Drug Safety

, Volume 40, Issue 5, pp 365–372 | Cite as

Causality Assessment in Pharmacovigilance: Still a Challenge

Current Opinion


Causality in pharmacovigilance is a difficult and time consuming exercise. This paper presents the challenges in determining causation by drug therapy. The first is that causation is complex and needs to be viewed from the context of the patient treated, rather than the drug product. Multiple causal vectors should be considered if we are to tackle the many issues involved in, for example, medication error and the many other factors that lead to bad outcomes from therapy, including failure to recognise known risk factors. The aim of pharmacovigilance is not only a bureaucratic exercise in public health norms, but is mainly concerned with small minorities of statistical outliers—and even individuals—whose experiences from harms may together form messages about causation that will prevent further at-risk patients from exposure, or at least assist with earlier recognition of drug-related harm and better management of such harm. This requires more time, more data, more analysis and more patient and clinical involvement in reporting useful clinical detail. The paradigm shift back towards gathering more case data relating to possible causation can be selective and would not be just retrogressive, nor necessarily too costly. Greater transparency of hypotheses and availability of anonymised case data will enrol more expertise into evaluations and hypothesis testing, and the provision of more complete and useful information should reduce clinical burdens from bad patient outcomes as well as their overall costs to society.


  1. 1.
    Finney DJ. An international drug safety programme. J New Drugs. 1963;3:262–5.CrossRefPubMedGoogle Scholar
  2. 2.
    Edwards IR, Lindquist M (eds) Pharmacovigilance: critiques and ways forward (2017). ISBN 978-3-319-40399-1 ISBN 978-3-319-40400-4 (eBook),pp v–vii. doi:10.1007/978-3-319-40400-4.
  3. 3.
    Bate A, Lindquist M, Edwards IR, Olsson S, Orre R, Lansner A, De Freitas RM. A Bayesian neural network method for adverse drug reaction signal generation. Eur J Clin Pharmacol. 1998;54:315–21.CrossRefPubMedGoogle Scholar
  4. 4.
    Meyboom RH, Egberts AC, Edwards IR, et al. Principles of signal detection in pharmacovigilance. Drug Saf. 1997;16:35–365.CrossRefGoogle Scholar
  5. 5.
    Agbabiaka TB, Savovic J, Ernst E. Methods for causality assessment of adverse drug reactions: a systematic review. Drug Saf. 2008;31(1):21–37.CrossRefPubMedGoogle Scholar
  6. 6.
    Théophile H, Arimone Y, Miremont-Salamé G, et al. Comparison of three methods (consensual expert judgement), (algorithmic and probabilistic approaches) of causality assessment of adverse drug reactions. Drug Saf. 2010;33:1045. doi:10.2165/11537780-000000000-00000.CrossRefPubMedGoogle Scholar
  7. 7.
    von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370:1453–7. doi:10.1016/S0140-6736(07)61602-X.CrossRefGoogle Scholar
  8. 8.
    Vandenbroucke JP, von Elm E, Altman DG, Gotzsche PC, Mulrow CD, Pocock SJ, Poole C, Schlesselman JJ, Egger M. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. PLoS Med. 2007;4:e297. doi:10.1371/journal.pmed.0040297.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Paludetto M-N, Olivier-Abbal P, Montastruc J-L. Is spontaneous reporting always the most important information supporting drug withdrawals for pharmacovigilance reasons in France? Pharmacoepidemiol Drug Saf. 2012;21(12):1289–94.CrossRefPubMedGoogle Scholar
  10. 10.
    McNaughton R, Huet G, Shakir S. An investigation into drug products withdrawal from the EU market between 2002 and 2011 for safety reasons and the evidence used to support the decision-making. BMJ Open. 2014;4:e004221. doi:10.1136/bmjopen-2013-004221.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Whitehead AN. Science and philosophy (Philosophical Society. Ebook) New York; 1948 (ISBN: 978-1-4976-7615-2).Google Scholar
  12. 12.
    Popper, K. The logic of scientific discovery (Taylor & Francis e-Library ed.). London: Routledge/Taylor & Francis e-Library; 2005. pp. 47–50 (Section 6 footnote *3 ISBN 0203994620).Google Scholar
  13. 13.
    Tuttle J, Chen RT, Rantala H, Cherry JD, Rhodes PH, Hadler S. The risk of Guillain-Barré syndrome after tetanus-toxoid-containing vaccines in adults and children in the United States. Am J Public Health. 1997;87(12):2045–8.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Aronson JK, Hauben M. Anecdotes that provide definitive evidence. BMJ. 2006;333(7581):1267–9.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hitchcock C. Probabilistic causation. http://plato.stanford.edu/entries/causation-probabilistic/#CauMarCon.508.Accessed 22nd Sept 2016.
  16. 16.
    Taleb NN. The black swan. New York: Random House; 2010. ISBN 978-0-679-60418-1.Google Scholar
  17. 17.
    Edwards IR. What are the real lessons to be learned from Vioxx? Drug Saf. 2005;28(8):651–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Coulter DM, Edwards IR, Savage RL. Survey of neurological problems with amiodarone in the New Zealand Intensive Medicines Monitoring Programme. N Z Med J. 1990;103(885):98–100.PubMedGoogle Scholar
  19. 19.
    Aronson JK, Ferner RE. Joining the DoTS: new approach to classifying adverse drug reactions. BMJ. 2003;327(7425):1222–5.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ferner RE, Aronson JA. EIDOS: a mechanistic classification of adverse drug effects. Drug Saf. 2010;33:15–23.CrossRefPubMedGoogle Scholar
  21. 21.
    Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58:295–300.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Howick J, Glasziou P, Aronson JK. The evolution of evidence hierarchies: what can Bradford Hill’s ‘Guidelines for Causation’ contribute? J R Soc Med. 2009;102:186–94.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Castor O, Edwards IR. Reflections on attribution and decisions in pharmacovigilance. Drug Saf. 2010;33(10):1–5.Google Scholar
  24. 24.
    Effective communications in pharmacovigilance: the Erice declaration. http://www.who-umc.org/graphics/24752.pdf Accessed 10 Jan 2017.

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Uppsala Monitoring CentreWHO Collaborating Centre for International Drug MonitoringUppsalaSweden

Personalised recommendations