Virgilio Vintildeas MD MPH PhD

Ceara LLC

Known side effects

Unavoidable

Avoidable

Medication Errors

Product Quality Defects

Preventable Adverse Events

Injury or Death

Remaining Uncertainties

Unexpected Side Effects

Unstudied UsesUnstudied Populations

Main Business Objectives

bullMinimize Risks for Patients

bullMinimize Risks for Company

bullMeet Global Regulatory Requirements 1048782Full compliance

bullProlong Life-Cycle of Products

bullProvide Competitive Advantage

bullSpontaneous reports (SRs)

ndashHealth Care Professionals (HCPs)

ndashNon Health Care Professionals (non-HCPs)

bullLiterature cases

bullThe internet

bullSolicited reportsndashClinical trials phases I-IVndashObservational Post-Marketing Surveillance (PMS) studies

bullStimulated reportsndashPatient support programsndashDisease managementndashMarketing surveysndashRegistriesndashPharmacoeconomicsndashClass action lawsuitsndashQuality of life questionnaires

bullSpontaneously reported from any source physicians pharmacists consumers lawyers etc

bullEvery attempt to obtain medical verification of consumer reports

bullEmphasize report quality over source type triage appropriately

bullReport consumer cases to HA if required even if they can not be medically confirmed (only mandatory in US and Canada)

bullInclude consumer reports in Periodic Safety Update Reports (PSURs)

bullInclude consumer reports in signal detectionanalysis

bullProtect patient privacy

bullCompanies should screen at least two major databases at least once a month

bullLiterature screening should cover cases in local journals

bullDo not monitor broadcast and lay media but do not ignore potential cases from these sources

bullTreat unspecified generics as your own brand

bullNew challenge

bullldquoIdentifiable patient refers to a real person that can be validated

bullSurfing non-company web sites is unnecessary but should be done selectively to manage specific safety issues

bullScreen all company web sites for AEs daily

bullMaintain global consistency in approach

bullClinical Studies Phase I-IV

bullObservational Post marketing Surveillance studies

bullInvestigator and sponsor causality required for reporting purpose

bullImportant to distinguish from ldquosolicitedrdquo reports

bullUsually originate in the course of interaction with patients

bullHandle as study reports -causality is needed even if difficult to assess

bullReport under guidelines for post-marketing studies

bullPrioritize by the value of the case

bullHighest priority for seriousunlabeled followed by seriouslabeled then non-seriousunlabeled

bullNon-seriouslabeled should not be followed up if the 4 criteria are met

bullTreat special issues and events that might lead to label changes as high priority

bullFor priority cases obtain as much information as possible during the initial contact

bullThe extent of follow-up detail solicited should be driven by the seriousness and expectedness (use CIOMS triage algorithm)

bullFor serious unlabeled cases follow up until the long-term outcome is known

bullIf reporter does not cooperate with telephone follow-up send written reminders

bullAcknowledgment letters should be sent to suppliers of follow-up

bullDo not encourage rechallenge

bullLimited Size

bullShort Duration

bullNarrow Population

bullNarrow Set of Indications

bullConcomitant Medications

No of Patients

2000

Threshold for ADR

1 500 (Lymphoma from Azathioprine)

1 1000 (Eye Damage from Practolol)

1 5000 (MI in Older Women from OCP)

1 10000 (Anaphylaxis from Penicillin)

1 50000 (Aplastic Anemia from Chloramphenicol)

Probability

098

086

033

018

004

bullVolume of use

bullDuration on Market

bullSeverity of Reaction

bullLabelled Status

bullNew Molecular Entities

bullManufacturer

bullPublicity

bullCalendar Year

bullAwareness of Reporting

bullAdverse Event Recognition

bullUnder Reporting

bullEstimated Exposure Data

bullQuality of Reports

bullBroad Exposure

bullCost Effective

bullSignal Generation

bullRepresents Every Day Use

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

Known side effects

Unavoidable

Avoidable

Medication Errors

Product Quality Defects

Preventable Adverse Events

Injury or Death

Remaining Uncertainties

Unexpected Side Effects

Unstudied UsesUnstudied Populations

Main Business Objectives

bullMinimize Risks for Patients

bullMinimize Risks for Company

bullMeet Global Regulatory Requirements 1048782Full compliance

bullProlong Life-Cycle of Products

bullProvide Competitive Advantage

bullSpontaneous reports (SRs)

ndashHealth Care Professionals (HCPs)

ndashNon Health Care Professionals (non-HCPs)

bullLiterature cases

bullThe internet

bullSolicited reportsndashClinical trials phases I-IVndashObservational Post-Marketing Surveillance (PMS) studies

bullStimulated reportsndashPatient support programsndashDisease managementndashMarketing surveysndashRegistriesndashPharmacoeconomicsndashClass action lawsuitsndashQuality of life questionnaires

bullSpontaneously reported from any source physicians pharmacists consumers lawyers etc

bullEvery attempt to obtain medical verification of consumer reports

bullEmphasize report quality over source type triage appropriately

bullReport consumer cases to HA if required even if they can not be medically confirmed (only mandatory in US and Canada)

