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 Evaluating Treatment Patterns in Men with BPH: A MarketScan Database Study (AVO114462) - Study Report - May 28, 2010 Revised: June 14, 2010 Prepared for: PharmD, MPH GlaxoSmithKline

3 Please direct comments and questions to: PharmD, PhD Vice President Xcenda 4114 Woodlands Parkway, Suite 500 Palm Harbor, FL Phone: Fax: PharmD, MS Director Xcenda 4114 Woodlands Parkway, Suite 500 Palm Harbor, FL Phone: Fax: GlaxoSmithKline 2

4 1.0 OVERVIEW METHODOLOGY Data Source: MarketScan Operational Definitions Sample Selection Assessment of Treatment Patterns RESULTS Patient Selection Algorithm Treatment Pattern Analysis for Medications of Interest Treatment Pattern Analysis for Medications of Interest in BPH Subset CONCLUSIONS... 9 GlaxoSmithKline 3

5 1.0 OVERVIEW Evaluating Treatment Patterns and Outcomes in Men with BPH In collaboration with GlaxoSmithKline, Xcenda assessed the treatment patterns and trends using alpha-blocker (AB) therapy and 5 alpha reductase inhibitor (ARI) therapy in patients with and without diagnosed benign prostatic hypertrophy (BPH), within the MarketScan database. The purpose of this study was to evaluate the proportion of men treated over the initial treatment year with any of the following medications of interest: AB monotherapy, 5ARI monotherapy, early combination AB + 5ARI (defined as 5ARI added to existing AB therapy within 30 days), delayed combination (defined as addition of 5ARI to existing AB therapy after 30 days) and 5ARI prior to AB therapy. Within each of these cohorts, this study assessed the proportion of patients who had a benign prostatic hyperplasia (BPH) diagnosis recorded in their claims. We investigated whether all patients who are assumed to have enlarged prostate based on their treatment patterns are actually diagnosed with BPH. This report highlights the methodology and results of this analysis. 2.0 METHODOLOGY 2.1 Data Source: MarketScan The MarketScan Database contains commercial and Medicare medical and pharmacy claims data that is sourced directly from health plans and employers, representing approximately million individuals annually. This database was the first in the United States to profile the healthcare experience of retirees with Medicare supplemental insurance paid for by employers. The database includes the Medicare-covered portion of payment, the employer-paid portion, and any patient out-ofpocket expenses. It provides detailed cost, use, and outcomes data for healthcare services performed in both inpatient and outpatient settings. For most of the population, the medical claims are linked to outpatient prescription drug claims and person-level enrollment data through the use of unique patient or enrollee identifiers. Beneficiaries in the MarketScan Medicare Supplemental database have drug coverage; therefore, drug data are available and provide additional valuable information. This feature makes the database a powerful tool for pharmacoeconomic and outcomes research and provides valuable insight into the drug use and spending patterns of older Americans. 2.2 Operational Definitions Key study variables are operationally defined below. Study Period: The time period from January 1, 2003 through June 30, This period allowed for a sufficient number of patients to be evaluated in the study based on the selection criteria described below, and treatment patterns to be assessed 6 months prior to and 12 months after the index date. Index Date: Date of the first fill for an EP-related prescription. Enrollment Period: The period of time during which patients were enrolled into the study. It spans from July 1, 2003 to June 30, Pre-index Period: A 6-month period prior to the index date used to evaluate baseline characteristics of the patients. Assessment Period: A 12-month period after the index date to assess the additional treatment patterns. Medication(s) of Interest: targeted medications for treatment patterns for this investigation that included ABs and 5ARIs alone and in combination GlaxoSmithKline 4

