Post-market Authorized Generic Evaluation (PAGE) U01FD005272-02 November 18 th , 2016 David Page Richard Hansen Peggy L. Peissig Jingjing Qian Richard Berg Motiur Rahman Michael Caldwell Ning Cheng James Linneman Enrique Seoane- Yasser Alatawi Vazquez
Project Overview 2
Specific Aim 1 • To determine and compare switchback rates, medical service utilization, and clinical outcomes between authorized generics (AGs) and generics using healthcare claim data with electronic medical records. 3
Aim 1 Methods • Study design : a retrospective cohort study • Study population : Marshfield Clinic (MC) Security Health Plan (SHP) claims data with linked electronic health records (EHR) data in 1999-2014 • Inclusion criteria : – Continuous enrollment (CE) in 6-mon prior to generic introduction through at least the first Rx fill after generic availability – At least 1 brand Rx in 6-mon prior and 1 Rx fill of a medication in the therapeutic area within 12-mon after generic availability – At least 1 MC healthcare encounter/year during eligible periods 4
Aim 1 Methods (cont’d) Branded Generic treatment entry initiation Pre-index Non-switchers: stay on brand Brand Switchers: switchback to brand Brand Index date Switchback for generic switch Generic Generic Switchers: stay on generic switch Index date for switchback Generic switch : switch from a brand drug to an authorized or independent generic drug within 30 months following generic entry Switchback : among those who had a brand to generic switch, generic to brand switchback rates were calculated in 30 months following the index switch date 5
Aim 1 Methods (cont’d) • Revised drugs of interest : Drugs Generic Switch Switchback alendronate x x amlodipine x x citalopram x x gabapentin x x glimepiride x losartan x metformin x paroxetine x x sertraline x x simvastatin x x 6
Rates of Switching Time from generic entry to generic switch by drug Drugs Switch Type Brand to AG Brand to OG All drugs (n=5234) 1138 (23%) 3762 (77%) Alendronate (n=930) 41 (5%) 832 (95%) Amlodipine (n=1487) 289 (20%) 1156 (80%) Citalopram (n=813) 74 (10%) 670 (90%) Gabapentin (n=279) 25 (11%) 199 (89%) Paroxetine (n=669) 302 (48%) 328 (52%) Sertraline (n=730) 278 (40%) 417 (60%) Simvastatin (n=636) 176 (30%) 408 (70%) *Factors associated with a higher likelihood of generic switch in the overall drug cohort included pre-index defined daily dose and all- cause hospitalization 7
Rates of Switching Back to Brand Brand switchback rate from AG vs. OG Factors Brand to Generic Switchback Hazard 95% Confidence Ratio Interval IG (REF=AG) 0.86 0.65-1.15 Age 1.02 * 1.01-1.02 Male 0.59 * 0.44-0.80 Proportion of pre-index brand medication use 2.43 * 1.45-4.07 Defined daily dose prior to switching 0.85 0.72-1.01 Charlson comorbidity index 1.02 0.90-1.16 Pre-index hospitalization 0.87 0.52-1.48 Pre-index ED visit 1.02 0.67-1.56 Count of pre-index outpatient visits 1.02 1.00-1.02 *P<0.05, multivariable Cox proportional hazards model 8
Health Services Use & Outcomes Adjusted medical service utilization and outcomes for AG vs. OG users Lower Upper Estimate CI CI P-Value Outcome Number of all-cause outpatient visists per year 1.05 1 1.1 0.071 Number of all-cause urgent 1.08 0.9 1.29 0.395 care visits per year All-cause emergency department visits Any visit 1.33 1.11 1.61 0.003 Number per year 1.23 1.02 1.47 0.026 All-cause hospitalizations Any visit 1.14 0.91 1.43 0.257 Number per year 1.09 0.81 1.46 0.582 Medication discontinuation 0.95 0.8 1.12 0.508 Favors OG 1 Favors AG 2 0.5 Estimate *Medical service utilization and outcomes were measured during a 12-month period after generic switch. Generalized logistic regression was used to model binary outcomes and negative binomial regression were used to mode count outcomes. Age, defined daily dose, and Charlson score were controlled as covariates in these models. 9
Specific Aim 2 • To analyze brand versus generic adverse event reporting rates in the FDA Adverse Event Reporting System (FAERS) 10
Methods • Data – FAERS data 2004-2014 • Approach – Method 1 – verbatim assignment by name – Method 2 – assign reports to manufacturer • Exclude direct reports • Sensitivity analyses around which reports to include, such as primary suspect, serious, US only, validated • Analyses – Disproportionality analyses – Segmented regression 11
