SafetyGlossary Term
ICH E2A Section II.B
The systematic evaluation of the likelihood that an adverse event was caused by the investigational product or another factor, using established criteria to determine the relationship between exposure and outcome.
Causality assessment represents a critical analytical process in pharmacovigilance, requiring investigators and sponsors to evaluate whether observed adverse events are attributable to the investigational product, underlying disease, concomitant medications, or other factors. This determination influences regulatory reporting obligations, risk-benefit evaluations, and ultimately the decisions made about product development and labeling. While establishing definitive causality is often impossible, standardized approaches enable consistent and defensible assessments.
Several factors inform causality assessment, including temporal relationship between drug exposure and event onset, biological plausibility based on known pharmacological mechanisms, the presence of alternative explanations, results of dechallenge and rechallenge when available, and the pattern of similar events across the trial population. Some assessment systems use categorical ratings such as "definite," "probable," "possible," "unlikely," and "unrelated," while others employ numerical algorithms. The choice of assessment methodology should be prespecified in the protocol or pharmacovigilance plan to ensure consistency.
The investigator bears primary responsibility for providing a causality assessment for each adverse event, drawing upon their clinical expertise and knowledge of the participant's medical history. However, the sponsor also independently evaluates causality, particularly for serious events, and may reach a different conclusion than the investigator. Regulatory guidelines specify that if either the investigator or sponsor considers an event possibly related to the investigational product, it should be treated as such for reporting purposes. This conservative approach ensures that potential safety signals are not missed due to overly restrictive causality judgments.
Investigator assessment
"The investigator assessed the participant's rash as "probably related" to the study drug based on the temporal relationship with drug initiation, improvement upon dose reduction, and absence of other explanatory factors such as new medications or allergen exposures."
Sponsor-investigator disagreement
"Although the investigator considered the cardiac arrhythmia unrelated to the study drug, the sponsor assessed it as possibly related given the known class effects of similar compounds, and the event was reported as a suspected adverse drug reaction."
A response to a medicinal product that is noxious and unintended, where a causal relationship between the product and the adverse event is at least a reasonable possibility.
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product.
The strictest warning required by the FDA to appear on prescription drug labeling, alerting prescribers and patients to serious risks that may lead to death or severe injury.
A standardized one-page format developed by the Council for International Organizations of Medical Sciences for reporting suspected adverse drug reactions from clinical trials to regulatory authorities.
A specific situation or condition in which a drug, procedure, or treatment should not be used because it may be harmful to the patient.
ICH E2A Section II.B
The systematic evaluation of the likelihood that an adverse event was caused by the investigational product or another factor, using established criteria to determine the relationship between exposure and outcome.
Causality assessment represents a critical analytical process in pharmacovigilance, requiring investigators and sponsors to evaluate whether observed adverse events are attributable to the investigational product, underlying disease, concomitant medications, or other factors. This determination influences regulatory reporting obligations, risk-benefit evaluations, and ultimately the decisions made about product development and labeling. While establishing definitive causality is often impossible, standardized approaches enable consistent and defensible assessments.
Several factors inform causality assessment, including temporal relationship between drug exposure and event onset, biological plausibility based on known pharmacological mechanisms, the presence of alternative explanations, results of dechallenge and rechallenge when available, and the pattern of similar events across the trial population. Some assessment systems use categorical ratings such as "definite," "probable," "possible," "unlikely," and "unrelated," while others employ numerical algorithms. The choice of assessment methodology should be prespecified in the protocol or pharmacovigilance plan to ensure consistency.
The investigator bears primary responsibility for providing a causality assessment for each adverse event, drawing upon their clinical expertise and knowledge of the participant's medical history. However, the sponsor also independently evaluates causality, particularly for serious events, and may reach a different conclusion than the investigator. Regulatory guidelines specify that if either the investigator or sponsor considers an event possibly related to the investigational product, it should be treated as such for reporting purposes. This conservative approach ensures that potential safety signals are not missed due to overly restrictive causality judgments.
Investigator assessment
"The investigator assessed the participant's rash as "probably related" to the study drug based on the temporal relationship with drug initiation, improvement upon dose reduction, and absence of other explanatory factors such as new medications or allergen exposures."
Sponsor-investigator disagreement
"Although the investigator considered the cardiac arrhythmia unrelated to the study drug, the sponsor assessed it as possibly related given the known class effects of similar compounds, and the event was reported as a suspected adverse drug reaction."
A response to a medicinal product that is noxious and unintended, where a causal relationship between the product and the adverse event is at least a reasonable possibility.
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product.
The strictest warning required by the FDA to appear on prescription drug labeling, alerting prescribers and patients to serious risks that may lead to death or severe injury.
A standardized one-page format developed by the Council for International Organizations of Medical Sciences for reporting suspected adverse drug reactions from clinical trials to regulatory authorities.
A specific situation or condition in which a drug, procedure, or treatment should not be used because it may be harmful to the patient.