Makena Withdrawal? A Look at the Timeline and Other Accelerated Approvals

Regulatory NewsRegulatory News | 01 November 2019 |  By 

Earlier this week, an FDA advisory committee recommended that the agency withdraw Amag Pharmaceutical’s preterm birth drug Makena, a treatment that brought in more than $1 billion in sales before failing a confirmatory trial.

The agency is now faced with the task of whether to take the committee’s vote and pull Makena from the market or allow it to remain until another confirmatory trial can be completed. Keeping Makena on the market would also present a rare situation, as according to a recent study, the agency makes a decision that runs counter to its advisory committees only about one in five times.

The failed Makena trial of more than 1,700 women, mostly in Russia and Ukraine, published last month found no difference between the treatment or placebo groups for either coprimary efficacy outcome. The study also said Makena “did not decrease recurrent PTB [pre-term birth] and was not associated with increased fetal/early infant death.”

But the example of Makena is illustrative of how long it can take between winning an accelerated approval, being bought or sold, generic versions launching and then completing the confirmatory study and either establishing a benefit or preparing to withdraw from the market.


FDA offered accelerated approval to Makena in February 2011 based on an early study, but the approval was contigent on Makena’s sponsor completing two postmarketing requirements (PMRs) on assessing clinical maternal and neonatal outcomes, which were originally expected to be completed in 2016 and 2018, respectively, but then were later extended by two years.

Although the first confirmatory trial had already commenced in November 2009, the last study visit came almost nine years later, in October 2018.

And while the study was ongoing, Amag, which bought Makena in 2014 for $675 million, brought in more than $1 billion from the drug, with the majority coming ahead of generic competition in 2018 ($387.2 million in 2017 sales, $334.1 million in 2016 and $251.6 million in 2015).

In March 2019, more than eight years after the accelerated approval, Amag announced that the trial did not demonstrate a statistically significant difference between Makena and placebo.

At the FDA advisory committee on Tuesday, experts discussed whether to keep Makena on the market and ultimately nine committee members voted to recommend that FDA withdraw approval and seven voted to leave the product on the market and require a new confirmatory trial. But Amag also noted that five of the six who practice obstetrics voted to keep Makena on the market and generate more data.

Minority of Confirmatory Studies Fail

If Makena was a cancer drug, by FDA’s numbers, its failed confirmatory trial would be in the minority of such trials conducted. A review published in JAMA Oncology by FDA officials in March 2018 found that 55% of oncology treatments granted accelerated approval over the last 25 years have gone on to demonstrate a clinical benefit. And FDA says that the PMRs for about half of those indications were fulfilled in a median of 3.4 years after gaining accelerated approval.

But there are always exceptions — and not just those in oncology like Eli Lilly’s Lartruvo (olaratumab), Pfizer’s Mylotarg (gemtuzumab ozogamicin) and Roche’s Avastin (bevacizumab) — others have never completed the required postmarketing studies.

For instance, FDA in 2016 withdrew the accelerated approval for EMD Serono’s fertility drug Luveris (lutropin alpha for injection) after a required postmarketing study was not completed. Similarly, FDA withdrew the approval of the familial adenomatous polyposis (FAP) indication for Pfizer’s Celebrex (celecoxib) in 2012 after a postmarketing study was never completed.

And in December 2011, FDA also requested that GlaxoSmithKline voluntarily withdraw the rituximab-naïve indication for Bexxar (tositumomab) injection because the postmarketing study was not completed.


© 2023 Regulatory Affairs Professionals Society.

Discover more of what matters to you

No taxonomy