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Signal detection and signal management at the Signal detection and signal management at the N th l d Ph i il C tN th l d Ph i il C tNetherlands Pharmacovigilance CentreNetherlands Pharmacovigilance Centre
EudraVigilance Information Day 1 July 2009EudraVigilance Information Day 1 July 2009
Eugène van Puijenbroek, MD, PhD
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Signal detection/ t th istrengthening
Risk/benefitRisk/benefit analysis
Si l d iSignal detection
• Starts prior to reporting ADRs!Starts prior to reporting ADRs!
• Aimed at timely detection of possible signalsAimed at timely detection of possible signals
• Should be as transparent as possibleShould be as transparent as possible
Th b ildi f i lThe building stones of a signal
• Motive of the reporter• Nature of reportsp
– Completeness of information– Clinical information
Time course
qualitative
– Time course• Information from literature• Pharmacological mechanismg• Information from other databases• Disproportionality
quantitative
• Etc., etc.
Si l d iSignal detection
Patient
Physician Pharmacistqualitative
y
Lareb
quantitative
A h i i l d iApproaches in signal detection
• Qualitative signal detection Di ti– Diagnostic process
– Case by case analysis
• Quantitative signal detection– i.e. ROR, PRR, Chi square– Bayesian approaches
• Complementary approachesComplementary approaches– Preferably in parallel
Case by case analysisCase by case analysis
• For every case report received• For every case report received
• At different moments in time• At different moments in time…..
• By pharmacists and physicians• By pharmacists and physicians……
C b l iCase by case analysis
Check serious Eudra-
Assessor Scientific
reportsEudraVigilance
Assessor Scientific meeting
databasePatient / HP
MAHs
WHO
F i l iFrom signal to action
Regulatory Quartely aspects
yreport
signal detailed analysis
selectionSignal database
Scientific aspects
Publication
D il d l iDetailed analysis
• Aim / motive • Information SPC/EPAR• Description of cases in Lareb database• Statistical information
– Lareb databaseLareb database– WHO database– EudraVigilance
• Information from Literature• Information from Literature• Pharmacological mechanism• What should be done?• Health impact and signal strength
S l i f i lSelection of signals
• Subjective process
• All aspects of detailed analysis taken into account
• Health impact and signal strength to be evaluated
Further actionFurther action….
Analysis Quarterly report Publicationinformation SPC/EPAR x x (x)( )
cases lareb database x x x
possible pharmacol mechanism x x xpossible pharmacol. mechanism x x x
information from literature x x x
statistical information ( )statistical information x x (x)
What should be done? x x (x)
i di ti i l t thindication signal strength x
indication health impact x
Q lQuarterly report
• Observations– Signals
• Overviews• Overviews– i.e. for new chemical entities– Media attention
• Short notes– i.e. Inconsistencies in SPCs– Administrative issuesAdministrative issues
• In urgent cases MEB is informed i di l !immediately!
P bli iPublications
• 30-35 publications annually
• National journals and Drug Bulletin– Immediate action is required– Stated in SPC, but apparently not known in daily practice
• International journalsNew signals not published previously– New signals not published previously
– Methodology
Q i i hQuantitative approach
• Part of case by case approach
• Screening database
R i Odd R iReporting Odds Ratio
ADR Other ADRsDrug a bOther drugs c d
( )( )
*==(ROR)RatioOddsReporting
daba
( )
( ))/(
*(ROR)RatioOddsReporting
b
cbd
c
( )))+/(()+/(
=)(dccbaa
PRRtioonalRiskRapropororti
Quantitative approach: in case by caseQuantitative approach: in case by case analysis
• Available in all assessments
C l l t d i l ti• Calculated in real time
• Reporting Odds Ratiosp g– Lareb database– WHO database
• Detailed analysis – Adjustment of ROR in logistic regression analysis
A l i i t i b t– Analysis in certain subsets– Stratification
• Also available for WHO data• In future also for EudraVigilance data?g
Quantitative approach: screeningQuantitative approach: screening database
• Screening all associations for possible signals
P l i b d• Preselection based on:– Number of reports > n– Labelled ADR yes/noy– Minimum lower level 95% CI ROR– Date
• Short assessment and redefine parameters
• Short assessment can be followed by detailed analysis
• Complementary to case by case analysis!
Quantitative approach: screeningQuantitative approach: screening database
Selected associations
Short assessmentassess e
Yes
D t il d Signal
More info required?
Redefine cut off values
Yes
Detailed analysis
Signal databaseNo
P i i i i i lPrioritising signals
What determines value of the signal?What determines value of the signal?
• Science?• Science?– New signal?
• Regulatory?g y– Need for amendment SPC/EPAR?– ‘Dear Health Care Professional letter’?
S i / ithd l f k t?– Suspension/withdrawal from market?• Physician
– Can ADR be treated?Can ADR be treated?– Risk/benefit analysis?
• Patients – Quality of life?– Which risk will I accept?
Determinants for selecting a signalDeterminants for selecting a signal
• Aim: insight into factors contributing to the selection and dissemination of possible signals originating from our system
• 42 signals (single ADR and drug) included and matched with 168 controls
van Puijenbroek et al Br J Clin Pharmacol 2001 Nov;52(5):579-86van Puijenbroek et al. Br J Clin Pharmacol. 2001 Nov;52(5):579 86.
Independent factorsIndependent factors
OR (95% CI)OR (95% CI)
Disproportinal association 3.5 (1.4-8.4)
Index report is a ‘serious’ ADR 3.8 (1.3-11)
Critical term present 4.7 (1.8-13)
ADR being unlabelled 6.1 (2.3-16)ADR being unlabelled 6.1 (2.3 16)
S f i i i i i lSystems for prioritising signals
• Qualitative– SNIP criteria
WHO t i t– WHO triage system– Subjective selection
• Quantitative• Quantitative – Impact analysis
• MHRA-Evidence en Public health impact*p• Lareb-Signal strength en Public health impact
*Heeley et al. Drug Safety. 2005;28(10):901-906y g y ; ( )
Heeley et al. Drug Safety. 2005;28(10):901-906ee ey e a ug Sa e y 005; 8( 0) 90 906
Signal strength and Public health impact
Signal strength• Value of the cases• Disproportionality• Disproportionality• Data from other databases (WHO/EudraVigilance)• Literature
Health impact• Seriousness of the ADR• Type of drug• Population of users• Indication for useIndication for use
TTransparancy
• Selection of the signals is still based on a subjective processprocess
• By underpinning the signal as much as possibleBy underpinning the signal as much as possible, others can determine their own view about the signal
Transparancy
• Database online
• Available on the internet– Quarterly reports– Quarterly reports– Signals– Publications t
• www.lareb.nl
SummarySummary• Signal detection at Lareb is based on both qualitativeSignal detection at Lareb is based on both qualitative
and quantitative approach
• Detailed analysis is core of signal detection as well as selection/prioritisationp
• Prioritisation at this moment is mainly based on ysubjective elements.
•
