US FDA Tried, But Failed, To Take Compounding Issue Off The Table At Makena AdComm
Executive Summary
Clinicians and patients would look for 17P wherever they could find it if AMAG’s FDA-approved formulation of the preterm birth drug comes off the market, panelists said; Cowen analysts believe the potential for safety concerns posed by compounded formulations will save Makena from the regulatory chopping block.
Seemingly everyone wanted to discuss the issue of compounding at the recent US Food and Drug Administration advisory committee meeting on the future of AMAG Pharmaceuticals Inc.'s preterm birth drug Makena.
Everyone, that is, except the FDA.
Under certain circumstances, the active ingredient in Makena (hydroxyprogesterone caproate injection, also known as 17P) may be compounded, “but that’s pretty much all the details that I can provide regarding compounding,” said Christine Nguyen, deputy director for safety in the Division of Bone, Reproductive and Urologic Products.
Nguyen’s comment came in response to a committee member’s question as to whether 17P could still be compounded if Makena’s accelerated approval were withdrawn due to the failure of the PROLONG confirmatory trial.
“I understand the compounding issue is important. However, it is not before the committee today, so that is not something we could be prepared to discuss.” – FDA’s Christine Nguyen
“I understand the compounding issue is important,” Nguyen said. “However, it is not before the committee today, so that is not something we could be prepared to discuss.”
The advisory committee thought otherwise, however, particularly since the FDA had requested discussion on the potential consequences for patients and clinical practice of withdrawing Makena’s accelerated approval. (Also see "AMAG’s Explanation For Makena's Failed Confirmatory Trial Faces Skeptical US FDA" - Pink Sheet, 27 Oct, 2019.)
Getting 17P ‘Wherever They Can Find It’
If Makena were withdrawn, the prospect that prescribers and patients would turn to compounded formulations of 17P is “just is something that makes sense that it might happen,” Annie Ellis, the panel’s patient representative, said.
Michael Lindsay, director of the division of maternal fetal medicine at Emory University, warned that the issue of prescribers and patients using a potentially ineffective medicine for preventing preterm birth will not just go away if the agency takes Makena off the market.
“The genie is out of the bottle, and people know that there are medications that would be used for patients who have had preterm deliveries,” Lindsay said. “They’re going to still want to get access to those medications.”
When Makena was first approved, it carried a high price tag that made it unaffordable for some people who were paying out of pocket and, consequently, some patients continued to use compounded formulations of 17P, said Kimberly Hickey, chief of maternal fetal medicine at Walter Reed National Military Medical Center.
“We continue to believe the agency will likely take the view that FDA-validated manufacturing is in the best interest of patient health (despite the controversial/unsupportive clinical data).” – Cowen analysts
“That would be my expectation if this is taken off the market and is not approved, then people are going to look for that equivalent wherever they can find” it, she said. “People will look for progesterone wherever they can find it. They won’t just say, ‘I’m not going to treat you.’”
Some analysts believe the potential for safety concerns with compounded formulations will be the key factor driving the FDA’s eventual decision on Makena’s regulatory future following a split panel vote. Nine members of the Bone, Reproductive and Urologic Drugs Advisory Committee supported withdrawal, and seven favored keeping the drug available under accelerated approval with a requirement for a new confirmatory study. (Also see "Makena Withdrawal Dilemma: Advisory Cmte. Split Offers No Clear Direction For US FDA" - Pink Sheet, 29 Oct, 2019.)
“We do not believe the agency will remove the product given the sensitive population it treats and the likelihood that clinicians will want to keep utilizing the product which would force them to source 17P through less-regulated compounding facilities,” Cowen analysts Ken Cacciatore and Stacy Ku said in a 1 November note.
“Despite the negative vote, we continue to believe the agency will likely take the view that FDA-validated manufacturing is in the best interest of patient health (despite the controversial/unsupportive clinical data),” said the Cowen analysts, who also suggested there may be a reimbursement issue at play.
“Makena and the generics are now also reimbursed products, and withdrawal would force patients back into private pay via the compounders,” the analysts said. “This could potentially be another consideration for the agency, especially considering that nearly 50% of all US childbirths are covered via Medicaid.”
