3:28 PM
Nov 07, 2018
 |  BC Extra  |  Politics & Policy

FDA draft guidance calls prospective meta-analyses ‘gold standard’

FDA issued draft guidance asking sponsors planning to submit meta-analyses with regulatory applications to take a prospective approach to identifying suspected therapy-related safety signals. The gold standard, the agency said, are analyses planned prior to the start of the component trials from which data will be pooled, and where the component trials were designed with the meta-analysis in mind.

Analyses of data pooled from multiple clinical trials can help FDA and trial sponsors identify safety signals that may be too rare to identify in a single trial. The tool can save sponsors time and money by alleviating the need for a new trial designed to specifically investigate a suspected safety signal and also avoids putting additional patients at risk in such trials.

The draft guidance applies to pre- and postmarket meta-analyses for which data sources are randomized controlled trials. While meta-analyses are not required components for all regulatory submissions, FDA may ask a sponsor for one or it may perform one itself if a safety signal is suspected.

The agency said meta-analyses should still include a hypothesis defined prior to selecting trial data to include in the analysis, even if the component trials were not specifically designed with the meta-analysis in mind.

Two meta-analyses FDA recommends against including in a regulatory submission are: meta-analyses reported in the literature without a credible record of prespecified data selection and hypotheses; and meta-analyses based solely on safety results appearing in the literature, which could introduce a publication bias.

The guidelines would apply to meta-analyses in all disease areas and to those supporting INDs, NDAs, BLAs and label expansions. The agency recommended in guidance in 2008 that sponsors of Type II diabetes drug trials perform prospective meta-analyses for drug-related cardiovascular risks from Phase II and Phase III data, and perform postmarket cardiovascular outcomes trials.

An analysis by BioCentury of clinical trials for novel drug candidates in the indication showed the number of trials and candidates has dwindled since FDA issued the guidelines (see "CVOT damage in diabetes").

FDA has since revisited that guidance: on Oct. 25, FDA's Endocrinologic and Metabolic Drugs Advisory Committee recommended the agency modify diabetes drug safety guidelines to soften or eliminate requirements for postmarket cardiovascular outcomes trials of new Type II diabetes drug candidates, and replace them with a mandate for premarket studies powered to detect signals of CV risk (see "FDA Panel Backs Shifting Diabetes CV Safety Studies to Premarket").

Comments are due by Feb. 4.

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