bullInclude consumer reports in Periodic Safety Update Reports (PSURs)

bullInclude consumer reports in signal detectionanalysis

bullProtect patient privacy

bullCompanies should screen at least two major databases at least once a month

bullLiterature screening should cover cases in local journals

bullDo not monitor broadcast and lay media but do not ignore potential cases from these sources

bullTreat unspecified generics as your own brand

bullNew challenge

bullldquoIdentifiable patient refers to a real person that can be validated

bullSurfing non-company web sites is unnecessary but should be done selectively to manage specific safety issues

bullScreen all company web sites for AEs daily

bullMaintain global consistency in approach

bullClinical Studies Phase I-IV

bullObservational Post marketing Surveillance studies

bullInvestigator and sponsor causality required for reporting purpose

bullImportant to distinguish from ldquosolicitedrdquo reports

bullUsually originate in the course of interaction with patients

bullHandle as study reports -causality is needed even if difficult to assess

bullReport under guidelines for post-marketing studies

bullPrioritize by the value of the case

bullHighest priority for seriousunlabeled followed by seriouslabeled then non-seriousunlabeled

bullNon-seriouslabeled should not be followed up if the 4 criteria are met

bullTreat special issues and events that might lead to label changes as high priority

bullFor priority cases obtain as much information as possible during the initial contact

bullThe extent of follow-up detail solicited should be driven by the seriousness and expectedness (use CIOMS triage algorithm)

bullFor serious unlabeled cases follow up until the long-term outcome is known

bullIf reporter does not cooperate with telephone follow-up send written reminders

bullAcknowledgment letters should be sent to suppliers of follow-up

bullDo not encourage rechallenge

bullLimited Size

bullShort Duration

bullNarrow Population

bullNarrow Set of Indications

bullConcomitant Medications

No of Patients

2000

Threshold for ADR

1 500 (Lymphoma from Azathioprine)

1 1000 (Eye Damage from Practolol)

1 5000 (MI in Older Women from OCP)

1 10000 (Anaphylaxis from Penicillin)

1 50000 (Aplastic Anemia from Chloramphenicol)

Probability

098

086

033

018

004

bullVolume of use

bullDuration on Market

bullSeverity of Reaction

bullLabelled Status

bullNew Molecular Entities

bullManufacturer

bullPublicity

bullCalendar Year

bullAwareness of Reporting

bullAdverse Event Recognition

bullUnder Reporting

bullEstimated Exposure Data

bullQuality of Reports

bullBroad Exposure

bullCost Effective

bullSignal Generation

bullRepresents Every Day Use

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

Main Business Objectives

bullMinimize Risks for Patients

bullMinimize Risks for Company

bullMeet Global Regulatory Requirements 1048782Full compliance

bullProlong Life-Cycle of Products

bullProvide Competitive Advantage

bullSpontaneous reports (SRs)

ndashHealth Care Professionals (HCPs)

ndashNon Health Care Professionals (non-HCPs)

bullLiterature cases

bullThe internet

bullSolicited reportsndashClinical trials phases I-IVndashObservational Post-Marketing Surveillance (PMS) studies

bullStimulated reportsndashPatient support programsndashDisease managementndashMarketing surveysndashRegistriesndashPharmacoeconomicsndashClass action lawsuitsndashQuality of life questionnaires

bullSpontaneously reported from any source physicians pharmacists consumers lawyers etc

bullEvery attempt to obtain medical verification of consumer reports

bullEmphasize report quality over source type triage appropriately

bullReport consumer cases to HA if required even if they can not be medically confirmed (only mandatory in US and Canada)

bullInclude consumer reports in Periodic Safety Update Reports (PSURs)

bullInclude consumer reports in signal detectionanalysis

bullProtect patient privacy

bullCompanies should screen at least two major databases at least once a month

bullLiterature screening should cover cases in local journals

bullDo not monitor broadcast and lay media but do not ignore potential cases from these sources

bullTreat unspecified generics as your own brand

bullNew challenge

bullldquoIdentifiable patient refers to a real person that can be validated

bullSurfing non-company web sites is unnecessary but should be done selectively to manage specific safety issues

bullScreen all company web sites for AEs daily

bullMaintain global consistency in approach

bullClinical Studies Phase I-IV

bullObservational Post marketing Surveillance studies

bullInvestigator and sponsor causality required for reporting purpose

bullImportant to distinguish from ldquosolicitedrdquo reports

bullUsually originate in the course of interaction with patients

bullHandle as study reports -causality is needed even if difficult to assess

bullReport under guidelines for post-marketing studies

bullPrioritize by the value of the case

bullHighest priority for seriousunlabeled followed by seriouslabeled then non-seriousunlabeled

bullNon-seriouslabeled should not be followed up if the 4 criteria are met

bullTreat special issues and events that might lead to label changes as high priority

bullFor priority cases obtain as much information as possible during the initial contact

bullThe extent of follow-up detail solicited should be driven by the seriousness and expectedness (use CIOMS triage algorithm)

bullFor serious unlabeled cases follow up until the long-term outcome is known

bullIf reporter does not cooperate with telephone follow-up send written reminders

bullAcknowledgment letters should be sent to suppliers of follow-up

bullDo not encourage rechallenge

bullLimited Size

bullShort Duration

bullNarrow Population

bullNarrow Set of Indications

bullConcomitant Medications

No of Patients

2000

Threshold for ADR

1 500 (Lymphoma from Azathioprine)

