1.0 OBJECTIVE:
1.1 To define a standardized process for Signal Detection, Signal Evaluation, and Signal Management for all medicinal products.
1.2 To ensure compliance with World Health Organization (WHO) and European Union Good Pharmacovigilance Practices (EU-GVP) Module IX.
1.3 To ensure early identification of potential safety risks and timely implementation of risk-minimization actions.
2.0 SCOPE:
2.1 Applies to all marketed products for which the company is the Marketing Authorization Holder (MAH) or has PV responsibility.
2.2 Covers signals identified from
2.2.1 Individual Case Safety Reports (ICSR)
2.2.2 aggregate reports (PSUR/PBRER: Periodic Safety Update Report/Periodic Benefit–Risk Evaluation Report)
2.2.3 Literature
2.2.4 Clinical/Bioequivalence studies
2.2.5 Regulatory authority communications
2.2.6 Scientific publications
2.2.7 PQC (Product Quality Complaint) linked AEs
2.2.8 Social media or market feedback (where applicable)
3.0 RESPONSIBILITIES:
3.1. Pharmacovigilance (PV) Department:
3.1.1 Perform routine signal detection activities.
3.1.2 Review ICSRs, safety database trends, and scientific literature.
3.1.3 Evaluate safety information and justify signal validation or refutation.
3.1.4 Maintain Signal Log and Signal Evaluation Reports.
3.2. Qualified Person for Pharmacovigilance (QPPV):
3.2.1 Oversees the signal management system.
3.2.2 Approves decisions on validated signals.
3.2.3 Ensures timely communication to authorities.
3.3. Regulatory Affairs (RA):
3.3.1 Communicate validated signals to health authorities.
3.3.2 Update SmPC/PI (product information) where required.
3.3.3 Ensure implementation of risk-minimization measures.
3.4. Quality Assurance (QA):
3.4.1 Ensure documentation control & audit readiness.
4.0 DEFINATIONS:
4.1 Signal: Information suggesting a new or changed risk that may impact product safety and requires further evaluation.
4.2 Validated Signal: A signal supported by sufficient evidence requiring detailed assessment.
4.3 Refuted Signal: A signal that, after evaluation, is not considered a true risk.
4.4 Emerging Safety Issue (ESI): Safety information requiring rapid communication to authorities.
4.5 Signal Management: Entire process from detection to decision-making & communication.
5.0 PROCEDURE:
5.1 Signal detection shall be conducted systematically and periodically by reviewing all relevant sources such as
5.1.1 ICSRs,
5.1.2 Published literature,
5.1.3 Clinical study data,
5.1.4 Aggregate reports,
5.1.5 PQC-related AEs,
5.1.6 Regulatory authority alerts,
5.1.7 External safety databases.
5.2 Signal detection activities shall be performed at defined intervals, including
5.2.1 Routine review: Monthly
5.2.2 Literature review: Weekly
5.2.3 Product-specific review: Quarterly
5.2.4 PSUR/PBRER review: At each cycle
5.3 Following Methods shall be used for signal detection
5.3.1 Review of case frequencies
5.3.2 Disproportionate reporting patterns
5.3.3 Clustering of similar AEs
5.3.4 Unexpected severity or outcomes
5.3.5 Lack of efficacy trends
5.3.6 Serious unexpected cases
5.3.7 Assessing biologically plausible events
5.4 Initial Signal Screening:
5.4.1 PV performs preliminary review of newly identified safety information.
5.4.2 Identify if information is:
5.4.2.1 Potential signal
5.4.2.2 Known ADR
5.4.2.3 Non-relevant
5.4.2.4 Requires follow-up
5.4.3 Document all outcomes in the Signal Screening Log.
5.5 Signal validation:
5.5.1 A signal shall validate if:
5.5.1.1 Supported by ≥1 well-documented case
5.5.1.2 Event is medically plausible
5.5.1.3 Pattern is consistent over time
5.5.1.4 Literature or regulator reports support it
5.5.1.5 Severity is high (e.g., death, serious ADR)
5.5.2 PV prepares Signal Validation Summary, including:
5.5.2.1 Event details
5.5.2.2 Case details
5.5.2.3 Product relationship
5.5.2.4 Medical plausibility
5.5.2.5 Frequency
5.5.2.6 Literature support
5.5.3 QPPV decides on:
5.5.3.1 Validated signal
5.5.3.2 Refuted signal
5.5.3.3 Requires more data
5.6 Signal Evaluation:
5.6.1 For validated signals, PV prepares a Signal Evaluation Report, including:
5.6.1.1 Summary of all cases
5.6.1.2 Trend analysis
5.6.1.3 Comparison with product class effects
5.6.1.4 Literature evidence
5.6.1.5 Medical assessment
5.6.1.6 Benefit–risk impact
5.6.2 Recommendations:
5.6.2.1 Update SmPC/PI
5.6.2.2 Strengthen warnings
5.6.2.3 Modify contraindications
5.6.2.4 Update RMP
5.6.2.5 Additional studies
5.6.2.6 No action required
5.6.2.7 QPPV approves the evaluation.
5.7 Signal Prioritization:
5.7.1 Signals classified as:
5.7.1.1 High priority: death, life-threatening, pediatric events, pregnancy risks
5.7.1.2 Medium priority: new ADRs, frequency increase
5.7.1.3 Low priority: known ADR with slight changes
5.8 Regulatory Communication:
5.8.1 RA prepares regulatory notification, including:
5.8.1.1 Summary of signal
5.8.1.2 Assessment report
5.8.1.3 Supporting case data
5.8.2 Submit as per country requirements:
5.8.2.1 Immediate reporting for ESIs (Emerging Safety Issues.
5.8.2.2 Periodic reporting via PSUR/PBRER
5.8.3 Track submission in Signal Regulatory Log.
5.9 Risk Minimization Measures:
5.9.1 Depending on signal outcome:
5.9.1.1 Update SmPC/PI sections (warnings, ADRs)
5.9.1.2 Issue Direct Healthcare Professional Communication (DHPC)
5.9.1.3 Update educational materials
5.9.1.4 Strengthen RMP
5.9.1.5 Increase frequency of safety monitoring
5.10 Documentation and Record Keeping:
5.10.1 Following documents shall maintain:
5.10.1.1 Signal Screening Log
5.10.1.2 Signal Validation and Evaluation Reports
5.10.2 Records shall retain for minimum 5 years.
5.10.3 Regulatory submission proofs like Regulatory communications / Letter shall be retained for 5 years.
5.11 Training:
5.11.1 All Pharmacovigilance (PV), Regulatory Affairs (RA), and Quality Assurance (QA) staff shall be trained on this SOP.
5.11.2 Training must be completed before handling signal-related tasks.
5.12 Deviations:
5.12.1 Any deviation from this SOP shall follow the deviation & Corrective and preventive action (CAPA) SOP.
5.12.2 QPPV shall be informed for any late signal action or missed detection.
6.0 REFERENCES:
6.1 WHO Technical Report Series (TRS) – PV guidance
6.2 EU Good Pharmacovigilance Practices (GVP)
6.3 Company QMS SOPs (Document Control, Training, Audit, Risk Management, Deviation & CAPA)
7.0 RECORDS:
Sr No. Title Document No.
1 Signal Screening Log F/PV007/001 – 00
2 Signal Validation and Evaluation Reports F/PV007/002 – 00
8.0 REVISION HISTORY.
Amendment Date: Update Summary Version No.
NA New SOP 01