily dosing of 0.5 mg of dutasteride in reducing the risk of biopsy-detectable prostate cancer (PCa) in men with suspicious prostate-specific antigen (PSA) and an initial negative prostate biopsy (i.e., men considered at increased risk for prostate cancer). The eligible patients completed a 4-week run-in, followed by a randomization in a 1:1 ratio, and stratified by center to either 0.5 mg dutasteride or placebo administered once daily. The expected duration for any given enrolled subject was approximately 53 months. Subjects underwent transrectal ultrasound (TRUS)-guided biopsies in accordance with the protocol at year 2 and year 4. The biopsy population, used in the economic analyses presented in this report, was composed of 3,305 patients in the dutasteride group and 3,424 patients in the placebo group. Seven hundred ninety two principal investigators across 42 countries were involved in the trial. This document summarizes the methods and the results of a within-trial economic analysis of the REDUCE clinical trial. The analysis was conducted from an approved economic analysis plan. Analyses of the clinical and safety endpoints within the trial were reported in Andriole et al (2010). 2. OBJECTIVE The objective of this project was to conduct an economic analysis of the use of dutasteride or placebo for the prevention of PCa, using data from the REDUCE clinical trial. We achieved this objective as follows We identified and summarized the resource use experienced by patients on each treatment We costed out the resource use identified in previous step and analyzed the costs experienced by patients on each treatment We performed a cost-effectiveness analysis of the use of dutasteride compared with placebo Analyses were performed among patients in the REDUCE population and among patients in several subpopulations extracted from the REDUCE trial. 1

10 3. METHODS 3.1. Analysis Populations The primary analysis population (i.e., the global population) was the biopsy population 1, which was defined in GlaxoSmithKline (GSK) statistical analysis plan as all patients in the efficacy population who had at least one post-baseline biopsy reviewed by the Central Pathology Laboratory. The efficacy population consisted of all randomized patients meeting the following criteria: Patients who had a negative prostate biopsy, as determined by the Central Pathology Laboratory, upon entry into the study; Patients who received at least one dose of study treatment. We performed sensitivity analyses by using different subpopulations, including a population in which only patients within countries in the North American region (United States [US], Canada, and Puerto Rico) were analyzed and the populations defined by levels of baseline PSA 2. These added analyses were performed to understand the effect that some methodological assumptions may have on the results. Details of each population are presented in Table 1. Table 1. Analysis Populations Analysis Global population North American subpopulation analysis Baseline PSA subpopulations Baseline PSA tertiles < 4.9 ng/ml Baseline PSA tertiles <6.8 ng/ml Baseline PSA tertiles 6.8 ng/ml Description All biopsy population patients in REDUCE All patients in the global population who were from the North American region (US, Canada, and Puerto Rico) All patients in the global population who had a baseline PSA within predefined tertiles All patients in the global population who had a baseline PSA < 4.9 ng/ml All patients in the global population who had a baseline PSA between 4.9 and <6.8 ng/ml All patients in the global population who had a baseline PSA 6.8 ng/ml PSA = prostate-specific antigen; REDUCE = Reduction by Dutasteride of Prostate Cancer Events; US = United States. An additional analysis of the global population (labeled Adjusted Global Analysis ) was performed in which patients on each treatment who had less than 1 year follow-up after PCa was detected had their costs replaced with the average costs for patients on the 1 Biopsy population was used instead of safety population in order to align with population used in the New England Journal article 2 PSA levels (i.e., tertile cut-offs) were defined as seen in the REDUCE clinical trial (Andriole et al., 2010) 2

11 respective treatment who had 1 or more years of follow-up after PCa was detected. The purpose of this analysis was to examine the impact on potential costs if men diagnosed with PCa were followed long enough to incur the full costs of PCa treatment. This analysis could serve as a proxy for costs experienced by men in the real world because it accounted for complete cost of PCa as can be seen in the real world Types of Analyses Performed Three types of analysis were performed: 1. Resource use analysis: This analysis summarized resource use by treatment and between treatments. 2. Cost analysis: This analysis summarized the cost experienced by men on different treatments and between treatments. 3. Cost-effectiveness analysis: This analysis presented the cost-effectiveness of the use of dutasteride compared with the use of placebo as experienced by men who were on these specific treatments within the clinical trial. Because costs were not collected within the clinical trial, US-specific unit costs were obtained and applied to specific resource use collected within the trial for all patients within the biopsy population. These unit costs were applied to the resource use, regardless of the country from which a patient came Description of the Resource Use and Costs Data Resource use data were collected during the REDUCE trial within the general clinical case report form (CRF). The main resource use categories summarized were concomitant medications, macroscopic hematuria and hematospermia, acute urinary retention (AUR), urinary tract infection (UTI), surgical and nonsurgical procedures, and unscheduled biopsies. The following subsections describe the analyses conducted on the resource use data we collected. We will highlight the general consideration associated with each resource use; for a list of assumptions, see Appendix A General Considerations A resource use event was included in the economic analysis if it happened during the trial period. For each subject, the start of the trial period was defined as the treatment start date minus 7 days. To ensure we captured all resource use associated with each patient, we considered that a window of a week before the treatment start. For each subject, the end of the trial period was defined as the latest available date from one of the following: treatment stop date, date of visits 3 through 10, or date of withdrawal from trial. Because 3

