For drugs approved by the US Food and Drug Administration (FDA) based on limited evidence, a recent study published in the British Medical Journal found “noticeable variability” in the degree to which novel drugs were studied in the postmarket period.

The authors, including Yale University professors Harlan Krumholz and Joe Ross, urged FDA to take a cautious approach in increasing its reliance on surrogate markers, smaller and shorter trials, and evidence derived from registries or observational studies, as “high quality postapproval evidence does not necessarily accumulate and may require additional regulatory requirements. 

“For many novel drugs, the problem is not that postapproval studies are poorly designed or have negative efficacy results, but rather that they are not being published or performed at all,” the study says. The study looked at drugs initially approved by FDA between 2005 and 2012 on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease as primary endpoints or both.

After an average follow-up of 5.5 years, for 35% of these approved indications, no postapproval studies of the originally approved indication were identified. The median total number of postapproval studies identified was one study for indications approved on the basis of a single pivotal trial, three for indications approved on the basis of pivotal trials that used surrogate markers as primary endpoints and one for single/surrogate trial approvals.

“More worrisomely, only 18%, 2% and 5%, respectively, of these groups of approvals had one or more randomized, controlled, double blind study using a clinical outcome for the primary endpoint (as opposed to a surrogate marker) that was published after approval and showed superior efficacy,” Ross told Focus.

The study’s authors also noted that the findings are consistent with previous studies showing that even postapproval studies required by FDA for drugs and devices are not always performed in a timely manner.

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