1 1000 (Eye Damage from Practolol)

1 5000 (MI in Older Women from OCP)

1 10000 (Anaphylaxis from Penicillin)

1 50000 (Aplastic Anemia from Chloramphenicol)

Probability

098

086

033

018

004

bullVolume of use

bullDuration on Market

bullSeverity of Reaction

bullLabelled Status

bullNew Molecular Entities

bullManufacturer

bullPublicity

bullCalendar Year

bullAwareness of Reporting

bullAdverse Event Recognition

bullUnder Reporting

bullEstimated Exposure Data

bullQuality of Reports

bullBroad Exposure

bullCost Effective

bullSignal Generation

bullRepresents Every Day Use

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullSpontaneous reports (SRs)

ndashHealth Care Professionals (HCPs)

ndashNon Health Care Professionals (non-HCPs)

bullLiterature cases

bullThe internet

bullSolicited reportsndashClinical trials phases I-IVndashObservational Post-Marketing Surveillance (PMS) studies

bullStimulated reportsndashPatient support programsndashDisease managementndashMarketing surveysndashRegistriesndashPharmacoeconomicsndashClass action lawsuitsndashQuality of life questionnaires

bullSpontaneously reported from any source physicians pharmacists consumers lawyers etc

bullEvery attempt to obtain medical verification of consumer reports

bullEmphasize report quality over source type triage appropriately

bullReport consumer cases to HA if required even if they can not be medically confirmed (only mandatory in US and Canada)

bullInclude consumer reports in Periodic Safety Update Reports (PSURs)

bullInclude consumer reports in signal detectionanalysis

bullProtect patient privacy

bullCompanies should screen at least two major databases at least once a month

bullLiterature screening should cover cases in local journals

bullDo not monitor broadcast and lay media but do not ignore potential cases from these sources

bullTreat unspecified generics as your own brand

bullNew challenge

bullldquoIdentifiable patient refers to a real person that can be validated

bullSurfing non-company web sites is unnecessary but should be done selectively to manage specific safety issues

bullScreen all company web sites for AEs daily

bullMaintain global consistency in approach

bullClinical Studies Phase I-IV

bullObservational Post marketing Surveillance studies

bullInvestigator and sponsor causality required for reporting purpose

bullImportant to distinguish from ldquosolicitedrdquo reports

bullUsually originate in the course of interaction with patients

bullHandle as study reports -causality is needed even if difficult to assess

bullReport under guidelines for post-marketing studies

bullPrioritize by the value of the case

bullHighest priority for seriousunlabeled followed by seriouslabeled then non-seriousunlabeled

bullNon-seriouslabeled should not be followed up if the 4 criteria are met

bullTreat special issues and events that might lead to label changes as high priority

bullFor priority cases obtain as much information as possible during the initial contact

bullThe extent of follow-up detail solicited should be driven by the seriousness and expectedness (use CIOMS triage algorithm)

bullFor serious unlabeled cases follow up until the long-term outcome is known

bullIf reporter does not cooperate with telephone follow-up send written reminders

bullAcknowledgment letters should be sent to suppliers of follow-up

bullDo not encourage rechallenge

bullLimited Size

bullShort Duration

bullNarrow Population

bullNarrow Set of Indications

bullConcomitant Medications

No of Patients

2000

Threshold for ADR

1 500 (Lymphoma from Azathioprine)

1 1000 (Eye Damage from Practolol)

1 5000 (MI in Older Women from OCP)

1 10000 (Anaphylaxis from Penicillin)

1 50000 (Aplastic Anemia from Chloramphenicol)

Probability

098

086

033

018

004

bullVolume of use

bullDuration on Market

bullSeverity of Reaction

bullLabelled Status

bullNew Molecular Entities

bullManufacturer

bullPublicity

bullCalendar Year

bullAwareness of Reporting

bullAdverse Event Recognition

bullUnder Reporting

bullEstimated Exposure Data

bullQuality of Reports

bullBroad Exposure

bullCost Effective

bullSignal Generation

bullRepresents Every Day Use

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullSolicited reportsndashClinical trials phases I-IVndashObservational Post-Marketing Surveillance (PMS) studies

bullStimulated reportsndashPatient support programsndashDisease managementndashMarketing surveysndashRegistriesndashPharmacoeconomicsndashClass action lawsuitsndashQuality of life questionnaires

bullSpontaneously reported from any source physicians pharmacists consumers lawyers etc

