Clinical Investigators and their sites should establish a systematic way of assessing causality when adverse events and serious adverse events occur. The Bradford Hill Critera are an established practical way of determining these events. [1]
- Strength of Association: a strong association between a treatment and an adverse event indicates causation. For example, each time the drug was given to a subject, it caused vomiting within a predictable time period.
- Consistency: established adverse event attributions or previous determinations in similar situations indicate causation.
- Specificity: an established mechanism of action connecting the treatment and the adverse event indicates causation.
- Temporality: exposure to the product must occur before the disease or event, and not after a latency period. However, temporality is not sufficient to establish causation.
- Biological Gradient: a dose response effect is a strong argument for causation.
- Plausibility: the causal relationship is biologically plausible.
- Coherence: the known facts fit the natural history and biology of the disease.
- Experiment: epidemiologic studies indicate causation.
- Analogy: a similar agent causes the same type of AE.
[1] Klein, G., Johnson, P. and Morgan R., Medical Monitoring of Clinical Research Studies. J. Clin. Res. Best Practices. 2021: Vol 17 (1)