Drug Disposition

In this part, the Dx3 checklist is aimed at assessing whether there is available evidence of an intrinsic disposition of the drug to produce the adverse event in general. Assessing this part requires expertise and literature review.

Strong Evidence of Drug Disposition: Mechanistic Knowledge

Strong evidence of disposition of the drug toward the adverse event here means, in accordance with the adopted conceptual framework, that there is evidence of a plausible mechanism by which the drug could produce the event alone or together with another drug [7, 9, 19].

Good Evidence of Drug Disposition: Correlation Indicating Causality

Good evidence of drug disposition here means that there is statistical evidence suggesting a causal relationship between the drug and the adverse event and that temporality matches the drug’s known properties.

Moderate Evidence of Drug Disposition: Correlation

Moderate evidence indicates that there is a correlation between the drug and the adverse event described in the literature, but there is no evidence that this is causal in the sense ‘intrinsic to the drug’.

Patient Disposition (Vulnerability)

In this part, the Dx3 checklist is aimed at assessing whether the patient has an intrinsic disposition toward the reported event that makes them particularly vulnerable to it. If so, this does not automatically rule out that the drug played a causal role in triggering that event in this specific case. It could, however, indicate that the disposition is mainly, or even only, in the patient context. In the practice of medicine, causal evaluations need to be done in the context of the specific patient, and will depend on the level of evidence of drug disposition and evidence of mutuality. Note that different assessors will still have different judgements, and here the realistic aim of this approach is not necessarily to create consensus, but rather to provide a common language for the discussion.

Strong Evidence of Vulnerability

Strong evidence of patient vulnerability to the reported event indicates a disposition or pre-disposition of the patient and their context (e.g. concomitant drugs) toward that event.

Good Evidence of Vulnerability

Good evidence of patient vulnerability indicates that, although the patient does not have a history of the reported event, they belong to a sub-population that is known to be generally more physiologically disposed or pre-disposed to that event.

Moderate Evidence of Vulnerability

Moderate evidence of patient vulnerability indicates that the patient belongs to a sub-population that has a correlation with the reported (or similar) events, but there is no medical understanding of such a correlation.

Patient–Drug Interaction (Mutuality)

In this part, the Dx3 checklist is aimed at assessing whether there is evidence of an interaction between the drug and the patient that could produce the reported event in this specific case. Evidence of this type indicates a causal relationship between the drug and the event in the patient.

Strong Evidence of Mutuality

Strong evidence of a patient-drug interaction indicates that there is a plausible explanation of how the drug could cause the reported event in this particular patient, where the event is a result of the mutual manifestation of dispositions belonging to the patient and the drug. It could also mean that the drug made a difference with respect to the event, for instance confirmed by repeated dechallenge and/or rechallenge. We will comment briefly on the entries concerning mutuality, since they might be less immediate than the other sections to pharmacovigilance professionals.

There is a plausible mechanism of vulnerability of the patient to this drug.

If an elder patient reports symptoms of liver failure from a drug that is known to be metabolised in the liver, the reported event could be caused by the combination of a disposition of liver susceptibility in the patient and a disposition of the drug’s metabolic pattern.

The drug was a difference-maker, or trigger, for the reported event in this patient.

If the patient takes more than one drug, then the introduction of the suspected drug might nevertheless have worked as a trigger or tipping-point for the reported event. This means that this drug made a difference with respect to that event for this patient, among the other concomitant drugs, supported by repeated dechallenge and/or rechallenge.

There is evidence of dose–response.

If the event is reported to be more intense when the dose is increased, or weaker when decreased, this suggests that the drug has a disposition that acts in a linear, additive way in that patient toward the event. However, the event could also be caused by a confounder.

There is pattern of interference with the dose–response intensity of the reported event.

If the dose–response pattern of the adverse event is reported to change in correlation with a change in the patient’s context, this suggests that there is a causal interaction between the drug and the patient, and that this interaction can be interfered with by an external element. This point might need an example. Say that a patient experiences decreasing tremor at decreased doses of lithium (dose–response). This is a strong evidence of mutuality, yet it is possible that the events are due to a confounder that is also decreasing in parallel with the decreased doses of lithium. However, if a drug is added that interferes with the metabolism of lithium (ibuprofen, for instance) and tremor increases again, this is a further evidence of a causal connection between lithium and tremor.

Good Evidence of Mutuality

Temporality is plausible with an interaction between patient’s disposition and the drug’s properties.

Temporality of the reported event should be expected to vary according to the drug’s properties, but also according to the patient vulnerability.

There is positive de-challenge and/or re-challenge once.

If the reported event improves or reappears in correlation with discontinuation and re-administration of the drug in this patient, this suggests that the event is caused by an intrinsic disposition of the drug in the patient. However, the event could also be caused by a confounder.

The intensity of the event matches the combination of the patient’s and the drug’s dispositions.

An adverse event can be more intense than expected from previous cases or the literature, according to an increased vulnerability of this particular patient toward that event.

Moderate Evidence of Mutuality

Moderate evidence of a patient-drug interaction indicates that the patient belongs to a sub-population that has a correlation to adverse events from this or similar drugs, but there is no medical understanding of this correlation.

There is a correlation of this or similar drugs and adverse events in similar patients.

If the patient belongs to a sub-population that has been observed to have a higher incidence of this or a similar adverse event in concomitance with this or a similar drug(s), then this can indicate that they have a common disposition that makes them a manifestation partner for this type of event. The reason for this could be biological (e.g. gender or ethnicity), social (e.g. socio-economic status, community), or a combination of these.

Overall Conclusion

The overall conclusion for assessment of ICSRs should include an assessment of the three types of dispositions and how they relate. It is neither sufficient nor necessary to sum up the conclusion in a single word (e.g. yes, no, probable, certain, possible). The conclusion will depend on the assessor’s case-specific considerations, but as a general rule, the confidence in a causal relationship based on the Dx3 approach will be strongest in the case of the following combination of evidence:

strong evidence of drug disposition

moderate or no evidence of vulnerability

strong evidence of mutuality

and weakest in the case of the following combination of evidence:

moderate or no evidence of drug disposition

strong evidence of vulnerability

moderate or no evidence of mutuality.

Other important considerations for making an argument for the overall evaluations are:

Whenever there is strong evidence of both drug disposition and mutuality, the possibility of a causal connection should be investigated further, even when there is strong evidence of vulnerability.

Whenever there is strong evidence of drug disposition and the evidence of mutuality is good, or vice versa, a further investigation to assess causality should be seriously considered, even when there is strong evidence of vulnerability.

In both cases, the checklist might be used to formulate follow-up questions to the reporter.