GSK Medicine: Study No.: Title: Rationale: Objectives: Indication: Study Investigators/Centers: Research Methods:

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: Rosiglitazone,rosiglitazone/metformin,rosiglitazone/glimepiride Study No.: WWE113497/WEUS253 Title: Incidence of Neoplasms in Rosiglitazone Clinical Trials Rationale: This study was an updated analysis of all reports of neoplasms in rosiglitazone s (RSG) clinical trials database (including double blind and open label extension studies) as of 11/04/2004, undertaken to address regulatory concerns regarding the PPAR agonists and carcinogenicity and to update a previous evaluation of RSG and neoplasms. Objectives: Specific objectives of the study were: 1. To determine the incidence rates of various neoplasms (malignant, benign and unspecified) in the RSG clinical trial database and for comparator arms (placebo or active therapies). 2. To determine the incidence rates of various neoplasms (malignant, benign and unspecified) in the RSG clinical trial database over time to determine if the rate of certain neoplasms of interest increases over time. 3. To determine the incidence rates of neoplasms of special interest, including malignant bladder, colorectal, liver, pancreas, breast, kidney, and prostate neoplasms. 4. To compare the incidence rate of neoplasms in RSG clinical trial program to the incidence rate obtained from Surveillance, Epidemiology and End Results (SEER) Indication: Type 2 Diabetes Study Investigators/Centers: GSK Research Methods: Data Source: The validated database used contains data as of 11/04/2004, and includes information on 9,542 RSG treated subjects (9,704 patient-years of exposure) who were on treatment for an average of 12.2 months. The RSG clinical trial database includes 755 subjects on placebo (221 patient-years) and 4062 subjects treated with other comparator antidiabetic drugs (2219 patient-years). The patients on comparator antidiabetic drugs were on therapy for an average of 6.6 months and those on placebo for a mean of 3.5 months. Study Design: Retrospective analysis of integrated clinical trials data Study Population: Type 2 diabetic patients who were on RSG, placebo, or other comparator antidiabetic drugs. Study Exposures, Outcomes: Exposures Exposure was defined as receiving RSG, placebo, or other antidiabetic drugs. For the analysis, study subjects were categorized into either RSG or non-rsg. The RSG arm includes all subjects who received one of the following regimens: RSG Monotherapy; RSG+Sulphonyurea (SU); RSG+Metfromin (MET); RSG+Insulin; RSG+SU+MET. The non-rsg arm includes subjects who received one of the following regimens: SU Monotherapy; MET Monotherapy; Insulin Monotherapy; SU+MET. Outcome Definitions Neoplasm in Clinical Trials The outcomes of the study are malignant, benign, and unspecified neoplasms. All neoplasms coded to MedDRA System Organ Class (SOC) of neoplasms benign, malignant and unspecified (including cysts and polyps) were captured. In addition, events mapping to the following SOC(s) of gastrointestinal disorders, reproductive system and breast disorders and skin and subcutaneous tissue disorders were reviewed and non-malignant tumors (e.g., polyps) were identified and compiled. Neoplasm of Special interest Neoplams of special interest that were assessed in this analysis include the following malignant neoplasms: bladder, colorectal, liver, pancreas, breast, kidney, and prostate.

