The Food and Drug Administration (FDA) has released draft guidance on meta-analysis of randomised controlled clinical trials to evaluate the safety of human medicines or biological products. The FDA stated that conducting meta-analysis to evaluate safety questions presents a unique opportunity to detect and quantify the risk of a safety event and may help provide a more precise estimate of the risk of uncommon serious adverse events by combining information from multiple trials.
Meta-analysis is described as the “combining of evidence from relevant studies using appropriate statistical methods to allow inference to be made to the population of interest.” The draft guidance explains that meta-analysis is useful in detecting and quantifying an increased risk over the background rate of a safety event. With aggregating data, a sponsor may be able to give a greater statistical power and robust estimate, compared to an individual study.
Using study data only the FDA has access to, the FDA may initiate their own meta-analysis in response to safety signals that the FDA are aware of.
The draft guidance outlines the principles which underlie the best practices for safety meta-analysis, including the way the FDA intends to factor adherence to those principles into their decision making. According to the FDA, the most important principles include:
- “Prespecification and transparency are recommended, as they enable a thorough evaluation of the meta-analysis.
- The criteria for selecting which trials to include should be determined prior to conducting the meta-analysis. The selection of the studies should not be based on the trial outcomes, but rather on trial quality and consistency of critical design elements, and should be executed by parties masked to the outcomes of the trials, whenever possible.
- The quality and relevance of the individual trials and the quality of the trial data are critical determinants of the quality of the meta-analysis itself. Outcome ascertainment and adequacy of exposure periods are two of the most important determinants of trial quality.
- Meta-analysis conducted to meet safety objectives often requires re-purposing trials that were originally designed to meet efficacy objectives. This can be challenging, particularly if subject-level data are not available.
- Meta-analysis based solely on published trials is particularly problematic because of the potential for bias and error, both known and unrecognised.
- Generally accepted principles of good statistical practice should be followed in selecting the statistical methods to be used for meta-analysis (but this guidance is not prescriptive as to the choice of method).”
To read the FDA draft guidance on meta-analysis of randomised controlled clinical trials to evaluate the safety of human drugs or biological products, please click here.