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Adverse Drug Reaction
Causality Assessment
Sirinoot Palapinyo, RPh
February,2015
Outline
• Introduction
• Method used for causality assessment
• Algorithms
Introduction
Steps of
Monitoring
• Adverse events identification
• Causality assessment
• Management
• Documentation
• Report to pharmac...
A
Assessment
• Causality assessment
probability
an observed adverse event
• Adverse events with high causal association (p...
Methods used for
Causality Assessment
- Taofikat B. Agbabiaka, J. Savovi´c and Edzard, E. Methods for causality assessment ...
Method Global Introspection Algorithms
Probabilistic or Bayesian
approaches
Details
Clinical judgment; an expert
panel con...
Algorithms
for causality assessment
Algorithms for causality evaluation tools
• Early 17s: Principle of disease to drugs in
individual patients
• 1981: Intern...
Meyboom RH
IR.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 a...
General algorithms
• Karch and Lasagna algorithm (1977) : Three tables
• Begaud algorithm (1977) -> French criteria : Thre...
Begaud algorithm (1977) -> French
• Three-stage process
• Assessment of three chronological criteria
(challenge, dechallen...
Jones algorithms
Jones JK. Adverse drug reactions in the community health
setting: approaches to recognizing, counseling, ...
Naranjo’s algorithm
• Total score: Definite > 8; probable 5-8; possible 1-4; doubtful <0
• Modified Naranjo’s algorithm
Nara...
• WHO-UMC
• Which algorithm is the best
• If I selected others such as Naranjo’s algorithm to
evaluate my patients, How can I report...
Comparison of
algorithms
Algorithm characteristics
Algorithms Advantage Limitation
Karch &
Lasagna
No specific advantage in comparison to
others
• R...
• 120 patients from 4 groups were chosen at random:
• Proven hypersensitivity to b-lactams(n=30)
• Without proven hypersen...
K=1
K=0.12
Conclusion
• Jones algorithm compared favourably with the
Naranjo algorithm in scoring drug hypersensitivity
reactions, it...
Khan, L.M., Al-Harthi, S.E., Osman, A.M.,
AbdulSattar, M.A., Ali, A.S., Dilemmas of the
causality assessment tools in the ...
Evaluation terms
Definite
Highly
probable
Definite Definite Certain Certain
Probable Probable Probable Probable Probable Prob...
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
...
Limitation of
• Complexity. Ambiguous instructions
• Mixed cases included into the cholestatic group
• Atypical time or
to...
• Among 187 enrollees,
complete agreement was reached for 50 (27%) with the expert
opinion process and for 34 (19%) with a...
Conclusion
• The structured
produced higher agreement rates and likelihood
scores than RUCAM
there was still considerable ...
• CIOMS/RUCAM scale had better interobserver
reliability (reproducibility) than the NARANJO
scale.
• In the assessment rou...
AL
• ALDEN scores were strongly correlated with those
of the EuroSCAR case-control analysis for drugs
associated with EN (...
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...
Conclusion
• No standard algorithms
• Understand the limitations
• Types of ADRs
• Populations
• Gap of knowledge
Thank you
Adverse drug reaction causality assessment
Adverse drug reaction causality assessment
Adverse drug reaction causality assessment
Adverse drug reaction causality assessment
Adverse drug reaction causality assessment
Adverse drug reaction causality assessment
Adverse drug reaction causality assessment
Adverse drug reaction causality assessment
Adverse drug reaction causality assessment
Adverse drug reaction causality assessment
Adverse drug reaction causality assessment
Adverse drug reaction causality assessment
Adverse drug reaction causality assessment
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Adverse drug reaction causality assessment

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Adverse drug reaction causality assessment

Presented by Sirinoot Palapinyo, RPh, PharmD.

Published in: Health & Medicine

Adverse drug reaction causality assessment

  1. 1. Adverse Drug Reaction Causality Assessment Sirinoot Palapinyo, RPh February,2015
  2. 2. Outline • Introduction • Method used for causality assessment • Algorithms
  3. 3. Introduction
  4. 4. Steps of Monitoring • Adverse events identification • Causality assessment • Management • Documentation • Report to pharmacovigilance centre/regulatory authority
  5. 5. A Assessment • Causality assessment probability an 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
  6. 6. Methods used for Causality 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.
  7. 7. Method Global Introspection Algorithms Probabilistic 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
  8. 8. Algorithms for causality assessment
  9. 9. 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 RH IR.Causal or casual? The role of causality assessment in pharmacovigilance.
  10. 10. Meyboom RH IR.Causal or casual? The role of causality assessment in pharmacovigilance.
  11. 11. 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)
  12. 12. 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
  13. 13. 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)
  14. 14. 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
  15. 15. 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
  16. 16. • WHO-UMC
  17. 17. • Which algorithm is the best • If I selected others such as Naranjo’s algorithm to evaluate my patients, How can I report to WHO ?
  18. 18. Comparison of algorithms
  19. 19. Algorithm characteristics Algorithms 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 & brief Type A ADR • Dependability and validity not confirmed in children • Drug interaction WHO-UMC Mainly 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)
  20. 20. • 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
  21. 21. K=1 K=0.12
  22. 22. Conclusion • Jones algorithm compared favourably with the Naranjo algorithm in scoring drug hypersensitivity reactions, it is a simpler algorithm to use • The Begaud algorithm the Jones algorithm, may be more specific with better predictive values.
  23. 23. 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)
  24. 24. 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
  25. 25. Specific algorithms • CIOMS/RUCAM for DILI • ALDEN score ( E
  26. 26. 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
  27. 27. 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
  28. 28. • 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)
  29. 29. Conclusion • The structured produced higher agreement rates and likelihood scores than RUCAM there was still considerable interobserver variability in both. • Accordingly, a more objective, reliable, and reproducible means of assessing DILI causality is still needed.
  30. 30. • 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
  31. 31. 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 B Louet H.
  32. 32. ALDEN scores
  33. 33. ALDEN scores
  34. 34. • Which algorithm is the best • If I selected others such as Naranjo’s algorithm to evaluate my patients, How can I report to WHO ?
  35. 35. Conclusion • No standard algorithms • Understand the limitations • Types of ADRs • Populations • Gap of knowledge
  36. 36. Thank you

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