2 Data Analysis Methods: The incidence rates of neoplasms (benign, malignant and unspecified) per 100 patient years were calculated with corresponding 95% confidence intervals (CIs). Life tables were constructed to examine the incidence rate of neoplasms (benign, malignant and unspecified) and neoplasms of special interest over time in rosiglitazone treated patients. Neoplasm Rates Observed in Clinical Trials Comopared to SEER The incidence rates of neoplasms in the RSG program were compared with published epidemiological data. National cancer incidence rates were obtained from the Surveillance, Epidemiology, and End Results (SEER) program's 2001 data. The Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute is an authoritative source of information on cancer incidence and survival in the United States. The SEER Program currently collects and publishes cancer incidence and survival data from 14 population-based cancer registries and three supplemental registries covering approximately 26 percent of the US population. Information on more than 3 million in situ and invasive cancer cases is included in the SEER database, and approximately 170,000 new cases are added each year within the SEER coverage areas. The SEER Registries routinely collect data on patient demographics, primary tumor site, morphology, stage at diagnosis, first course of treatment, and follow-up for vital status. The SEER Program is the only comprehensive source of population-based information in the United States that includes stage of cancer at the time of diagnosis and survival rates within each stage. The SEER program is considered the standard for quality among cancer registries around the world. The number of expected cases was calculated by multiplying age-specific national incidence rates by the percentage of RSG treated patients in each age group from the RSG clinical trial database. Standardized incidence ratios (SIRs) were calculated by dividing the total number of observed cases per 100,000 subjects by the total number of expected cases per 100,000 subjects. Limitations: The total number of subjects and the average length of observation (exposure) per subject were considerably greater for subjects in the RSG group compared to placebo and other comparator arms. The incidence rate of most tumors increases with age so that longer observation periods are expected to yield a greater number of events. These studies were not intended to access the incidence of new onset tumors and therefore no screening for previously undiagnosed tumors was implemented and reported tumor events were not necessarily confirmed or adjudicated. The latency period for the effect of some carcinogens can be as long as 15 to 20 years; although, observed associations between carcinogens and cancer can also be observed in much shorter time frames. The analysis is limited by the follow-up available in the RSG clinical trial database. Finally, the RSG clinical trial database has undergone migration from WHO to MedDRA. The clinical team has identified some instances where the MedDRA preferred term selected in the recoding processes were less specific than one might expect based on verbatim terms reported by the investigators. It remains unclear whether or not this conversion impacts the results of this study. Study Results: Exposure to Rosiglitazone, placebo and comparator agents in the RSG clinical trial database Table 1 gives the total number of subjects exposed to RSG, placebo and comparator agents as well as the total patient-years of exposure. Incidence rates Table 2 provides the incidence rates of malignant, benign and unspecified neoplasms for RSG exposed subjects compared to non-rsg exposed subjects. Neoplasm (malignant, benign and unspecified) in Clinical Trials In the current database population, where there is considerably longer exposure to RSG compared to the active comparator groups and placebo, the incidence rates of neoplasms (benign, malignant and unspecified) per 100 patient years were generally similar in all treatment regimens examined in Tables 3A 3C. The confidence intervals for the RSG group are entirely contained by, or overlap with the confidence intervals for the non-rsg group. For some specific types of neoplasms, there were no cases or only isolated reports of these tumors in the RSG or the comparator group and therefore comparing the incidence rates was not possible. The crude rate of