12 patients may not have had complete start and stop dates, we implemented partial-date imputation rules: For all dates with missing day of the month, we imputed the 15th of that month (midpoint of the month). For all dates with missing day and month, we imputed the 2nd of July (midpoint of the year). Start and stop dates for macroscopic hematuria and hematospermia, UTI, and nonsurgical procedures also were collected within the trial. Duration of resource use was calculated as the number of days between the start and stop dates of the event plus one. The algorithms for inclusion of resource use events and for calculation of duration are presented in Appendix B Concomitant Medications The concomitant medications were summarized by the following categories: Concomitant medications related to significant sexual dysfunction adverse events (i.e., impotence, decreased libido, and ejaculation disorders) and breast disorders); Concomitant medication related to UTI; Concomitant medications associated with the treatment of benign prostatic hyperplasia (BPH) and PCa (nonsurgical drug therapies). We summarized the number of patients with concomitant medications overall and in the above categories. We also examined alpha-blocker use as a subcategory to concomitant medications associated with the treatment of BPH. All concomitant medications included in the analyses were verified with a clinical consultant. A list of included concomitant medication is presented in Appendix C Macroscopic Hematuria and Hematospermia Only resource use associated with macroscopic hematuria and hematospermia episodes that were determined to be unrelated to a trial-specified biopsy were included in the analysis. Specifically, inpatient and outpatient visits were considered. The number and proportion of patients experiencing hematuria and hematospermia episodes were summarized both among patients within the analysis population and separately by inpatient and outpatient episodes. We also summarized the length of hospitalization for inpatient episodes among patients within the analysis population with at least one hospitalization and among all patients with at least one hospitalization. 4

13 Acute Urinary Retention All resource use associated with AUR episodes were included in the analysis, regardless of whether they were related to BPH or not. Specifically, inpatient and outpatient visits were considered. The number and proportion of patients experiencing AUR episodes were summarized both among patients within the analysis population and separately by inpatient and outpatient episodes. We also summarized the length of hospitalization for treating AUR episodes among patients within the analysis population with at least one hospitalization and among all patients with at least one hospitalization Urinary Tract Infection Resource use associated with UTI episodes was included in the analysis. Specifically, inpatient and outpatient visits related to antibiotic therapy recorded in the concomitant medications were summarized. The number and proportion of patients experiencing UTI episodes were summarized both among patients within the analysis population and separately by inpatient and outpatient episodes. We also summarized the length of hospitalization for treating UTI episodes among all patients within the analysis population, among patients within the analysis population with at least one hospitalization, and among all patients with at least one hospitalization. Antibiotic therapy was summarized with the concomitant medications Surgical and Nonsurgical Procedures Surgical procedures related to BPH, PCa, and other conditions that were performed at least once during the trial period were included in the analysis. The following prostatic surgical interventions were analyzed: Adenomectomy Electroresection Thermotherapy, microwave, or radiofrequency Laser resection of the prostate Prostatectomy, open Prostatectomy, retropubic with or without nerve-sparing Prostatectomy, partial Prostatectomy, suprapubic Prostatectomy, transvesical Prostatectomy, perineal Prostatectomy, laparoscopic Transurethral resection of the prostate 5

