Modular Program Report

Transcription

1 Modular Program Report Disclaimer The following report(s) provides findings from an FDA initiated query using Sentinel. While Sentinel queries may be undertaken to assess potential medical product safety risks, they may also be initiated for various other reasons. Some examples include determining a rate or count of an identified health outcome of interest, examining medical product use, exploring the feasibility of future, more detailed analyses within Sentinel, and seeking to better understand Sentinel capabilities. Data obtained through Sentinel are intended to complement other types of evidence such as preclinical studies, clinical trials, postmarket studies, and adverse event reports, all of which are used by FDA to inform regulatory decisions regarding medical product safety. The information contained in this report is provided as part of FDA s commitment to place knowledge acquired from Sentinel in the public domain as soon as possible. Any public health actions taken by FDA regarding products involved in Sentinel queries will continue to be communicated through existing channels. FDA wants to emphasize that the fact that FDA has initiated a query involving a medical product and is reporting findings related to that query does not mean that FDA is suggesting health care practitioners should change their prescribing practices for the medical product or that patients taking the medical product should stop using it. Patients who have questions about the use of an identified medical product should contact their health care practitioners. The following report contains a description of the request, request specifications, and results from the modular program run(s). If you are using a web page screen reader and are unable to access this document, please contact the Sentinel Operations Center for assistance at info@sentinelsystem.org.

2 Request ID: cder_mpl1p_wp006_nsdp_v01 Overview for Request cder_mpl1p_wp006_nsdp_v01 Request Description: This report contains estimates of the length of follow-up time for new users of immunosuppressive drugs (adalimumab, alemtuzumab, certolizumab, dalfampridine, dimethyl fumarate, etanercept, fingolimod, glatiramer acetate, golimumab, infliximab, interferon beta-1a, interferon beta-1b, mitoxantrone, natalizumab, pegylated intereferon beta-1a, teriflunomide, and ustekinumab) and for patients diagnosed with Crohn's disease, multiple sclerosis, psoriasis, and ulcerative colitis in the Sentinel Distributed Database (SDD). Sentinel Modular Program Tool Used: Cohort Identification and Descriptive Analysis (CIDA) tool, version 4.0.0, and a Rapid Analytic Development and Response (RADaR) module Data Source: Data from January 1, 2000 to the most recent available data from 16 health plans contributing to the SDD were included in this report (see Appendix A for data availability dates for each Data Partner). This request was distributed to Data Partners on June 30, Study Design: The purpose of this request was to examine follow-up time for patients with incident exposures to select immunosuppressive drugs used to treat multiple sclerosis or psoriasis. The number of patients with incident exposures and follow-up time was stratified by age group and year. In addition, follow-up time for patients with prevalent Crohn's disease, multiple sclerosis, psoriasis, and ulcerative colitis diagnoses was examined and stratified by age group. Cohort Eligibility Criteria: Patients were required to be continuously enrolled in plans with both medical and drug coverage for at least six months (183 days) before their index date, during which gaps in coverage of up to 45 days were allowed. The first valid exposure per patient was included. Members who had an exposure in the six months before their exposure of interest were excluded from the cohort. The following age groups were included in the cohort: 18-30, 31-64, and 65+ years. Analysis 1, Exposures of Interest: The exposures of interest were immunosuppressive drugs used to treat multiple sclerosis and psoriasis. The drugs were defined using National Drug Codes (NDCs) and Healthcare Common Procedure Coding System (HCPCS) codes. Please refer to Appendix B for specific codes and Appendix C for generic names and brand names. Analysis 2, Events of Interest: The events of interest were diagnoses of Crohn's disease, multiple sclerosis, psoriasis, and ulcerative colitis. The conditions were defined using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis codes. Please refer to Appendix D for specific codes. Follow-Up Time: The number of patients with follow-up time was assessed in one-year increments from years. Percentages of patients with follow-up time within each stratum were assessed in the following increments: <3, 3+, 4+, 5+, 6+, 7+, 8+, 9+, 10+, 11+, 12+, 13+, 14+, 15+, and 16+ years. Follow-up began on the day of the first exposure or event of interest and continued until either 1) the end of a patient's enrollment, 2) death, or 3) the end of Data Partners' data. Please refer to Appendices E and F for detailed specifications of parameters used in this request. Limitations: Algorithms used to define exposures and events are imperfect; thus, it is possible that there may be misclassification. Notes: Please contact the Sentinel Operations Center Query Fulfillment Team (qf@sentinelsystem.org) for questions and to provide comments/suggestions for future enhancements to this document.

