Skip to main content
Log in

Methods for Causality Assessment of Adverse Drug Reactions

A Systematic Review

  • Review Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Numerous methods for causality assessment of adverse drug reactions (ADRs) have been published. The aim of this review is to provide an overview of these methods and discuss their strengths and weaknesses. We conducted electronic searches in MEDLINE (via PubMed), EMBASE and the Cochrane databases to find all assessment methods. Thirty-four different methods were found, falling into three broad categories: expert judgement/global introspection, algorithms and probabilistic methods (Bayesian approaches). Expert judgements are individual assessments based on previous knowledge and experience in the field using no standardized tool to arrive at conclusions regarding causality. Algorithms are sets of specific questions with associated scores for calculating the likelihood of a cause-effect relationship. Bayesian approaches use specific findings in a case to transform the prior estimate of probability into a posterior estimate of probability of drug causation. The prior probability is calculated from epidemiological information and the posterior probability combines this background information with the evidence in the individual case to come up with an estimate of causation. As a result of problems of reproducibility and validity, no single method is universally accepted. Different causality categories are adopted in each method, and the categories are assessed using different criteria. Because assessment methods are also not entirely devoid of individual judgements, inter-rater reliability can be low. In conclusion, there is still no method universally accepted for causality assessment of ADRs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Fig.1
Table III

Similar content being viewed by others

References

  1. Schneeweiss S, Hasford J, Gottler M, et al. Admissions caused by adverse drug events to internal medicine and emergency departments in hospitals: a longitudinal population-based study. Eur J Clin Pharmacol 2002; 58: 285–91

    Article  PubMed  Google Scholar 

  2. Prince BS, Goetz CM, Rihn TL, et al. Drug-related emergency department visits and hospital admissions. Am J Hosp Pharm 1992; 49: 1696–700

    PubMed  CAS  Google Scholar 

  3. Liu BA, Knowles SR, Mittmann N, et al. Reporting of fatal adverse drug reactions. Can J Clin Pharmacol 2001; 8: 84–8

    PubMed  CAS  Google Scholar 

  4. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998; 279: 1200–5

    Article  PubMed  CAS  Google Scholar 

  5. World Health Organization (WHO), Uppsala Monitoring Centre. The use of the WHO-UMC system for standardized case causality assessment. WHO [online]. Available from URL: http://www.who-umc.org/graphics/4409.pdf [Accessed 2007 Oct 26]

  6. Macedo AF, Marques FB, Ribeiro CF, et al. Causality assessment of adverse drug reactions: comparison of the results obtained from published decisional algorithms and from the evaluations of an expert panel. Pharmacoepidemiol Drug Saf 2005; 14: 885–90

    Article  PubMed  Google Scholar 

  7. Arimone Y, Begaud B, Miremont-Salame G, et al. Agreement of expert judgment in causality assessment of adverse drug reactions. Eur J Clin Pharmacol 2005; 61: 169–73

    Article  PubMed  Google Scholar 

  8. Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965; 85: 295–300

    Google Scholar 

  9. Hutchinson TA, Lane DA. Assessing methods for causality assessment of suspected adverse drug reactions. J Clin Epidemiol 1989; 42: 5–16

    Article  PubMed  CAS  Google Scholar 

  10. Wiholm BE. The Swedish drug-event assessment methods. Special workshop — regulatory. Drug Inf J 1984; 18: 267–9

    PubMed  CAS  Google Scholar 

  11. Miremont G, Haramburu F, Begaud B, et al. Adverse drug reactions: physicians’ opinions versus a causality assessment method. Eur J Clin Pharmacol 1994; 46: 285–9

    Article  PubMed  CAS  Google Scholar 

  12. Irey NS. Tissue reactions to drugs. Am J Pathol 1976; 82: 613–48

    PubMed  CAS  Google Scholar 

  13. Karch FE, Lasagna L. Toward the operational identification of adverse drug reactions. Clin Pharmacol Ther 1977; 21: 247–54

    PubMed  CAS  Google Scholar 

  14. Dangoumau J, Evreux JC, Jouglard J. Method for determination of undesirable effects of drugs [in French]. Therapie 1978; 33: 373–81

    PubMed  CAS  Google Scholar 

  15. Begaud B, Evreux JC, Jouglard J, et al. Imputation of the unexpected or toxic effects of drugs: actualization of the method used in France. Therapie 1985; 40: 111–8

