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

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 Science Center for Drug Evaluation and Research - FDA FDA Science Board

2. Outline • Background/Context • AERS • Drug Utilization Contracts • Epidemiology Research Contracts • General Practitioners Research Database FDA Science Board

3. 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 FDA Science Board

4. 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 FDA Science Board

5. Background: Premarket • Pre-approval safety conference • Advisory committee • public record of the safety and efficacy basis for the approval FDA Science Board

6. 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 FDA Science Board

7. 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) FDA Science Board

8. 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 FDA Science Board

9. Adverse Event Reports by Year FDA Science Board

10. 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 FDA Science Board

11. 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 FDA Science Board

12. 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 FDA Science Board

13. Supplements to AERS • Drug Utilization Data Resources • Epidemiology Research Contracts • Additional Resources FDA Science Board

14. 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 FDA Science Board

15. 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 FDA Science Board

16. Uses of drug utilization data • 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 FDA Science Board

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. Awardees • HMO Research Network • Vanderbilt University • Kaiser Foundation Research • Ingenix (i3Drug Safety) • Total budget: $1.6 million ($400K ea) • Awarded: September 2005 FDA Science Board

19. 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 FDA Science Board

20. 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 FDA Science Board

21. 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 FDA Science Board

22. 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 FDA Science Board

23. 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 FDA Science Board

24. 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 FDA Science Board

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

26. GPRD • Limitations • UK population • Different health care standards and practice • Different prescribing patterns • National formulary—cost containment • Complex data structure—requires highly specialized training FDA Science Board

27. All Data Sources Are Valuable Epidemiologic Studies Case Reports Randomized Clinical Trials Drug Utilization Medical Records/ Administrative Data FDA Science Board

28. 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 FDA Science Board