3 Table of Contents Glossary List of Terms Found in this Report and their Definitions Table 1a Table 1b Table 2a Table 2b Summary of Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Age Group Proportion of Patients with Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Age Group Summary of Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Year Proportion of Patients with Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Year Table 3a Summary of Follow-Up Time for Patients Diagnosed with Crohn's Disease, Multiple Sclerosis, Psoriasis, or Ulcerative Colitis in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Condition and Age Group Table 3b Proportion of Patients with Follow-Up Time After Diagnosis of Crohn's Disease, Multiple Sclerosis, Psoriasis, or Ulcerative Colitis in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Condition and Age Group Appendix A Dates of Available Data for Each Data Partner up to Request Date (June 30, 2017) Appendix B Appendix C Appendix D List of Healthcare Common Procedure Coding System (HCPCS) Codes and Descriptions Used to Define Immunosuppressive Drugs in this Request List of Generic Names and Brand Names Used to Define Immunosuppressive Drugs in this Request List of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) Diagnosis Codes Used to Define Crohn's Disease, Multiple Sclerosis, Psoriasis, and Ulcerative Colitis in this Request Appendix E Specifications Defining Parameters Used in this Request for Analysis 1 Appendix F Specifications Defining Parameters Used in this Request for Analysis 2

4 Glossary of Terms for Analyses Using Cohort Identification and Descriptive Analysis (CIDA) Tool* Amount Supplied - number of units (pills, tablets, vials) dispensed. Net amount per NDC per dispensing. Blackout Period - number of days at the beginning of a treatment episode that events are to be ignored. If an event occurs during the blackout period, the episode is excluded. Care Setting - type of medical encounter or facility where the exposure, event, or condition code was recorded. Possible care settings include: Inpatient Hospital Stay (IP), Non-Acute Institutional Stay (IS), Emergency Department (ED), Ambulatory Visit (AV), and Other Ambulatory Visit (OA). For laboratory results, possible care settings include: Emergency department (E), Home (H), Inpatient (I), Outpatient (O), or Unknown or Missing (U). Along with the Principal Diagnosis Indicator, forms the Care Setting/PDX Ambulatory Visit (AV) - includes visits at outpatient clinics, same-day surgeries, urgent care visits, and other same-day ambulatory hospital encounters, but excludes emergency department encounters. Emergency Department (ED) - includes ED encounters that become inpatient stays (in which case inpatient stays would be a separate encounter). Excludes urgent care visits. Inpatient Hospital Stay (IP) - includes all inpatient stays, same-day hospital discharges, hospital transfers, and acute hospital care where the discharge is after the admission date. Non-Acute Institutional Stay (IS) - includes hospice, skilled nursing facility (SNF), rehab center, nursing home, residential, overnight non-hospital dialysis and other non-hospital stays. Other Ambulatory Visit (OA) - includes other non overnight AV encounters such as hospice visits, home health visits, skilled nursing facility visits, other non-hospital visits, as well as telemedicine, telephone and consultations. Cohort Definition (drug/exposure) - indicates how the cohort will be defined: 01: Cohort includes only the first valid treatment episode during the query period; 02: Cohort includes all valid treatment episodes during the query period; 03: Cohort includes all Days Supplied - number of days supplied for all dispensings in qualifying treatment episodes. Eligible Members - number of members eligible for an incident treatment episode (defined by the drug/exposure and event washout periods) with drug and medical coverage during the query period. Enrollment Gap - number of days allowed between two consecutive enrollment periods without breaking a continuously enrolled Episodes - treatment episodes; length of episode is determined by days supplied in one dispensing or consecutive dispensings bridged by the episode gap. Episode Gap - number of days allowed between two (or more) consecutive exposures (dispensings/procedures) to be considered the same treatment episode. Event Deduplication - specifies how events are counted by the MP algorithm: 0: Counts all occurrences of an HOI during an exposure episode; 1: de-duplicates occurrences of the same HOI code and code type on the same day; 2: de-duplicates occurrences Exposure Episode Length - number of days after exposure initiation that is considered "exposed time." Exposure Extension Period - number of days post treatment period in which the outcomes/events are counted for a treatment episode. Extensions days are added after any episode gaps have been bridged Lookback Period - number of days wherein a member is required to have evidence of pre-existing condition Maximum Episode Duration - truncates exposure episodes after a requester-specified number of exposed days. Applied after any gaps are bridged and extension days added to the length of the exposure episode. Member-Years - sum of all days of enrollment with medical and drug coverage in the query period preceded by an exposure Minimum Days Supplied - specifies a minimum number of days in length of the days supplied for the episode to be considered. Minimum Episode Duration - specifies a minimum number of days in length of the episode for it to be considered. Applied after any gaps are bridged and extension days added to the length of the exposure episode. Monitoring Period - used to define time periods of interest for both sequential analysis and simple cohort characterization Principal Diagnosis (PDX) - diagnosis or condition established to be chiefly responsible for admission of the patient to the hospital. 'P' = principal diagnosis, 'S' = secondary diagnosis, 'X' = unspecified diagnosis, '.' = blank. Along with the Care Setting values, forms Query Period - period in which the modular program looks for exposures and outcomes of interest. Treatment Episode Truncation Indicator - indicates whether the exposure episode will be truncated at the occurrence of a requester-specified code. Washout Period (drug/exposure) - number of days a user is required to have no evidence of prior exposure (drug dispensing/procedure) and continuous drug and medical coverage prior to an incident treatment episode. Washout Period (event/outcome) - number of days a user is required to have no evidence of a prior event (procedure/diagnosis) and continuous drug and medical coverage prior to an incident treatment episode. Years at Risk - number of days supplied plus any episode gaps and exposure extension periods all divided by *all terms may not be used in this report

