1. DSaRM Advisory Committee May 18, 2005 Active Surveillance for Drug Safety Signals: Past, Present, and Future Mary Willy, Ph.D. Division of Drug Risk Evaluation Office of Drug Safety Center for Drug Evaluation and Research Food and Drug Administration Mary Willy, Ph.D. Division of Drug Risk Evaluation Office of Drug Safety Center for Drug Evaluation and Research Food and Drug Administration

2. DSaRM Advisory Committee May 18, 2005 2 OutlineOutline Background History Examples of Programs Challenges Possible U.S. Applications Background History Examples of Programs Challenges Possible U.S. Applications

3. DSaRM Advisory Committee May 18, 2005 3 Components of a Comprehensive Postmarketing Surveillance Program at CDER Drug Utilization data: * Outpatient * Inpatient * Longitudinal External Health care databases: *General popn *Special popn’s Passive Surveillance Background Incidence Rates Active Surveillance

4. DSaRM Advisory Committee May 18, 2005 4 Background: ODS Epidemiology Activities Case reports - putting into perspective –Reporting rates, background rates, literature Use of drug utilization data –Problems with underreporting Further study in population databases –Claims databases –Electronic medical record databases –National surveys Case reports - putting into perspective –Reporting rates, background rates, literature Use of drug utilization data –Problems with underreporting Further study in population databases –Claims databases –Electronic medical record databases –National surveys

5. DSaRM Advisory Committee May 18, 2005 5 Future Activity: Active Surveillance Definition: regular periodic collection of case reports (of drug events) from health care providers or facilities. –Focus on events, settings, or drugs of interest Allows collection of more complete data One system is unlikely to address all drug safety problems Definition: regular periodic collection of case reports (of drug events) from health care providers or facilities. –Focus on events, settings, or drugs of interest Allows collection of more complete data One system is unlikely to address all drug safety problems

6. DSaRM Advisory Committee May 18, 2005 6 Potential Purposes of Active Surveillance Identify drug safety signal Validate drug safety signal identified through passive surveillance Identify drug safety signal Validate drug safety signal identified through passive surveillance

7. DSaRM Advisory Committee May 18, 2005 7 History of Active Surveillance 1960s: FDA initiated joint project with NIH and large HMO to develop medical record linkage –First attempt to link scanned forms from doctor visits, laboratory tests, pharmacy data, and other hospitalization information –Program failed because computer technology still in infancy 1960s: FDA initiated joint project with NIH and large HMO to develop medical record linkage –First attempt to link scanned forms from doctor visits, laboratory tests, pharmacy data, and other hospitalization information –Program failed because computer technology still in infancy

8. DSaRM Advisory Committee May 18, 2005 8 History of Active Surveillance 1970s: efforts to collect drug exposure information from hospitalized patients Early programs did not meet FDA needs –Lack of funding –Underdeveloped computer technology –Low yield of new information 1970s: efforts to collect drug exposure information from hospitalized patients Early programs did not meet FDA needs –Lack of funding –Underdeveloped computer technology –Low yield of new information

9. DSaRM Advisory Committee May 18, 2005 9 Strategies for Surveillance Drug-based –Systems follow large numbers of patients exposed to new molecular entities after their launch for all or specified events. Setting-based –Systems implemented in hospitals or emergency departments (ED) (or other settings) to detect relevant drug-related events likely to present there (e.g. anaphylaxis in ED). Disease-based –Systems include comprehensive disease- specific registries for selected drug- induced diseases. Drug-based –Systems follow large numbers of patients exposed to new molecular entities after their launch for all or specified events. Setting-based –Systems implemented in hospitals or emergency departments (ED) (or other settings) to detect relevant drug-related events likely to present there (e.g. anaphylaxis in ED). Disease-based –Systems include comprehensive disease- specific registries for selected drug- induced diseases.