14 Transurethral drainage of prostatic abscess Radioactive seeding of the prostate (brachytherapy) Incision of periurethral stricture Other The number and proportion of patients experiencing surgical procedures were summarized both among patients within the analysis population and separately by inpatient and outpatient episodes. We also summarized the length of hospitalization for surgical procedures among patients within the analysis population and among all patients with at least one hospitalization. Summarization of surgical procedures also considered whether surgical procedures were related to BPH, PCa, or other conditions. 3 Nonsurgical interventions for PCa included external beam radiation therapies or other types of radiation therapy. The number and proportion of patients experiencing nonsurgical procedures were summarized both among patients within the analysis population and separately by inpatient and outpatient episodes. We also summarized the length of hospitalization for nonsurgical procedures among patients within the analysis population and among all patients with at least one hospitalization. The nonsurgical interventions listed as drug therapies were summarized in the concomitant medication category Unscheduled Biopsies The unscheduled biopsies recorded in the Local Pathology Results CRF page of the trial were included for analysis. We summarized the unscheduled biopsies as a whole and whether they related to high-grade prostatic intraepithelial neoplasia and atypical small acinar proliferation Unit Costs Because unit cost data were not collected from the participating centers in the REDUCE study, they were obtained from readily available secondary sources. Specifically, US unit cost data sources were obtained from the following resources: Drug acquisition costs were obtained from the 2010 Red Book for Windows (2010). Wholesale acquisition were extracted to estimate the cost of prescription drugs. Outpatient visits, outpatient procedures, and drug administration costs were obtained from the Resource-Based Relative Value Scale, published by the Centers for Medicare and Medicaid Services for the US (Ingenix, 2008). This source 3 It is important to note that some procedures could be related more than one condition. 6

15 contains a comprehensive listing of values for Current Procedural Terminology and Healthcare Common Procedure Coding System codes (AMA, 2008). Inpatient costs were obtained from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample, compiled by the Agency for Healthcare Research and Quality (HCUPnet, 2008). This source contains a national representative sample of hospital inpatient stays for a variety of International Statistical Classification of Diseases and Related Health Problems and Healthcare Common Procedure Coding System codes. Charges obtained from HCUP were converted to costs using Friedman et al., Concomitant medications to treat adverse events, UTIs, BPH, and PCa were verified with a clinical consultant (Castro R, communication June 1, 2010). Surgical and nonsurgical procedures were also verified with a clinical consultant (Castro R, communication April 2, 2010). Some patients reported use of a 5-alpha reductase inhibitor (5ARI), such as finasteride and dutasteride, to treat BPH (i.e., not as a chemoprevention agent). When 5ARI use was reported for treating BPH, we assumed generic alpha-blockers would be used in its place in order to avoid any double-dosing of 5ARIs. All costs were reported in 2010 US dollars. Unit costs are presented in Appendix D Cost Calculations The costs of concomitant medications were calculated by multiplying the duration of use (in days) by the frequency of use and by the cost of the listed dose. Upon the advice of GSK, duration of use was calculated from the start and stop date of the medication. The total cost of concomitant medications for a patient was calculated by summing the costs of all concomitant medications taken by that patient. Inpatient costs were calculated by multiplying the hospital length of stay (in days) by the cost per day. Upon the advice of GSK, hospital length of stay was assumed to be equal to the value reported in a hospital duration variable if its value was not missing. If this variable had a missing value then, when possible, the value was calculated from the start and stop date of a hospitalization (see details in Appendix B). If the calculated duration was negative then the resource use data was excluded from our analysis. Finally, if both the hospital duration value and the calculated length of stay were missing then an average length of stay, as reported in the clinical trial, was used instead. In each resource use category, total outpatient costs for a patient were calculated by summing the costs of outpatient resources for that patient. Outpatient costs were designated by the unit cost and obtained from standard costing sources. In each resource use category, total outpatient costs for a patient were calculated by summing the costs of outpatient resources for that patient. 7

