Basic concepts of pharmacovigilance

The most fundamental ideas in pharmacovigilance: harm (Adverse Drug Reactions), safety, and causation.

1. Adverse Drug Reactions (ADRs)

• Definitions:
  • Side-effect: An unintended effect of a medicine, which can be undesirable or beneficial.
  • Adverse Drug Reaction (ADR): An unintended and noxious effect attributable to a medicine at normal doses.
  • Adverse Event (AE): Any undesirable occurrence during treatment, where a causal link to the medicine has not been established.
  • Suspected ADR: This is the key term for reports where a health professional suspects a drug caused an event. Spontaneous reporting systems are based on these.
• Classification Systems:
  • Traditional (Type A/B):
    • Type A (Augmented): Dose-related, predictable from the drug’s pharmacology, common, and often reversible (e.g., bleeding with warfarin).
    • Type B (Bizarre): Not dose-related, unpredictable, uncommon, and can be serious (e.g., anaphylaxis with penicillin).
    • Additional categories (C, D, E) were later added for chronic, delayed, and end-of-use effects.
  • DoTS Classification: A more modern system based on:
    • Dose-relatedness (Toxic, Collateral, Hypersusceptibility)
    • Time course (e.g., first dose, early, late, delayed, withdrawal)
    • Susceptibility (e.g., age, genetics, disease)
• Nature, Mechanisms, and Predisposing Factors:
  • ADRs often mimic natural diseases, but a few are unique drug-induced syndromes.
  • Mechanisms include exaggerated therapeutic effect, effects at other sites, secondary pharmacological actions, and immunological responses.
  • Factors increasing the risk of ADRs include age (very young/old), gender, genetics, impaired organ function, specific diseases, and taking multiple drugs (polypharmacy), which can lead to drug interactions.
• Public Health Burden: ADRs remain a significant cause of illness, hospital admissions, and death, representing a major form of iatrogenic (doctor-induced) disease.

2. The Concept of Safety

• Definition: Safety is the relative absence of harm. Absolute safety is unattainable. A drug is considered “safe” when the probability of harm is acceptably low in the context of the disease being treated and the drug’s expected benefits.
• Risk: The probability of an adverse outcome.
  • Absolute Risk: The actual probability (e.g., 1 in 100). This is more useful for decision-making.
  • Relative Risk: A ratio comparing the risk in treated vs. untreated groups (e.g., a two-fold increase). This can be misleading without knowing the baseline risk.
  • The “Rule of Three”: A statistical tool used when zero events are observed. It estimates the upper limit of the potential risk (e.g., if 0 reactions in 900 patients, the true risk is unlikely to be higher than 1 in 300).
• Safety in Practice:
  • Intrinsic Safety: Some drugs are inherently safer than others.
  • User-dependent Safety: Safety often depends on how the drug is used (e.g., dose, monitoring, avoiding in certain patients).
  • Levels of Knowledge: Safety knowledge is categorized as Well-established, Established, Provisional (new drugs), or Limited (e.g., orphan drugs).
• Risk-Benefit Balance: Judging safety is inseparable from efficacy. A balance between harms and benefits is struck at two levels:
  1. Population level (by regulators).
  2. Individual level (by clinicians and patients).

3. Causation – Was the Drug Responsible?

• In Individual Cases: Assessing whether a specific AE in a patient was caused by the drug. Key factors to consider are:
  • Temporal relationship: Did the event occur after starting the drug? Did it improve when stopped (dechallenge) or recur when restarted (rechallenge)?
  • Alternative causes: Are there other diseases, medications, or factors that could explain the event?
  • Nature of the event: Is it a known drug reaction?
  • Plausibility: Is there a known mechanism or is it seen with similar drugs?
• From Study Data:
  • Randomized Trials: Differences between groups are likely causal if chance, bias, and issues with randomization can be ruled out.
  • Non-randomized (Observational) Studies: An observed “association” could be due to:
    1. Chance
    2. Bias (systematic error)
    3. Confounding (a third factor linked to both the drug and the outcome)
    4. Causation
  • Bradford-Hill Criteria: A framework of nine criteria (e.g., strength of association, consistency, specificity, biological gradient) used to judge whether an observed association is likely to be causal. The more criteria met, the more likely the link is causal, but judgement is always required.