6 The study design is graphically depicted in Figure 1. Figure 1. Study Design Study Period Enrollment Period 01/01/ /01/2003 6/30/2007 6/30/2008 History period Index Treatment Follow-up Period (6 months) Date (12 months) 2.3 Sample Selection Males aged 50 years between July 1, 2003 and June 30, 2007 were eligible for study inclusion. Included patients were those treated with an AB, 5ARI, an AB and concomitant 5ARI within 12 months of starting AB therapy, or an AB and 5ARI prior to the AB but within 6 months. The index date was defined as the date of the first fill for a medication of interest. Patients were required to be eligible for health plan services at least 6 months prior to and 12 months post-index date. Patients were excluded if they were diagnosed with prostate or bladder cancer (Table 1), used finasteride 1 mg tablets (for the treatment of male-pattern baldness), or had prostate surgery within 1 month of the index date (Table 2). Sub-set analyses were performed in those men treated with the medication(s) of interest plus a diagnosis for BPH (ICD-9-CM 222.2, 600.xx). Table 1. Exclusion ICD-9 Codes Exclusion ICD-9 Codes Prostate cancer 185, , 233.4, 236.5, 239.5, V10.46 Bladder cancer 188, 198.1, 223.3, 233.7, 239.4, V10.51 GlaxoSmithKline 5

7 Table 2. CPT-4 Codes for Prostate-related Surgeries Surgeries of Interest Transurethral electrosurgical resection of the prostate CPT or ICD-9-CM Codes Transurethral resection of the prostate 52612, 52614, 52620, Laser coagulation Laser vaporization Prostatectomy 55801, 55821, Transurethral microwave thermotherapy Transurethral needle ablation Transurethral water-induced thermotherapy ICD-9-CM indicates International Classification of Diseases, Ninth Revision, Clinical Modification; CPT, Current Procedural Terminology 2.4 Assessment of Treatment Patterns 1)The primary outcomes of interest in this analysis included the initial prescription of interest filled by patients and subsequent fills of medication. Patients were placed into cohorts based on the presence and timing of these events. Specifically, there were 5 cohorts constructed: 1. AB monotherapy 2. 5ARI monotherapy 3. AB+5ARI combination therapy, early 5ARI starters (within 30 days) 4. AB+5ARI combination therapy, delayed 5ARI starters (more than 30 days but within 1 year) 5. AB+5ARI combination therapy, 5ARI before AB This study conducted a descriptive analysis of treatment patterns within 1 year of initiating treatment with the medications of interest. The presence of a BPHdiagnosis was evaluated in the 6 month preperiod and 1 year post-index assessment period on all patients initiating treatment. 2) Adescriptive analysis of treatment patterns was also performed on the subset of patients who received a BPHdiagnosis (ICD-9: 222.2, 600.xx). GlaxoSmithKline 6

8 3.0 RESULTS 3.1 Patient Selection Algorithm Evaluating Treatment Patterns and Outcomes in Men with BPH A total of 585,932 patients received the medications of interest in the enrollment period. After all inclusion/exclusion criteria were applied, 248,393 patients remained qualified for this analysis and formed the final patient sample (Figure 2). Figure 2. Patient Selection Algorithm 3.2 Treatment Pattern Analysis for Medications of Interest The distribution of patients by treatment cohorts can be seen in Table 2. The majority (80.8%) of patients received AB monotherapy (n=200,631), while 7.5% received 5ARI monotherapy (n=18,681), and 11.7% of patients received combination therapy with both AB and 5ARI (n=29,081). The proportion of early and late 5ARI starters was similar: 4.1% (n=10,294) early starters compared to 4.9% (n=12,052) late starters. Overall 43% of the study sample had a BPH diagnosis recorded in their claims (107,038 patients out of 248,393). The number and percent of patients who had a benign prostatic hyperplasia (BPH) diagnosis recorded in their claims within each cohort of interest is also shown in Table 2. The highest percent, 69.5% was found among delayed 5ARI starters, and 68% among early 5ARI starters, while only 39% of the AB monotherapy cohort received a BPH diagnosis. GlaxoSmithKline 7

