Adverse drug reaction (ADR)

An adverse drug reaction (ADR) is a noxious and unintended response to a medicinal product for which a causal relationship between the medicinal product and the reaction is at least a reasonable possibility. Unlike an adverse event (AE), an adverse drug reaction implies a causal relationship that cannot reasonably be ruled out.

The term is used in clinical research, pharmacovigilance, and regulatory reporting. Its interpretation differs slightly depending on whether the medicinal product is investigational or marketed.

Regulatory definitions

ICH E6(R3) (Guideline for Good Clinical Practice)

For investigational medicinal products during pre-approval clinical development, ICH E6(R3) defines an adverse drug reaction as:

Unfavourable and unintended responses, such as a sign (e.g., laboratory results), symptom or disease related to any dose of a medicinal product where a causal relationship between a medicinal product and an adverse event is a reasonable possibility 1.

The ICH E6(R3) guideline further notes that the level of certainty regarding relatedness may vary. Suspected ADRs with a high level of certainty should be reflected in the reference safety information (RSI) and/or the investigator’s brochure (IB).

For marketed medicinal products, ICH E6(R3) refers to the definition provided in ICH E2A (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting):

A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function 2.

This definition originated in the WHO Technical Report No. 498 (1972) 3 and was subsequently incorporated into ICH E2A.

Relationship to adverse events

An adverse drug reaction (ADR) is a subset of adverse events (AEs). Every ADR is an adverse event, but not every adverse event is an ADR.

The distinction is based on causality. An adverse event is any untoward medical occurrence associated with the use of a medicinal product, regardless of whether the product is considered responsible. An adverse drug reaction is an adverse event for which a causal relationship with the medicinal product is considered at least reasonably possible.

For a broader comparison of related safety reporting terms, see Adverse event terminology.

Causality assessment

Classification of an event as an adverse drug reaction is based on causality assessment. Investigators and sponsors evaluate whether available clinical information supports a reasonable possibility that the medicinal product contributed to the event.

The method used for causality assessment may vary according to the study protocol, sponsor procedures, or applicable regulatory requirements. Regulatory authorities may also recommend specific methods for causality assessment in pharmacovigilance.

Related terminology

  • Adverse event
  • Causality assessment
  • Pharmacovigilance
  • Serious adverse event
  • Suspected unexpected serious adverse reaction (SUSAR)

References

  1. International Council for Harmonisation. 2026. ICH E6(R3): Consolidated Guideline for Good Clinical Practice.
    Available at: https://database.ich.org/sites/default/files/ICH%20E6%28R3%29_Step4_FinalConsolidatedGuideline_2026_0616_.pdf ↩︎
  2. International Council for Harmonisation. 1994. ICH E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.
    Available at: https://database.ich.org/sites/default/files/E2A_Guideline.pdf ↩︎
  3. World Health Organization. 1972. International Drug Monitoring: the Role of National Centres, report of a WHO meeting held in Geneva from 20 to 25 September 1971.
    Available at: https://iris.who.int/handle/10665/40968 ↩︎