3 neoplasms in all RSG exposed patients [1.610 per 100 patient-years (95% C.I. = ) for malignant neoplasms (Table 3A), per 100 patient-years (95% C.I. = ) for benign neoplasms (Table 3B) and per 100 patient-years (95% C.I. = ) for unspecified neoplasms (Table 3C)] was similar to that of the all non-rsg group [1.438 per 100 patient-years (95% C.I. = ) for malignant neoplasms (Table 3A), per 100 patient-years (95% C.I. = ) for benign neoplasms (Table 3B) and per 100 patientyears (95% C.I. = ) for unspecified neoplasms (Table 3C)] as summarized in table 2 below. Incidence rate of malignant, benign, and unspecified neoplasms over time There was no increase in the estimated incidence rate for malignant, benign and unspecified neoplasms in this database over the 4.50 years of follow-up (Tables 4A 4C). Neoplasm of Special Interest There does not appear to be a trend towards an increase in the estimated rate of any of the above mentioned neoplasms of interest over time (Data not shown). Neoplasm Rates Observed in Clinical Trials Compared to SEER Diabetes has been associated with an increased risk for a variety of malignancies (Table 5). The standardized incidence ratio compares the number of observed cases to the number of expected cases according to SEER 2001 (Table 6). Importantly, the expected cases from SEER are the number of expected cases of malignant neoplasms for the general population and not for a diabetic population. Given that the incidence rate of certain cancers appears to be elevated for diabetic patients (see Table 5), the expected number of cases according to SEER will underestimate the expected number of cases for the diabetic population participating in the RSG clinical trials program. The SIRs in Table 6 indicate that the incidence rate of malignant bladder, colorectal, liver, melanoma, pancreatic neoplasms in T2DM population receiving RSG was greater than expected based on data for the general population. However, the magnitude of the increases observed are generally consistent with data in the published literature demonstrating an increased risk for colorectal, liver and pancreatic cancer in patients with T2DM (see Table 5). For subjects treated with RSG, the incidence rates of breast, kidney and prostate malignant neoplasms are lower than the general population. The lower incidence rates of breast and prostate cancer are consistent with data from the literature (Table 5); in contrast to the incidence rate of kidney cancer which appears to be elevated in type 2 diabetic patients relative to the general population. A non-statistically significant 2.23-fold increase in the incidence rate of malignant melanoma was observed. The study further investigated the observed 2.23-fold higher incidence rate of malignant melanoma in the RSG clinical trial database compared to SEER The currently available published data is minimal and not robust enough to ascertain if there is an increased rate of melanoma in the diabetic population. Considering this, the Aetna database 1 was evaluated to assess the relationship, if any, between type 2 diabetes mellitus and melanoma. In the Aetna study, the risk of melanoma was higher in the diabetic population compared to the general population (adjusted relative risk = 1.63; 95% CI = ). Further, the incidence rate of melanoma is known to be higher in Caucasians. Given that 74% of subjects in the RSG clinical trial database are White, the standardized incidence ratios for malignant melanoma was recalculated after stratifying by ethnicity. The SIR for malignant melanoma for Whites was still elevated and non-significant (SIR = 1.90, 95% CI =0.70, 4.14). It is consistent with the increased risk of melanoma for diabetic subjects observed in the Aetna study. Conclusion: The incidence rate per 100 patient years of exposure for any malignant, benign or unspecified neoplasm was similar for RSG and non-rsg treatment regimens. There was no trend for increased incidence of any malignant, benign, or unspecified neoplasm with rosiglitazone therapy over time. The very small number of events for some specific tumors makes the incidence rate unstable and significantly limits any conclusions regarding possible differences between treatments. The SIR for cancers associated with diabetes was similarly increased in RSG treated subjects versus the SEER database. 1 Oliveria SA, Koro CE, Ulcickas Yood M, Sowell M. Cancer Incidence among Patients Treated with Antidiabetic Pharmacotherapy. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 2008;2(1):47-57

4 Date updated: 04-Jun-2008

5 Table 1: Exposure to antidiabetic drugs and placebo in the RSG clinical trial database as of November 4th 2004 Group # of Pts Mean length of exposure (+-SD) in months Median length of exposure in months Total PY exposure All RSG* (±2.34) All NON RSG* (± 4.78) Placebo (± 2.36) Active Comparator* (± 4.96) *All RSG= RSG mono, RSG+SU, RSG+MET, RSG+Insulin, RSG+SU+MET All NON-RSG= Placebo, SU Mono, MET Mono, SU+MET, Insulin Mono Active comparator = SU Mono, MET Mono, SU+MET, Insulin Mono

6 Table 2: Incidence rates of malignant, benign and unspecified Neoplasms comparing RSG to non-rsg exposure categories in the RSG clinical trial database as of November 4th 2004 Incidence Rate per 100 patient-years All RSG All NON RSG Malignant Neoplasms ( ) ( ) Benign Neoplasms ( ) ( ) Unspecified Neoplasms ( ) ( )

7 Table 3A: Incidence Rates of Malignant Neoplasms Per 100 Patient-years by Exposure Category Category All RSG 9542 (9704.0) All NON-RSG 4817 (2439.8) Any case (155) ( ) Basal cell-skin (31) ( ) Bladder (6) ( ) Breast* (9) ( ) Colorectal (11) ( ) Esophagus (4) ( ) Kidney (2) ( ) Larynx (1) ( ) Leiomyosarcoma (1) ( ) Leukemia (3) ( ) Liver (5) ( ) Lung (15) ( ) Lymphoma (2) ( ) Myeloma (3) ( ) Ovary* (2) ( ) Pancreas (5) ( ) Pharynx (1) ( ) (35) ( ) (8) ( ) (2) ( ) (2) ( ) (1) ( ) (2) ( ) (4) ( ) (1) ( ) (1) ( )

8 Category All RSG 9542 (9704.0) All NON-RSG 4817 (2439.8) Prostate** (21) ( ) Skin (2) ( ) Skin-Melanoma (7) ( ) (6) ( ) Spleen (1) ( ) Stomach (4) ( ) Unspecified Primary (7) ( ) Unspecified Site (19) ( ) (2) ( ) (5) ( ) Uterus* (2) ( ) (1) ( ) * Patient-years for females; ** Patient-years for males All RSG= RSG mono, RSG+SU,RSG+MET,RSG+Insulin,RSG+SU+MET N = number of patient; Pt-Yr = patients-year; = none reported ; Values of are actually < Two patients were excluded due to missing onset day (one with benign skin neoplasm and one with malignant esophagus cancer)