5 Table 1a: Summary of Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Age Group Number of Users by Years of Follow-Up Time Age Group (Years) <1 1-<2 2-<3 3-<4 4-<5 5-<6 6-<7 7-<8 8-<9 9-<10 10-<11 11-<12 12-<13 13-<14 14-<15 15-< Adalimumab ,281 4,263 2,332 1, ,915 20,342 12,380 7,910 5,442 4,209 2,865 2,174 1, ,403 1,824 1, Alemtuzumab Certolizumab ,243 2,731 1, Dalfampridine ,566 1,835 1, Dimethyl Fumarate ,289 3,497 3,290 1, Etanercept ,422 2,204 1, ,806 15,861 11,081 7,728 5,491 4,106 2,984 2,453 1,641 1, ,894 1,571 1, Fingolimod ,074 1,475 1, Glatiramer Acetate , ,024 4,747 3,139 2,269 1,903 1,361 1, Golimumab ,765 2,522 1,720 1, Infliximab ,662 2,336 1, ,272 7,949 5,411 3,731 2,790 2,162 1,979 1, ,165 1,685 1,379 1, Interferon Beta-1A ,851 3,501 2,588 2,054 1,715 1,

6 Table 1a: Summary of Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Age Group Number of Users by Years of Follow-Up Time Age Group (Years) <1 1-<2 2-<3 3-<4 4-<5 5-<6 6-<7 7-<8 8-<9 9-<10 10-<11 11-<12 12-<13 13-<14 14-<15 15-< Interferon Beta-1B ,452 1, Mitoxantrone , Natalizumab ,544 1,726 1, Pegylated Interferon Beta-1A Teriflunomide ,707 1, Ustekinumab ,676 3,218 1,951 1,