16 Total costs were calculated by summing the costs of concomitant medication, the inpatient costs, and the outpatient costs. It was possible for a patient to not incur any costs. The cost analysis is an analysis of the cost of resources as incurred in the REDUCE trial. As a result, the cost of the study drug, dutasteride, was excluded in the cost analysis (i.e., study drug was provided by the study sponsor free of charge to patients) but was included in the cost-effectiveness analysis. Dutasteride, as a chemoprevention, is dosed at 0.5 mg daily. Dutasteride s wholesale acquisition cost per day for the cost-effectiveness analysis was obtained from the Redbook at a cost of $3.62 per day (Redbook for Windows, 2010) Calculation of Quality-Adjusted Life-year Utilities were not collected within REDUCE; thus, quality-adjusted life-years (QALYs) could not be estimated directly from the REDUCE data. As a result, indirect data from the REDUCE trial and results found in published literature were used to constructed an algorithm to estimate QALYs for each patient. We calculated per-patient QALYs using health status (i.e., healthy, no PCa or BPH; BPH and no PCa; and PCa) and occurrence of events such as ejaculatory dysfunction, impotence, UTIs, AURs, and BPH-related surgeries from the patient data within the REDUCE trial. Utilities values were obtained from the published literature. The utilities and utility decrements used are presented in Table 2. The occurrences of ejaculatory dysfunction, impotence, UTIs, AURs, and BPH-related surgeries, as obtained from the REDUCE trial, are presented in Table 3. Table 2. Summary of Utility Values Used to Calculate Quality-Adjusted Life-years Parameter Utility Value Sources/Assumptions All health states: age-specific utilities years Mittmann et al., years years years years years Health state-specific utilities Healthy men: no Assumption PCa or BPH PCa: high-grade Brenmer et al., 2007 cancer a PCa: low-grade cancer a Brenmer et al.,

17 Parameter Utility Value Sources/Assumptions BPH Ackerman et al., 2000 Utility decrements/improvements BPH symptom Ackerman et al., 2000 improvement due to use of dutasteride a AUR b Ackerman et al., 2000 BPH-related Ackerman et al., 2000 surgery c Ejaculatory Ackerman et al., 2000 dysfunction d Impotence Ackerman et al., 2000 UTI e Ackerman et al., 2000 AUR = acute urinary retention; BPH = benign prostatic hyperplasia; PCa = prostate cancer; TURP = transurethral resection of the prostate; UTI = urinary tract infection. a Symptom improvement due to dutasteride was obtained from Ackerman et al. (2000); the value of is used in sensitivity analysis. Symptom improvement utility was calculated as the average of ( significant remission/no adverse-event risk adverse utility minus no remission/no adverse-event risk adverse utility [= ] + significant remission/no adverse event nonrisk adverse utility minus no remission/no adverse event nonrisk adverse utility [= ]) + average of ( moderate remission/no adverse-event risk adverse utility minus no remission/no adverse-event risk adverse utility [= ] and moderate remission/no adverse-event nonrisk adverse utility minus no remission/no adverse event nonrisk adverse utility [= ]). b Decrement in BPH utility due to having AURs was obtained from Ackerman et al. (2000). Annual decrement was calculated as BPH utility minus average of urinary retention risk adverse utility and nonrisk adverse utility measured in their study. The AUR disutility was assumed to occur for 1 week (= 96.3 average (93.2, 71.9) 52 weeks a year). c Decrement in BPH utility due to having BPH-related surgery was obtained from Ackerman et al. (2000). Annual decrement was calculated as BPH utility minus average of TURP procedure risk adverse utility and nonrisk adverse utility. The BPH-related surgery disutility was assumed to occur for 2 weeks (= 96.3 average [97.5, 92.7] [2 52]). d Decrement in quality of life due to ejaculatory dysfunction in men on dutasteride was obtained from Ackerman et al. (2000). Annual decrement was calculated as BPH utility minus the average utility among men categorized as no remission/ejaculatory dysfunction risk adverse and nonrisk adverse within this study. Adverse events were assumed to occur for 6 months (= 96.3 average [98.2, 91.7] [6/12]). e Decrement in quality of life due to severe UTI in men on dutasteride was obtained from Ackerman et al. (2000). Annual decrement of was calculated as base utility 1 minus the average utility among men categorized as risk adverse and nonrisk adverse within this study (= average [98.2, 94.4] average [97.2, 89.3 ] 100). Symptoms are assumed to occur for a duration of 1 week. Thus, the annual decrement is estimated at ( * 7 days / 365 days in a year) and was applied to men reporting a UTI hospitalization. Men reporting a nonhospitalized UTI received no utility decrement. 9

