Limitations of randomised controlled trials as evidence of drug safety

The pinnacle of the hierarchy of evidence is the systematic review and meta-analysis. One step below this is the randomised controlled trial. These are 'gold standard' measures of medical knowledge, assessing outcomes and the efficacy of healthcare interventions. However, they rarely provide 'gold standard' information on adverse drug effects and drug safety.

Randomised controlled trials involve a carefully vetted and selected patient population who are exposed to treatment for a relatively short duration. Drugs are later used in practice in a much wider group of patients, who may have multiple comorbidities, and over a much longer period of time. There are numerous examples of now well-established adverse drug reactions that were not apparent when the drug entered the market. For example, ACE inhibitor-associated angioedema was recognised only after marketing. In the years after ACE inhibitors were marketed, the rates of emergency department presentations with angioedema markedly rose...