    PubMed  CAS  Google Scholar 

  16. Kramer MS, Leventhal JM, Hutchinson TA, et al. An algorithm for the operational assessment of adverse drug reactions: I. Background, description, and instructions for use. JAMA 1979; 242: 623–32 36

    Article  PubMed  CAS  Google Scholar 

  17. Blanc S, Leuenberger P, Berger JP, et al. Judgments of trained observers on adverse drug reactions. Clin Pharmacol Ther 1979; 25: 493–8

    PubMed  CAS  Google Scholar 

  18. Emanueli A, Sacchetti G. An algorithm for the classification of untoward events in large scale clinical trials. Agents Actions Suppl. 1980; 7: 318–22

    PubMed  CAS  Google Scholar 

  19. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239–45

    Article  PubMed  CAS  Google Scholar 

  20. Jones JK. Adverse drug reactions in the community health setting: approaches to recognizing, counseling, and reporting. Fam Community Health 1982; 5: 58–67

    Article  PubMed  CAS  Google Scholar 

  21. Evreux JC, Loupi E, Descotes J, et al. Evaluation of the documentation on adverse effects of drugs: proposition 2. Imputability [in French]. Therapie 1982; 37: 657–70

    PubMed  CAS  Google Scholar 

  22. Kitaguchi T, Nojiri T, Suzuki S, et al. Some assessment systems for industry post marketing adverse drug reaction (ADR) Information. Iyakuhin Kenkyu 1983; 14: 980–92

    Google Scholar 

  23. Lagier G, Vincens M, Castot A. Imputability in drug monitoring: principles of the balanced drug reaction assessment method and principal errors to avoid. Therapie 1983; 38: 303–18

    PubMed  CAS  Google Scholar 

  24. Cornelli U. The phase IV monitoring studies: example of Naproxen Na multi-centre Italian trial. In: Crescioni C, James JM, editors. ostmarketing clinical trials — the phase V studies. Paris: Editions de Sante, 1984: 89–105

    Google Scholar 

  25. Stephens MD. Assessment of causality in industrial setting. Special workshop — industrial. Drug Inf J 1984; 18: 307–13

    Google Scholar 

  26. Castle WM. Assessment of causality in industrial settings. Drug Inf J 1984; 18: 297–302

    Google Scholar 

  27. Turner WM. The Food and Drug Administration algorithm. Special workshop — regulatory. Drug Inf J 1984; 18: 259–66

    PubMed  CAS  Google Scholar 

  28. Venulet J, Ciucci A, Berneker GC. Standardised assessment of drug-adverse reaction associations: rationale and experience. Int J Clin Pharmacol Ther Toxicol 1980; 18: 381–8

    PubMed  CAS  Google Scholar 

  29. Loupi E, Ponchon AC, Ventre JJ, et al. Imputability of a teratogenic effect [in French]. Therapie 1986; 41: 207–10

    PubMed  CAS  Google Scholar 

  30. Stricker BHC. Diagnosis and causality assessment of drug-induced hepatic injury. In: Dukes MNG, ed. Drug-induced hepatic injury. Amsterdam: Elsevier, 1985: 1–13

    Google Scholar 

  31. Benichou C, Danan G. Causality assessment in the European pharmaceutical industry: presentation of the preliminary results of a new method. Drug Inf J 1992; 26: 589–92

    Article  Google Scholar 

  32. Hoskins RE, Mannino S. Causality assessment of adverse drug reactions using decision support and informatics tools. Pharmacoepidemiol Drug Saf 1992; 1: 235–49

    Article  Google Scholar 

  33. Danan G, Benichou C. Causality assessment of adverse reactions to drugs: I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol 1993; 46: 1323–30

    Article  PubMed  CAS  Google Scholar 

  34. Hsu PH, Stoll RW. Causality assessment of adverse events in clinical trials: II. An algorithm for drug causality assessment. Drug Inf J 1993; 27: 387–94

    Article  Google Scholar 

  35. Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology 1997; 26: 664–9

    Article  PubMed  CAS  Google Scholar 

  36. Koh Y, Shu CL. A new algorithm to identify the causality of adverse drug reactions. Drug Saf 2005; 28: 1159–61

    Article  PubMed  Google Scholar 

  37. Horn JR, Hansten PD, Chan LN. Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother 2007; 41: 674–80

    Article  PubMed  Google Scholar 

  38. Mashford ML. The Australian method of drug-event assessment. Special Workshop — regulatory. Drug Inf J 1984; 18: 271–3