18 Table 3. Summary of Data From the REDUCE Trial Used to Calculate Quality-Adjusted Life-years Parameter Value Sources/Assumptions Incidence of AURs Dutasteride 1.6 Andriole et al., 2010 Placebo 6.7 Andriole et al., 2010 Incidence of BPH-related surgeries Dutasteride 1.4 Andriole et al., 2010 Placebo 5.1 Andriole et al., 2010 Ejaculatory dysfunction (year 1) Dutasteride 2.2% Clinical trial study report for ARI40006 titled A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy and Safety of Dutasteride 0.5mg Administered Orally Once Daily for Four Years to Reduce the Risk of Biopsy-Detectable Prostate Cancer Placebo 0.4% Clinical trial study report for ARI40006 titled A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy and Safety of Dutasteride 0.5mg Administered Orally Once Daily for Four Years to Reduce the Risk of Biopsy-Detectable Prostate Cancer Ejaculatory dysfunction (subsequent years) Dutasteride 0.1% Clinical trial study report for ARI40006 titled A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy and Safety of Dutasteride 0.5mg Administered Orally Once Daily for Four Years to Reduce the Risk of Biopsy-Detectable Prostate Cancer Placebo 0.03% Clinical trial study report for ARI40006 titled A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy and Safety of Dutasteride 0.5mg Administered Orally Once Daily for Four Years to Reduce the Risk of Biopsy-Detectable Prostate Cancer 10

19 Parameter Value Sources/Assumptions Impotence (year 1) Dutasteride 6.9% Clinical trial study report for ARI40006 titled A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy and Safety of Dutasteride 0.5mg Administered Orally Once Daily for Four Years to Reduce the Risk of Biopsy-Detectable Prostate Cancer Placebo 3.5% Clinical trial study report for ARI40006 titled A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy and Safety of Dutasteride 0.5mg Administered Orally Once Daily for Four Years to Reduce the Risk of Biopsy-Detectable Prostate Cancer Impotence (subsequent years) Dutasteride 0.3% Clinical trial study report for ARI40006 titled A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy and Safety of Dutasteride 0.5mg Administered Orally Once Daily for Four Years to Reduce the Risk of Biopsy-Detectable Prostate Cancer Placebo 0.2% Clinical trial study report for ARI40006 titled A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy and Safety of Dutasteride 0.5mg Administered Orally Once Daily for Four Years to Reduce the Risk of Biopsy-Detectable Prostate Cancer AUR = acute urinary retention; BPH = benign prostatic hyperplasia; PCa = prostate cancer; REDUCE = Reduction by Dutasteride of Prostate Cancer Events; UTI = urinary tract infection. Adverse events were obtained from Table 92: Subjects with Study Drug-Related Reproductive System and Breast Disorder AEs of Special Interest by Year of Onset (Safety Population) (Clinical trial study report for ARI40006 titled A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy and Safety of Dutasteride 0.5mg Administered Orally Once Daily for Four Years to Reduce the Risk of Biopsy-Detectable Prostate Cancer ). The algorithm used to calculate QALYs for each patient is presented in Appendix E. 11

20 3.7. Resource Use and Cost Outliers For health care resource use and cost, outliers are a possibility. As an initial step, we reviewed the raw data to ensure that each patient s data were correct and that obvious outliners did not exist. The following is a list of changes that were made as a result of this data review: For one patient, we observed that the patient was denoted as having received 4.12 mg subcutaneous Decapeptyl without any duration of dosing information. Decapeptyl is not available as 4.12 mg. It is available at a dose of 3.75 mg (Decapeptyl, 2009). The dose frequency was imputed to once every 4 weeks at a dose of 3.75 mg, as outlined by the Decapeptyl product label. Several patients were denoted as having received 22.5 mg subcutaneous Eligard, dosed either one time daily or once every 3 months. The Eligard product label denotes that a 22.5-mg dose should be administered once every 6 months (Eligard, 2010). Thus, the dose frequency was changed from once a day or once every 3 months to once every 6 months as outlined by the Eligard product label. A patient was denoted as having received 30 mg intramuscular Eligard once every 3 days. The Eligard product label denotes that a 30-mg dose should be administered once every 4 months (Eligard, 2010). The dose frequency was changed from once every 3 days to once every 4 months as outlined by the Eligard product label. A patient was denoted as having received a dose of 100 mg oral Urion Uno (alfuzosin). Urion Uno is recommended to be dosed at 10 mg once daily (Alfuzosin, 2010). As a result, the dosing for this patient was assumed to be 10 mg. A patient was denoted as having received a dose of 100 mg oral Xatral (alfuzosin). However, Xatral is recommended to be dosed at 10 mg once daily (Alfuzosin, 2010). As a result, the dosing for this patient was assumed to be 10 mg. A patient was denoted as having received Doxil. Upon investigation of Doxil use in the patient (i.e., comparison of drug start date and recommended dosing as outlined by the product label), it was noted that Doxil use would have been commenced and completed prior to the patient s entry into the REDUCE trial. Doxil use in this patient was excluded from the analysis. 4. STATISTICAL METHODS Three types of analysis were performed, as described in Section 3.2. The statistical methodology for each analysis type is described in the following subsections. 12

