Signal detection for small and medium

size enterprises (SMEs)

Joerg Seebeck, MD
PAREXEL Int.

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 Background: definition “signal”
Information that arises from one or multiple sources (including
observation and experiments), which suggests a new potentially
causal association, or a new aspect of a known association,
between an intervention and an event or set of related events, either
adverse or beneficial, which would command regulatory, societal or
clinical attention, and is judged to be of sufficient likelihood to justify
verificatory and, when necessary, remedial actions.

Hauben and Aronson: Defining “Signal” and its Subtypes in Pharmacovigilance Based on a Systematic Review of
Previous Definitions: Drug Safety 2009, 32 (2), 99-110

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 Differences between small, medium and
large pharmaceutical corporations
• SMEs differ from large pharmaceutical corporations in
terms of:
– Safety staff numbers
– Number of products
– Number of AEs
– Available Safety Databases
• Q: Impact on signal detection and follow up strategy ?

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 Definition: small, medium large

* Up to several 100,000 p.A.

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 Considered process steps

Approach - Classification - Data analysis

- Manual - Decision support - Additional data sources
- Automatic methods
(DM method)

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SIGNAL DETECTION

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 General considerations (I)
• MAHs: Obligation to review safety data
• Signal detection methods are designed to
support expert reviewers (oversight,
objectivity)
• Appropriateness of data mining method
depends on product portfolio
• No data mining technique is superior per
se 7
General considerations (II)

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 Two principal ways to look at
data: dynamic (trend) vs static

Time (multiple scans) Single scan (over whole DB)

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 Example: manual analysis
SOC/PT Cumulat. Q1/2008 Q2/2008 Q3/2008 Q4/2008 Comment
historic
Fanconi syndrome 2

Foetal 3 1 1 3 Underlying cases

anticonvulsant indicate drug
syndrome interaction with new
drug XY (see
benefit risk report)
Heart disease 4
congenital
Hip dysplasia 2 Actual
quarter
Hypertelorism of 2 1
orbit
Hypospadia 1

Limb malformation 4

Low set ears 2 10

Example: manual analysis + thresholds for
event numbers + ratio (actual/historic)

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Example: Automatic between drug
comparison (PRR)

Reference data pool

- needs to be sufficiently large
Evans et al. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous 12
drug reaction reports. Pharmacoepidemiolgy and Drug Safety, 2001; 10: 483-486
 The power of using PRRs within a
drug class
Fluvastatin and hepatic reactions: a signal from spontaneous reporting in Italy.
Conforti et al.; Drug Saf. 2006;29(12):1163-72.

Italian Governmental Safety Database (GIF):

- 35,757 reports (total)
- 1,260 ADRs related to statins
- 178 of those included hepatic reactions
- 69 of those were attributed to fluvastatin (market share < 10 %)
- PRR (fluvastatin against statin group) ↑ ↑ ↑
 Characteristics of safety data
product portfolios of SMEs
• Low number of products
• Low number of AEs
• Focus on specific therapeutic areas
• Focus on specific subject demographics
→ Database (can) lack the necessary diversity to
to provide a suitable background for
disproportionality analyses (e.g. PRR)

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Comparison – signal detection methods

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SIGNAL TRIAGE

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 General considerations
• Every signal needs to be reviewed
(regardless of the method of its detection)
• Assessment has to be documented
• Problem: large number of false-positive
results (workload)
• Triage/classification necessary

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Triage strategy

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 Understanding expert signal
prioritisation

Drug Safety 2008, 31(9), 727-735

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 Approach
(multi-criteria decision analysis; MADA)

• Identification of ADR-related attributes

impacting the decision process
• Grouping of related attributes
• Ranking of attributes (weight)
• Testing of attributes (model vs. expert
assessment)
• Iterative improvement of model
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Groups of ranked attributes
 Partitioning of ADRs into three
subsets

Highest priority
Performance assessment

Ranking of 27 ADRs
for drug A:
Safety Surveillance
Physician (SSP) vs
model, before and
after amendment of
the model
 Conclusion
• MADA model: allows to identify and
analyse the impact of attributes on the
decision process for signal prioritisation
• Future:
– Expanded testing planned (larger group of
drugs and experts)
– Support of signal triage process
SIGNAL VERIFICATION

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Signal verification (staggered approach)

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 THANK YOU FOR YOUR
ATTENTION - QUESTIONS ?
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