10. DSaRM Advisory Committee May 18, 2005 10 Current Surveillance Systems Outside FDA – Setting-Based Drug Abuse Warning Network (DAWN) –Funded by Substance Abuse and Mental Health Services Administration –Surveillance setting: emergency department (nationally representative) and medical examiners (not nationally representative) –Recently revised; collects data from 22 metro areas Ages 6-97 years Any kind of drug-related event Chart review of cases Drug Abuse Warning Network (DAWN) –Funded by Substance Abuse and Mental Health Services Administration –Surveillance setting: emergency department (nationally representative) and medical examiners (not nationally representative) –Recently revised; collects data from 22 metro areas Ages 6-97 years Any kind of drug-related event Chart review of cases

11. DSaRM Advisory Committee May 18, 2005 11 Pros/Cons of DAWN for Active Surveillance for Drug Safety Signals Pros –Nationally representative Cons –Newly revised so not able to study trends Pros –Nationally representative Cons –Newly revised so not able to study trends

12. DSaRM Advisory Committee May 18, 2005 12 Current Surveillance Systems Outside FDA – Setting-Based Toxic Exposure Surveillance System (TESS) –Poisoning surveillance database since 1983 Maintained by the American Association of Poison Control Centers (AAPCC) 64 poison control centers in the U.S. Serves nearly the entire U.S. population Provides information, but mainly collects data on calls to Poison Control Centers regarding poisonings Toxic Exposure Surveillance System (TESS) –Poisoning surveillance database since 1983 Maintained by the American Association of Poison Control Centers (AAPCC) 64 poison control centers in the U.S. Serves nearly the entire U.S. population Provides information, but mainly collects data on calls to Poison Control Centers regarding poisonings

13. DSaRM Advisory Committee May 18, 2005 13 Pros/Cons of TESS for Active Surveillance for Drug Safety Signals Pros –Data from most of country –Can collect information on any drug, including over-the-counters Cons –Limited data available to FDA –Information not validated –Only included if call to PCC is made Pros –Data from most of country –Can collect information on any drug, including over-the-counters Cons –Limited data available to FDA –Information not validated –Only included if call to PCC is made

14. DSaRM Advisory Committee May 18, 2005 14 Current Surveillance Systems Outside FDA – Disease-Based Acute Liver Failure Study Group –Funded by NIH –25 adult and 25 pediatric sites collecting data and sera Patients hospitalized with severe hepatotoxicity Subset of patients identified with drug- related hepatotoxicity Acute Liver Failure Study Group –Funded by NIH –25 adult and 25 pediatric sites collecting data and sera Patients hospitalized with severe hepatotoxicity Subset of patients identified with drug- related hepatotoxicity

15. DSaRM Advisory Committee May 18, 2005 15 Pros/Cons of ALFSG for Active Surveillance for Drug Safety Signals Pros –Detailed, validated information on patients Cons –Not nationally representative –Collects data on only most severe hepatotoxicity events: acute liver failure or serious hepatotoxicity May miss cases that die before reach experts Pros –Detailed, validated information on patients Cons –Not nationally representative –Collects data on only most severe hepatotoxicity events: acute liver failure or serious hepatotoxicity May miss cases that die before reach experts

16. DSaRM Advisory Committee May 18, 2005 16 Current Surveillance Systems Outside FDA – Drug-Based United Kingdom Prescription Event Monitoring System (PEM) –Started in 1980 –Funded mainly by unconditional grants from pharmaceuticals –Newly approved drugs identified as important for monitoring Prescribers of this new drug sent green cards to complete; average cohort of patients studied >10,000 United Kingdom Prescription Event Monitoring System (PEM) –Started in 1980 –Funded mainly by unconditional grants from pharmaceuticals –Newly approved drugs identified as important for monitoring Prescribers of this new drug sent green cards to complete; average cohort of patients studied >10,000

17. DSaRM Advisory Committee May 18, 2005 17 Pros/Cons of PEM for Active Surveillance for Drug Safety Signals Pros –Involves majority of physicians in the country Cons –Typical cohort size (10,000) may not be large enough to capture rare events –Does not monitor hospitals or over-the-counter drugs –58% response rate; 52% contain clinically relevant data –U.S. does not have national prescription system Pros –Involves majority of physicians in the country Cons –Typical cohort size (10,000) may not be large enough to capture rare events –Does not monitor hospitals or over-the-counter drugs –58% response rate; 52% contain clinically relevant data –U.S. does not have national prescription system