21 4.1. Statistical Methodology for Resource Use Analyses Each resource use was considered as a categorical variable (i.e., whether a patient had a specific resource use or not). The frequency of occurrence of the resource, the proportion of patients experiencing the resource, and the 95% confidence intervals (CIs) around the proportion of patients experiencing the resources were summarized for each treatment group. Length of stay in the hospital for macroscopic hematuria and hematospermia, AURs, UTIs, and surgical and nonsurgical procedures, as well as duration of alpha-blocker use, were analyzed as continuous variables. In these cases, we summarized the means, standard deviations, medians, and ranges (minimum and maximum). These outcomes were reported among all patients within the analyzed population and among all patients within the analyzed population who had at least one hospitalization for each treatment group. Statistical comparisons were made between treatment groups (i.e., placebo vs. dutasteride). For continuous variables, we summarized treatment differences using mean differences and standard errors. P values, using two sample t-tests to test whether the mean differences are zero, were reported. For categorical summaries, we summarized the treatment differences using relative risk and 95% CI. A resource use with a relative risk greater than 1 would mean that the risk of having a resource use is higher for patients in the placebo group than for patients in the dutasteride group. The higher the relative risk, the greater is the risk of having the resource use. The interpretation is reversed when the relative risk is lower than 1. No adjustments were made for multiple comparisons. Resource use analyses were run for all populations except the adjusted global population Statistical Methodology for Cost Analyses Costs were analyzed as continuous variables. Specifically, we estimated means and standard deviations among each resource use category for each treatment group. Statistical comparisons between treatment groups (i.e., placebo vs. dutasteride) were made by treatment differences (i.e., mean differences and standard errors). Two sample t-tests were used to produce P values to test whether the mean differences are zero. Because resource use data and therefore cost data can be heavily skewed (i.e., their distributions usually have long and heavy tails), we should use caution in interpreting the results of the t-tests and the 95% CIs. For this reason, we also produced P values using a nonparametric test, the Wilcoxon rank sum test, to test whether the cost distributions in the two treatment groups were the same. Cost analyses were run for all populations, including the adjusted global population. 13

22 4.3. Statistical Methodology for Cost-effectiveness Analysis The cost-effectiveness analyses were run for all populations. Table 4 describes the specific cost-effectiveness analyses that were run. The global analysis was an analysis of the REDUCE trial population and allowed for the most useful comparative data when looking at similar published economic evaluations. The North American analysis acted as a sensitivity analysis to the global analysis, in that only countries that are similar to the US in terms of relative costs and similar health care systems were included. Analyses of other populations also were reported as a form of sensitivity analysis. Table 4. Cost-effectiveness Analyses Perspectives Analysis Type a Resource Use, Cost Data Efficacy Data Global analysis Fully pooled All patients, US dollars All biopsy population patients North American analysis Baseline PSA analyses Fully pooled Fully pooled North American region patients (US, Canada, and Puerto Rico), US dollars All patients grouped by baseline PSA tertiles, US dollars Adjusted global Fully pooled All patients, adjusted US analysis b dollars PSA = prostate-specific antigen; US = United States. All biopsy population patients in North American region (US, Canada, and Puerto Rico) All biopsy population patients grouped by baseline PSA tertiles All biopsy population patients a Fully pooled = both efficacy and resource use data were taken from the full multicountry patient group. b The adjusted global analysis is an analysis of the global analysis patients in which patients on each treatment who had less than 1 year follow-up after PCa was detected had their costs replaced with the average costs for patients on the respective treatment who had 1 or more years of follow-up after PCa was detected. Within the cost-effectiveness analysis, the following incremental cost-effectiveness ratios (ICERs) were calculated: Incremental cost per PCa case avoided, Incremental cost per QALY gained. The incremental cost per PCa avoided was calculated as follows: ICER PCa = (Cost D Cost P ) (PCa P PCa D ), where Cost D is the mean total cost incurred in patients in the dutasteride arm, Cost P is the mean total cost incurred in patient in the placebo arm, PCa D is the total number of PCas incurred in patients in the dutasteride arm, and PCa P is the total number of PCas incurred in patients in the placebo arm. 14

