DRAP Guidelines on National Pharmacovigilance System: Adverse Events

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. One of the key aspects covered in the guidance relates to the assessment of adverse events.

What is Causality Assessment?

Causality assessment evaluates the likelihood that a therapeutic good caused an observed adverse reaction. 

This structured approach links an adverse event to a suspected drug and plays a crucial role in:

• Defining the Drug-ADR relationship.
• Detecting signals.
• Supporting evidence-based risk minimization actions.

Methods of Causality Assessment for Single Case Safety Reports

According to the guidance, causality assessment methods are categorized into three types:

1. Algorithms: E.g., Naranjo Algorithm, RUCAM.
2. Global Introspection: Qualitative (e.g., WHO-UMC system) or quantitative (e.g., French imputability system).
3. Probabilistic Methods: E.g., Bayesian approaches.

The assessment considers:

• Temporal association between drug administration and event.
• Pharmacological knowledge about the drug.
• Medical plausibility.
• Exclusion of other causes.

Naranjo Algorithm for Causality Assessment

The Naranjo Algorithm determines the likelihood of ADRs using a 10-question questionnaire. Responses (Yes, No, or Do Not Know) are weighted, with scores determining causality from doubtful (unlikely) to definite (certain).

WHO-UMC System for Standardized Case Causality Assessment

As explained by the authority, this practical tool evaluates case reports by combining clinical-pharmacological data and observation quality. It emphasizes unknown and unexpected reactions over statistical likelihood.

Criteria to be used in this regard include:

• Timing of the event.
• Alternative explanations (e.g., other diseases or drugs).
• Response to drug withdrawal (de-challenge).
• Response to re-exposure (re-challenge).

Classification Categories:

• Certain: Plausible timing, withdrawal response, observable condition, and rechallenge confirmation.
• Probable/Likely: Reasonable time relationship, unlikely alternative causes, and recovery upon withdrawal.
• Possible: Event with reasonable timing but could be explained by other causes; withdrawal information might be lacking.
• Unlikely: Improbable timing or plausible alternative causes.
• Conditional/Unclassified: Limited or insufficient data, with additional information needed.
• Unassessable/Unclassifiable: Insufficient or contradictory data that cannot be supplemented.

Causality Assessment for Case Series

Case series involve patients with similar exposures and outcomes, providing additional context beyond single case assessments. 

These assessments use Bradford Hill Criteria:

1. Strength of Association: Comparing observed vs. expected reports.
2. Temporal Relationship: ADR occurs after drug exposure, fitting pharmacological expectations.
3. Consistency: Reports from diverse sources support the association.
4. Biologic Plausibility: Fits known drug mechanisms.
5. Coherence: Aligns with existing knowledge.
6. Dose-Response Relationship: Evidence of ADR variation with dose changes.
7. Specificity: The reaction aligns with specific drug mechanisms.
8. Experimental Evidence: Supported by prior studies.
9. Analogy: Similar reactions observed with related drugs.

Causality Assessment by Stakeholder

Healthcare Professionals:

Trained HCPs perform initial assessments using WHO-UMC or Naranjo methods before reporting to NPC, PPCs, or registration holders.

Hospitals:

Pharmacovigilance officers assess AEs and AEFIs, with their evaluations reviewed by hospital pharmacovigilance committees and forwarded to PPCs.

Public Health Programmes (PHPs):

Expert Safety Review Panels (ESRPs) assess AE and AEFI reports using WHO-UMC methods and forward findings to NPC.

Provincial Pharmacovigilance Centres (PPCs):

PPC officers assess reports from therapeutic goods sale points, HCPs, and patients. Hospital-submitted reports are reviewed, and case series are evaluated using Bradford Hill Criteria.

National Pharmacovigilance Centre (NPC):

NPC officers review reports from stakeholders and assess causality for completeness. Priority-based inclusion criteria help manage high-report volumes, and findings are shared with WHO-UMC’s VigiBase.

Assessment of Medication Errors and Near Misses

According to the guidance, medication errors often result from systemic failures rather than individual mistakes. Analysis to be conducted in such cases involves:

1. Identifying root causes, such as poor system designs.
2. Evaluating interrelated elements like communication, drug labeling, work environment, and staff competency.

Key Elements to Analyze:

• Patient information accuracy.
• Accessible drug information.
• Communication clarity among providers.
• Standardized drug labeling and storage.
• Equipment and technology usage.
• Staff training and education.

Tools for Pharmacovigilance

As further stated in the document, the tools for reporting and data collection introduced under the existing legal framework include:

1. Adverse Drug Reaction Reporting Form.
2. Med Vigilance E-Reporting System.
3. VigiMobile App and Med Safety App.
4. Industry E-Reporting System.
5. CIOMS Form-I.
6. E2B XML Reporting.

Tools for assessment and signal detection include:

1. Naranjo Algorithm.
2. WHO-UMC Causality Assessment System.
3. Bradford Hill Criteria.
4. VigiLyze for Signal Detection.

Tools for data storage and coding, as per the guidance, are:

1. VigiFlow: National database.
2. MedDRA: Medical terminology coding.
3. WHO-Drug Dictionary: Drug classification and coding.

Conclusion

In summary, causality assessment forms the foundation of pharmacovigilance by determining the relationship between drugs and adverse events. Using tools like the Naranjo Algorithm, WHO-UMC system, and Bradford Hill Criteria, pharmacovigilance stakeholders can systematically evaluate individual and case series reports. Enhanced tools for reporting, data storage, and signal detection support a robust framework for ensuring the therapeutic safety of the products allowed for marketing and use in Pakistan.

Source

https://www.dra.gov.pk/wp-content/uploads/2024/10/NPVG-guidelines-reviewed-final-10-10-24.pdf

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