Analysis and Comment

Drug safety

Anecdotes that provide definitive evidence

BMJ 2006; 333 doi: 10.1136/bmj.39036.666389.94 (Published 14 December 2006)
Cite this as: BMJ 2006;333:1267

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  1. Jeffrey K Aronson, reader in clinical pharmacology1,
  2. Manfred Hauben, medical director of risk management strategy2
  1. 1Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford University, Oxford OX2 6HE
  2. 2Risk Management Strategy, Pfizer, New York, USA
  1. Correspondence to: J K Aronson jeffrey.aronson{at}clinpharm.ox.ac.uk
  • Accepted 30 October 2006

When a criminal is caught in the act, other evidence is unnecessary. Should the same be true for adverse drug reactions?

Many adverse drug reactions are first reported anecdotally. Anecdotal reports, by which we mean either individual cases or small case series, are generally regarded as providing poor quality evidence. They therefore usually require formal verification through robust epidemiological studies or clinical trials, although a minority are actually verified.1 However, we propose that some adverse drug reactions are so convincing, even without traditional chronological causal criteria such as challenge tests, that a well documented anecdotal report can provide convincing evidence of a causal association and further verification is not needed. Such reactions could serve as gold standards for use, for example, when validating pharmacovigilance systems or assessing the quality of systematic reviews of adverse drug reactions and the methods used to perform them. Specificity of an adverse drug reaction has previously been discussed as a concept2 but to our knowledge has never been fully developed.

Definitive adverse events

We have identified four types of spontaneously reported adverse events for which causal or contributory attribution to the drug is either irrefutable or demonstrable with a high level of confidence (table⇓):

  • Extracellular or intracellular tissue deposition of the drug or a metabolite

  • Specific anatomical location or pattern of injury

  • Physiological dysfunction or direct tissue damage that can be proved by physicochemical testing

  • Infection as a result of administration of a potentially infective agent or because of demonstrable contamination.

In each case the diagnosis can be established definitively, or with a high degree of certainty, in the individual patient. In some cases the diagnostic value of the event can be enhanced by further investigation, but the conclusion will always be related to the person affected.

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Examples of definitive anecdotal adverse drug reactions

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