9 Table 3B: Incidence Rates of Benign Neoplasms Per 100 Patient-years by Exposure Category Category All RSG 9542 (9704.0) All NON-RSG 4817 (2439.8) Bladder (3) ( ) Breast* (7) ( ) CNS-meninges (3) ( ) Colo-rectal (17) ( ) Eye (2) ( ) Hemangioma (2) ( ) Lipoma (29) ( ) Neuroma (1) ( ) (2) ( ) (1) ( ) (2) ( ) (1) ( ) Ovary* (1) ( ) Parathyroid (1) ( ) Prostate** (4) ( ) Skin (32) ( ) Unspecified Site (4) ( ) (6) ( ) (3) ( ) Uterus* (13) ( ) (5) ( ) * Patient-years for females; ** Patient-years for males All RSG= RSG mono, RSG+SU,RSG+MET,RSG+Insulin,RSG+SU+MET N = number of patient; Pt-Yr = patients-year; = none reported; Values of are actually < Two patients were excluded due to missing onset day (one with benign skin neoplasm and one with malignant esophagus cancer)

10 Table 3C: Incidence Rates of Unspecified Neoplasms Per 100 Patient-years by Exposure Category Category All RSG 9542 (9704.0) All NON-RSG 4817 (2439.8) Any case (45) ( ) Colo-rectal (29) ( ) Kidney (2) ( ) Lung (2) ( ) Mouth (1) ( ) Thyroid (7) ( ) Unspecified Site (1) ( ) (11) ( ) (9) ( ) (1) ( ) (1) ( ) Upper GI Polyp (4) ( ) * Patient-years for females; ** Patient-years for males All RSG= RSG mono, RSG+SU,RSG+MET,RSG+Insulin,RSG+SU+MET Pt-Yr = patients-year; = none reported; = none reported; Values of are actually < Two patients were excluded due to missing onset day (one with benign skin neoplasm and one with malignant esophagus cancer).

11 Table 4A: Life Table for All Malignant Neoplasms in Rosiglitazone Treated Patients (N = 9542) Interval in Years (Lower-Upper) Number Failed Number Censored Hazard* Standard Error * Hazard = instantaneous probability of adverse events in question Two patients were excluded due to missing onset day (one with benign skin neoplasm and one with malignant esophagus cancer)

12 Table 4B: Life Table for All Benign Neoplasms in Rosiglitazone Treated Patients (N = 9542) Interval in Years (Lower-Upper) Number Failed Number Censored Hazard* Standard Error * Hazard = instantaneous probability of adverse events in question Two patients were excluded due to missing onset day (one with benign skin neoplasm and one with malignant esophagus cancer)

13 Table 4C: Life Table for All Unspecified Neoplasms in Rosiglitazone Treated Patients (N = 9542) Interval in Years (Lower-Upper) Number Failed Number Censored Hazard* Standard Error * Hazard = instantaneous probability of adverse events in question Two patients were excluded due to missing onset day (one with benign skin neoplasm and one with malignant esophagus cancer)

14 Table 5: The Relative Risk of Various Malignant Cancers of Interest in the Diabetic Compared to the General Population* Malignant Cancer Relative Risk Bladder Colorectal Liver Pancreas Breast Kidney Prostate *For a complete review and references, refer to the report The Incidence of Cancer in the Diabetic Population generated on June 30 th 2004 (UM2005/00187/00).

15 Table 6: Standardized Incidence Ratios (SIRs) for Malignant Neoplasms in Rosiglitazone Treated Patients Compared to SEER 2001 Site Observed Rate per 100,000 subjects Expected Rate per 100,000 subjects*** SIR 95% CI Colorectal , 1.74 Bladder , 2.93 Breast* , 1.44 Liver ,10.46 Lung , 1.55 Pancreas , 4.94 Prostate** , 1.13 Kidney , 2.79 Melanoma , 4.60 * Female Patients ** Male Patients *** Based on SEER incidence 2001