9 Table 2. Numbers of Patients by Treatment Cohorts and BPH Subset Medication(s) of Interest Entire Cohort N (100%) Without BPH Diagnosis N (%) With BPH Diagnosis N (%) AB monotherapy 200, ,307 (61.0%) 78,324 (39.0%) 5ARI monotherapy 18,681 9,456 (49.6%) (49.4%) Early 5ARI 30 days 10,294 3,293 (32.0%) 7,001 (68.0%) Delayed 5ARI 1 year 12,052 3,674 (30.5%) 8,378 (69.5%) 5ARI before AB 6,735 2,625 (39.0%) 4,110 (61.0%) Trend analysis of the proportion of patients with a BPH diagnosis within each cohort is presented in Figure 3. The proportion of patients with a BPH diagnosis has slightly increased between in each cohort, except from the delayed 5ARI starters. Figure 3. Proportion of Patients Receiving BPH Diagnosis Over Time GlaxoSmithKline 8

10 3.3 Treatment Pattern Analysis for Medications of Interest in BPH Subset Figure 4 depicts the trend of treatment patterns over time among patients with a BPH diagnosis. The proportion of patients with AB monotherapy among patients with a BPH diagnosis decreased from 78.9% in 2003 to 69.5% in Or, reversely, the proportion of BPH patients receiving 5ARI therapy increased from 21.1% in 2003 to 30.5% in The proportion of patients receiving combination therapy over the years was as follows: 14.5% in 2003, 15.1% in 2004, 19.3% in 2005, 20.8% in 2006, and 19.4% in 2007 (this includes early combo, delayed combo, and 5ARI before AB). Figure 4. Treatment Patterns Over Time for Patients with a BPH Diagnosis During the last year in the analysis (2007), the proportion of patients in the treatment groups were as follows: AB monotherapy, 69.5% (n=9,889); 5ARI monotherapy, 11.1% (n=1,578); Early 5ARI + AB, 7.3% (n=1,032), Delayed 5ARI + AB, 8.9% (n=1,266); and 5ARI then AB, 3.3% (n=465). 4.0 CONCLUSIONS Previous results of Xcenda and GlaxoSmithKline collaborations have shown that combination therapy and early 5ARI initiation has a beneficial effect on outcomes measured among men living with enlarged prostate (EP). The present assessment sheds light on the treatment patterns and proportion of those treated for EP who actually had a benign prostatic hyperplasia (BPH) diagnosis. While all these patients probably had BPH based on their treatment patterns, only approximately 68-70% of those on the recommended form of combination therapy had a BPH diagnosis, and only 38-39% of those on AB monotherapy had a BPH diagnosis. A small improvement in recording the BPH diagnosis over time was observed. GlaxoSmithKline 9

11 Evaluating Treatment Patterns and Outcomes in Men with BPH: A MarketScan Database Study (AVO114462) - Study Protocol - April 23, 2010 Prepared for: PharmD, MPH GlaxoSmithKline

12 Please direct comments and questions to: PharmD, PhD Vice President Xcenda 4114 Woodlands Parkway, Suite 500 Palm Harbor, FL Phone: Fax: PharmD, MS Director Xcenda 4114 Woodlands Parkway, Suite 500 Palm Harbor, FL Phone: Fax: GlaxoSmithKline Page 2 of 10

13 TABLE OF CONTENTS Evaluating Treatment Patterns and Outcomes in Men with BPH 1.0 BACKGROUND STUDY PURPOSE AND OBJECTIVES METHODS Data Source Unique Features of MarketScan Claims Data Limitations of the MarketScan Claims Data Operational Definitions Sample Selection Inclusion Criteria Exclusion Criteria Study Design Assessment of Treatment Patterns ANALYTIC APPROACH Baseline Variables Statistical Analysis CONFIDENTIALITY AND QUALITY CONTROL PROCEDURES GlaxoSmithKline Page 3 of 10