    PubMed  CAS  Google Scholar 

  39. Lane DA, Kramer MS, Hutchinson TA, et al. The causality assessment of adverse drug reactions using a Bayesian approach. Pharm Med 1987; 2: 265–83

    Google Scholar 

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

    Article  Google Scholar 

  41. Hutchinson TA. Computerized Bayesian ADE assessment. Drug Inf J 1991; 25: 235–41

    Article  Google Scholar 

  42. Lanctot KL, Kwok MCO, Naranjo CA. Computerized Bayesian evaluation of adverse events. Drug Inf J 1995; 29: 319–25

    Article  Google Scholar 

  43. Meyboom RHB, Hekster YA, Egberts ACG, et al. Causal or casual? The role of causality assessment in pharmacovigilance. Drug Saf 1997; 17: 374–89

    Article  PubMed  CAS  Google Scholar 

  44. Meyboom RHB. Causality assessment revisited. Pharmacoepidemiol Drug Saf 1998; 7 Suppl. 1:S63–5

    Article  PubMed  Google Scholar 

  45. Macedo AF, Marques FB, Ribeiro CF, et al. Causality assessment of adverse drug reactions: comparison of the results obtained from published decisional algorithms and from the evaluations of an expert panel, according to different levels of imputability. J Clin Pharm Ther 2003; 28: 137–43

    Article  PubMed  CAS  Google Scholar 

  46. Karch FE, Smith CL, Kerzner B, et al. Adverse drug reactions: a matter of opinion. Clin Pharmacol Ther 1976; 19: 489–92

    PubMed  CAS  Google Scholar 

  47. Arimone Y, Begaud B, Miremont-Salame G, et al. A new method for assessing drug causation provided agreement with experts’ judgment. J Clin Epidemiol 2006; 59: 308–14

    Article  PubMed  Google Scholar 

  48. Venulet J. Aspects of standardization as applied to the assessment of drug-event associations. Drug Inf J 1984; 18: 199–210

    PubMed  CAS  Google Scholar 

  49. Begaud B. Standardized assessment of adverse drug reactions: the method used in France. Special workshop — clinical. Drug Inf J 1984; 18: 275–81

    PubMed  CAS  Google Scholar 

  50. Lanctot KL, Naranjo CA. Computer-assisted evaluation of adverse events using a Bayesian approach. J Clin Pharmacol 1994; 34: 142–7

    PubMed  CAS  Google Scholar 

  51. Leventhal JM, Hutchinson TA, Kramer MS, et al. An algorithm for the operational assessment of adverse drug reactions: III. Results of tests among clinicians. JAMA 1979; 242: 1991–4

    Article  PubMed  CAS  Google Scholar 

  52. Venulet J. Recognition and assessment of adverse drug reactions in children. Bratisl Lek Listy 1991; 92: 540–3

    PubMed  CAS  Google Scholar 

  53. Frick PA, Cohen LG, Rovers JP. Algorithms used in adverse drug event reports: a comparative study. Ann of Pharmacother 1997; 31: 164–7

    CAS  Google Scholar 

  54. Hutchinson TA, Leventhal JM, Kramer MS, et al. An algorithm for the operational assessment of adverse drug reactions: II. Demonstration of reproducibility and validity. JAMA 1979; 242: 633–8

    Article  PubMed  CAS  Google Scholar 

  55. Karch FE, Lasagna L. Adverse drug reactions: a critical review. JAMA 1975; 234: 1236–41

    Article  PubMed  CAS  Google Scholar 

  56. Kane-Gill SL, Kirisci L, Pathak DS. Are the Naranjo criteria reliable and valid for determination of adverse drug reactions in the intensive care unit? Ann Pharmacother 2005; 39: 1823–7

    Article  PubMed  Google Scholar 

  57. Venulet J, Ciucci AG, Berneker GC. Updating of a method for causality assessment of adverse drug reactions. Int J Clin Pharmacol Ther Toxicol 1986; 24: 559–68

