Meta-Analyses of Randomized Trials: FDA Offers Draft Guidance

Regulatory NewsRegulatory News
| 06 November 2018 | By Zachary Brennan 

The conducting of meta-analyses 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combining information from multiple trials, the US Food and Drug Administration (FDA) said Tuesday as it released new draft guidance.

The 26-page draft defines meta-analysis 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 says meta-analyses are most useful in detecting and quantifying an increased risk over the background rate of a safety event. And with aggregating data, a sponsor may be able to provide a higher statistical power and more robust estimate than may be possible with an individual study.

But investigators must make important decisions on studies to include in a meta-analysis, whether they should be included based on prospective and objective criteria, how to deal with incomplete data, analyze the results and account for publication bias.

FDA Commissioner Scott Gottlieb said: “Our goal is to encourage more pooled studies to evaluate important safety events. Meta-analyses can be conducted in the pre-and post-market setting, and the recommendations in this draft guidance, when finalized, will apply to both. Sponsors apply the principles described in this draft guidance when planning and conducting a meta-analysis of randomized controlled trials to better assess the safety of a drug product.”

FDA also may ask sponsors to conduct a prospective meta-analysis, as it has recommended in draft guidance for sponsors of new therapies to treat type 2 diabetes. In addition, the agency may initiate its own meta-analysis in response to safety signals that FDA is aware of, using study data only FDA has access to.

The draft further describes in detail the principles underlying best practices for safety meta-analysis and the way that FDA intends to factor adherence to those principles into its decision making. According to FDA, the most important principles in the guidance 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 unrecognized.
  • 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).”
Meta-Analyses of Randomized Controlled Clinical Trials to Evaluate the Safety of Human Drugs or Biological Products Guidance for Industry


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