Dispositions and Causality Assessment in Pharmacovigilance: Proposing the Dx3 Approach for Assessing Causality with Small Data Sets

Abstract

A new approach is proposed for assessing causality in pharmacovigilance. The Dx3 approach is designed to qualitatively evaluate three types of dispositions when assessing whether a particular medicine has or could have caused a certain adverse event. These are: the drug disposition; the pre-disposition of the patient taking the drug (vulnerability) and; the disposition of the patient–drug interaction (mutuality). Each of these three types of dispositions will represent valuable causally relevant evidence for assessing a potential signal of harm. A checklist is provided to guide the assessment of causality for both single individual case safety reports (ICSRs) and case series. Different types of causal information are ranked according to how well suited they are for establishing a disposition. Two case examples are used to demonstrate how the approach can be used in practice for assessment purposes. One aim of the approach is to offer a qualitative way to assess causality and to make the reasoning of different assessors more transparent. A second aim is to encourage the collection of more qualitatively rich patient narratives in the ICSRs. Crucially, we believe this approach can support the inclusion of the single ICSR as a valid and valuable form of evidence.

Gilteritinib and the risk of intracranial hemorrhage: a case series of a possible, under-reported side effect

“…For each case, a causality assessment was performed according to the Dx3 method [ 8 ]. This approach allows a qualitative assessment of the relationship between the use of a drug and AEs, by using a checklist to guide the analysis of the following three domains: the drug disposition, the pre-disposition of the patient (vulnerability), and the disposition of the patient–drug interaction (mutuality).…”

Severe Gastrointestinal Toxicity Following the Use of Gilteritinib: A Case Series and Analysis of Postmarketing Surveillance Data

“…Data about clinical history, comorbidities and treatment details were collected with a specific focus on GI adverse drug reactions (ADRs) onset and recovery, seriousness, outcome, dechallenge, rechallenge, relevant laboratory tests or diagnostic procedures and concomitant drugs. For each case, a causality assessment was performed according to the Dx3 method [20]. This approach allows us to qualitatively assess the relationship between the use of a medicine and AEs using a checklist to guide the analysis of the following three domains: the drug disposition, the pre-disposition of the patient (vulnerability) and the disposition of the patient-drug interaction (mutuality).…”

The power of small data for personalized cancer care

“…They also provide guidance, checklists, and examples on how to conduct such causal assessments. 21 It should be noted that here I aim to emphasize the significant, and at some points, irreplaceable role of small data throughout the causation building process. That does not mean other research methods, such as randomized controlled trials, cohort studies, case-control studies, and lab models, contribute little to the process.…”

“…individual case safety reports). 21 This approach argues that three types of dispositions—the drug disposition, the predisposition of the patient taking the drug (vulnerability), and the disposition of the patient–drug interaction (mutuality)—can be qualitatively evaluated to understand causality in pharmacovigilance. They also provide guidance, checklists, and examples on how to conduct such causal assessments.…”