14 1.0 BACKGROUND Benign prostatic hyperplasia (BPH), also known as enlarged prostate (EP), is the fourth most commonly diagnosed medical condition in older men 1. The condition affects more than 50% of men aged 50 years and close to 90% of men by the time they reach 80 years of age 2. According to current BPH guidelines, recommended medical therapy for moderate to severe, bothersome lower urinary tract symptoms (LUTS) due to benign prostatic enlargement comprises α-adrenergic blockers (ABs), 5-α-reductase inhibitors (5ARIs), and combination therapy 3. ABs decrease smooth muscle tone in the prostate, urethra, and bladder, providing rapid symptomatic relief. However, ABs have no effect on prostate volume and have been shown to be ineffective in reducing prostate-related complications such as acute urinary retention (AUR) and prostate surgery 4. In contrast, 5ARIs reduce prostate size and improve urinary symptoms after 3 to 6 months of therapy. Historically, clinicians have shown reluctance to treat with 5ARI therapy, a practice that may be associated with adverse outcomes that include more AUR and prostate-related surgery. As such, there is a trend toward using combination therapy with an AB and a 5ARI, using the AB for rapid symptom control and the 5ARI for disease modification 5. To capture this effect, this study will quantify the latest treatment trends for men treated for BPH. Xcenda is the premier provider of strategies and services that discover and communicate the value of pharmaceuticals and other healthcare technologies. We depend on proven methodology, a strong systems capability, and effective communication techniques to facilitate change. We are leaders and innovators who are uncompromising in our determination to uncover hidden insights and shatter previous limitations. 2.0 STUDY PURPOSE AND OBJECTIVES The purpose of this study is to evaluate the proportion of men treated with AB monotherapy, 5ARI monotherapy, early combination, and late combination. 3.0 METHODS The methodology described below will be utilized in selecting patients and performing statistical analyses to address the research objectives. 3.1 Data Source Data for this analysis will be obtained from Medstat, now a part of Thomson Healthcare, the creator of the MarketScan data warehouse. Since its creation, this warehouse has evolved into a suite of proprietary databases containing the largest collection of employer-based patient claims data in the United States, representing an estimated 58% of the total US population: Americans with employerprovided health insurance. MarketScan claims data reflect real-world treatment patterns and costs by tracking over 33 million covered lives as they travel through the healthcare system, offering detailed information about all aspects of care. Data from individual patients are integrated from all providers of 1 Issa MM, Fenter TC, Black L, Grogg AL, Kruep EJ. An assessment of the diagnosed prevalence of diseases in men 50 years of age or older. Am J Manag Care. 2006;12(4 Suppl):S83-S89. 2 Naslund MJ, Issa MM, Grogg AL, Eaddy MT, Black L. Clinical and economic outcomes in patients treated for enlarged prostate. Am J Manag Care. 2006;12(4 Suppl):S111-S Ponholzer A, Madersbacher S. Lower urinary tract symptoms and erectile dysfunction; links for diagnosis, management and treatment. Int J Impot Res. 2007;19(6): McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Eng J Med. 2003;349: Barkin J, Guimarães M, Jacobi G, et al. Alpha blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5 alpha reductase inhibitor dutasteride. Eur Urol. 2003;44: GlaxoSmithKline Page 4 of 10

15 care, maintaining all healthcare utilization and cost record connections at the patient level. Over the years, the original claims-centric databases have been clinically enriched, fully integrating health and productivity (workplace absence, short-term disability, workers compensation), lab test results, and, recently, health risk assessment data. In 2006, Thomson Healthcare acquired the Solucient hospital databases. These datasets have become part of the MarketScan family Unique Features of MarketScan Claims Data Large sample size. Containing data on over 33 million patients, the database is large enough to allow creation of a nationally representative data sample of Americans with employerprovided health insurance and Medicaid. Complete episodes of care. MarketScan claims databases capture the full continuum of care in all settings, including: physician office visits; hospital stays; retail, mail-order, and specialty pharmacies; and carve-out care. Linking hospital discharge records with claims data at the patient level has significantly increased the capability of MarketScan data to capture the continuity a patient s drug therapy between the inpatient and outpatient setting. Strong longitudinal tracking at the patient level. The stability of MarketScan data sources allows superior continuity of patients over multiple years, generally longer than other claims databases. This is due to the majority of MarketScan data sourced from large employers. Employer-provided data also allow tracking of patients across health plans. This tracking ability is useful because people change health plans more often than they change jobs, and these data are able to capture patients who are lost in plan-based data sources upward of 17% of patients in those databases. In the most recent year of MarketScan Commercial and Medicare Supplemental data, 15 million patients (75%) have at least 12 months of continuous enrollment. Detailed prescription drug information. In addition to complete information on outpatient prescriptions, the new MarketScan Hospital Drug Database provides researchers with inpatient drug utilization data derived from hospital discharge records. These data and a proprietary projection methodology allow researchers to understand drug use in the inpatient and outpatient environment, including hospital use patterns, switching behavior, combination therapy, and patient characteristics to help determine if introduction or earlier use of a product would improve clinical and overall cost outcomes and to analyze diagnosis volumes. High-quality coding. Key examples include: o Diagnosis coded on 99% of all claims o Procedure coded on 85% of physician claims o Fully paid and adjudicated claims o Complete payment/charge information, including amount of patient responsibility o Complete outpatient prescription drug information, including patient copayments, mailorder, injectables, specialty pharmacies, all carve-outs, manual and electronically submitted claims, and plan/formulary summaries Limitations of the MarketScan Claims Data The MarketScan claims databases are based on a large convenience sample. Because the sample is not random, it may contain biases or fail to generalize well to other populations. The data come mostly from large employers; medium and small firms are not represented. GlaxoSmithKline Page 5 of 10

