The new article provides a detailed description of processes and procedures associated with signal management.
Table of content
The Drug Regulatory Authority of Pakistan (DRAP), a country’s agency in the sphere of healthcare products, has published a new revision of the guidelines on the national pharmacovigilance system. The document provides an overview of the applicable regulatory requirements, as well as additional clarifications and recommendations to be taken into consideration by medical device manufacturers and other parties involved in order to ensure compliance.
At the same time, the authority reserves the right to make changes to the document, should such changes be reasonably necessary to reflect corresponding amendments to the underlying legislation.
Definition of a Signal
According to the definition provided in the guidance, a signal represents reported information suggesting a possible causal relationship between an adverse event (AE) and a therapeutic good that is previously unknown or incompletely documented.
A signal typically arises from:
- Individual case safety reports (ICSRs),
- Aggregated data,
- Scientific literature,
- Observations or experiments.
Key Definitions:
WHO Definition: A signal indicates the potential need for review or action based on multiple reports highlighting possible causal relationships.
CIOMS Definition (2010): Signals represent new or potentially causal associations, or novel aspects of known relationships, between an intervention and an event. These signals warrant verification for further action.
Responsibilities of NPC, DRAP
The National Pharmacovigilance Centre (NPC), under the DRAP, plays a central role in signal management. Its responsibilities include:
- Monitoring the National ADR Database for new risks or changes in risk-benefit balances.
- Evaluating and identifying signals, then submitting validated signals to the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) for advice.
- Undertaking the entire signal management process, including detection, validation, prioritization, evaluation, confirmation, and communication.
- Recommending regulatory actions or risk minimization measures to concerned boards or committees for implementation in Pakistan.
Signal Management Process
As further explained by the authority, signal management is a multi-step, structured approach used to evaluate data from various sources, such as ICSRs, active surveillance systems, scientific literature, and clinical studies, to identify potential risks associated with therapeutic goods.
Key aspects include:
- Signal detection from any source.
- Validation of identified signals to confirm sufficient evidence.
- Prioritization based on public health impact.
- Comprehensive assessment to confirm or refute the signal.
- Recommendation of regulatory or risk minimization actions.
- Communication and tracking of outcomes.
Signal Management Steps
- Signal Detection
Signal detection involves identifying patterns in data using Qualitative (Hypothesis-Driven) Detection, assessors propose causal relationships based on observations or hypotheses, or Quantitative (Data Mining) Detection: statistical tools like Bayesian and Frequentist methods analyze disproportionality in ADR databases. Techniques include Information Component (IC) – measures reporting disproportionality in the VigiLyze database, and Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR).
Triggers for signals include:
- Unexpected ADRs.
- Unusual patterns in known ADRs.
- Severe events (e.g., Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis).
- Life-threatening outcomes.
- Signal Validation
This step verifies whether the detected signal has sufficient supporting evidence. Criteria include:
- Strength and clinical relevance of the evidence.
- Mechanistic plausibility and patient data.
- Analysis of additional sources (e.g., risk management plans, clinical trials).
Validated signals justify further analysis, while non-validated signals are not pursued.
- Signal Prioritization
Validated signals are prioritized based on the following:
- Public health impact.
- Potential to affect the therapeutic good’s risk-benefit balance.
- Media or public concern (e.g., signals following mass immunization).
- Signal Assessment
Assessment involves a thorough evaluation of all evidence, including:
- Clinical and non-clinical data.
- Observational and experimental studies.
- Global databases and risk management plans.
The assessment determines whether the signal confirms a new risk or changes a known risk.
- Recommendations for Action
Based on the assessment, NPC formulates regulatory or remedial actions, such as:
- Adding new warnings or contraindications.
- Restricting or removing indications.
- Proposing risk minimization strategies.
These recommendations are communicated to relevant stakeholders for implementation.
- Exchange of Information
The NPC coordinates with provincial pharmacovigilance centres (PPCs), registration holders, healthcare professionals, and media to disseminate information about confirmed signals and associated actions.
Signal Management at NPC
The Pharmacovigilance Officers (POs) or Signal Review Groups at NPC oversee the entire signal management process.
Key activities include:
- Detection: Using tools like VigiLyze to identify signals through IC value rises or qualitative observations.
- Validation: Gathering evidence from literature, case series, clinical trials, and regulatory history.
- Prioritization: Focusing on signals with significant public health implications.
- Assessment: Comprehensive evaluation of clinical and non-clinical evidence.
- Confirmation: Refuting or validating signals before presenting them to PRAEC.
- Regulatory Action: Collaborating with PRAEC to recommend risk minimization measures or other remedial actions.
Tools and Techniques in Signal Management
The document further describes in detail the key tools and techniques to be used in signal management.
Quantitative Methods for Signal Detection
- Bayesian Approach: Uses prior and posterior probabilities to detect disproportionality in reporting.
- Frequentist Approach: Relies on statistical comparisons to establish unexpected patterns.
Qualitative Techniques
- Hypothesis-driven exploration of possible causal relationships.
Conclusion
In summary, the signal management process is a cornerstone of pharmacovigilance, enabling the detection, validation, and assessment of potential risks associated with therapeutic goods. Through systematic steps, NPC ensures public safety by identifying new risks, refining known risks, and implementing timely regulatory actions. Collaboration with PRAEC and robust data analysis methods, including tools like VigiLyze, strengthens this framework, ensuring optimal safety of therapeutic goods in Pakistan.
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