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