dsarm advisory committee may 18, 2005 active surveillance for drug safety signals: past, present,...

DSaRM Advisory Committee DSaRM Advisory Committee May 18, 2005May 18, 2005

Active Surveillance for Drug Active Surveillance for Drug Safety Signals: Past, Present, and Safety Signals: Past, Present, and

FutureFuture

Active Surveillance for Drug Active Surveillance for Drug Safety Signals: Past, Present, and Safety Signals: Past, Present, and

FutureFuture

Mary Willy, Ph.D.Mary Willy, Ph.D.

Division of Drug Risk EvaluationDivision of Drug Risk EvaluationOffice of Drug SafetyOffice of Drug Safety

Center for Drug Evaluation and Research Center for Drug Evaluation and Research

Food and Drug AdministrationFood and Drug Administration

Mary Willy, Ph.D.Mary Willy, Ph.D.

Division of Drug Risk EvaluationDivision of Drug Risk EvaluationOffice of Drug SafetyOffice of Drug Safety

Center for Drug Evaluation and Research Center for Drug Evaluation and Research

Food and Drug AdministrationFood and Drug Administration

2DSaRM Advisory Committee DSaRM Advisory Committee May 18, 2005May 18, 2005

OutlineOutlineOutlineOutline

• Background• History• Examples of Programs• Challenges• Possible U.S. Applications

• Background• History• Examples of Programs• Challenges• Possible U.S. Applications


Components of a Comprehensive Components of a Comprehensive Postmarketing Surveillance Program at Postmarketing Surveillance Program at

CDERCDER

Components of a Comprehensive Components of a Comprehensive Postmarketing Surveillance Program at Postmarketing Surveillance Program at

CDERCDERDrug Utilization data:* Outpatient * Inpatient* Longitudinal

External Health care databases:

*General popn*Special popn’s

Passive Surveillance

Background Incidence Rates

Active

Surveillance


Background: ODS Background: ODS Epidemiology ActivitiesEpidemiology 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


Future Activity:Future Activity:Active SurveillanceActive Surveillance

Future Activity:Future Activity:Active SurveillanceActive 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


Potential Purposes of Active Potential Purposes of Active SurveillanceSurveillance

Potential Purposes of Active Potential Purposes of Active SurveillanceSurveillance

• Identify drug safety signal• Validate drug safety signal identified

through passive surveillance

• Identify drug safety signal• Validate drug safety signal identified

through passive surveillance


History of Active SurveillanceHistory of Active SurveillanceHistory of Active SurveillanceHistory 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


History of Active SurveillanceHistory of Active SurveillanceHistory of Active SurveillanceHistory 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


Strategies for SurveillanceStrategies for SurveillanceStrategies for SurveillanceStrategies 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.


Current Surveillance Systems Current Surveillance Systems Outside FDA – Setting-BasedOutside 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


Pros/Cons of DAWNPros/Cons of DAWN for Active Surveillance for Drug for Active Surveillance for Drug

Safety SignalsSafety Signals

Pros/Cons of DAWNPros/Cons of DAWN for Active Surveillance for Drug for Active Surveillance for Drug


• Pros– Nationally representative

• Cons– Newly revised so not able to study

trends

• Pros– Nationally representative

• Cons– Newly revised so not able to study

trends




• 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


Pros/Cons of TESSPros/Cons of TESS for Active Surveillance for Drug for Active Surveillance for Drug


Pros/Cons of TESSPros/Cons of TESS for Active Surveillance for Drug for Active Surveillance for Drug

Safety SignalsSafety 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


Current Surveillance Systems Current Surveillance Systems Outside FDA – Disease-BasedOutside FDA – Disease-BasedCurrent Surveillance Systems Current Surveillance Systems Outside FDA – Disease-BasedOutside 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


Pros/Cons of ALFSGPros/Cons of ALFSG for Active Surveillance for Drug for Active Surveillance for Drug


Pros/Cons of ALFSGPros/Cons of ALFSG for Active Surveillance for Drug for Active Surveillance for Drug


– 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


Current Surveillance Systems Current Surveillance Systems Outside FDA – Drug-BasedOutside FDA – Drug-Based

Current Surveillance Systems Current Surveillance Systems Outside FDA – Drug-BasedOutside 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


Pros/Cons of PEMPros/Cons of PEM for Active Surveillance for Drug for Active Surveillance for Drug


Pros/Cons of PEMPros/Cons of PEM for Active Surveillance for Drug for Active Surveillance for Drug


– 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


Current Surveillance Systems Current Surveillance Systems Outside FDA Outside FDA – – Setting-BasedSetting-BasedCurrent Surveillance Systems Current Surveillance Systems Outside FDA Outside FDA – – Setting-BasedSetting-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


Pros/Cons of French System Pros/Cons of French System for Active Surveillance for Drug for Active Surveillance for Drug


Pros/Cons of French System Pros/Cons of French System for Active Surveillance for Drug for Active Surveillance for Drug


• 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


Challenges of Active SurveillanceChallenges of Active SurveillanceChallenges of Active SurveillanceChallenges 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.


Application: Rare Adverse Event? Application: Rare Adverse Event? Application: Rare Adverse Event? 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


Application: High background?Application: High background?Application: High background?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


Application: Hospital-Related Application: Hospital-Related Events?Events?

Application: Hospital-Related Application: Hospital-Related Events?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


ConclusionsConclusionsConclusionsConclusions• 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


Unanswered QuestionsUnanswered QuestionsUnanswered QuestionsUnanswered 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?


Future DirectionsFuture DirectionsFuture DirectionsFuture 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

dsarm advisory committee may 18, 2005 active surveillance for drug safety signals: past, present,...

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