In clinical trials, safety reporting is a critical issue. This includes the reporting of safety information (adverse events or adverse reactions) from the investigational sites to the sponsor and then from sponsor to the regulatory agencies (FDA, EU) and distribution of the safety information to other investigational sites and IRBs. There have been many regulatory guidelines regarding the reporting of the safety information. However, none of the guidelines give clear instruction on how to categorize the causality for adverse events or adverse reactions.
In recent FDA’s guidance “Safety Reporting Requirements for INDs and BA/BE Studies”, it reiterates the concept of “reasonable possibility” for causality assessment, but does not provide the causality categories.
“Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of
safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug. Suspected adverse reactions are the subset of all adverse events for which there is a reasonable possibility that the drug caused the event. Inherent in this definition, and in the requirement to report suspected adverse reactions, is the need for the sponsor to evaluate the available evidence and make a judgment about the likelihood that the drug actually caused the adverse event. We consider the application of the reasonable possibility causality standard to be consistent with the discussion about causality in the International Conference on Harmonization (ICH) E2A Guideline (“ICH E2A guidance”)." IND
In FDA’s guidance “Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment”, they cited WHO, the
2000, Safety Monitoring of Medicinal Product. Uppsala
“FDA does not recommend any specific categorization of causality, but the categories probable, possible, or unlikely have been used previously. If a causality assessment is undertaken, FDA suggests that the causal categories be specified and described in sufficient detail to understand the underlying logic in the classification.”The regulatory guidance leaves the sponsor to decide what to be considered as ‘reasonable possibility’. The sponsor can design the data collection form (SAE form or adverse event case report form) using various categories for causality assessment/reporting.
For data collection purpose, what categories should be collected for causality assessment?
In ICH E2A CLINICAL SAFETY DATA MANAGEMENT: DEFINITIONS AND STANDARDS FOR EXPEDITED REPORTING”, there is a paragraph regarding the causality assessment and causality categories.
“Many terms and scales are in use to describe the degree of causality (attributability) between a medicinal product and an event, such as certainly, definitely, probably, possibly or likely related or not related. Phrases such as "plausible relationship," "suspected causality," or "causal relationship cannot be ruled out" are also invoked to describe cause and effect. However, there is currently no standard international nomenclature. The expression "reasonable causal relationship" is meant to convey in general that there are facts (evidence) or arguments to suggest a causal relationship. “
In FDA guidance for reviewer “Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review, the following categories are referenced:
Causality assessment by investigator (definitely; probably; possibly; unlikely related)
In ICH E2B “MAINTENANCE OF THE ICH GUIDELINE ON CLINICAL SAFETY DATA MANAGEMENT: DATA ELEMENTS FOR TRANSMISSION OF INDIVIDUAL CASE SAFETY REPORTS “, the following causality categories are referenced in the examples provided in the guidelines. It turns out that these categories seem to be the most commonly used in practice.
The CDISC, CDASH considered causality assessment (relationship to study treatment) as a sponsored defined field. However, it recommends the categories listed in ICH E2B example:
“Sponsored-defined terminology will be used to indicate the relationship between the AE and the study treatment (e.g. ICH E2B examples: Not Related, Unlikely Related, Possibly Related, Related). “
EU regulations regarding the safety report are generally consistent with the ICH guidance (specifically ICH EB2) and do not provide any specific guidance on specific causality categories to use.
EMA Guideline on Good Pharmacovigilance Practice (GPV) recommends the following:
Different methods may be applied for assessing the causal role of a medicinal product on the reported adverse event (e.g. WHO-UMC system for standardised case causality assessment). In this situation, the levels of causality, which correspond to a reasonable possibility of causal relationship, should be established in advance in order to determine when an adverse event is considered as an adverse reaction.Some sponsors used the causality categories from WHO 2000 Safety Monitoring of Medicinal Product that used the following categories. Definitely Probably Possibly Unlikely Conditional Related Related Related Related. For example, A FDA communication with Cangene Corporation indicated the following AE causality categories are used: Definitely related, Probably related, Possibly related, Unlikely related, and Conditional. This is the same as the above-mentioned WHO-UMC system for standardised case causality assessment.
The causality categories described by the Uppsala Monitoring Centre are as follows. However, the following categories may be modified in the practical use.
1. Certain: a clinical event, including laboratory test abnormality, occurring in a plausible time relationship to drug administration, and which cannot be explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be clinically plausible. The event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary.
2. Probable/Likely: a clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not required to fulfil this definition.
3. Possible: a clinical event, including laboratory test abnormality, with a reasonable time sequence to administrations of the drug, but which could also be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear.
4. Unlikely: a clinical event, including laboratory test abnormality, with a temporal relationship to drug administration which makes a causal relationship improbable, and in which other drugs, chemicals or underlying disease provide plausible explanations.
5. Conditional/Unclassified: a clinical event, including laboratory test abnormality, reported as an adverse reaction, about which more data is essential for a proper assessment, or the additional data is under examination.
6. Unassessable/Unclassifiable: a report suggesting an adverse reaction which cannot be judged because information is insufficient or contradictory, and which cannot be supplemented or verified.
Some sponsors may use the following categories and definitions for AE causality. For example, an NDA review memo from FDA indicated that the sponsor used the following causality categories: probable, possible, unlikely and not assessable. The instructions for the AE causality assessment are explained below:
Relationship to Investigational ProductThe assessment of the relationship of an adverse event to the administration of study drug (none, unlikely (remote), possible, probable, not assessable) is a clinical decision based on all available information at the time of the completion of the case report form.
None – includes: (1) the existence of a clear alternative explanation (e.g. mechanical bleeding at surgical site); or (2) non-plausibility (e.g., the patient is struck by an automobile at least where there is no indication that the drug caused disorientation that may have led to the event; cancer developing a few days after drug administration).
Unlikely (remote) – a clinical event, including lab abnormality, with an improbable time sequence to drug administration and in which other drugs, chemicals or underlying disease provide plausible explanation.
Possible – a clinical event including lab abnormality, with a reasonable time sequence to administration of the drug, which could also be explained by concurrent disease* or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear.
Probable – a clinical event including lab abnormality, with a reasonable time sequence to administration of the drug, unlikely to be attributed to concurrent disease* or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge).
Not assessable – a report of an AE which cannot be judged because information is insufficient or contradictory, and which cannot be supplemented or verified.
Table below summarized various causality categories:
Not Related, Unlikely Related, Possibly Related, Related)
Not Related, Unlikely Related, Possibly Related, Related).
Certain, Probable/Likely, Possible, Unlikely, Conditional/Unclassified
None, Unlikely, Possible, Probable, Not assessable
Due to the fact that there is no clear regulatory guidance on the use of the causality categories, different sponsors could use different causality categories. The consequence is that the so-called drug–related adverse events (or the new term adverse drug reactions) can not be directly compared across the studies by different sponsors. The biases can arise if we attempt to compare the results from different studies conducted by different sponsors where the different causality categories are used.