    PubMed  CAS  Google Scholar 

  58. Benichou C. Criteria of drug-induced liver disorders. Report of an International Consensus Meeting. J Hepatol 1990; 11: 272–6

    Article  PubMed  CAS  Google Scholar 

  59. Naranjo CA, Lane D, Ho-Asjoe M, et al. A Bayesian assessment of idiosyncratic adverse reactions to new drugs: Guillain-Barre syndrome and zimeldine. J Clin Pharmacol 1990; 30: 174–80

    PubMed  CAS  Google Scholar 

  60. Naranjo CA, Lanctot KL. A consultant’s view on the role of Bayesian differential diagnosis in the safety assessment of pharmaceuticals. Drug Inf J 1992; 26: 593–601

    Article  Google Scholar 

  61. Naranjo CA, Lanctot KL, Lane DA. The Bayesian differential diagnosis of neutropenia associated with antiarrhythmic agents. J Clin Pharmacol 1990; 30: 1120–7

    PubMed  CAS  Google Scholar 

  62. Pere JC, Begaud B, Haramburu F, et al. Computerized comparison of six adverse drug reaction assessment procedures. Clin Pharmacol Ther 1986; 40: 451–61

    Article  PubMed  CAS  Google Scholar 

  63. Ennis M, Ohmann C, Lorenz W, et al. Prediction of risk for pseudoallergic reactions and histamine release in patients undergoing 37 anaesthesia and surgery: a computer-aided model using independence-Bayes. Agents Actions 1988; 23: 366–9

    Article  PubMed  CAS  Google Scholar 

  64. Koch-Weser J, Sellers EM, Zacest R. The ambiguity of adverse drug reactions. Eur J Clin Pharmacol 1977; 11: 75–8

    Article  PubMed  CAS  Google Scholar 

  65. Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs: II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol 1993; 46: 1331–6

    Article  PubMed  CAS  Google Scholar 

  66. Michel DJ, Knodel LC. Comparison of three algorithms used to evaluate adverse drug reactions. Am J Hosp Pharm 1986; 43: 1709–14

    PubMed  CAS  Google Scholar 

  67. Busto U, Naranjo CA, Sellers EM. Comparison of two recently published algorithms for assessing the probability of adverse drug reactions. Br J Clin Pharmacol 1982; 13: 223–7

    Article  PubMed  CAS  Google Scholar 

  68. Kramer MS. Assessing causality of adverse drug reactions: global introspection and its limitations. Drug Inf J 1986; 20: 433–7

    Google Scholar 

  69. Hutchinson TA, Flegel KM, HoPingKong H, et al. Reasons for disagreement in the standardized assessment of suspected adverse drug reactions. Clin Pharmacol Ther 1983; 34: 421–6

    Article  PubMed  CAS  Google Scholar 

  70. Stephens MD. The diagnosis of adverse medical events associated with drug treatment. Adverse Drug React Acute Poisoning Rev 1987; 6: 1–35

    PubMed  CAS  Google Scholar 

  71. Naranjo CA, Kwok MC, Lanctot KL, et al. Enhanced differential diagnosis of anticonvulsant hypersensitivity reactions by an integrated Bayesian and biochemical approach. Clin Pharmacol Ther 1994; 56: 564–75

    Article  PubMed  CAS  Google Scholar 

  72. Aronson JK, Ferner RE. Clarification of terminology in drug safety. Drug Saf 2005; 28: 851–70

    Article  PubMed  Google Scholar 

  73. Castle W. Adverse drug reactions: scope and limitations of causality assessment and the use of algorithms. Int J Risk Saf Med 1991; 2: 185–91

    Google Scholar 

  74. Kelly WN. The quality of published adverse drug event reports: review. Ann Pharmacother 2003; 37: 1774–8

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

No sources of funding were used to assist in the preparation of this review. T.B. Agbabiaka and J. Savovic have both been supported by research fellowships sponsored by Dr Willmar Schwabe Pharmaceuticals, Germany. The authors have no conflicts of interest that are directly relevant to the contents of this review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Taofikat B. Agbabiaka.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Agbabiaka, T.B., Savović, J. & Ernst, E. Methods for Causality Assessment of Adverse Drug Reactions. Drug-Safety 31, 21–37 (2008). https://doi.org/10.2165/00002018-200831010-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-200831010-00003

Keywords

Navigation