18. DSaRM Advisory Committee May 18, 2005 18 Current Surveillance Systems Outside FDA – Setting-Based French Pharmacovigilance System –Started in 1973; 1979 decentralized system –Network of 31 regional centers Located in department of clinical pharmacology in University Hospitals Collect adverse events, provide information back to professionals, conduct research –Identify some cases during clinical rounds Centers connected by national database Financed by French Medicines Agency based on performance and scientific publications French Pharmacovigilance System –Started in 1973; 1979 decentralized system –Network of 31 regional centers Located in department of clinical pharmacology in University Hospitals Collect adverse events, provide information back to professionals, conduct research –Identify some cases during clinical rounds Centers connected by national database Financed by French Medicines Agency based on performance and scientific publications

19. DSaRM Advisory Committee May 18, 2005 19 Pros/Cons of French System for Active Surveillance for Drug Safety Signals Pros –Involves different regions of country in data collection Cons –Represents mostly university experience Pros –Involves different regions of country in data collection Cons –Represents mostly university experience

20. DSaRM Advisory Committee May 18, 2005 20 Challenges of Active Surveillance Obtaining timely information Obtaining validated information Obtaining information from both in- patient and out-patient settings Finding signals for rare events Having a system that efficient Obtaining broad enough scope across U.S. Obtaining timely information Obtaining validated information Obtaining information from both in- patient and out-patient settings Finding signals for rare events Having a system that efficient Obtaining broad enough scope across U.S.

21. DSaRM Advisory Committee May 18, 2005 21 Application: Rare Adverse Event? Adverse event: Acute liver failure Low background of event (1/million person years) Could active surveillance help identify? –A disease-based surveillance program for acute liver failure events might identify cases Challenge is attribution of disease to drug Adverse event: Acute liver failure Low background of event (1/million person years) Could active surveillance help identify? –A disease-based surveillance program for acute liver failure events might identify cases Challenge is attribution of disease to drug

22. DSaRM Advisory Committee May 18, 2005 22 Application: High background? Adverse event: acute myocardial infarction High background of event (4 per 1,000 persons) Could active surveillance help identify? –A drug-based surveillance program might help collect information Adverse event: acute myocardial infarction High background of event (4 per 1,000 persons) Could active surveillance help identify? –A drug-based surveillance program might help collect information

23. DSaRM Advisory Committee May 18, 2005 23 Application: Hospital-Related Events? Adverse event: anesthesia-related event Difficult to collect data from surgical setting Could active surveillance help identify? –A setting-based surveillance system might identify cases Monitor hospitals for event of interest and prior drug exposure Adverse event: anesthesia-related event Difficult to collect data from surgical setting Could active surveillance help identify? –A setting-based surveillance system might identify cases Monitor hospitals for event of interest and prior drug exposure

24. DSaRM Advisory Committee May 18, 2005 24 ConclusionsConclusions Active surveillance is a complex process –Multiple strategies might best be utilized Current surveillance systems outside the FDA may provide useful information but are limited Progress in computerized medicine will make the development of timely active surveillance program more likely Active surveillance is a complex process –Multiple strategies might best be utilized Current surveillance systems outside the FDA may provide useful information but are limited Progress in computerized medicine will make the development of timely active surveillance program more likely

25. DSaRM Advisory Committee May 18, 2005 25 Unanswered Questions How would active surveillance complement the passive surveillance system in place? Would active surveillance be any faster at finding signals? How would a signal be identified? How would active surveillance complement the passive surveillance system in place? Would active surveillance be any faster at finding signals? How would a signal be identified?

26. DSaRM Advisory Committee May 18, 2005 26 Future Directions Request for Information (RFI) – Active Surveillance Programs in the United States for the Identification of Clinically Serious Adverse Events Associated with Medical Products; announced April 11, 2005 –http://www.fedbizopps.gov/ Office of Drug Safety will continue to explore opportunities for active surveillance Department of Health and Human Services promoting development of linked health information that might be used in future for active surveillance Request for Information (RFI) – Active Surveillance Programs in the United States for the Identification of Clinically Serious Adverse Events Associated with Medical Products; announced April 11, 2005 –http://www.fedbizopps.gov/ Office of Drug Safety will continue to explore opportunities for active surveillance Department of Health and Human Services promoting development of linked health information that might be used in future for active surveillance