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In my past columns over the years I have often lamented that academia (medical, nursing, pharmacy schools) have not really gotten into the field of drug safety other than via epidemiology. Very little academic research has been or is being done in this field. In fact, as we move towards more flexible study design with the aim of studying fewer patients to demonstrate drug efficacy before approval, we will be losing safety data. Unlike efficacy, which is often statistically base, drug safety requires fairly large numbers of patients to understand the safety profile and find infrequent ADRs. We would very much like to see drug safety and pharmacovigilance become an active area of research, study and training for health care practitioners.

This posting has been prepared with Pierre Biron MD, retired Professor of Pharmacology at the University of Montreal, Canada. Prof. Biron is well known in the PV field and has authored many papers on the subject as well as several books on the topic (some of which I co-authored). This posting summarizes the information and documentation that should be examined in the study and work up of ADRs to determine whether the reaction is likely due to the drug or not. One might say it is a semi-quantitative way of categorizing an ADR in terms of causality. Such a method of describing the strength of the drug causality of the adverse event would be very useful in product labeling. This would allow the prescriber and patient to judge the likelihood of the ADR being due to the drug and help decide what work-up should or should not be done to find other possible causes.

Have a look. We’d be very interested in readers’ opinions!

Previous Documentation

1.Suspected/Suspect product

2.Adverse Event

Patient’s History

3.Prior experience specific to the ADR 

4.Pharmaceutical history

5.Medical history: the concomitant morbidity

Clinical Presentation


Proposed scale for ranking the prior documentation concerning the AE and the suspect drug:

Level 4 – Fully labeled
Level 3 – Recognized but not yet fully labeled
Level 2 – Anecdotal or predictable
Level 1 – Unpublished and unpredictable
Level 0 – Unreported worldwide (from manufacturer’s and WHO/UMC Vigibase international ADR database)

Proposed scale for quantifying causality assessment:

Level 4 – Definite ( > 95% confidence in causality)
Level 3 – Probable (50% to 95% confidence in causality)
Level 2 – Possible (5% to 50% confidence in causality)
Level 1 – Unlikely, doubtful ( <5% but not 0% confidence in causality)
Level 0 – Causality assessment impossible (insufficient case data)
Level -1 – Causality ruled out (after reviewing the case data)

For regulatory purposes in most jurisdictions, levels 1 to 4 are usually ranked as “possibly related” or having “a reasonable possibility.” In civil lawsuits, levels 3 and 4 may be deemed sufficient to infer causality (“more likely than not”). In criminal cases, even more than level 4 may be required, such as 99.9% confidence in causality.

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