Drug safety assessment in clinical trials: methodological challenges and opportunities

Trials. 2012 Aug 20:13:138. doi: 10.1186/1745-6215-13-138.


Randomized controlled trials are the principal means of establishing the efficacy of drugs. However pre-marketing trials are limited in size and duration and exclude high-risk populations. They have limited statistical power to detect rare but potentially serious adverse events in real-world patients. We summarize the principal methodological challenges in the reporting, analysis and interpretation of safety data in clinical trials using recent examples from systematic reviews. These challenges include the lack of an evidentiary gold standard, the limited statistical power of randomized controlled trials and resulting type 2 error, the lack of adequate ascertainment of adverse events and limited generalizability of trials that exclude high risk patients. We discuss potential solutions to these challenges. Evaluation of drug safety requires careful examination of data from heterogeneous sources. Meta-analyses of drug safety should include appropriate statistical methods and assess the optimal information size to avoid type 2 errors. They should evaluate outcome reporting biases and missing data to ensure reliable and accurate interpretation of findings. Regulatory and academic partnerships should be fostered to provide an independent and transparent evaluation of drug safety.

Publication types

  • Review

MeSH terms

  • Adverse Drug Reaction Reporting Systems* / standards
  • Bias
  • Data Interpretation, Statistical
  • Drug-Related Side Effects and Adverse Reactions*
  • Endpoint Determination
  • Evidence-Based Medicine / methods*
  • Evidence-Based Medicine / standards
  • Humans
  • Meta-Analysis as Topic
  • Patient Safety
  • Patient Selection
  • Randomized Controlled Trials as Topic / methods*
  • Randomized Controlled Trials as Topic / standards
  • Reproducibility of Results
  • Research Design* / standards
  • Risk Assessment
  • Risk Factors
  • Sample Size
  • Treatment Outcome