March 31, 2006 FDA Science Board 1

CDER's Office of Drug Safety: Electronic Tools for Risk

Assessment and Evaluation

Paul J. Seligman, M.D., M.P.H.Director

Office of Pharmacoepidemiology and Statistical ScienceCenter for Drug Evaluation and Research - FDA

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Outline• Background/Context• AERS• Drug Utilization Contracts• Epidemiology Research Contracts• General Practitioners Research

Database

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Background: Premarket

• Randomized clinical trials are the basis for most approved drugs’ indications– These trials are typically powered and

designed around efficacy, rather than safety endpoints

– Safety assessment suffered from lack of organized to approach to wealth of monitoring data

• Reviewer guidance• Electronic analytic tools

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Background: Premarket

• Often, the nature and extent of safety signals identified in trials cannot be fully characterized prior to approval– Randomized clinical trials (RCTs) may not be

large enough to detect rare events– The trial environment can fail to account for

“real world” use:• Comorbid illnesses• Concomitant medications

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Background: Premarket

• Pre-approval safety conference• Advisory committee

– public record of the safety and efficacy basis for the approval

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Drug Safety Program: Overview

• CDER’s Post-Marketing Drug Safety Risk Assessment Program:– ongoing clinical development of the drug– Phase IV studies– tracking adverse events of marketed drugs (note:

includes medication errors)– monitoring the utilization of marketed drugs– soliciting/performing population-based epidemiologic

studies

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Drug Safety Program: Overview

• Role expanding/evolving– pre-marketing safety assessment– pharmacovigilance planning– risk minimization action plans (RiskMAPs) – risk communication

• MedWatch• patient information

– medication error prevention (names, packaging)

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The Adverse Event Reporting System - AERS

• Computerized Oracle database• Contents: > 3 million adverse drug experience

reports from– sponsors - mandatory reporting– health care providers & consumers - voluntary

reporting through MedWatch– also medication error reports through MedWatch,

USP, ISMP• Steady increase in numbers of reports submitted

each year

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Adverse Event Reports by Year

CDER/CBER Post-Marketing Adverse Event Reports ReceivedAE RS Database/PSI Reporting for Marc h 29, 2006

0

50,000

100,000

150,000

200,000

250,000

300,000

350,000

400,000

450,000

500,000

1990 1991 1992 1993 1994 1995 1996 1997 Post-Marketing

AERS

1998 1999 2000 2001 2002 2003 2004 2005 2006

FDA Calendar Year

FollowUp Adjustment (SRS only)*Non-Serious Periodic (non-AERS)PeriodicExpeditedmedwatch Direct

AERS

SRS

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Data Mining

• What is Data Mining?– A statistical technique, by which large

databases are searched (i.e., “mined”) to detect strong, consistent associations that occur at higher than expected frequencies

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Data Mining in AERS• AERS can be mined for drug-event

combinations that occur more frequently than expected.

• Early warning system– problems with marketed drugs– drug-drug interactions– gender, age, other subgroup differences– understanding AE patterns within a drug class

• Supplement to, not replacement for, the work of safety evaluators, epidemiologists

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WebVDME

• The Web Visual Data Mining System (WebVDME)– “User-friendly,” web-based, desktop data

mining software– Jointly developed by FDA and Lincoln

Technologies, Inc. under a CRADA– Currently in production in ODS for use by

safety evaluators and epidemiologists for pharmacovigilance purposes

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Supplements to AERS

• Drug Utilization Data Resources• Epidemiology Research

Contracts• Additional Resources

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Drug Utilization Data Resources• IMS Health

– IMS National Sales Perspectives• measures the volume of drug products sold from manufacturers into various

retail and non-retail channels of distribution in terms of sales dollars, units, and market share.

– National Disease and Therapeutic Index (NDTI)• provide descriptive information on the patterns and treatment of diseases

encountered in office-based practices in the continental U.S. • Verispan, LLC.

– Vector One National (VONA)• quantify the number of prescriptions dispensed in the retail setting• demographic information on the population exposed

– Total Patient Tracker (TPT)• quantify the number of unique patients getting a prescription filled for a drug in

the retail setting• demographic information on the population exposed

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Drug Utilization Data Resources

• Premier - Inpatient Information, adults and pediatrics– The Premier MarketRx Advisor database provides

information on medication usage and describes national patterns of drug utilization in the inpatient setting from over 450 acute care facilities and 18 million inpatient records

– The Premier Pediatric database provides information on medication usage and characterizes pediatric inpatient drug utilization from 37 free-standing children’s hospitals at the patient-level

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• quantifying the number of prescriptions dispensed in a retail setting

• demographic information on the population exposed• in association with spontaneous case report data to

understand the context within which ADRs occur • with supplemental data obtained from population-

based claims or record-linked databases, to estimate patient exposure time for a particular drug product

Uses of drug utilization data

Epidemiology Contracts

• Scope of Work:– Conduct pharmacoepidemiologic studies of

drug safety using automated data– Supplement automated data with data from

medical records, death certificates, patient or physician surveys

– For selected projects, provide analytical datasets to FDA for analysis

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Awardees

• HMO Research Network• Vanderbilt University• Kaiser Foundation Research• Ingenix (i3Drug Safety)

• Total budget: $1.6 million ($400K ea)• Awarded: September 2005

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HMO Research Network

• 3.2 million covered lives• 8 HMOs (MA[2] , OR, MN, WA, CO, GA,

NM)• 6 of 8 sites have electronic medical

records• Primary Investigator: Rich Platt

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Vanderbilt University

• 2.2 million covered lives• Tennessee and Washington Medicaid• Ethnically diversified• High risk populations• Linkage to vital statistics, cancer registry• Primary Investigator: Wayne Ray

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Kaiser Foundation Research Institute

• 6.1 million covered lives• Kaiser – northern & southern CA• Electronic medical records• Linkage to vital statistics and cancer

registry• Primary Investigator: Joe Selby

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Ingenix

• 12 million covered lives• Insured, geographically diverse population• Some laboratory data available• Allows access to i3Aperio – web-based

tool for selected feasibility studies• Primary Investigator: Arnold Chan

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Epidemiology Contracts– provide FDA access to data resources that can be

used to conduct drug safety analyses to the benefit of the public’s health,

– to respond expeditiously to urgent public safety concerns,

– to provide a mechanism for collaborative pharmacoepidemiological research designed to test hypotheses, particularly those arising from suspected adverse reactions reported to FDA, and

– to enable rapid access to U.S. population-based data sources to ensure public health safety when necessary

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Epidemiologic Databases

• Limitations– Outpatient prescriptions only– No OTC, herbal, alternative– Data time-lag– Formulary issues (slow market penetration)– Study completion time– Difficulty in death ascertainment

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GPRD

• The General Practice Research Database (GPRD)– UK-based electronic medical records– Longitudinal– Complex relational file structure– FDA has in-house access via Internet

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GPRD

• Limitations– UK population– Different health care standards and practice– Different prescribing patterns– National formulary—cost containment– Complex data structure—requires highly

specialized training

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All Data Sources Are Valuable

Randomized Clinical Trials

Epidemiologic Studies

Case Reports

Drug Utilization Medical Records/Administrative Data

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Conclusions• All data have relative strengths and weaknesses

– RCTs: poor external validity, expensive to conduct, difficult to recruit subjects, BUT strong internal validity

– Observational studies: poor internal validity, BUT easier to conduct, good external validity

• The kind of data we use depends on the nature of the question and what’s available