23 The incremental cost per QALY gained was calculated as follows: ICER QALY = (Cost D Cost P ) (QALY D QALY P ), where Cost D is the mean total cost incurred in patients in the dutasteride arm, Cost P is the mean total cost incurred in patient in the placebo arm, QALY D is the mean total QALYs incurred in patients in the dutasteride arm, and QALY P is the mean total QALYs incurred in patients in the placebo arm. In this analysis, we also considered the uncertainty due to sampling variation surrounding the estimate of the ICER AB. As a result, in addition to the base-case estimates of the ICERs, we ran 1,000 bootstrap replications to calculate the median and bootstrapped 95% CIs of the ICERs. Construction of cost-effectiveness acceptability curves is presented in Appendix F. 5. DEVIATIONS FROM THE ANALYSIS PLAN During the course of the project, several deviations from the analysis plan occurred. A complete list of deviations is presented in Appendix G. 6. RESULTS Results of the three types of analyses are presented in the following subsections. These results are presented for the global population and each of the subpopulations. The number of patients in each population or subpopulation is presented in Table 5. Full results tables are shown in Appendix H. Table 5. Populations, by Treatment Population a Dutasteride Placebo Global population 3,305 3,424 North American region subpopulation Baseline PSA < 4.9 subpopulation 1,095 1,173 Baseline PSA 4.9 and < 6.8 subpopulation 1,121 1,138 Baseline PSA 6.8 subpopulation 1,086 1,105 PSA = prostate-specific antigen. a The number of patients reported within the different tertile levels sum to 6,718. This number is less than the number of patients in the full REDUCE population (6,729) and is due to patient having missing baseline PSA data. All patient counts reported in the table above are as seen in the REDUCE publication (Andriole et al., 2010). 15

24 6.1. Results of Resource Use Analyses Global Analysis See Appendix H, Tables H-1a, H-2a, H-3a, H-4a, and H-5a, for full details. Imputed dates across treatment groups were similar. Specifically, 25% of patients in the placebo and dutasteride arm had imputed dates for concomitant medications. Approximately 4% of patients in the placebo and dutasteride arm had imputed dates for non-concomitant medication resources. Overall, in each treatment group in the global population analysis, the number of patients with hospitalizations for macroscopic hematuria, macroscopic hematospermia, AUR, UTI, surgical procedures, and nonsurgical procedures was small; less than 2% for each resource use in the dutasteride group and less than 5% for each resource use in the placebo group (Table H-2a). As a result, in each treatment group, the median number of hospitalized days was found to be zero for all resource categories (Table H-1a). Note that for all resource categories except macroscopic hematospermia there were more patients hospitalized in the placebo group than in the dutasteride group. The number of patients who had at least one hospitalization was greater in the placebo group (298) than in the dutasteride group (119) (Table H-2a). The maximum hospitalization duration was 36 days for a surgical procedure in the placebo group and 26 days for an AUR in dutasteride group. Moreover, in both treatment groups the mean number of days hospitalized was small (less than 1 day for all resource use categories). The mean difference between the placebo and dutasteride groups was positive (i.e., placebo minus dutasteride) for AUR (0.08; 95% CI: ), UTI (0.04; 95% CI: ), and surgical procedures (0.23; 95% CI: ). Surgical procedures related to BPH had mean differences and CIs similar to overall surgical procedures (0.21; 95% CI: ). The number of patients who took alpha-blockers during the trial period was greater in the placebo group (862 [25.2%]) than in the dutasteride group (713 [21.6%]) (Table H-4a). However, the mean number of days of alpha-blocker use was slightly larger for dutasteride group (232.5) compared with the placebo group (229.4) (Table H-3a), with a 95% CI of ( to 21.04). Table H-5a in Appendix H presents the number and proportion of patients with resource use responses by treatment and the risk of having resource use in the placebo group relative to the dutasteride group. In each treatment group, the proportion of patients having a resource use was lower than 10% for macroscopic hematuria, macroscopic hematospermia, AUR, and UTI and between 10% and 30% for concomitant medications and unscheduled biopsies. Note that an immediate consequence of this fact is that, for each resource use category, more than 70% of the patients did not have a use of that 16