16 3.2 Operational Definitions Evaluating Treatment Patterns and Outcomes in Men with BPH Key study variables are operationally defined below. Study Period: The time period from January 1, 2000 through December 31, This period allows for a sufficient number of patients to be evaluated in the study, based on the selection criteria described below, and treatment patterns to be assessed 6 months prior to and 12 months after the index date. Index Date: Date of the first fill for a BPH-related prescription. Enrollment Period: The period of time during which patients are enrolled into the study; spans from July 1, 2000 to December 31, Pre-index Period: A 6-month period prior to the index date used to evaluate baseline characteristics of patients. Assessment Period: A 12-month period after the index date to assess the additional treatment patterns. 3.3 Sample Selection Males aged 50 years between January 1, 2000 and December 31, 2008 will be eligible for study inclusion. Included patients will be those diagnosed and treated for EP with an AB, a 5ARI, or a concomitant 5ARI within 6 months of starting AB therapy Inclusion Criteria To be included in the study, patients will be required to: 1) Have a prescription for an AB (alfuzosin, doxazosin, tamsulosin, or terazosin) or a 5ARI (finasteride or dutasteride) in the enrollment period 2) Be continuously eligible to receive medical and pharmacy services from 6 months prior to through 12 months following their index treatment date; eligibility requirements after the index date may be modified depending on the effective sample size 3) Be aged 50 years or older at the time of their index date Exclusion Criteria Patients who do not fulfill all of the above inclusion criteria will be excluded from the analysis. In addition, patients will be excluded if they: 1) Were diagnosed with prostate or bladder cancer during the study period 2) Used finasteride 1 mg tablets (for the treatment of male pattern baldness) in the study period 3) Had prostate surgery within 1 month of index Table 1. Inclusion and Exclusion ICD-9 Codes Inclusion ICD-9 Codes Enlarged prostate Exclusion ICD-9 Codes 222.2, 600.xx Prostate cancer 185, , 233.4, 236.5, 239.5, V10.46 Bladder cancer 188, 198.1, 223.3, 233.7, 239.4, V10.51 GlaxoSmithKline Page 6 of 10

17 Table 2. ICD-9-CM and CPT-4 Codes for AUR and Prostate-related Surgeries Outcomes of Interest CPT or ICD-9-CM Codes Transurethral electrosurgical resection of the prostate Transurethral resection of the prostate 52612, 52614, 52620, Laser coagulation Laser vaporization Prostatectomy 55801, 55821, Transurethral microwave thermotherapy Transurethral needle ablation Transurethral water-induced thermotherapy Acute urinary retention* (excluding ), *ICD-9-CM codes were used to identify this outcome ICD-9-CM indicates International Classification of Diseases, Ninth Revision, Clinical Modification; CPT, Current Procedural Terminology 3.4 Study Design The study will be a descriptive analysis of treatment patterns within 1 year of initiating treatment for BPH. Patients identified for study inclusion will be placed into cohorts based on specific treatment patterns, which will include but are not limited to AB monotherapy, 5ARI monotherapy, early combination, and late combination. 3.5 Assessment of Treatment Patterns The primary outcomes of interest in this analysis include the initial BPH prescription filled by patients and subsequent fills of BPH-related medication. Patients will be placed into cohorts based on the presence and timing of these events. GlaxoSmithKline Page 7 of 10