bullEvery attempt to obtain medical verification of consumer reports

bullEmphasize report quality over source type triage appropriately

bullReport consumer cases to HA if required even if they can not be medically confirmed (only mandatory in US and Canada)

bullInclude consumer reports in Periodic Safety Update Reports (PSURs)

bullInclude consumer reports in signal detectionanalysis

bullProtect patient privacy

bullCompanies should screen at least two major databases at least once a month

bullLiterature screening should cover cases in local journals

bullDo not monitor broadcast and lay media but do not ignore potential cases from these sources

bullTreat unspecified generics as your own brand

bullNew challenge

bullldquoIdentifiable patient refers to a real person that can be validated

bullSurfing non-company web sites is unnecessary but should be done selectively to manage specific safety issues

bullScreen all company web sites for AEs daily

bullMaintain global consistency in approach

bullClinical Studies Phase I-IV

bullObservational Post marketing Surveillance studies

bullInvestigator and sponsor causality required for reporting purpose

bullImportant to distinguish from ldquosolicitedrdquo reports

bullUsually originate in the course of interaction with patients

bullHandle as study reports -causality is needed even if difficult to assess

bullReport under guidelines for post-marketing studies

bullPrioritize by the value of the case

bullHighest priority for seriousunlabeled followed by seriouslabeled then non-seriousunlabeled

bullNon-seriouslabeled should not be followed up if the 4 criteria are met

bullTreat special issues and events that might lead to label changes as high priority

bullFor priority cases obtain as much information as possible during the initial contact

bullThe extent of follow-up detail solicited should be driven by the seriousness and expectedness (use CIOMS triage algorithm)

bullFor serious unlabeled cases follow up until the long-term outcome is known

bullIf reporter does not cooperate with telephone follow-up send written reminders

bullAcknowledgment letters should be sent to suppliers of follow-up

bullDo not encourage rechallenge

bullLimited Size

bullShort Duration

bullNarrow Population

bullNarrow Set of Indications

bullConcomitant Medications

No of Patients

2000

Threshold for ADR

1 500 (Lymphoma from Azathioprine)

1 1000 (Eye Damage from Practolol)

1 5000 (MI in Older Women from OCP)

1 10000 (Anaphylaxis from Penicillin)

1 50000 (Aplastic Anemia from Chloramphenicol)

Probability

098

086

033

018

004

bullVolume of use

bullDuration on Market

bullSeverity of Reaction

bullLabelled Status

bullNew Molecular Entities

bullManufacturer

bullPublicity

bullCalendar Year

bullAwareness of Reporting

bullAdverse Event Recognition

bullUnder Reporting

bullEstimated Exposure Data

bullQuality of Reports

bullBroad Exposure

bullCost Effective

bullSignal Generation

bullRepresents Every Day Use

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullSpontaneously reported from any source physicians pharmacists consumers lawyers etc

bullEvery attempt to obtain medical verification of consumer reports

bullEmphasize report quality over source type triage appropriately

bullReport consumer cases to HA if required even if they can not be medically confirmed (only mandatory in US and Canada)

bullInclude consumer reports in Periodic Safety Update Reports (PSURs)

bullInclude consumer reports in signal detectionanalysis

bullProtect patient privacy

bullCompanies should screen at least two major databases at least once a month

bullLiterature screening should cover cases in local journals

bullDo not monitor broadcast and lay media but do not ignore potential cases from these sources

bullTreat unspecified generics as your own brand

bullNew challenge

bullldquoIdentifiable patient refers to a real person that can be validated

bullSurfing non-company web sites is unnecessary but should be done selectively to manage specific safety issues

bullScreen all company web sites for AEs daily

bullMaintain global consistency in approach

bullClinical Studies Phase I-IV

bullObservational Post marketing Surveillance studies

bullInvestigator and sponsor causality required for reporting purpose

bullImportant to distinguish from ldquosolicitedrdquo reports

bullUsually originate in the course of interaction with patients

bullHandle as study reports -causality is needed even if difficult to assess

bullReport under guidelines for post-marketing studies

bullPrioritize by the value of the case

bullHighest priority for seriousunlabeled followed by seriouslabeled then non-seriousunlabeled

bullNon-seriouslabeled should not be followed up if the 4 criteria are met

bullTreat special issues and events that might lead to label changes as high priority

bullFor priority cases obtain as much information as possible during the initial contact

bullThe extent of follow-up detail solicited should be driven by the seriousness and expectedness (use CIOMS triage algorithm)

bullFor serious unlabeled cases follow up until the long-term outcome is known

bullIf reporter does not cooperate with telephone follow-up send written reminders

bullAcknowledgment letters should be sent to suppliers of follow-up

bullDo not encourage rechallenge

bullLimited Size

bullShort Duration

bullNarrow Population

bullNarrow Set of Indications

bullConcomitant Medications

No of Patients

2000

Threshold for ADR

1 500 (Lymphoma from Azathioprine)

1 1000 (Eye Damage from Practolol)

1 5000 (MI in Older Women from OCP)

1 10000 (Anaphylaxis from Penicillin)

1 50000 (Aplastic Anemia from Chloramphenicol)