25 respective resource, and therefore their cost for the respective resource was zero. The concomitant medications had the largest proportion of patients in both treatment groups (25% dutasteride and 29% placebo). Four and three times as many placebo patients than dutasteride patients had resource use for AUR and inpatient/outpatient surgical procedures, respectively (AUR relative risk = 4.19; 95% CI: ;inpatient/outpatient surgical procedures relative risk = 3.02, 95% CI: ). Relative risk values between 1 and 2 and CIs with lower limits above 1 were observed for concomitant medications, macroscopic hematuria, UTI, and unscheduled biopsies. The relative risk of macroscopic hematospermia was lower than 1 (0.79), but the CI included 1 ( ) Subpopulation Analyses See Appendix H, Tables H-1b through H-1e, H-2b through H-2e, H-3b through H-3e, H-4b through H-4e, and H-5b through H-5e, for full details. No notable differences were observed between the summary results of the resource use for number of days hospitalized in the global population compared with the summary results of the resource use for number of days hospitalized in other subpopulations (i.e., North American region, baseline PSA 4.9, baseline PSA 4.9 and < 6.8, and baseline PSA 6.8) (Tables H-1b through H-1e, H-2b through H-2e). The analysis of alpha-blocker use in the subpopulation groups produced similar results as the results for the global population analysis (Tables H-3b through H-3e, H-4b through H-4e). We observed slight differences in the mean duration of alpha-blocker use in the North American and the baseline PSA 4.9 and < 6.8 subpopulations. Specifically, in these subpopulations, the mean number of days of alpha-blocker use was higher in the placebo group (229.3 in North American region, in baseline PSA 4.9 and < 6.8) than in the dutasteride group (217.3 in North American region, in baseline PSA 4.9 and < 6.8). However, the 95% CIs for mean differences between treatments still contained the value zero in each subpopulation. The subpopulation results of categorical analysis of resource use were found to be similar to the global biopsy population (Tables H-5b through H-5e). We noticed the following differences in CIs: there was no difference in risk between dutasteride and placebo groups (i.e., the 95% CI contained 1) for outpatient surgical procedures in three baseline PSA subpopulations: macroscopic hematuria in the North American subpopulation, baseline PSA between 4.9 and < 6.8 subpopulation, and concomitant medication in the baseline PSA 6.8 subpopulation. However, because the subpopulation analyses involved low numbers of patients with specific resource uses, we should be cautious in interpreting these subpopulation results. 17

26 6.2. Results of Cost Analyses Global Analysis See Appendix H Tables H-6a and H-7a, for full details. Table 6 through Table 8 present a summary of these tables. Mean total costs were $1,300 higher in the placebo group ($3,177) than in the dutasteride group ($1,877). The 95% CI of the difference between mean total costs was ($ $1,794.66). Both the t-test (P < 0.001) and the Wilcoxon test (P < 0.001) showed that the total cost was statistically significantly different between the two treatment groups. Because the observed sum of ranks in the dutasteride group ( ) was smaller than the expected sum of rank ( ) (calculated under the null hypothesis of no difference between the total costs in the two treatment groups), the total costs in the dutasteride group were significantly lower than the total costs in the placebo group. We noted that concomitant medications and surgical procedures (in- or outpatients) were the main contributors to the total mean cost for each treatment group. The mean cost of concomitant medications was similar for the placebo ($1,004) and the dutasteride ($1,028) groups, with 95% CI for difference between means ( $161.75, $113.19). The t-test (P = 0.730) showed no difference between the mean concomitant medication costs between placebo and dutasteride, while the Wilcoxon test (P = 0.005) showed that the placebo and dutasteride concomitant medication cost distributions were statistically significantly different. The inconsistency suggests non-normal cost distribution and, in this case, it is safer to trust the Wilcoxon P-value. The mean cost of alpha-blockers were slightly larger in the placebo group ($830) than in the dutasteride group ($818), with 95% CI for the difference between means ( $89.15, $111.71). This resulted because, even though there were fewer patients in the dutasteride arm taking an alpha blocker, the patients in the dutasteride arm who were on alpha-blockers had a greater number of days on alpha-blocker therapy than patients in the placebo arm who were on alpha-blockers (Table H-3a). Similar to the results for the overall concomitant medications, only the Wilcoxon test (P = 0.004) showed a statistically significantly difference between the placebo and dutasteride groups. The mean cost of inpatient or outpatient surgical procedures was $1,036 higher in the placebo group ($1,576) than in the dutasteride group ($539); the 95% CI of the difference between mean costs was ($ $1,426.97). Both the t-test (P < 0.001) and the Wilcoxon test (P < 0.001) showed that the surgical procedures cost was statistically significantly different between the two treatment groups. We also noted that while 29% of patients in the placebo group and 25% of the patients in dutasteride group had used concomitant medications, only 5% of patients in the placebo group and 2% in the dutasteride group had inpatient or outpatient surgical procedures. Finally, we noted that significant differences in mean costs between placebo and dutasteride, although of lower 18