Adverse Drug Reaction Causality Assessment

Sirinoot Palapinyo, RPhFebruary,2015

Outline

• Introduction

• Method used for causality assessment

• Algorithms

Introduction

Steps of Monitoring

• Adverse events identification

• Causality assessment

• Management

• Documentation

• Report to pharmacovigilance centre/regulatory authority

AAssessment

• Causality assessmentprobabilityan observed adverse event

• Adverse events with high causal association (probable and certain) with the drug are likely to recur

• An important component of the evaluation of the benefit/harm profiles of drugs

• Thus, providing information on this causal link may be useful in preventing future recurrences.

The use of the WHO-UMC system for standardised case causality assessment. [Last accessed on 2015 Feb 8]. Available from: graphics/4409.pdf

Methods used forCausality Assessment

- Taofikat B. Agbabiaka, J. Savovi´c and Edzard, E. Methods for causality assessment of adverse drug reactions: A systematic review. Drug Safety 2008; 31 (1): 21-37

- Hutchinson TA, Dawid AP, Spiegelhalter DJ, et al. Computer- ized aids for probabilistic assessment of drug safety: I. A spreadsheet program. Drug Inf J 1991; 25: 29-39

- Arimone Y, Miremont-Salamé G, Haramburu F, Molimard M, Moore N, Fourrier-Réglat A, Bégaud B. Inter-expert agreement of seven criteria in causality assessment of adverse drug reactions. Br J Clin Pharmacol. 2007c; 64(4):482–8.

Method Global Introspection AlgorithmsProbabilistic or Bayesian

approaches

Details

Clinical judgment; an expert panel considering all available data relevant to a suspected

ADR

Sets of specific questions with

associated scores for calculating the

likelihood of a cause-effect relationship

Probability for causality calculated from prior

knowledge &need the specific findings in a case

Pros

• Most common approach: major role in the identification and rating of potential ADRs

• More sensitivity

• More reliable and reproducible measurement (Least inter- and intra-rater contradiction)

• Simplicity

• Overcome the numerous limitations associated with expert judgements & algorithms The Bayesian Adverse Reactions Diagnostic Instrument (BARDI)

• Valid and internally consistent assessment

Cons

• inter- and intra-rater contradiction

• Subjectivity& Imprecision• Poor reproducibility

because it is mainly based on expert clinical judgements

• No one universal algorithm

• Scoring can be arbitrary

• Responses to questions can be subjective

• Poor specificity• Complex calculations • Requires more time

and more expertise

Algorithmsfor causality assessment

Algorithms for causality evaluation tools

• Early 17s: Principle of disease to drugs in individual patients

• 1981: International meeting in Morges, Switzerland concluded 9 important points in causality assessment

Meyboom RHIR.Causal or casual? The role of causality assessment in pharmacovigilance.

Meyboom RHIR.Causal or casual? The role of causality assessment in pharmacovigilance.

Algorithms

More than thirty algorithms of causality evaluation tools were developed

• General algorithms : UMC

• Specific algorithms : for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method (CIOMS/RUCAM)

General algorithms• Karch and Lasagna algorithm (1977) : Three tables

• Begaud algorithm (1977) -> French criteria : Three-stage process

• Jones algorithm (1979) : Yes-No series

• Kramer (1979) : 56 questions

• Naranjo’s algorithm (1981) : 10 questions

• WHO-UMC : Grades of certainty (Certain, Probable/Likely, Possible, Unlikely)

• Thai algorithm

Begaud algorithm (1977) -> French

• Three-stage process

• Assessment of three chronological criteria (challenge, dechallenge, and rechallenge)

• Assessment of clinical and biological findings

• Combination of chronological and symptomatological assessments to obtain a 3-degree global score (1: doubtful, 2: possible, 3: probable)

Jones algorithms

Jones JK. Adverse drug reactions in the community health setting: approaches to recognizing, counseling, and reporting. Clin Comm Health. 1982;5(2):58-

No score calculation

Naranjo’s algorithm

• Total score: Definite > 8; probable 5-8; possible 1-4; doubtful <0• Modified Naranjo’s algorithm

Naranjo C.A., Busto U., Sellers E.M., Sandor P., I. Ruiz, E.A., Roberts, et al.A method for estimating the probability of adverse drug reactions. Pharmacol. Ther., 30 (1981), pp. 239–245

• WHO-UMC

• Which algorithm is the best

• If I selected others such as Naranjo’s algorithm to evaluate my patients, How can I report to WHO ?