Drugs • Alendronate • Losartan • Amlodipine • Metoprolol XR • Azithromycin • Modafinil • Carbamazepine XR • Oxcarbazepine • Escitalopram • Sertraline • Lamotrigine • Venlafaxine ER • Leflunomide • Zolpidem 12
Events • Coded by Preferred Terms (PT) or Standardized MedDRA Query (SMQ) • Drug specific events defined by label • Universal events - Accidents & injuries - Lack of efficacy - Anaphylactic reactions - Ischemic heart disease - Embolic & thrombotic events - Hematopoietic cytopenias - Hemorrhages - Death 13
Report Percentage 100 120 20 40 60 80 0 Report Type as Percentage of Total US US, PS -8 US, Serious, valid, PS US BRAND% US, PS -7 US, Serious, valid, PS US US, PS -6 US, Serious, valid, PS AG% US US, PS -5 US, Serious, valid, PS GENERIC% US US, PS -4 US, Serious, valid, PS US US, PS -3 US, Serious, valid, PS US US, PS -2 US, Serious, valid, PS US US, PS -1 ---- Inclusive of all drugs --- US, Serious, valid, PS Generic Entry US US, PS 0 US, Serious, valid, PS US US, PS 1 US, Serious, valid, PS US US, PS 2 US, Serious, valid, PS US US, PS 3 US, Serious, valid, PS US US, PS 4 US, Serious, valid, PS US US, PS 5 US, Serious, valid, PS US US, PS 6 US, Serious, valid, PS US US, PS 7 US, Serious, valid, PS US US, PS 8 US, Serious, valid, PS US US, PS 9 US, Serious, valid, PS US 10 US, PS 14 US, Serious, valid, PS
Lamotrigine – Labeled Events 15
Segmented Regression Full Segmented Total US Adverse Events US Serious Adverse Events Regression Model* (unadjusted for FDA EVENT MFR FDA EVENT MFR prescription sales) time time time time time time Intercept β 0 147 524 525 41 88 90 (P= 0.71) (P= 0.01) (P=0.005) (P=0.46) (P=0.03) (P=0.17) Trend before AG entered into market 87 22 15 17 5 7 (Period 1) β 1 (P=0. 37) (P= 0.64) (P= 0.07) (P=0.08) (P=0.46) (P=0.72) Level change after AG but before other -139 -166 -62 -18 -18 19 IG entered into market (Period 2) β 2 (P= 0.71) (P= 0.39) (P= 0.72) (P=0.62) (P=0.52) (P=0.81) Trend change after AG but before other -80 11 -17 -22 -5 -13 IG entered into market (Period 2) β 3 (P= 0.51) (P= 0.87) (P= 0.83) (P=0.06) (P=0.56) (P=0.63) Level change after other IG entered into 27 -197 -112 9 -2 -1 market (Period 3) β 4 (P= 0.92) (P= 0.12) (P= 0.40) (P=0.73) (P=0.90) (P=0.99) Trend change after other IG entered into -12 -38 -1 7 0.48 8 market (Period 3) β 5 (P= 0.89) (P= 0.42) (P= 0.99) (P=0.42) (P=0.94) (P=0.68) Lamotrigine 16
Methodological Challenges • Limited Authorized Generic Formulations – Only specific formulations available as AG • Lamotrigine chewable • Extended release carbamazepine, metoprolol, venlafaxine • Authorized Generic Availability – Strength of connection between brand and AG • Greenstone and Pfizer – Dual marketing of AG and ANDA-approved generic • Dr. Reddy’s Simvastatin 17
Methodological Approach • Illustrated with alendronate – Which report types? – Which time? – Ignore the AG? • Illustrated with carbamazepine XR – Multiple formulations with and without AG? 18
Sensitivity Analysis: Report Type? Alendronate – Gastritis 19
Sensitivity Analysis: Count All Time? Alendronate 20
Sensitivity Analysis: Ignore AG? Alendronate 21
Sensitivity Analysis: Modified Formulations? Carbamazepine 22
4000 3500 Sensitivity 3000 2500 REPORTS 2000 Brand Analysis: 1500 1000 500 0 • FDA_date 2 0 0 4 2 0 0 5 2 0 0 6 2 0 0 7 2 0 0 8 2 0 0 9 2 0 1 0 2 0 1 1 2 0 1 2 2 0 1 3 2 0 1 4 2 0 1 5 AG/IG Entry YEAR FDA_Time EVENT_Time MFR_Time • Event_date 200 • Report_date 150 REPORTS Authorized 100 Generic 50 0 2 0 0 4 2 0 0 5 2 0 0 6 2 0 0 7 2 0 0 8 2 0 0 9 2 0 1 0 2 0 1 1 2 0 1 2 2 0 1 3 2 0 1 4 2 0 1 5 AG/IG Entry YEAR FDA_Time EVENT_Time MFR_Time 1600 1400 1200 1000 800 REPORTS 600 Generic 400 200 0 2 0 0 4 2 0 0 5 2 0 0 6 2 0 0 7 2 0 0 8 2 0 0 9 2 0 1 0 2 0 1 1 2 0 1 2 2 0 1 3 2 0 1 4 2 0 1 5 AG/IG Entry YEAR Alendronate FDA_Time EVENT_Time MFR_Time 23
Suicide / Suicidal Ideation in FAERS 24
Suicide / Suicidal Ideation in SHP Sertraline Gabapentin Methylphenidate Zolpidem BRAND GENERIC BRAND GENERIC BRAND GENERIC BRAND GENERIC SAMPLE SIZE 7468 19015 3330 20597 6169 1630 7678 13215 Event count 35 249 14 103 25 16 39 123 (n, %) (0.5%) (1.3%) (0.4%) (0.5%) (0.4%) (1.0%) (0.5%) (0.9%) Unadjusted p- <.0001 Ref 0.6873 Ref 0.0106 Ref 0.0007 Ref value Hazard Ratio 0.53 1.07 0.37 0.85 Ref Ref Ref Ref (95% CI) (0.3- 0.8) (0.5- 2.4) (0.1- 1.0) (0.5- 1.4) Adjusted p- 0.0031 Ref 0.8666 Ref 0.0506 Ref 0.5279 Ref value 25
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