7 Table 1b: Proportion of Patients with Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Age Group Number of Users by Years of Follow-Up Time Age Group (Years) < Total (n) Adalimumab % 20.9% 13.2% 8.2% 4.9% 2.7% 1.3% 0.6% 0.3% 0.1% 0.1% 0.0% 0.0% 0.0% 0.0% 17, % 28.3% 19.5% 13.5% 8.8% 5.6% 3.2% 1.8% 1.0% 0.6% 0.3% 0.1% 0.0% 0.0% 0.0% 90, % 35.4% 25.2% 17.8% 12.3% 8.5% 5.3% 3.0% 1.7% 0.9% 0.4% 0.1% 0.0% 0.0% 0.0% 8,423 Alemtuzumab % 16.7% 14.3% 9.5% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 16.9% 11.6% 7.4% 4.9% 3.4% 2.5% 1.6% 0.7% 0.4% 0.3% 0.0% 0.0% 0.0% 0.0% % 17.6% 11.6% 8.0% 6.1% 3.9% 2.8% 1.1% 0.8% 0.3% 0.0% 0.0% 0.0% 0.0% 0.0% 363 Certolizumab % 21.0% 11.4% 6.0% 2.6% 0.9% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 2, % 22.1% 13.3% 7.4% 3.5% 1.0% 0.1% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 11, % 27.9% 15.5% 8.3% 3.7% 0.8% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 1,560 Dalfampridine % 23.8% 14.6% 11.3% 6.7% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 35.7% 25.1% 16.9% 9.2% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 8, % 39.8% 28.3% 20.7% 12.4% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 928 Dimethyl Fumarate % 7.9% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 1, % 13.1% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 12, % 13.7% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 633 Etanercept % 28.5% 19.4% 13.1% 8.7% 5.9% 3.9% 2.4% 1.6% 1.0% 0.6% 0.3% 0.1% 0.1% 0.0% 9, % 36.7% 26.7% 19.6% 14.2% 10.4% 7.2% 5.1% 3.3% 2.2% 1.5% 0.9% 0.3% 0.2% 0.1% 77, % 43.0% 31.9% 23.3% 16.9% 12.4% 8.8% 6.2% 3.9% 2.4% 1.4% 0.8% 0.3% 0.2% 0.1% 8,333 Fingolimod % 15.3% 8.7% 4.8% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 25.3% 14.8% 6.6% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 6, % 21.4% 15.9% 7.1% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 126 Glatiramer Acetate % 29.5% 20.3% 14.6% 9.9% 7.0% 4.5% 3.3% 2.2% 1.7% 1.4% 1.0% 0.5% 0.2% 0.1% 3, % 38.6% 29.3% 21.4% 15.8% 11.4% 7.9% 5.7% 4.2% 3.0% 2.3% 1.7% 1.1% 0.6% 0.1% 24, % 39.3% 29.5% 21.8% 16.1% 11.1% 6.9% 4.3% 2.5% 1.8% 1.5% 0.7% 0.5% 0.3% 0.0% 865 Golimumab % 15.6% 9.1% 5.1% 1.6% 0.4% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 1, % 25.2% 15.7% 9.9% 5.2% 1.2% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 10, % 18.5% 12.3% 7.9% 4.7% 1.4% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 1,387 Infliximab % 27.6% 18.6% 12.1% 7.9% 4.5% 2.7% 1.7% 1.0% 0.7% 0.5% 0.3% 0.2% 0.1% 0.0% 10, % 36.4% 26.8% 19.6% 14.0% 8.9% 5.6% 3.7% 2.4% 1.6% 1.2% 0.9% 0.6% 0.3% 0.0% 38, % 47.4% 37.0% 27.7% 20.4% 12.7% 7.8% 4.3% 2.1% 1.3% 0.8% 0.5% 0.3% 0.1% 0.0% 9,940 Interferon Beta-1A % 37.1% 26.9% 19.0% 12.9% 9.1% 6.5% 4.6% 3.3% 2.5% 1.7% 1.4% 1.1% 0.5% 0.1% 3, % 44.6% 34.2% 25.5% 18.8% 14.1% 10.3% 7.9% 5.8% 4.5% 3.3% 2.5% 1.8% 1.1% 0.3% 19, % 48.4% 36.9% 25.2% 16.4% 12.1% 8.6% 5.3% 3.6% 3.2% 2.5% 1.7% 0.8% 0.5% 0.1% 775