Comparison of algorithms

Algorithm characteristicsAlgorithms Advantage Limitation

Karch & Lasagna

No specific advantage in comparison to others

• Reliability & validity not well established

Begaud More specific than Jones algorithm • Consume more time than others

Jones Shorter and quicker to complete & detect the least ADR ?

• Cannot identified actual cause

Kramer More specific than others

• Clinicians can disagree on the weighted values, make subjective judgments for some questions

• Unexpected ADR may not score well

Naranjo Simple & briefType A ADR

• Dependability and validity not confirmed in children

• Drug interaction

WHO-UMCMainly planned as convenient tool

for the assessment of individual case reports

• Non probabilistic method and creates extensive unpredictability in evaluation

• Hard to remember

Thai Type B ADR • Less acceptance (Vs modified Naranjo’s)

• 120 patients from 4 groups were chosen at random:

• Proven hypersensitivity to b-lactams(n=30)

• Without proven hypersensitivity to b-lactams(n=30)

• Proven hypersensitivity to NSAIDs

• Without proven hypersensitivity to NSAIDs

K=1

K=0.12

Conclusion

• Jones algorithm compared favourably with the Naranjo algorithm in scoring drug hypersensitivity reactions, it is a simpler algorithm to use

• The Begaud algorithmthe Jones algorithm, may be more specific with better predictive values.

Khan, L.M., Al-Harthi, S.E., Osman, A.M., AbdulSattar, M.A., Ali, A.S., Dilemmas of the causality assessment tools in the diagnosis of adverse drug reactions, Saudi Pharmaceutical Journal (2015)

Evaluation terms

Definite Highly probable Definite Definite Certain Certain

Probable Probable Probable Probable Probable Probable Probable

Possible Possible Possible Possible Possible Possible Possible

Conditional Doubful Remote Unlikely Doubful Unlikely Unlikely

Karch & Lasagna Begaud Jones Kramer Naranjo WHO-

UMC Thai

Specific algorithms

• CIOMS/RUCAM for DILI

• ALDEN score (E

Evaluation of

• Points are summed and the total compared to this chart:

• 0 or lower: relationship with the drug excluded

• 1-2: unlikely

• 3-5: possible

• 6-8: probable

• >8: highly probable

Limitation of • Complexity. Ambiguous instructions

• Mixed cases included into the cholestatic group

• Atypical time or to onset

• Arbitrary risk factors: age ≥ 55y, alcohol, pregnant

• Unclear criteria for competing drug(s) Subjective interpretation of the drug hepatotoxic

• Among 187 enrollees,complete agreement was reached for 50 (27%) with the expert opinion process and for 34 (19%) with a five-category RUCAM scale (P = 0.08), and the two methods demonstrated a modest correlation with each other (Spearman's r = 0.42, P = 0.0001)

Conclusion• The structured

produced higher agreement rates and likelihood scores than RUCAMthere was still considerable interobserver variability in both.

• Accordingly, a more objective, reliable, and reproducible means of assessing DILI causality is still needed.

• CIOMS/RUCAM scale had better interobserver reliability (reproducibility) than the NARANJO scale.

• In the assessment routines for signal detection at pharmacovigilance centres, the CIOMS/RUCAM scale is the preferred tool for caus- ality assessment in hepatotoxicity

AL

• ALDEN scores were strongly correlated with those of the EuroSCAR case-control analysis for drugs associated with EN (r = 0.90, P < 0.0001)

Clin Pharmacol Ther. 2010 Jul;88(1):60-8. doi: 10.1038/clpt.2009.252. Epub 2010 Apr 7.ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis: comparison with case-control analysis.Sassolas BLouet H.

ALDEN scores

ALDEN scores

• Which algorithm is the best

• If I selected others such as Naranjo’s algorithm to evaluate my patients, How can I report to WHO ?

Conclusion

• No standard algorithms

• Understand the limitations

• Types of ADRs

• Populations

• Gap of knowledge

Thank you