Post-market Authorized Generic Evaluation (PAGE) U01FD005272-02 - - PowerPoint PPT Presentation

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Post-market Authorized Generic Evaluation (PAGE) U01FD005272-02 - - PowerPoint PPT Presentation

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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

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SLIDE 1

Post-market Authorized Generic Evaluation (PAGE)

U01FD005272-02

November 18th, 2016 Peggy L. Peissig Richard Berg Michael Caldwell James Linneman Richard Hansen Jingjing Qian Motiur Rahman Ning Cheng Yasser Alatawi David Page Enrique Seoane- Vazquez

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SLIDE 2

Project Overview

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SLIDE 3

Specific Aim 1

  • To determine and compare switchback rates,

medical service utilization, and clinical

  • utcomes between authorized generics (AGs)

and generics using healthcare claim data with electronic medical records.

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SLIDE 4

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

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SLIDE 5

Aim 1 Methods (cont’d)

Branded treatment initiation Generic entry

Generic switch Non-switchers: stay on brand Switchback

Index date for generic switch Index date for switchback

Switchers: stay on generic Switchers: switchback to brand

Pre-index Brand Brand Generic

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

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SLIDE 6

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

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SLIDE 7

Rates of Switching

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%) 7

*Factors associated with a higher likelihood of generic switch in the overall drug cohort included pre-index defined daily dose and all- cause hospitalization Time from generic entry to generic switch by drug

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SLIDE 8

Rates of Switching Back to Brand

Factors Brand to Generic Switchback Hazard Ratio 95% Confidence 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

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*P<0.05, multivariable Cox proportional hazards model

Brand switchback rate from AG vs. OG

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SLIDE 9

Health Services Use & Outcomes

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*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.

Adjusted medical service utilization and outcomes for AG vs. OG users

Outcome Estimate Lower CI Upper CI P-Value

1.05 1 1.1 0.071 1.08 0.9 1.29 0.395 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 Number of all-cause

  • utpatient visists per year

Number of all-cause urgent care visits per year 1

Estimate

0.5 2

Favors OG Favors AG

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SLIDE 10

Specific Aim 2

  • To analyze brand versus generic adverse event

reporting rates in the FDA Adverse Event Reporting System (FAERS)

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SLIDE 11

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

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SLIDE 12

Drugs

  • Alendronate
  • Amlodipine
  • Azithromycin
  • Carbamazepine XR
  • Escitalopram
  • Lamotrigine
  • Leflunomide
  • Losartan
  • Metoprolol XR
  • Modafinil
  • Oxcarbazepine
  • Sertraline
  • Venlafaxine ER
  • Zolpidem

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SLIDE 13

Events

  • Coded by Preferred Terms (PT) or

Standardized MedDRA Query (SMQ)

  • Drug specific events defined by label
  • Universal events

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  • Accidents & injuries
  • Lack of efficacy
  • Anaphylactic reactions
  • Ischemic heart disease
  • Embolic & thrombotic events
  • Hematopoietic cytopenias
  • Hemorrhages
  • Death
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SLIDE 14

Report Type as Percentage of Total

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20 40 60 80 100 120

US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS US US, PS US, Serious, valid, PS

  • 8
  • 7
  • 6
  • 5
  • 4
  • 3
  • 2
  • 1

1 2 3 4 5 6 7 8 9 10

BRAND% AG% GENERIC%

  • --- Inclusive of all drugs ---

Report Percentage Generic Entry

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SLIDE 15

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Lamotrigine – Labeled Events

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SLIDE 16

Segmented Regression

Full Segmented Regression Model* (unadjusted for prescription sales)

Total US Adverse Events US Serious Adverse Events FDA time EVENT time MFR time FDA time EVENT time MFR time

Intercept β0

147 (P= 0.71) 524 (P= 0.01) 525 (P=0.005) 41 (P=0.46) 88 (P=0.03) 90 (P=0.17)

Trend before AG entered into market (Period 1) β1

87 (P=0. 37) 22 (P= 0.64) 15 (P= 0.07) 17 (P=0.08) 5 (P=0.46) 7 (P=0.72)

Level change after AG but before other IG entered into market (Period 2) β2

  • 139

(P= 0.71)

  • 166

(P= 0.39)

  • 62

(P= 0.72)

  • 18

(P=0.62)

  • 18

(P=0.52) 19 (P=0.81)

Trend change after AG but before other IG entered into market (Period 2) β3

  • 80

(P= 0.51) 11 (P= 0.87)

  • 17

(P= 0.83)

