For 16 years, the standard of care for pregnant women with a history of preterm delivery has been a weekly injection of progesterone. It still is, but after recent activity at the FDA and at ACOG, the future of therapy for preterm delivery seems very much in doubt.
On October 25, results of the 1708-patient PROLONG study demonstrating no effect for 17-hydroxyprogesterone acetate (17P) appeared in the American Journal of Perinatology. This study was essentially commissioned by the FDA when granting fast-track approval to this medication, sold by the trade name Makena.
Four days later, a FDA advisory committee voted 9-7 to recommend pulling Makena off the market. However, five of the six obstetricians on the panel voted with the dissenters. The FDA is not obligated to follow the advisory committee’s recommendation.
Meanwhile, the American College of Obstetricians and Gynecologists (ACOG) promptly issued a statement upholding the weekly-progesterone standard of care, citing possible problems with the PROLONG trial.
Thus, in the course of four days, the standard of care for preterm delivery prevention was undermined, and ACOG and the FDA seemed set on a possible collision course if the standard of care is dependent on an unapproved drug. (To be fair, compounded progesterone has always been widely prescribed for this indication.)
What happens next?
My guess is the FDA leaves Makena on the market. ACOG still recommends it, it’s very safe, and further research will be essentially impossible if Makena is off the market. Dr. Hugh Miller, a wise maternal-fetal medicine expert who was also an investigator on the PROLONG study, thinks removing Makena from the market would be a mistake. “I think it would be a travesty for this drug to be withdrawn,” Miller emailed me, “and there is virtually no chance it will get further study if it is.” (Miller asked me to note in full transparency that he has received funding from AMAG, the manufacturer of Makena.)
Weekly 17P is likely to remain the standard of care for women with a prior preterm delivery because a) results from large studies conflict, and b) it feels better to do something than to do nothing (particularly when ‘something’ is safe), but I think skeptics will have leeway to not prescribe. ACOG communicated its endorsement of this standard to the FDA during the advisory committee process, according to Dr. Chris Zahn, ACOG’s VP of practice activities, and has issued three advisory statements to clinicians (1, 2, and 3).
Here’s the backstory:
Studies suggesting progesterone prevents preterm delivery date back to the 1960s, but the work that changed practice was the 2003 Meis study in the New England Journal of Medicine that showed weekly 17P reduced the risk of preterm delivery dramatically. Because progesterone has a long history in obstetric practice, and is very safe, it quickly became the standard of care, even as skeptics pointed to problems with the Meis study, particularly the very high rate of recurrent preterm delivery in all study participants.
Because there was no FDA-approved formulation of 17P (in castor oil), clinicians worked with a host of compounding pharmacies to obtain this therapy for women desperate to prevent another preterm delivery, a condition that impacts nearly 10 percent of deliveries and can cause lifelong impairment.
I’ve written previously about the sordid tale that brought Makena to market in 2011. In the intervening years, the drug was acquired by AMAG Pharmaceuticals, and that company has worked hard to repair the political damage done by KV Pharmaceuticals, the company that won approval for Makena (and since went out of business).
Makena - expensive, FDA approved - competed with compounded 17P - inexpensive, FDA tolerated - until ironically, the tragic 2012 meningitis outbreak caused by tainted steroid injections sullied the reputation of compounding pharmacies everywhere.
Meanwhile, the PROLONG trial, mandated by the FDA as a condition of fast-track approval of Makena, began enrolling subjects at 93 sites around the world. ACOG cites the authors of the study who called out a sample size too small to demonstrate treatment efficacy, and possible bias in enrolling some subjects, as reasons to discount the study’s findings.
(It’s an aside, but the authors opted for fast publication - before the FDA committee meeting - in the low-prestige American Journal of Perinatology (impact factor 1.6) instead of slower publication in the New England Journal of Medicine (impact factor 70.7) or one of the leading OBGYN journals with impact factors of 4-6. I think this speaks to the democratizing influence of the internet on medical knowledge.)
Patients tend to follow their healthcare provider’s advice when it comes to decisions about treatments like progesterone, although this latest controversy won’t make this decision easier. Many clinicians and researchers believe there is a subset of patients who benefit from progesterone - we just don’t know how to identify that group. Maybe further research is, in fact, needed.