Probability

098

086

033

018

004

bullVolume of use

bullDuration on Market

bullSeverity of Reaction

bullLabelled Status

bullNew Molecular Entities

bullManufacturer

bullPublicity

bullCalendar Year

bullAwareness of Reporting

bullAdverse Event Recognition

bullUnder Reporting

bullEstimated Exposure Data

bullQuality of Reports

bullBroad Exposure

bullCost Effective

bullSignal Generation

bullRepresents Every Day Use

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullCompanies should screen at least two major databases at least once a month

bullLiterature screening should cover cases in local journals

bullDo not monitor broadcast and lay media but do not ignore potential cases from these sources

bullTreat unspecified generics as your own brand

bullNew challenge

bullldquoIdentifiable patient refers to a real person that can be validated

bullSurfing non-company web sites is unnecessary but should be done selectively to manage specific safety issues

bullScreen all company web sites for AEs daily

bullMaintain global consistency in approach

bullClinical Studies Phase I-IV

bullObservational Post marketing Surveillance studies

bullInvestigator and sponsor causality required for reporting purpose

bullImportant to distinguish from ldquosolicitedrdquo reports

bullUsually originate in the course of interaction with patients

bullHandle as study reports -causality is needed even if difficult to assess

bullReport under guidelines for post-marketing studies

bullPrioritize by the value of the case

bullHighest priority for seriousunlabeled followed by seriouslabeled then non-seriousunlabeled

bullNon-seriouslabeled should not be followed up if the 4 criteria are met

bullTreat special issues and events that might lead to label changes as high priority

bullFor priority cases obtain as much information as possible during the initial contact

bullThe extent of follow-up detail solicited should be driven by the seriousness and expectedness (use CIOMS triage algorithm)

bullFor serious unlabeled cases follow up until the long-term outcome is known

bullIf reporter does not cooperate with telephone follow-up send written reminders

bullAcknowledgment letters should be sent to suppliers of follow-up

bullDo not encourage rechallenge

bullLimited Size

bullShort Duration

bullNarrow Population

bullNarrow Set of Indications

bullConcomitant Medications

No of Patients

2000

Threshold for ADR

1 500 (Lymphoma from Azathioprine)

1 1000 (Eye Damage from Practolol)

1 5000 (MI in Older Women from OCP)

1 10000 (Anaphylaxis from Penicillin)

1 50000 (Aplastic Anemia from Chloramphenicol)

Probability

098

086

033

018

004

bullVolume of use

bullDuration on Market

bullSeverity of Reaction

bullLabelled Status

bullNew Molecular Entities

bullManufacturer

bullPublicity

bullCalendar Year

bullAwareness of Reporting

bullAdverse Event Recognition

bullUnder Reporting

bullEstimated Exposure Data

bullQuality of Reports

bullBroad Exposure

bullCost Effective

bullSignal Generation

bullRepresents Every Day Use

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullNew challenge

bullldquoIdentifiable patient refers to a real person that can be validated

bullSurfing non-company web sites is unnecessary but should be done selectively to manage specific safety issues

bullScreen all company web sites for AEs daily

bullMaintain global consistency in approach

bullClinical Studies Phase I-IV

bullObservational Post marketing Surveillance studies

bullInvestigator and sponsor causality required for reporting purpose

bullImportant to distinguish from ldquosolicitedrdquo reports

bullUsually originate in the course of interaction with patients

bullHandle as study reports -causality is needed even if difficult to assess

bullReport under guidelines for post-marketing studies

bullPrioritize by the value of the case

bullHighest priority for seriousunlabeled followed by seriouslabeled then non-seriousunlabeled

bullNon-seriouslabeled should not be followed up if the 4 criteria are met

bullTreat special issues and events that might lead to label changes as high priority

bullFor priority cases obtain as much information as possible during the initial contact

bullThe extent of follow-up detail solicited should be driven by the seriousness and expectedness (use CIOMS triage algorithm)

bullFor serious unlabeled cases follow up until the long-term outcome is known

bullIf reporter does not cooperate with telephone follow-up send written reminders

bullAcknowledgment letters should be sent to suppliers of follow-up

bullDo not encourage rechallenge

bullLimited Size

bullShort Duration

bullNarrow Population

bullNarrow Set of Indications

bullConcomitant Medications

No of Patients

2000

Threshold for ADR

1 500 (Lymphoma from Azathioprine)

1 1000 (Eye Damage from Practolol)

1 5000 (MI in Older Women from OCP)

1 10000 (Anaphylaxis from Penicillin)

1 50000 (Aplastic Anemia from Chloramphenicol)

