Why aren’t we more skeptical of progesterone for preventing preterm birth?
The research is weak. The industry is corrupt. And there are alternatives that work.
I recently got curious about what ever happened with Makena, the once controversial but now mainstream progesterone drug that promises to prevent preterm birth. My curiosity turned out to be timely. Makena is about to go before the FDA to review new data, and stands to lose its approval for use in preventing of preterm birth.
It turns out Makena doesn’t work for the one indication for which it is FDA approved: prevention of a subsequent preterm birth in a person who has had a spontaneous preterm birth in a prior pregnancy. That’s according to new research sponsored by the company that markets Makena, AMAG Pharmaceuticals. They were required to conduct a proper research study to test their product as a condition of the accelerated “orphan drug” approval process Makena won in 2011.
This should be a shocking turn of events, but it has gone remarkably unnoticed by the obstetric community, and prescribing practices don’t seem likely to change. When the preliminary data were released in March, it was barely a blip on anyone’s radar. The long-awaited PROLONG trial finally was published Friday, along with tepid statements from the American College of Obstetricians and Gynecologists and the Society for Maternal Fetal Medicine. Both organizations touted the need for more research and individualized decision making, and declined to update their clinical guidelines that recommend offering the drug routinely.
It should shock us because the advent of Makena utterly transformed how we deliver and pay for maternity care, and has cost taxpayers and employers billions of dollars.
For nothing.
There’s no benefit.
The company’s own research says so.
Why the complacency and inertia? There are a lot of other things we could have spent billions of dollars on to improve maternity care.
Makena was the first darling of “value-based” maternity care
When Makena came on the market, the price tag per prescription was higher than the average per-pregnancy spend on all other care combined in the prior year. (See Table.)
To be sure, there was blowback against this high price in the beginning. Progesterone formulations had been around for decades and the Makena formulation, known as 17-alpha hydroxyprogesterone caproate, or 17-OHP, could be sourced from compounding pharmacies for just $10-$20 per weekly injection, or about $300 per pregnancy. KV Pharmaceuticals earned fast-track FDA approval by arguing that high preterm birth rates were a public health crisis, then unexpectedly announced the price would increase 100-fold a week after the FDA announcement. In response to public outcry, the price was eventually negotiated down to about $14,000 per pregnancy for commercial payers and $6000 per pregnancy for Medicaid, according to media reports.
Although they reduced the price, KV Pharmaceuticals still managed to convince the public that weekly Makena injections were one of the most valuable uses of our maternity care dollars because they might reduce the scourge of preterm birth and because compounding pharmacies lacked the oversight to safely and reliably meet the need. They masterfully reframed a fight about prices or the intracacies of compounding pharmacy regulation into a debate about the value of a healthy, full-term baby.
Paying for value is the antidote to our current fee-for-service system, where we actually incentivize worse outcomes (NICUs drive profits for hospitals, after all.) In the era of healthcare reform, the landscape was shifting. We could improve outcomes and reduce costs by incentivizing evidence-based care.
Some of the earliest such “pay for performance” programs in maternity care tied Medicaid payments to recommending Makena. In some states, like North Carolina, providers could earn a bonus from Medicaid when they screened for Makena eligibility. In other states, like Louisiana, they would actually lose part of the standard payment unless they recommended Makena. At least a dozen states have implemented similar programs.
Within just a year or so, Makena emerged from their pricing public relations crisis as the literal definition of “high value care.”
How did they pull that off?
The pricing scandal was not the only bad behavior
If the pricing scandal sounds familiar, it’s because we have seen similar stories emerge with drugs ranging from Epi-pens to insulin to HIV treatments thanks to financial engineering by hedge funds, regulatory loopholes, and the morally corrupt and illegal behavior of “pharma bros” like Martin Shkreli. And like some of these other stories, the industry stakeholders that brought us Makena were engaged in more bad behavior than just price gouging.
Less than two years before Makena gained approval, the company that manufactured it, KV Pharmaceuticals, was shut down by the FDA. A series of product recalls prompted an FDA inspection, which found major manufacturing and quality control issues, and a fraudulent cover-up of serious morphine dosing problems. The chairman and CEO was forced out of the company, sent to prison on felony charges, and banned from ever working with government health programs in the future, and the company was fined $17 million.
By 2010, the company was given clearance to begin selling medications again, but their annual report to investors that year warned that the future of the company was grim. “Based on current financial projections, we believe the continuation of our Company as a going concern is primarily dependent on our ability to address, among other factors…the timely FDA approval of [Makena] and its successful launch and product sales.”
In other words, the price gouging was a Hail Mary to try to save the company. They launched a massive marketing campaign and poured resources into suing Medicaid programs and compounding pharmacies to stifle competition. But still, KV Pharmaceuticals was in bankruptcy by 2012, laying off hundreds of employees and defaulting on their pensions.
A group of hedge funds stepped in, recapitalized the company, rebranded as Lumara Health, and sold off Makena to specialty pharmacy company, AMAG Pharmaceuticals, in a deal worth over a billion dollars, less than 5 years after buying the rights to the drug for just $83 million.
That’s a pretty sweet rate of return for a company that was under criminal investigation and marketing a drug that would turn out not to work.
Makena under new ownership: Profits soar, but where is the evidence?
