Signal detection and signal management at the Nth l d Ph ... · Nth l d Ph iil C tNetherlands...

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

Thank you for your attention!

Information?

ij b k@l b le.vanpuijenbroek@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.

•