  • 22

(P=0.06)

  • 5

(P=0.56)

  • 13

(P=0.63)

Level change after other IG entered into market (Period 3) β4

27 (P= 0.92)

  • 197

(P= 0.12)

  • 112

(P= 0.40) 9 (P=0.73)

  • 2

(P=0.90)

  • 1

(P=0.99)

Trend change after other IG entered into market (Period 3) β5

  • 12

(P= 0.89)

  • 38

(P= 0.42)

  • 1

(P= 0.99) 7 (P=0.42) 0.48 (P=0.94) 8 (P=0.68)

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Lamotrigine

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SLIDE 17

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

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SLIDE 18

Methodological Approach

  • Illustrated with alendronate

– Which report types? – Which time? – Ignore the AG?

  • Illustrated with carbamazepine XR

– Multiple formulations with and without AG?

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SLIDE 19

Sensitivity Analysis: Report Type?

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Alendronate – Gastritis

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SLIDE 20

Sensitivity Analysis: Count All Time?

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Alendronate

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SLIDE 21

Sensitivity Analysis: Ignore AG?

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Alendronate

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SLIDE 22

Sensitivity Analysis: Modified Formulations?

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Carbamazepine

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SLIDE 23

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Brand Authorized Generic Generic

Sensitivity Analysis:

  • FDA_date
  • Event_date
  • Report_date

Alendronate

500 1000 1500 2000 2500 3000 3500 4000

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

REPORTS YEAR FDA_Time EVENT_Time MFR_Time

AG/IG Entry

50 100 150 200

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 REPORTS YEAR

FDA_Time EVENT_Time MFR_Time

AG/IG Entry

200 400 600 800 1000 1200 1400 1600

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 REPORTS YEAR

FDA_Time EVENT_Time MFR_Time

AG/IG Entry

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SLIDE 24

Suicide / Suicidal Ideation in FAERS

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SLIDE 25

Suicide / Suicidal Ideation in SHP

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Sertraline Gabapentin Methylphenidate Zolpidem BRAND GENERIC BRAND GENERIC BRAND GENERIC BRAND GENERIC SAMPLE SIZE 7468 19015 3330 20597 6169 1630 7678 13215 Event count (n, %) 35 (0.5%) 249 (1.3%) 14 (0.4%) 103 (0.5%) 25 (0.4%) 16 (1.0%) 39 (0.5%) 123 (0.9%) Unadjusted p- value <.0001 Ref 0.6873 Ref 0.0106 Ref 0.0007 Ref Hazard Ratio (95% CI) 0.53 (0.3- 0.8) Ref 1.07 (0.5- 2.4) Ref 0.37 (0.1- 1.0) Ref 0.85 (0.5- 1.4) Ref Adjusted p- value 0.0031 Ref 0.8666 Ref 0.0506 Ref 0.5279 Ref

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SLIDE 26

Specific Aim 3

  • To develop a pilot surveillance system to

compare patient experience for authorized generics and independent generics with brand name drugs for differential adverse event signal detection.

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SLIDE 27

Marshfield’s Population

Security Health Plan MC Primary Service Area

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SLIDE 28

Analysis Decision Points

  • Analysis cohort (e.g. first-time users of the drug vs. switch cohort)
  • Maximum length of observation time (e.g. 365 days vs. 30 days)
  • Inclusion / Exclusion of those with events prior to drug exposure
  • Inclusion / Exclusion of those with events documented on a single date
  • Statistical model (e.g. PH model of time to first event, negative binomial)
  • Covariates
  • Gender
  • Age
  • Charlson comorbidity score
  • Diabetes indicator
  • Smoking indicator
  • MESA residency indicator
  • Estimated SHP rate for the event of interest
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SLIDE 29
  • Review the raw data
  • Initial model based analysis
  • Are numbers small?
  • Review unadjusted/adjusted significance
  • Are hazard ratios reasonable?

Initial screening

  • Evaluate results after varying decision points
  • Evaluate subsetting cohort to limit date of first

exposure

  • Gather extensive data pre-exposure
  • Evaluate associations with B/G and outcome
  • Develop propensity score to improve B/G comparability
  • Use another drug as secondary comparison group

Secondary analysis

  • Trained research coordinator review
  • Expert evaluation

Expert Review

Surveillance System Development Process

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SLIDE 30

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SLIDE 31

Contact Information

Richard Hansen, RPh, PhD

rah0019@auburn.edu Auburn University Harrison School of Pharmacy Department of Health Outcomes Research & Policy

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