Chapter 10 | Pharmacovigilance

Why is Pharmacovigilance Important?

• Thalidomide disaster (1950s-1960s) highlighted the importance of drug safety, the battle between harm vs. benefit, pharmaceutical company truthfulness, a strong regulatory system, and invaluable post-marketing clinical data.
• Clinical Trial Phases:
  • Phase 1: 20-100 healthy volunteers, tests for safety and effects.
  • Phase 2: 150-250 subjects with disease, tests for efficacy and effectiveness.
  • Phase 3: 250-4000 subjects with disease, random blind testing, FDA approval requested.
  • Phase 4: Post-marketing surveillance (Pharmacovigilance).

Definition of Terms

• Pharmacovigilance (WHO, 2002): Science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other possible drug-related problems.
• Adverse Drug Event/Experience (ADE): Untoward medical occurrence or injury during drug treatment, not necessarily causally related.
• Adverse Drug Reaction (ADR): Noxious and unintended response to a drug at normal doses with causal link.
• Adverse Effect: Negative or harmful patient outcome associated with treatment.
• Side Effect: Unintended but expected or known effect of a drug at normal doses related to pharmacological properties.
• Benefit: Positive therapeutic, health, social, or psychological effects of treatment.
• Benefit-Harm: Description of positive and negative effects of a medicine and their likelihood.
• Effectiveness: Probability of a medicine working positively as expected.
• Efficacy: Extent to which a medicine works positively under laboratory conditions and in a selected group of patients.
• Effectiveness-Risk: Comparison of the statistical chances of a medicine working as expected and/or causing harm.
• Harm: Damage or injury caused by a medicine, including death and social/psychological damage.
• Hazard: Intrinsic characteristics of a medicine with the potential to cause harm.
• Serious: Adverse event resulting in death, hospitalization, disability, or life-threatening condition.
• Severe: Indicates intensity (e.g., severe headache).
• Individual Case Safety Report (ICSR): Reports of adverse effects from health professionals or patients.
• Pharmacovigilance Reporting Systems: Systems relying on healthcare professionals and patients to report suspected adverse effects.

Types of ADRs

• Type A (Augmented): Extension of drug's pharmacology, dose-dependent, predictable. E.g., sedation with antihistamines.
• Type B (Bizarre/Idiosyncratic): Unrelated to drug's pharmacology, not dose-dependent, unpredictable, rare. E.g., hypersensitivity.
  • Drug Intolerance: Low threshold to normal pharmacological action of a drug. E.g., tinnitus with aspirin.
  • Hypersensitivity: Immune-mediated response, Type I (IgE), Type II (IgG or IgM), Type III (IgG-mediated), Type IV (cell-mediated).
  • Pseudoallergy: Direct mast cell activation. E.g., Red man syndrome with vancomycin.
  • Idiosyncratic Reactions: Uncommon response due to genetic abnormality. E.g., Hemolytic anemia in G6PD deficient patients.
• Type C (Continuous/Chronic): Long-term drug therapy. E.g., optic neuropathy with ethambutol.
• Type D (Delayed): Manifested long after drug exposure.
  • Carcinogenesis: E.g., anti-cancer drugs.
  • Teratogenesis: E.g., ACE inhibitors, isotretinoin.
• Type E (Ending of Use): Resulting from termination or sudden discontinuation. E.g., Addison’s disease with steroids.
• Type F (Failure of Therapy): Antimicrobial resistance, inappropriate medications, etc.

Signal

• Possible causal relationship between an adverse event and a drug.

Individual Case Safety Report (ICSR)

• Reports sent by health professionals or patients when an adverse effect has occurred.

WHO Programme for International Drug Monitoring

• Established in 1968 after the Thalidomide disaster.
• Vigibase®: Global ADR database.
• VigiFlow®: Web-based ICSR management system.

National Policy and Program on Pharmacovigilance

• AO 2011-0009.
• National Pharmacovigilance Center (NPVC): Collects and investigates reports, manages risks.

How to Report

• Online reporting at FDA website.
• www.fda.gov.ph

Main Sources of ADR Information

• Spontaneous reporting.
• Reporting by MAHs.
• ADRs reported in medical journals.

What Should Be Reported

• All SUSPECTED adverse drug reactions for medicines and vaccines.

Assessment of Causality

• WHO – UMC system for standardized case causality assessment (Certain, Probable/Likely, Possible, Unlikely, Conditional/Unclassified, Unassessable/Unclassifiable).

Assessment of Validity

• 4 Basic Elements: Identifiable patient, Identifiable reporter, Suspected drug, Adverse experience.