8 Table 1b: Proportion of Patients with Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Age Group Number of Users by Years of Follow-Up Time Age Group (Years) < Total (n) Interferon Beta-1B % 35.6% 26.2% 19.7% 14.2% 10.8% 7.8% 5.9% 4.7% 4.0% 2.6% 1.8% 1.0% 0.3% 0.1% 1, % 44.3% 35.3% 27.9% 21.3% 16.2% 11.5% 8.6% 6.5% 5.2% 4.3% 3.4% 2.2% 0.9% 0.3% 6, % 39.7% 29.8% 21.8% 15.3% 12.6% 10.7% 6.9% 6.1% 4.2% 3.1% 1.9% 1.1% 0.8% 0.0% 262 Mitoxantrone % 40.0% 30.5% 22.9% 18.1% 15.2% 12.4% 7.6% 6.7% 2.9% 1.9% 1.9% 1.0% 1.0% 0.0% % 33.6% 27.0% 21.3% 18.0% 13.7% 10.6% 7.9% 5.8% 4.3% 2.6% 2.0% 1.2% 0.4% 0.0% 2, % 16.3% 10.7% 7.6% 5.5% 3.5% 2.7% 1.3% 0.7% 0.4% 0.3% 0.2% 0.1% 0.1% 0.1% 1,806 Natalizumab % 26.6% 18.2% 11.4% 6.9% 3.5% 1.3% 0.6% 0.1% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 1, % 35.0% 24.4% 15.7% 10.0% 6.0% 3.3% 1.2% 0.2% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 8, % 46.3% 31.0% 18.0% 12.9% 7.8% 5.5% 2.0% 0.4% 0.4% 0.0% 0.0% 0.0% 0.0% 0.0% 255 Pegylated Interferon Beta-1A % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 75 Teriflunomide % 10.7% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 10.7% 0.1% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 3, % 8.1% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 308 Ustekinumab % 14.8% 7.2% 3.2% 0.9% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 2, % 18.3% 10.0% 4.9% 2.0% 0.2% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 13, % 26.2% 15.8% 8.7% 2.7% 0.3% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 998

9 Table 2a: Summary of Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Year Number of Users by Years of Follow-Up Time Year <1 1-<2 2-<3 3-<4 4-<5 5-<6 6-<7 7-<8 8-<9 9-<10 10-<11 11-<12 12-<13 13-<14 14-<15 15-< Adalimumab ,004 1, , ,039 2,140 1, , ,778 1,997 1,221 1, ,131 1, ,855 1,828 1,699 1,046 1,456 2, ,448 2,096 1,359 1,817 2, ,155 2,122 2,822 3, ,389 4,208 5, ,610 9, , Alemtuzumab

10 Table 2a: Summary of Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Year Number of Users by Years of Follow-Up Time Year <1 1-<2 2-<3 3-<4 4-<5 5-<6 6-<7 7-<8 8-<9 9-<10 10-<11 11-<12 12-<13 13-<14 14-<15 15-< Certolizumab ,218 1, , Dalfampridine

11 Table 2a: Summary of Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Year Number of Users by Years of Follow-Up Time Year <1 1-<2 2-<3 3-<4 4-<5 5-<6 6-<7 7-<8 8-<9 9-<10 10-<11 11-<12 12-<13 13-<14 14-<15 15-< Dimethyl Fumarate ,490 1,079 1,587 1, ,072 1,427 2, ,088 1, , Etanercept , , ,965 1,504 1, , ,740 1,856 1, , ,226 1, , ,219 1,426 1, ,145 2, ,271 1,983 1,249 1,725 2, ,578 1,755 2,283 3, ,376 3,029 3, ,051 4, ,

12 Table 2a: Summary of Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Year Number of Users by Years of Follow-Up Time Year <1 1-<2 2-<3 3-<4 4-<5 5-<6 6-<7 7-<8 8-<9 9-<10 10-<11 11-<12 12-<13 13-<14 14-<15 15-< Fingolimod Glatiramer Acetate ,067 1, ,