Probability

098

086

033

018

004

bullVolume of use

bullDuration on Market

bullSeverity of Reaction

bullLabelled Status

bullNew Molecular Entities

bullManufacturer

bullPublicity

bullCalendar Year

bullAwareness of Reporting

bullAdverse Event Recognition

bullUnder Reporting

bullEstimated Exposure Data

bullQuality of Reports

bullBroad Exposure

bullCost Effective

bullSignal Generation

bullRepresents Every Day Use

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullClinical Studies Phase I-IV

bullObservational Post marketing Surveillance studies

bullInvestigator and sponsor causality required for reporting purpose

bullImportant to distinguish from ldquosolicitedrdquo reports

bullUsually originate in the course of interaction with patients

bullHandle as study reports -causality is needed even if difficult to assess

bullReport under guidelines for post-marketing studies

bullPrioritize by the value of the case

bullHighest priority for seriousunlabeled followed by seriouslabeled then non-seriousunlabeled

bullNon-seriouslabeled should not be followed up if the 4 criteria are met

bullTreat special issues and events that might lead to label changes as high priority

bullFor priority cases obtain as much information as possible during the initial contact

bullThe extent of follow-up detail solicited should be driven by the seriousness and expectedness (use CIOMS triage algorithm)

bullFor serious unlabeled cases follow up until the long-term outcome is known

bullIf reporter does not cooperate with telephone follow-up send written reminders

bullAcknowledgment letters should be sent to suppliers of follow-up

bullDo not encourage rechallenge

bullLimited Size

bullShort Duration

bullNarrow Population

bullNarrow Set of Indications

bullConcomitant Medications

No of Patients

2000

Threshold for ADR

1 500 (Lymphoma from Azathioprine)

1 1000 (Eye Damage from Practolol)

1 5000 (MI in Older Women from OCP)

1 10000 (Anaphylaxis from Penicillin)

1 50000 (Aplastic Anemia from Chloramphenicol)

Probability

098

086

033

018

004

bullVolume of use

bullDuration on Market

bullSeverity of Reaction

bullLabelled Status

bullNew Molecular Entities

bullManufacturer

bullPublicity

bullCalendar Year

bullAwareness of Reporting

bullAdverse Event Recognition

bullUnder Reporting

bullEstimated Exposure Data

bullQuality of Reports

bullBroad Exposure

bullCost Effective

bullSignal Generation

bullRepresents Every Day Use

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullImportant to distinguish from ldquosolicitedrdquo reports

bullUsually originate in the course of interaction with patients

bullHandle as study reports -causality is needed even if difficult to assess

bullReport under guidelines for post-marketing studies

bullPrioritize by the value of the case

bullHighest priority for seriousunlabeled followed by seriouslabeled then non-seriousunlabeled

bullNon-seriouslabeled should not be followed up if the 4 criteria are met

bullTreat special issues and events that might lead to label changes as high priority

bullFor priority cases obtain as much information as possible during the initial contact

bullThe extent of follow-up detail solicited should be driven by the seriousness and expectedness (use CIOMS triage algorithm)

bullFor serious unlabeled cases follow up until the long-term outcome is known

bullIf reporter does not cooperate with telephone follow-up send written reminders

bullAcknowledgment letters should be sent to suppliers of follow-up

bullDo not encourage rechallenge

bullLimited Size

bullShort Duration

bullNarrow Population

bullNarrow Set of Indications

bullConcomitant Medications

No of Patients

2000

Threshold for ADR

1 500 (Lymphoma from Azathioprine)

1 1000 (Eye Damage from Practolol)

1 5000 (MI in Older Women from OCP)

1 10000 (Anaphylaxis from Penicillin)

1 50000 (Aplastic Anemia from Chloramphenicol)

Probability

098

086

033

018

004

bullVolume of use

bullDuration on Market

bullSeverity of Reaction

bullLabelled Status

bullNew Molecular Entities

bullManufacturer

bullPublicity

bullCalendar Year

bullAwareness of Reporting

bullAdverse Event Recognition

bullUnder Reporting

bullEstimated Exposure Data

bullQuality of Reports

bullBroad Exposure

bullCost Effective

bullSignal Generation

bullRepresents Every Day Use

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullPrioritize by the value of the case

bullHighest priority for seriousunlabeled followed by seriouslabeled then non-seriousunlabeled

bullNon-seriouslabeled should not be followed up if the 4 criteria are met

bullTreat special issues and events that might lead to label changes as high priority

bullFor priority cases obtain as much information as possible during the initial contact

bullThe extent of follow-up detail solicited should be driven by the seriousness and expectedness (use CIOMS triage algorithm)

bullFor serious unlabeled cases follow up until the long-term outcome is known

bullIf reporter does not cooperate with telephone follow-up send written reminders

bullAcknowledgment letters should be sent to suppliers of follow-up

bullDo not encourage rechallenge

bullLimited Size

bullShort Duration

bullNarrow Population

bullNarrow Set of Indications

bullConcomitant Medications

No of Patients

2000

Threshold for ADR

1 500 (Lymphoma from Azathioprine)

1 1000 (Eye Damage from Practolol)

1 5000 (MI in Older Women from OCP)

1 10000 (Anaphylaxis from Penicillin)

1 50000 (Aplastic Anemia from Chloramphenicol)