18 4.0 ANALYTIC APPROACH 4.1 Baseline Variables Evaluating Treatment Patterns and Outcomes in Men with BPH As certain covariates may be related to treatment selection, baseline demographic information will be captured. These variables will be summarized by cohort using standard summary statistics. The needed variables are provided in Table 3. Table 3. Confounding Variables (Covariates) Age Variable EP stage (to be calculated from codes) See Table 5 Charlson comorbidity index (to be calculated from ICD-9 codes) See Table 4 Number of unique diagnosis codes Presence of hematuria Urinary tract infections Bladder dysfunction , 596.0, 598.2, Criteria Incontinence , , , , Bladder stones 592.0, 592.1, 592.9, Bladder outlet obstruction 593.5, 596.0, Urologist visits Non EP-related prescriptions filled (and classes) EP-related costs Days supply, quantity Pre-index presence of AUR and prostate-related surgery See Table 2 Charge data from billing records Charlson comorbidity index: The Charlson comorbidity score is a claims-based index that contains 19 categories of comorbidities, primarily defined by ICD-9-CM diagnosis codes. Each category is associated with a weight, which is based on the adjusted risk of 1-year mortality. The overall comorbidity score reflects the cumulative increased likelihood of 1-year mortality; thus, higher scores represent a higher burden of comorbidity 6. By identifying those comorbidities related to mortality, the Charlson index effectively identifies high-severity, resource-intensive patients and is commonly used in the original or modified version as a form of risk adjustment 7. Romano et al expressed concern that the eclectic taxonomy of ICD-9-CM codes used to identify medical conditions in the Charlson index leads to non-reproducible identification of many diseases 8. Therefore, the ICD-9-CM codes used to identify comorbidities in this study will be obtained from Dartmouth-Manitoba Codes and Deyo et al, which are modifications to the original Charlson index. The diseases, weights, and associated ICD-9- CM codes are presented in Table 4. The process by which the Dartmouth-Manitoba and Deyo et al ICD-9-CM codes are used presents a dilemma. Certain ICD-9-CM codes are included as a comorbidity if they are present in either an index or prior hospital discharge record, while other codes are included only if recorded prior to the index 6 Charlson M, Pompei P, Ales K, MacKenzie C. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis. 1987;40(5): Needham DM, Sclaes DC, Laupacis A, Pronovost PJ. A systematic review of the Charlson comorbidity index using Canadian administrative databases: a perspective on risk adjustment in critical care research. J Crit Care. 2005;20(1): Romano P, et al. Adapting a clinical comorbidity index for use with ICD9-CM administrative data: differing perspectives. J Clin Epidemiol. 1993;46: GlaxoSmithKline Page 8 of 10

