Causality assessment Using causality models Prof E. P. van Puijenbroek, MD, PhD October 2018

Learning Objectives Know the difference between extrinsic and intrinsic causality Be able to apply two different causality models WHO model Naranjo algorithm

Extrinsic and intrinsic factors Causality models Practical examples Outline Extrinsic and intrinsic factors Causality models Practical examples

Question 1 It is important to annotate the strength of the causal relationship between drug and adverse drug reaction Agree Do not agree

Question 2 Do you think it is possible to determine the strength of the causal relationship between drug and adverse drug reaction? Agree Do not agree

Extrinsic factors “How well known is this ADR?” Literature and product information - MEB / EMA - Medline Background Incidence - Literature Prescription data - GIPdatabank.nl Databse - Lareb (NL) - Eudravigilance (EMA), Vigibase (WHO)

Intrinsic factors “What patient- or drug related factors play a role?” Pharmacological plausibility - kinetic, dynamic, chemical structure - latency, dechallenge - co-medication Patient-related - indication, comorbidity, renal function - Drug metabolism

Extrinsic and intrinsic factors Causality models Practical examples Outline Extrinsic and intrinsic factors Causality models Practical examples

When to use causality assessment? Regulatory requirements: e.g. causality assessment for each report mandatory when submitting reports to EMA Publications of case reports Individual patient care

Agbabiaka TB1,Savovic J,Ernst E Agbabiaka TB1,Savovic J,Ernst E. Methods for causality assessment of adverse drug reactions: a systematic review. Drug Saf. 2008;31(1):21-37.

Agbabiaka TB1,Savovic J,Ernst E Agbabiaka TB1,Savovic J,Ernst E. Methods for causality assessment of adverse drug reactions: a systematic review. Drug Saf. 2008;31(1):21-37.

Types of causality models Expert judgement/global introspection: individual assessments based on previous knowledge and experience. Algorithms: set of specific questions to estimate te strength of the causal relationship. Probabilistic methods (Bayesian approaches): Transform the prior estimate of probability into a posterior estimate of probability of drug causation.

WHO causality definitions 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, using a satisfactory rechallenge procedure if necessary. 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 drug or chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not required to fulfil this defenition. POSSIBLE A clinical event, including laboratory test abnormality, with a reasonable timne sequence to administration 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. 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 drug, chemicals or underlying disease provide plausible explanations.

WHO classification

Naranjo algorithm Systematic causality assessment - 10 questions - Sum score - 63 cases from the literature - only 3 assessors Naranjo et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;239-245

Naranjo algorithm - elements

Naranjo algorithm – sum score ≥ 9 5-8 1-4 ≤ 0 certain probable possible unlikely

Extrinsic and intrinsic factors Causality models Practical examples Outline Extrinsic and intrinsic factors Causality models Practical examples

Case 1 Reporter: pharmacist Female, 60 years Complaints: flu-like symptoms Suspect drug: risedronate (Actonel®) 1x / week 35 mg for osteoporosis Concomitant-medication: omeprazole and lormetazepam

Description symtoms Severe symptoms: muscle pain neck and shoulders, headaches, fever and general malaise, about half a day after ingestion Complaints take approximately 5 days After next intake same complaints increased

How do you rate the causality? Text How do you rate the causality? Unlikely Possible Probable Certain Why?

Course of reaction Switch to risedronate 5 mg once daily no effect on any of the symptoms Medication changed into alendronate (Fosamax®) 1x / week, 70 mg no complaints anymore

Background information Summary of Product Characteristics Literature Reported ADRs (WHO)

Background information Flu syndrome Flu syndrome was reported in 9,8% of patients enrolled in phase 3 Paget’s disease clinical trials with risedronate (Prod Info Actonel®, 2002). Flu-like symptoms Flu-like symptoms (muscle pain, bone pain, hot flushes, increased sweating) have been reported with the use of ibandronate (Anon, 1996). Flu-like symptoms nonspecific flu-like symptoms including fever, chills, bone pain, arthralgia, and myalgia have been described in some patients treated with zoledronic acid…

Background information WHO: - > 150 reports of flu-like symptoms and bisphosphonates Reporting Odds Ratio: ● Alendronate 0,92 (0,69-1,24) ● Pamidronate 10,7 (8,29-13,85) ● Risedronate 3,51 (2,20-5,59) ● Zoledronate 11,0 (7,98-15,17) - Association flu-like symptoms + alendronate n.s. - Association other bisphosphonates and this ADR statistical signal

Naranjo score ≥ 9 5-8 1-4 ≤ 0 certain probable possible unlikely

Summary Causation may be difficult to assess in practice There are various models of causality in use Validation leaves much to be desired, situations in which they are applied are often too specific

Learning Objectives To be able to use two different causality model for the assessment of adverse drug reactions - Causality scheme of Naranjo - Knowing the difference between extrinsic and intrinsic causality Evaluation of a case report, using elements that play a role in the assessment of ADRs

Exam question –example 1 Causality assessment van be divided into intrinsic and extrinsic factors. Classify the factors in the base below: A female patient, aged 60 years, suffered from dizziness due to orthostatic hypotension, a few hours after every administration of metoprolol for tachycardia. The dizziness resolved after 6 hours. Dizziness is described in the Summary of Product Characteristics (SmPC) of metoprolol as a frequently occuring adverse drug reaction (ADR). The patient’s medical history indicates that she also had sleep disorders and uses temazepam (a benzodiazepine). Which if the following classifications is TRUE? Description of the ADR in the SmPC and the frequency of the ADR are both intrinic factors Orthostatic hypotension can pharmacologically be explained, which is an extrinsic factor A positive dechallenge and a positive rechallenge are both intrinsic factors. Concomitant drug tamezepam can cause dizziness, which is an extrinsic factor.

Exam question – example 2 The Naranjo algorithm is a tool that can be used in the causality assessment of possible adverse drug reactions. In this algorithm, the following aspects play a role: 1) Severity 2) Dechallenge 3) Rechallenge 4) Alternative causes Which of the following statements is correct?  1 and 2 are true, 3 and 4 are false 2,3 and 4 are true, 1 is false All statements are true All statements are false

Literature causality assessment Taofikat B. Agbabiaka, Jelena Savovi, Edzard Ernst. Methods for Causality Assessment of Adverse Drug Reactions A Systematic Review. Drug Safety 2008; 31 (1): 21-37 Anonymous. The use of the WHO-UMC system for standardised case causality assessment. Website Uppsala Monitoring Centre. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/WHOcausality_assessment.pdf Naranjo et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;239-245

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