13 Table 2a: Summary of Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Year Number of Users by Years of Follow-Up Time Year <1 1-<2 2-<3 3-<4 4-<5 5-<6 6-<7 7-<8 8-<9 9-<10 10-<11 11-<12 12-<13 13-<14 14-<15 15-< Golimumab , , Infliximab , ,597 1, , ,490 1, , , , ,165 1, , , ,276 1, ,358 1,640 2, ,308 2, ,

14 Table 2a: Summary of Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Year Number of Users by Years of Follow-Up Time Year <1 1-<2 2-<3 3-<4 4-<5 5-<6 6-<7 7-<8 8-<9 9-<10 10-<11 11-<12 12-<13 13-<14 14-<15 15-< Interferon Beta-1A Interferon Beta-1B

15 Table 2a: Summary of Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Year Number of Users by Years of Follow-Up Time Year <1 1-<2 2-<3 3-<4 4-<5 5-<6 6-<7 7-<8 8-<9 9-<10 10-<11 11-<12 12-<13 13-<14 14-<15 15-< Mitoxantrone Natalizumab

16 Table 2a: Summary of Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Year Number of Users by Years of Follow-Up Time Year <1 1-<2 2-<3 3-<4 4-<5 5-<6 6-<7 7-<8 8-<9 9-<10 10-<11 11-<12 12-<13 13-<14 14-<15 15-< Pegylated Interferon Beta-1A Teriflunomide

17 Table 2a: Summary of Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Year Number of Users by Years of Follow-Up Time Year <1 1-<2 2-<3 3-<4 4-<5 5-<6 6-<7 7-<8 8-<9 9-<10 10-<11 11-<12 12-<13 13-<14 14-<15 15-< Ustekinumab , ,469 1, , Multiple Sclerosis Drugs ,123 1, , ,769 1,776 1, , ,351 1, , ,469 1,534 1, ,233 2, ,121 1, ,447 2, ,406 2,396 3,329 4, ,886 3,815 5, ,483 5, ,

18 Table 2a: Summary of Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Year Number of Users by Years of Follow-Up Time Year <1 1-<2 2-<3 3-<4 4-<5 5-<6 6-<7 7-<8 8-<9 9-<10 10-<11 11-<12 12-<13 13-<14 14-<15 15-< Psoriasis Drugs , , ,259 1,970 1,390 1, , ,240 4,059 2,672 1,997 1,361 1, ,793 3, ,128 5,580 3,940 2,403 2,554 1,646 2,589 4, ,782 5,597 3,485 3,251 2,156 3,244 6, ,513 4,893 4,559 2,819 3,997 7, ,215 6,300 3,973 5,446 8, ,951 5,973 7,956 10, ,176 11,404 14, ,558 20, ,

19 Table 2b: Proportion of Patients with Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Year Percentage of Users by Years of Follow-Up Time Year < Total (n) Adalimumab % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.00% 0.0% % 54.7% 47.7% 41.6% 37.6% 33.8% 30.1% 27.7% 25.8% 23.9% 21.6% 15.1% 0.0% 0.0% 0.0% % 52.0% 47.2% 42.4% 37.5% 35.2% 32.1% 30.2% 28.6% 26.2% 18.6% 0.1% 0.0% 0.0% 0.0% % 61.6% 56.7% 52.5% 47.5% 44.4% 41.1% 37.8% 33.8% 23.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 62.0% 54.1% 49.2% 43.7% 39.9% 35.9% 31.9% 22.8% 0.1% 0.0% 0.0% 0.0% 0.0% 0.0% 1, % 56.1% 47.9% 40.0% 35.2% 30.2% 26.0% 18.2% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 3, % 46.7% 38.1% 32.4% 26.2% 22.4% 14.1% 0.1% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 8, % 42.9% 35.6% 27.5% 22.5% 14.6% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 11, % 45.6% 35.1% 28.4% 18.1% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 11, % 44.6% 35.5% 22.9% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 11, % 44.1% 26.9% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 10, % 32.9% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 12, % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 13, % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 17, % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 12, % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 10 Alemtuzumab % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 100.0% 100.0% 50.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 25.0% 25.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 45.0% 35.0% 35.0% 25.0% 15.0% 15.0% 10.0% 10.0% 5.0% 5.0% 0.0% 0.0% 0.0% 0.0% % 19.5% 12.2% 12.2% 12.2% 9.8% 9.8% 7.3% 7.3% 7.3% 2.4% 0.0% 0.0% 0.0% 0.0% % 25.0% 15.0% 15.0% 15.0% 15.0% 15.0% 10.0% 5.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 30.2% 23.3% 14.0% 14.0% 11.6% 7.0% 7.0% 4.7% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 31.2% 22.6% 17.2% 14.0% 11.8% 8.6% 6.5% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 24.2% 19.4% 13.7% 11.3% 8.9% 6.5% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 20.5% 9.4% 5.5% 3.1% 2.4% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 24.0% 19.2% 16.3% 9.6% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 17.2% 16.1% 12.6% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 24.8% 16.5% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 21.2% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0