Manufacturing Under GMPs
AMAG and its experts touched on the compounding issue in their presentations to the advisory committee, although perhaps not as extensively as might have been expected for a company fighting to keep its drug – the only FDA-approved medicine for preventing recurrent preterm birth – on the market.
“Prior to the FDA approval of Makena, 17P was available only through pharmacy compounding, which is not held to good manufacturing standards, and that creates the potential for safety and efficacy concerns,” Julie Krop, AMAG's chief medical officer and executive VP-development and regulatory affairs, told the panel.
Sean Blackwell, chair of the department of obstetrics, gynecology and reproductive science at McGovern Medical School-UTHealth and lead author of the published PROLONG study results, also opined on what would happen if Makena and its generics were no longer available.
“It is my belief that many experts and clinicians will still consider the risks and benefits of 17P in a positive balance that supports its use,” Blackwell said. “If there is not a 17P FDA-approved version available, many will turn to a compounded 17P. Others will advise off-label, unproven medical therapies or choose a surgical option with cervical cerclage, which has not been proven to work and has a greater risk for patient harm.”
Society Guidelines Put The FDA In A Bind
The issues around compounding and continued use of 17P even in Makena’s absence highlight the quandary in which the FDA finds itself.
On the one hand, there is a failed confirmatory efficacy trial for an accelerated approval drug, and an advisory committee’s overwhelmingly negative conclusion that neither substantial evidence of effectiveness on prevention of recurrent preterm birth, nor clinical benefit on neonatal outcomes, have been demonstrated.
AMAG CMO Julie Krop
Discussing the potential for changes to professional society guidelines:
- “I think the committees are not going to make their decisions based on FDA, they’re going to make their decisions based on data. If new data comes out, that will affect their decisions. I don’t think they’re going to be affected necessarily just by what the FDA says. They typically are data-driven organizations that are focused on what is best for their patients and their patient population.”
On the other hand, the approved indication is a rare condition, the drug is manufactured under GMP regulations, and two major professional societies – the Society for Maternal-Fetal Medicine (SMFM) and American College of Obstetricians and Gynecologists (ACOG) – continue to recommend use of Makena’s active ingredient for preventing recurrent preterm birth, even after public release of the data from the failed PROLONG trial.
AMAG has attributed PROLONG’s failure to hit its coprimary efficacy endpoints to baseline differences in risk between subjects who enrolled in the confirmatory trial and those in the original Meis trial that led to accelerated approval. (Also see "AMAG’s Makena: Did Accelerated Approval Kill The Confirmatory Trial?" - Pink Sheet, 31 Oct, 2019.)
After the PROLONG study results were published on 25 October, the same day the agency’s advisory committee briefing document was released, ACOG and SMFM issued statements reaffirming support for use in certain women at risk for recurrent preterm birth.
AMAG CEO Bill Heiden
Discussing the advisory committee meeting:
- “My impression of the advisory committee was that the clinicians, the ob/gyns on that panel, were very supportive of the efficacy of Makena. … This advisory committee was kind of overpopulated with statisticians who are not clinicians and were purely looking at statistics and … struggled a little bit to say, ‘Well, I can’t figure out which patients benefited statistically if I look across these studies.’ Of course, the clinicians were saying that’s common with drugs. … There were some other constituents on that advisory committee that I think had a harder time really understanding the nuances of maternal health care.”
ACOG said its guidance is “based on a review of the best available literature. As such, we will continue to monitor this topic, evaluate additional literature and any further analyses as published, and address findings as needed in relevant clinical guidance.”
AMAG has pointed to the professional society guidelines as evidence that the clinical community remains supportive of Makena’s efficacy. Company executives reiterated this view in AMAG’s third quarter earnings call, held three days after the panel review. (See box.)
AMAG also has emphasized the expertise divide among those panelists who favored keeping the drug on the market and those who supported withdrawal.
Five of the six obstetrician/gynecologists and maternal-fetal medicine specialists on the committee voted for continued marketing. In contrast, all four biostatisticians on the committee voted for withdrawal, execs noted on the earnings call. (See box.)
Two of the three neonatologists on the committee also voted with the majority in favor of withdrawal.