Probability

098

086

033

018

004

bullVolume of use

bullDuration on Market

bullSeverity of Reaction

bullLabelled Status

bullNew Molecular Entities

bullManufacturer

bullPublicity

bullCalendar Year

bullAwareness of Reporting

bullAdverse Event Recognition

bullUnder Reporting

bullEstimated Exposure Data

bullQuality of Reports

bullBroad Exposure

bullCost Effective

bullSignal Generation

bullRepresents Every Day Use

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullFor priority cases obtain as much information as possible during the initial contact

bullThe extent of follow-up detail solicited should be driven by the seriousness and expectedness (use CIOMS triage algorithm)

bullFor serious unlabeled cases follow up until the long-term outcome is known

bullIf reporter does not cooperate with telephone follow-up send written reminders

bullAcknowledgment letters should be sent to suppliers of follow-up

bullDo not encourage rechallenge

bullLimited Size

bullShort Duration

bullNarrow Population

bullNarrow Set of Indications

bullConcomitant Medications

No of Patients

2000

Threshold for ADR

1 500 (Lymphoma from Azathioprine)

1 1000 (Eye Damage from Practolol)

1 5000 (MI in Older Women from OCP)

1 10000 (Anaphylaxis from Penicillin)

1 50000 (Aplastic Anemia from Chloramphenicol)

Probability

098

086

033

018

004

bullVolume of use

bullDuration on Market

bullSeverity of Reaction

bullLabelled Status

bullNew Molecular Entities

bullManufacturer

bullPublicity

bullCalendar Year

bullAwareness of Reporting

bullAdverse Event Recognition

bullUnder Reporting

bullEstimated Exposure Data

bullQuality of Reports

bullBroad Exposure

bullCost Effective

bullSignal Generation

bullRepresents Every Day Use

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullLimited Size

bullShort Duration

bullNarrow Population

bullNarrow Set of Indications

bullConcomitant Medications

No of Patients

2000

Threshold for ADR

1 500 (Lymphoma from Azathioprine)

1 1000 (Eye Damage from Practolol)

1 5000 (MI in Older Women from OCP)

1 10000 (Anaphylaxis from Penicillin)

1 50000 (Aplastic Anemia from Chloramphenicol)

Probability

098

086

033

018

004

bullVolume of use

bullDuration on Market

bullSeverity of Reaction

bullLabelled Status

bullNew Molecular Entities

bullManufacturer

bullPublicity

bullCalendar Year

bullAwareness of Reporting

bullAdverse Event Recognition

bullUnder Reporting

bullEstimated Exposure Data

bullQuality of Reports

bullBroad Exposure

bullCost Effective

bullSignal Generation

bullRepresents Every Day Use

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

No of Patients

2000

Threshold for ADR

1 500 (Lymphoma from Azathioprine)

1 1000 (Eye Damage from Practolol)

1 5000 (MI in Older Women from OCP)

1 10000 (Anaphylaxis from Penicillin)

1 50000 (Aplastic Anemia from Chloramphenicol)

Probability

098

086

033

018

004

bullVolume of use

bullDuration on Market

bullSeverity of Reaction

bullLabelled Status

bullNew Molecular Entities

bullManufacturer

bullPublicity

bullCalendar Year

bullAwareness of Reporting

bullAdverse Event Recognition

bullUnder Reporting

bullEstimated Exposure Data

bullQuality of Reports

bullBroad Exposure

bullCost Effective

bullSignal Generation

bullRepresents Every Day Use

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullVolume of use

bullDuration on Market

bullSeverity of Reaction

bullLabelled Status

bullNew Molecular Entities

bullManufacturer

bullPublicity

bullCalendar Year

bullAwareness of Reporting

bullAdverse Event Recognition

bullUnder Reporting

bullEstimated Exposure Data

bullQuality of Reports

bullBroad Exposure

bullCost Effective

bullSignal Generation

bullRepresents Every Day Use

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullAdverse Event Recognition

bullUnder Reporting

bullEstimated Exposure Data

bullQuality of Reports

bullBroad Exposure

bullCost Effective

bullSignal Generation

bullRepresents Every Day Use

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullBroad Exposure

bullCost Effective

bullSignal Generation

bullRepresents Every Day Use

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullInternational standard in general

ndashSerious unexpected suspected adverse reaction

ndashUnblind reportable Clinical Trial (CT) cases

ndashSuspected fatallife-treatening CT cases 7 calendars days

ndashAll other reportable serious suspected SRs and CTs 15 calendars days

ndashUpdate of labeling reference document as appropriate

ndashNotification to all investigators amp ethics committeesIRBs

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullNational requirements beyond accepted international standards Example of

ndashFrance all study-related serious adverse reactions

ndashIreland all serious adverse reactions irrespective of labelingunblinded occurring in domestic centers

ndashUSA all fatal amp life-treatening SAEs irrespective of causality within 7 days for very specific drugs genetically engineered

ndashFinland India Norway Slovakia Switzerland all domestic SAEs irrespective of causality