20 Table 2b: Proportion of Patients with Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Year Percentage of Users by Years of Follow-Up Time Year < Total (n) Certolizumab % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 41.4% 32.7% 25.9% 18.0% 13.9% 2.6% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 41.7% 32.9% 24.0% 19.5% 10.1% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 1, % 43.4% 32.5% 24.8% 14.2% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 1, % 41.6% 32.9% 20.1% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 1, % 41.3% 21.7% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 1, % 25.3% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 2, % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 2, % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 2, % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 1, % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0 Dalfampridine % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 51.9% 41.4% 33.8% 23.7% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 3, % 48.1% 39.0% 26.6% 0.1% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 1, % 50.9% 31.5% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 1, % 33.4% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.1% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 1, % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 1, % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0

21 Table 2b: Proportion of Patients with Follow-Up Time After Incident Use of Immunosuppressive Drugs in the Sentinel Distributed Database from January 1, 2000 to the Latest Available Data, by Drug and Year Percentage of Users by Years of Follow-Up Time Year < Total (n) Dimethyl Fumarate % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 31.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 6, % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 4, % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 2, % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 1, % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 2 Etanercept % 68.9% 63.5% 55.4% 44.0% 40.7% 38.4% 34.6% 33.0% 30.3% 29.3% 27.2% 25.1% 22.0% 14.3% % 77.9% 70.8% 54.9% 49.5% 46.7% 44.5% 40.6% 38.0% 35.2% 32.6% 30.2% 27.8% 20.5% 0.2% % 70.6% 53.9% 46.5% 40.6% 35.8% 33.2% 30.0% 28.1% 24.5% 23.2% 19.7% 8.1% 0.0% 0.0% % 61.6% 56.0% 50.8% 47.4% 43.1% 39.6% 36.8% 34.9% 32.9% 30.9% 24.1% 0.2% 0.0% 0.0% 1, % 58.8% 52.8% 48.7% 44.0% 40.1% 37.3% 34.5% 31.3% 28.4% 19.7% 0.1% 0.0% 0.0% 0.0% 1, % 64.0% 57.9% 52.2% 47.9% 44.1% 41.1% 38.4% 35.6% 26.1% 0.1% 0.0% 0.0% 0.0% 0.0% 1, % 59.4% 51.6% 45.4% 39.7% 36.2% 31.7% 27.5% 18.4% 0.1% 0.0% 0.0% 0.0% 0.0% 0.0% 3, % 55.0% 46.1% 39.0% 34.0% 29.1% 25.3% 18.4% 0.1% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 5, % 47.6% 38.5% 32.5% 26.2% 21.7% 14.4% 0.1% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 8, % 44.7% 36.9% 29.1% 23.9% 16.1% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 10, % 46.3% 36.2% 29.4% 19.2% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 9, % 45.5% 36.5% 24.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 9, % 44.2% 26.6% 0.1% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 9, % 32.8% 0.3% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 9, % 0.1% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 9, % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 7, % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 5, % 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 7