1. March 31, 2006FDA Science Board1 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 Science Center for Drug Evaluation and Research - FDA

2. March 31, 2006FDA Science Board2 Outline Background/Context AERS Drug Utilization Contracts Epidemiology Research Contracts General Practitioners Research Database

3. March 31, 2006FDA Science Board3 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

4. March 31, 2006FDA Science Board4 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

5. March 31, 2006FDA Science Board5 Background: Premarket Pre-approval safety conference Advisory committee –public record of the safety and efficacy basis for the approval

6. March 31, 2006FDA Science Board6 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

7. March 31, 2006FDA Science Board7 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)

8. March 31, 2006FDA Science Board8 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

9. March 31, 2006FDA Science Board9 Adverse Event Reports by Year

10. March 31, 2006FDA Science Board10 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

11. March 31, 2006FDA Science Board11 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

12. March 31, 2006FDA Science Board12 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

13. March 31, 2006FDA Science Board13 Supplements to AERS Drug Utilization Data Resources Epidemiology Research Contracts Additional Resources

14. March 31, 2006FDA Science Board14 Drug Utilization Data Resources IMS Health –IMS National Sales Perspectives m easures 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

15. March 31, 2006FDA Science Board15 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

16. March 31, 2006FDA Science Board16 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

17. 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

18. March 31, 2006FDA Science Board18 Awardees HMO Research Network Vanderbilt University Kaiser Foundation Research Ingenix (i3Drug Safety) Total budget: $1.6 million ($400K ea) Awarded: September 2005

19. March 31, 2006FDA Science Board19 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

20. March 31, 2006FDA Science Board20 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

21. March 31, 2006FDA Science Board21 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

22. March 31, 2006FDA Science Board22 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

23. March 31, 2006FDA Science Board23 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

24. March 31, 2006FDA Science Board24 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

25. March 31, 2006FDA Science Board25 GPRD The General Practice Research Database (GPRD) –UK-based electronic medical records –Longitudinal –Complex relational file structure –FDA has in-house access via Internet

26. March 31, 2006FDA Science Board26 GPRD Limitations –UK population –Different health care standards and practice –Different prescribing patterns –National formulary—cost containment –Complex data structure—requires highly specialized training

27. March 31, 2006FDA Science Board27 All Data Sources Are Valuable Randomized Clinical Trials Epidemiologic Studies Case Reports Drug UtilizationMedical Records/ Administrative Data

28. March 31, 2006FDA Science Board28 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