PV Modules
MODULE 13: SIGNAL DETECTION
A signal is: “Information that suggests a new causal association or a new aspect of a known association between a medicinal product and an adverse event.”
A signal does not confirm causality—it indicates that further evaluation is required.
Sources of Signals: Signals may come from:
A. Spontaneous Reporting Systems
- Individual Case Safety Reports (ICSRs)
- Company safety database
B. Scientific Literature
- Case reports
- Drug safety studies
C. Clinical & Epidemiological Studies
- Clinical trial data
- Post-marketing studies
D. Periodic Reports
- PSUR / PBRER
- DSUR
- PADER
E. Other Sources
- Social media (some agencies consider)
- Patient support programs
- Drug utilization data
Steps in Signal Detection
Step 1: Data Collection
Sources include:
- Safety databases (global & local)
- Literature screenings
- Periodic reports (PSUR, PBRER)
- Regulatory agency reports (e.g., FDA FAERS)
- Clinical trial data (DSUR)
Objective: Gather all AE data and identify unusual patterns.
Step 2: Statistical Methods
Used to detect disproportionality—i.e., whether a drug-event pair is reported more often than expected.
Common tools:
- PRR (Proportional Reporting Ratio)
- ROR (Reporting Odds Ratio)
- IC (Information Component – Bayesian)
Example:
If “Drug X – Liver Injury” shows a PRR > 2 → potential signal.
Step 3: Medical Review
Medical experts evaluate:
- Clinical relevance
- Biological plausibility
- Severity & medical seriousness
- Case quality (dechallenge/rechallenge)
- Time-to-onset pattern
- Consistency across cases
Outcome: Decide if the signal seems medically meaningful.
Step 4: Signal Validation
Determine whether the signal is:
- Valid
- Not valid
- Needs more data
Criteria used:
- Case quality
- Plausibility
- Consistency across sources
- Exposure data
Step 5: Signal Prioritization
High priority signals:
- Serious AEs (death, life-threatening)
- High frequency
- Preventable issues
- High public health impact
Low priority signals:
- Non-serious & rare events
- Weak biological plausibility
Step 6: Signal Assessment
A deep evaluation involving:
- Causality assessment
- Benefit–risk impact
- Case series analysis
- Literature review
- Comparison with similar drugs
Step 7: Regulatory Actions (If Confirmed)
Actions may include:
- Safety label update
- SPC / PI revisions
- Boxed warning addition
- Risk Minimisation Measures (RMMs)
- Updating RMP
- Health authority communication (DHPC, alert)
Examples of Signals
|
Drug |
Observed AE |
Signal Type |
Action |
|
Fluoroquinolones |
Tendon rupture |
New safety signal |
Label update |
|
Metformin |
Vitamin B12 deficiency |
Known, new aspect |
RMP update |
|
DPP-4 inhibitors |
Pancreatitis |
Potential signal |
Further assessment |
6. Important Terms
New Signal
Previously unknown; requires investigation.
Emerging Safety Issue
Urgent signal requiring immediate communication.
Potential Signal
Needs more data; not yet validated.
7. Case Example of Signal Detection
Drug: "Cardiotab"
Reported AE: Arrhythmia
Data:
- 15 cases reported in 3 months
- PRR = 3.5 (significant)
- Consistent time-to-onset (1–3 days)
- 3 positive rechallenge cases
- Plausible mechanism (QT prolongation)
Outcome:
→ Validated signal
→ Label updated
→ ECG monitoring added as RMM