Longtime readers (and longtime drug industry folks!) may remember the Makena story from 2011. That is a progesterone ester drug that has been given to women at risk of preterm labor, and it came into the news when a small company called KV Pharmaceuticals used an FDA program that encouraged modern trials of older medicines to get market exclusivity. Whereupon they ran the price up by nearly one hundred-fold.
There are quite a few stories like this, and I’ve written many times about how these grants of marketing exclusivity have probably been handed out too freely, given how valuable they can be. After KV got into this business, though, there was some question about the size of the actual market for Makena. At the same time, the FDA (in a rather odd move) announced that it would not bring actions against compounding pharmacies that provided the drug themselves, at whatever price they chose, which effectively negated some (perhaps all) of the market exclusivity the agency had just awarded. KV filed for bankruptcy the next year (this wasn’t their only problem, as that article shows), and emerged under a new name (Lumara). The pharmaceutical end of that business was bought in 2014 by another company, AMAG.
One thing that AMAG inherited was the FDA mandate to conduct a post-marketing trial to make sure that Makena actually worked. The trial that led to the KV approval had been done in 2003, and did not have robust outcomes data – it showed a reduction in preterm births, but nothing on overall mortality and morbidity results. There were other problems with the trial, actually, including treatment and control groups that may not have been comparable, and even the KV approval was controversial at the time. In March of last year, the new study reported its data: no benefit. No reduction even in preterm labor, much less other bad outcomes. The 2003 clinical trial appears to have been flawed all the way through. An FDA advisory committee said that the drug’s approval should be revoked.
So what we have is a drug that had been used for decades on the basis of not-very-good evidence that it could prevent preterm births. The FDA’s attempt to bring it into a modern regulatory environment relied on a single clinical trial that was not well run and (we now know) could not be reproduced, and led to bizarre market effects besides. It took eight more years to confirm that yes, this drug does not actually work. And now it’s been a year and half since that confirmation of non-efficacy, and Makena is still on the market and (presumably) still being prescribed. That last link above is a plea from almost a year ago for the FDA to pull the drug, and it’s well worth a read.
So, October of 2020, and the FDA is now formally proposing to withdraw marketing approval (thanks to Ed Silverman at Stat for that link). It’s worth noting that Makena was actually an accelerated approval, and the language of that process is particularly infuriating now:
FDA’s accelerated approval regulations, included in 21 CFR part 314, subpart H, describe the procedures for accelerated approval and the expedited withdrawal procedures for drugs approved under the accelerated approval pathway. These regulations state that FDA may grant marketing approval “on the basis of adequate and well- controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity” (§ 314.510).
Expedited withdrawal? Approval on the basis of adequate and well-controlled trials? I’m not seeing much sign of either of those. Makena (and the brand-name-less progesterone ester formulation it superseded in the market) has traced a long, slow trail through the US drug regulatory regime, and we now know that it doesn’t do anything to help anyone. Never has. It shouldn’t have been a drug in the first place. It shouldn’t have gotten a new life as a branded, FDA-approved one. It shouldn’t still be on the market over a year after it’s become clear that it’s worthless. This story does no credit to the FDA nor to the practice of medicine in general, and the sooner we can finally close it out, the better.