After acquiring Makena in 2014, AMAG Pharmaceuticals spent the next few years raking in hundreds of millions in revenue per year on the product, using proceeds to acquire Cord Blood Registry and to prepare to bring a controversial new female libido drug, Vyleesi, to market. They also continued their campaign to maintain their Makena monopoly, using the orphan drug pathway again to gain another 7 years of marketing exclusivity for its auto-injector drug delivery mechanism, and introducing a generic version of the original injection formulation to capture a share of this new market.
They also continued the FDA-mandated study to confirm that Makena indeed reduces preterm birth as suggested in early research, and to test for direct clinical benefit, such as improvement in neonatal mortality and morbidity — Makena was originally approved in 2011 without any such evidence, and against the recommendation of the FDA’s own statistical expert, who raised serious questions about aberrations in the study data.
To put the controversy about the 2003 study to rest, the FDA ordered a repeat of the trial, which is also just good scientific practice and typical with accelerated approvals. A research experiment is not considered proof unless it can be replicated with similar results. With a team of researchers, AMAG launched the PROLONG trial, setting out to repeat the 2003 study but with almost three times the number of participants, and heightened attention to the earlier data concerns.
By 2018 the PROLONG trial was wrapping up and the results were not good for Makena. It was part of a weakening of the overall body of evidence around progesterone over the previous few years. Parkland Hospital saw their repeat preterm birth rates go up instead of down when they introduced 17-OHP routinely for people with a history of preterm birth, and even saw a spike in gestational diabetes in women exposed to the drug.
Early promising results for vaginal progesterone (which is used, frequently but off-label, for other preterm birth risk factors like short cervix) were also weakening, and by 2016, researchers and policy makers were beginning to question whether progesterone treatments even make sense biologically. In a commentary on the heels of the disappointing results of the OPPTIMUM trial, which aimed and failed to replicate early results of vaginal progesterone, the study authors wrote that maybe it’s time to move on from the idea that progesterone is the silver bullet to prevent preterm birth. They wrote (emphasis mine):
Ostensibly, there is biological plausibility behind the administration of progesterone for prevention of preterm birth. Progesterone can inhibit contractions of the myometrium in vitro…, and antiprogestogens are used as abortifacients. However, progesterone levels are high during pregnancy, far above receptor saturation. There is no evidence that women delivering preterm have lower progesterone levels and administration of progesterone vaginally does not increase circulating concentrations. Therefore, the mechanism by which a modest additional amount of progesterone could achieve a therapeutic effect is unclear.
But those who had bought into the progesterone thesis (literally or just clinically), kept on studying in search of a positive result. They theorized that maybe progesterone only works if you start it early enough. They devised new ways to deliver it. They checked to see if it worked when you have multiple risk factors, or different risk factors, instead of just a prior preterm birth. (Both studies were halted early because it was already clear that it didn’t.)
And then they started blaming the women. They researched why some women would opt not to do “anything possible” for the health of their babies. They called women who still had a preterm birth despite using Makena “non-responders,” and studied what was wrong with them.
(Has it occurred to these researchers and clinicians that maybe their product is a “non-treatment”?)
It’s not like we don’t have alternatives to Makena that actually work
Our inability to tweak the technology or find the right way to deliver our miracle drug is not the reason we keep failing to improve our terrible outcomes in maternal and neonatal care. It’s because our system is broken, and because we have failed to implement at scale the things that do improve outcomes, including preventing preterm birth.
What if we had spent the $2 billion or so that we have spent on Makena and scaled up birth centers instead? We could have increased the number of people accessing this care model by a factor of 10x or more, and seen better population health outcomes as a result. A recent major federal study confirmed earlier reports that prenatal care in a midwife-led birth center model reduces the preterm birth rate, while also bringing down the cesarean rate, the frequency of infant hospitalizations and ER visits, and the cost of care, to the tune of an average savings of $2000 per pregnancy.
What if we used the $2 billion to train up a new perinatal workforce — one that reflects the racial and ethnic diversity of childbearing people and that is embedded in communities — to replicate the proven “JJ Way” model that has been saving lives and strengthening families in Florida for over a decade? Jennie Joseph would get to be the billionaire then, and maybe she could finally take a well-deserved nap. (Knowing Jennie, she would surely reinvest her fortune in doing more good deeds for her community.)
What if we had used the $2 billion to scale up group prenatal care? Multiple studies have shown these models decrease preterm birth rate — including narrowing racial disparities — and also improve outcomes like breastfeeding initiation, infant hospitalization rates, self-management of gestational diabetes, and satisfaction with care. With our Makena investment, we could have paid for group facilitation training for every OB/Gyn and midwife in the United States, and still had more than $1.9 billion leftover.
This may be the calculus that AMAG Pharmaceuticals is using as it plans its next moves to keep shareholders happy as the house of cards it has built with specious evidence and ruthless monopoly-making begins to wobble. In recent years, the company has built out a corps of care managers, positioning them to provide wrap-around education and services to people at risk of preterm birth. And over the last year, they have invested hundreds of thousands of dollars to help March of Dimes launch a new group prenatal care program.
I’m not buying it. The pharmaceutical industry has drained billions from the system, turning it into shareholder profits while preterm birth rate keeps climbing, babies keep dying, and community-based care models that actually do deliver value keep folding because the money runs out.
Yes, let’s invest in these enhanced models of maternity care, but let’s leave the pharma bros out of it.
photo by Marco Verch on Flickr.