19 discharge. In disease states such as cerebrovascular disease, tumors, and metastatic solid tumor, there is some inconsistency across the two modification methods. Dartmouth-Manitoba ICD-9-CM codes for tumors would only be assessed in previous and index discharge records. However, Deyo et al ICD-9-CM codes for tumors would be assessed in the previous records only; thus, the possibility for obtaining tumor comorbidities is higher with Dartmouth-Manitoba ICD-9-CM codes. In all instances where there are disparities with assessment of discharge records, the method assessing ICD-9-CM codes over all records will be used. Table 4. Charlson Comorbidity Index Assigned Weight of Medical Condition Medical Conditions ICD9-CM Codes Medical Condition Deyo et al 1 Myocardial infarction 410, 412* 410, 412* ICD9-CM Codes Medical Condition Dartmouth-Manitoba Codes Congestive heart failure , , 425, 428, Peripheral vascular disease 441*, 443.9*, 785.4*, V43.4*, (P) 440*, 441*, 442*, *, 447.1*, 785.4*, (P)*, (P)*, (P)*, (P)*, (P)*, (P)*, (P)*, (P)*, (P)*, (P)*, (P)* Cerebrovascular disease , 438* , , , 437.9, 438, 781.4, 784.3, 997.0, (P), (P) Dementia 290* 290*, * Chronic pulmonary disease *, *, 506.4* 415.0*, *, *M 496* Connective tissue disease / rheumatologic disorders *, 710.4*, *, *, 725* Ulcer disease *, *, *, *, , , , , 531.9, 532.9, 533.9, *, 714* Mild liver disease 571.2*, * 571.2*, *, * Diabetes *, 270.7* * 2 Hemiplegia or paraplegia 342*, 344.1* 342, 344 Moderate or severe renal disease 582*, *, 585*, 586*, 588* *, V45.1*, V56*, (P)*, (P)* Diabetes with end organ damage * * Any tumor, including leukemia and lymphoma , , *, *, *, 273.0*, 273.3*, V10.46*, 60.5 (P)*, (P*) 3 Moderate to severe liver disease *, * *, *, 39.1 (P)*, (P)* 6 Metastatic solid tumor * AIDS N/A (P) follows all ICD9-CM codes that describe procedures rather than diagnoses (Volume III). *The codes with asterisks are included in the definition of comorbidity if they are listed during either index or prior hospital discharges; other codes are included only if recorded prior to index discharge. Each asterisk applies to all codes within the indicated range. Rheumatologic disease was too rare to be included in the original adaptation of the comorbidity index; however, a recent revision for the Heart Disease Patient Outcomes Research Team includes ICD9-CM codes 710 and 714. In the Dartmouth-Manitoba algorithm, these comorbidities take precedence over less severe comorbidities involving the same organ system. For example, a patient with metastatic solid tumor would have that comorbidity code as present, and any associated primary malignancy diagnoses would be ignored. Moderate to severe liver disease and complicated diabetes are treated in the same way to avoid inadvertently double counting one chronic condition that may be characterized using multiple diagnosis codes in administrative data. GlaxoSmithKline Page 9 of 10

20 Table 5. Enlarged Prostate Disease Stage Stage Description ICD-9-CM Codes 0 Benign prostatic hypertrophy 222.2, 600.xx 1 With urinary tract infection Stage With bladder outlet obstruction Stage , 596.0, With hydronephrosis Stage xx 4 With renal failure Stage xx, 586.xx 5 With sepsis Stage xx 6 With shock Stage , Statistical Analysis Patients will be placed into cohorts based on pharmacotherapy patterns. Descriptive analyses will be used to evaluate the distribution of study variables by cohort. Differences across baseline variables will be conducted as appropriate. For categorical variables, chi-square tests will be conducted; for interval variables, Student s t tests and/or analysis of variance (ANOVA) tests of inter-cohort differences will be conducted. To ensure the accuracy of the data, the data will be reviewed for internal consistency and checked for influential outliers. All statistical tests performed will test a twosided hypothesis of no difference between treatment groups at a significance level of CONFIDENTIALITY AND QUALITY CONTROL PROCEDURES For all data sources, Xcenda adheres to a stringent set of policies and procedures to ensure that electronic protected health information (e-phi) is safeguarded to prevent unauthorized disclosure and unauthorized modification or destruction, which is essential for compliance with the Security Rule and the Privacy Rule, both of which are promulgated under the federal Health Insurance Portability and Accountability Act (HIPAA). Because of the diversity of organizational issues and the technical complexity of the systems and networks, Xcenda believes that protecting e-phi can be achieved most effectively with an organization-wide program. Xcenda s information security program consists of risk assessment policies, standards, training, administrative, technical, and physical controls, auditing and monitoring, and assigned responsibility for the management of the information security program. All necessary measures will be taken to ensure that the confidentiality and privacy of individuals are maintained. Patient data used in this analysis will be personally non-identifiable. GlaxoSmithKline Page 10 of 10