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullProtocol review -to ensure proper collection SAEsAEs

bullAdverse event coding glossary review

bullClinical trial report -safety sections

bullInvestigatorrsquos Brochure -safety sections update

bullIntegrated Safety Summary (ISS)

bullPreparation Periodic Safety Update reports

bullIND and EU Annual Safety Reports

bullCore Data Sheet ndashSafety Sections Update

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

Fully Validated System

Part 11 Compliance-Audit Trail-Electronic Signature

Global workflowconfiguration

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

Pharmacovigilance component

Global Safety System

Global Safety System

StandardQueries

Signal detectio

n

Clinical Database

Quality Complaints Database

Sales Databas

e

FlexibleQuery

Database

Power Analysis Graphic

PresentationsTool

External Database

Data warehouse

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

What is a signal

ldquoReported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously Usually more than one reports required to generate a signal depending on the seriousness of the event and the quality of the informationrdquo

T Delamothe(1992) -WHO definition

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

Purpose

ndashAssess benefitrisk ratio

ndashIdentification of potential issuessignal identification

ndashProvision of relevant information on potential side-effects to investigators and agencies

ndashProposetake action

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

Prerequisites

ndashAccuracy and completeness of data

ndashProper collection and follow-up of AE reports including proper source data verification

ndashStandardized coding and assessments

ndashPowerful analysis tool

ndashSignal identification tool ndashAdequate MethodologyTreshold

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

ndashReport(s) of unexpected and serious AEs

ndashExpected AEs

bullincreased frequency

bullgreater severity

bulllong-term sequelas

bullnew risk factors

ndashEvidence from formal studies

ndashChange in efficacy

ndashRisks are greater than with alternative therapies with similar efficacy

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

Single Case Report

Cluster of casesAbnormal Lab

findingsPreclinical Tox history

Signal of a possible change in thesafety profile of a development product

Competitor data

Safety Signalclass effect

Literature Report(s)

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

Number of reported cases poor

bullPre-defined threshold values eg expected morbiditymortality rate in treated population

bullStatistical signal detection system

bullEpidemiological investigation of signals

bullExcruciating review by physicians scientists and epidemiologists

bullReactive Sit and wait Do not trouble troubles until troubles trouble you

bullProactive Prompt action

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullNotification of ldquofirst ever event with product

bullEnter signalADE term II generate notification when defined threshold exceeded

bullTrend analysis notification of sudden increase in numbers of reports

bullProportional Reporting Ratio

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullIntegrate with Development Data Warehouse

bullUse AERs and WHO data for PRR method

bullCompare against competitor drugs in same class

bullCompare multiple arms in a trial for incidence rate differences

bullEvaluate integration of IMS sales data

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

Limitations

ndashBlinding

ndashSize of treated population rarridentify mainly frequent type A ADRs(wide exposure post-marketing)

ndashSelected population (exclusion criteria) versus misuse Post-Marketing

ndashHigh morbiditymortality population rarrearly judgment difficult

ndashLack of background prevalenceincidence rates

ndashPoor quality of spontaneous reports ndashUnconfirmed diagnosis

ndashSafety culture within the company rarrvery defensive approach rather than fact oriented

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

Safety Signal

Safety SignalAnalysis

Safety SignalAnalysis

Conclusion

Controversial

No problem

Safety signal

confirmation

No action

Closemonitoring

Action

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

Action to be taken varies according to the seriousness of the issue and the benefitrisk assessment

ndashAmend labelling ndashboxed warning

ndashAmend protocol eg dose exclusion criteria infusion rate etc

ndashKeep on hold a specific trial

ndashKeep on hold the whole project

ndashTerminate the project

ndashProduct recall

ndashSafety alert

ndashPost-marketing or epidemiological studies

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

Phase I Phase II

Phase III Phase IV

Safety SurveillanceMonitoring

ICH E2E ProactivePharmacovigilance Plan

Risk Management Program

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

bullPharmacovigilance specificationbullDiscussed with regulators pre-approval 1048782focus on early post-marketing periodbullEstablished risk of a drugbullpotential for significant unidentified riskbullpotential at risk populations and situations that have not been studied pre-approvalbullPharmacovigilance planbulldriven by the pharmacovigilance specificationsbullwill be shared and scrutinized by the regulators assessing the licensing application in the different ICH regionsbullPost-approval safety studiesbullfor products with risks or concernsbullat-risk groups which have not been studied

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

Patient Population Epidemiology bullIncidence-Prevalence bullNatural history ndashComorbidity bullDrug utilization patterns bullRisk -preventive factors bullEtiological factorsSafety Issues Review

Safety Monitoring bullPreclinical Safety data bullClinical pharmacology bullAEs from clinical trials bullHA ldquohot topicsrdquo bullExpected patient safety bullRisk management planSafety Signal EvaluationCT Design ndashSimulationsDisease awareness

Safety Signal Generation bullInternal and external bullSafety Monitoring Post-Marketing ReportsbullDrug utilizationbullLong term safetybullRisk Management bullAdditional benefits

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug

working towards

bullINTEGRATED

bullPROACTIVE

Development and life-cycle management of the drug