SafetyGlossary Term
ICH E2A Section II.B
The intentional re-administration of a suspected drug to a patient who previously experienced an adverse event while taking that drug, performed to help establish whether the drug caused the original event.
Rechallenge represents one of the strongest methods for establishing a causal relationship between drug exposure and an adverse event, as reoccurrence of the event upon re-exposure provides compelling evidence that the drug was responsible. When an adverse event resolves following drug discontinuation and then recurs when the drug is reintroduced, the temporal relationship strongly suggests causality. However, rechallenge is often ethically inappropriate and clinically unnecessary, particularly when the original event was serious or when alternative explanations for the event have been excluded.
The decision to perform a rechallenge requires careful consideration of the potential benefits of the information gained against the risks to the patient. Intentional rechallenge is generally contraindicated when the original reaction was severe, potentially life-threatening, or involved important organs such as the liver, heart, or hematopoietic system. In such cases, the risk of recurrence and potentially more severe reaction outweighs the value of confirming causality. Rechallenge may be considered when the original reaction was mild and self-limiting, when continued treatment with the drug offers significant benefit, and when informed consent has been obtained.
Inadvertent rechallenge occurs when a patient is re-exposed to a drug without awareness of the prior adverse reaction, often due to inadequate medical record documentation or patient communication. When such unintentional rechallenge occurs and the event recurs, this information strengthens the causality assessment even though the rechallenge was not planned. Safety databases capture rechallenge information as a key element in adverse event documentation, and positive rechallenge findings significantly influence the overall causality determination for individual cases and aggregate safety analyses.
Causality confirmation
"After the participant's rash resolved upon drug discontinuation, the investigator discussed the option of rechallenge. The participant agreed, and when the rash recurred within 48 hours of restarting the medication, the investigator documented a positive rechallenge supporting a "definite" causality assessment."
Inadvertent rechallenge
"The participant had discontinued the study drug due to elevated liver enzymes during a previous trial with the same compound. Upon enrollment in the current trial, the same pattern of enzyme elevation emerged, representing an inadvertent positive rechallenge that strengthened the evidence for hepatotoxicity."
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.
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.
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.
ICH E2A Section II.B
The intentional re-administration of a suspected drug to a patient who previously experienced an adverse event while taking that drug, performed to help establish whether the drug caused the original event.
Rechallenge represents one of the strongest methods for establishing a causal relationship between drug exposure and an adverse event, as reoccurrence of the event upon re-exposure provides compelling evidence that the drug was responsible. When an adverse event resolves following drug discontinuation and then recurs when the drug is reintroduced, the temporal relationship strongly suggests causality. However, rechallenge is often ethically inappropriate and clinically unnecessary, particularly when the original event was serious or when alternative explanations for the event have been excluded.
The decision to perform a rechallenge requires careful consideration of the potential benefits of the information gained against the risks to the patient. Intentional rechallenge is generally contraindicated when the original reaction was severe, potentially life-threatening, or involved important organs such as the liver, heart, or hematopoietic system. In such cases, the risk of recurrence and potentially more severe reaction outweighs the value of confirming causality. Rechallenge may be considered when the original reaction was mild and self-limiting, when continued treatment with the drug offers significant benefit, and when informed consent has been obtained.
Inadvertent rechallenge occurs when a patient is re-exposed to a drug without awareness of the prior adverse reaction, often due to inadequate medical record documentation or patient communication. When such unintentional rechallenge occurs and the event recurs, this information strengthens the causality assessment even though the rechallenge was not planned. Safety databases capture rechallenge information as a key element in adverse event documentation, and positive rechallenge findings significantly influence the overall causality determination for individual cases and aggregate safety analyses.
Causality confirmation
"After the participant's rash resolved upon drug discontinuation, the investigator discussed the option of rechallenge. The participant agreed, and when the rash recurred within 48 hours of restarting the medication, the investigator documented a positive rechallenge supporting a "definite" causality assessment."
Inadvertent rechallenge
"The participant had discontinued the study drug due to elevated liver enzymes during a previous trial with the same compound. Upon enrollment in the current trial, the same pattern of enzyme elevation emerged, representing an inadvertent positive rechallenge that strengthened the evidence for hepatotoxicity."
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.
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.
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.