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Table 4 Rationales for successful reclassification or removal of a safety concern

From: Risk Management Plans: reassessment of safety concerns based on Good Pharmacovigilance Practices Module V (Revision 2)—a company experience

Safety Concern

Rationales and Examples

IIRs or IPRs

Risk Characterization

 • Risk well-characterized; additional information not expected:

  - Risk of “Severe skin reactions” removed for combination product composed of active substances well-characterized in the meantime

 • No reasonable expectation that additional PV activities could further characterize the risk:

  - Risk of “Guillain-Barré syndrome” due to rarity of event

 • Causal association not supported [IPR]:

  - Risks of “Congestive Heart Failure” and “Anemia” removed as causal relationship not supported by accumulated scientific and clinical data

Risk Management/Minimization

 • Risk managed by routine RMMs; additional RMMs not required:

  - Risks of “Hyperglycemia” and “Urinary Tract Infection” removed as fully characterized and appropriately managed through product labels

 • Management of risk is fully integrated into routine clinical practice:

  - Risks with published management guidelines removed, e.g. “Lipid Abnormalities”

 • Risk is a known effect of mature product class:

  - Risk of “Hypertension” removed, as known to be associated with product class

Risk Not Compatible with Regulatory Definitions

 • Risk not an undesirable clinical outcome:

  - Risk of “Medication error” removed; clinical consequences of medication errors captured under other IIRs

  - “Exposure during pregnancy” with no evidence of maternal/infant sequelae; reclassified to MI

Othera

 • Subsuming of risks with the same underlying scientific concept:

  - Risk of “Opportunistic infections” subsumed under “Serious infections”

MI

MI Characterization

 • Adequate safety data available with respect to area of MI:

  - “Long-term safety” removed as MI once sufficient data available to confirm safety profile with long-term use

 • No reasonable expectation that additional PV activities could further characterize safety profile within area of MI:

  - “Use in the elderly” removed as MI where there remains insufficient exposure as condition prevalent in the young

MI Not Compatible with Regulatory Definitions

 • MI not within approved indication:

  - “Use in pediatric patients” removed for products not authorized in this population

  - “Use in nursing mothers” removed for products contraindicated in this population

 • No scientific rationale for different safety profile:

  - “Use in patients with severe renal/hepatic impairment” removed for products with minimal renal clearance/hepatic metabolism

Othera

 • Concept already covered by IIR/IPR:

  - “Use in patients with a history of malignancy” removed if malignancy was already listed as an IIR/IPR

  1. B-R Benefit-Risk, IIRs Important Identified Risks, IPRs Important Potential Risks, MI Missing Information, PV Pharmacovigilance, RMMs Risk Minimization Measures
  2. aNot specifically described in GVP Module V (rev 2), but based on information provided during the EMA information day/feedback from EU health authorities