With clinical trial data now showing that the injectable drug 17-α hydroxyprogesterone (Makena) failed to prevent preterm birth, should it stay on the market? That's the question before an to review the new information as well as other data.
While Makena was approved in 2011 under an accelerated pathway, a trial was required to show evidence of its efficacy. But that trial, which was formally published on Oct. 25, found no significant difference in reduction of preterm birth or neonatal morbidity versus placebo.
Technically, what's under review is a supplemental new drug application from manufacturer AMAG Pharmaceuticals, which is asking to add findings from the new trial to the drug label. But FDA officials are asking the agency's Bone, Reproductive and Urologic Drugs Advisory Committee to vote on whether Makena should be withdrawn from the market altogether, retain approval but with a new efficacy trial, or retain approval with no further actions taken.
The committee will also be asked whether the findings of the new trial verify the clinical benefit of Makena (although the published data appear to show the opposite) and if there is "substantial evidence" that Makena reduces the risk of recurrent preterm birth, based on the findings of this new trial and along with a study from 2003.
There are two important scientific and regulatory implications of this review for Makena noted by the FDA -- first, that the drug was approved under the accelerated approval pathway, which requires a confirmatory trial following its approval, and substantial evidence of effectiveness, which the confirmatory trial did not provide.
"The key issues are whether there remains substantial evidence of effectiveness of Makena on preterm birth, the unconfirmed clinical benefit of Makena on neonatal outcomes, and implications for Makena's marketing status," the FDA wrote.
Findings from the PROLONG trial were recently published, but AMAG conducted a series of analyses comparing the findings of PROLONG (known here as Trial 003) with the 2003 trial that initially provided evidence of the drug's effectiveness (Trial 002). These subanalyses were submitted to the FDA. Agency officials seemed skeptical, saying that they consider these analyses "hypothesis-generating."
"Generally, FDA does not support unplanned exploratory subgroups analyses, especially when the overall result does not demonstrate efficacy," they wrote. "When such post-hoc subgroup analyses are used to search for evidence of benefit, there is a high probability that any observed favorable subgroup results are due to chance alone."
AMAG drew attention to differences in study populations between Trial 002 and Trial 003, and that these may have contributed to the "discordant outcomes between the two trials."
But the FDA did its own analyses comparing the U.S. patients to the non-U.S. patients in Trial 003. Agency staff said they "calculated the rate difference between the Makena and placebo groups for each coprimary endpoint" as well as certain secondary endpoints, and did not find anything significant.
"The lack of evidence of an interaction between region and treatment and the lack of evidence of a treatment effect within the U.S. subgroup in Trial 003 does not provide support for regional differences explaining the differences in results between Trial 002 and 003," they said.
They also did not find evidence of a treatment effect when the agency conducted a subgroup analysis by race, specifically black/African American versus others.
Moreover, the FDA analysis seemed to reject AMAG's post hoc interpretation that Trial 002 had the "highest" risk population, based on at least one of five selective risk factors (history of two or more prior preterm births, black race, substance use in pregnancy, 12 years or less of education, unmarried with no partner), and described a trend towards decreasing efficacy for the drug in lower risk subpopulations.
But the FDA's exploratory analyses found that while certain risk factors may impact overall preterm birth or neonatal composite index rate, "there was no evidence in Trial 003 that they impact the treatment effect nor was there consistent convincing evidence of an effect within a specific subpopulation across the two trials."
Examining safety, the agency found no new safety issues with Makena, saying the safety profile remains unchanged, though they noted that the number of fetal and neonatal deaths are "too low to draw definitive conclusions."