The FDA says a drug for preventing preterm births does not work. The drugmaker has pushed back, enlisting support of Black women.

A patient advocacy group met with a staff member for U.S. Rep. Madeleine Dean in July 2021, seeking her support for a drug that is designed to reduce the risk of preterm birth. The advocates said the drug, called Makena, was needed especially for Black women, who are at higher risk of delivering premature babies.

But in telling Dean’s staffer about the drug — the subject of an FDA hearing that is to start Monday — the patient group left out two pieces of information. One, that it was funded partly by the drug’s manufacturer, which has U.S. offices in King of Prussia. And two, that the largest, most comprehensive study of the treatment found it did not work.

Critics say the meeting, first reported by the Los Angeles Times, illustrates the lengths to which drugmakers will go to secure support for treatments with an unclear benefit.

The Food and Drug Administration approved Makena through an accelerated process that is reserved for serious conditions that have limited treatments. The agency can approve such a drug based on preliminary data, provided the drugmaker follows up with a trial to confirm that it works.

But in dozens of cases, drugmakers fail to complete these follow-up trials by the agreed target date, selling billions of dollars’ worth of the medicines in the meantime, according to a new analysis from an oversight office at the U.S. Department of Health and Human Services. Among the priciest is Makena, for which taxpayers spent nearly $700 million from 2018 to 2021 through the Medicare and Medicaid insurance programs, the report’s authors estimated.

The FDA approved Makena in 2011 based on a study suggesting that it reduced the risk of preterm birth. But critics later identified statistical flaws in how that study was conducted. And when a larger, follow-up study failed to find any health benefit for the baby, the FDA proposed to withdraw its approval.

Drugmaker Covis Pharma, which has headquarters in Luxembourg, has pushed back, leading the agency to schedule the hearing that is to start Monday.

Makena is a synthetic version of the hormone progesterone, which is so named because it is “pro” gestation, said Shailen Shah, section head for the division of perinatology at Virtua Health, in South Jersey. Natural progesterone helps to maintain a healthy pregnancy in a variety of ways, so it was plausible that a synthetic version of it could reduce the risk of preterm birth, he said.

The drug is given via weekly injections in the second and third trimesters, at a total cost that can exceed $13,000.

The patient group that met with Dean’s staff is a coalition of women’s health groups called Preterm Birth Prevention Alliance, several of which have ties to the Black community.

Assembled by the National Consumers League, the alliance hoped the Montgomery County congresswoman could support the drug in her capacity as cochair of the Bipartisan Women’s Caucus, which has worked on maternal health issues, said league executive director Sally Greenberg. The group also met with the White House Domestic Policy Council, among other stakeholders.

Asked about the drugmaker’s involvement with the alliance, Greenberg said Covis and Makena’s previous manufacturer, AMAG Pharmaceuticals, was among many donors to the league, starting well before the FDA’s effort to withdraw the drug. Neither company played a role in the alliance’s advocacy for the drug, she said.

“We have a very strict fire wall,” she said. “No supporter ever dictates what we do.”

Dean and her office did not take any action as a result of the staffer’s meeting with the patient advocacy alliance, said Timothy Mack, a spokesperson for the congresswoman.

“We never knew that the alliance was paid for by the manufacturer, and noticed a number of prominent women organizations on the board,” he said. “Rep. Dean has not, nor [has] anyone in our office, taken any action since the staffer met with the Preterm Birth Prevention Alliance.”

Drugmakers have increasingly sought accelerated approval for their products since that pathway became an option in 1992, according to the report from the Office of Inspector General at the Department of Health and Human Services. One-quarter of such approvals (70 out of 278) were granted in 2020 and 2021.

But with 104 of the 278 approvals, manufacturers have yet to confirm the drugs’ effectiveness. In 35 of those cases, including Makena, follow-up trials were not completed by the agreed target date, yet manufacturers have continued to sell them at a brisk pace. From 2018 to 2021, Medicare and Medicaid spent more than $18 billion on drugs with delayed follow-up trials, the report authors estimated.

Before it was branded as Makena, the drug appeared in its original 2003 study to sharply reduce the risk of preterm delivery — as 36.3% of women who got the drug delivered their babies before the 37th week of pregnancy, compared with 54.9% of women who were injected with a placebo.

That won the drug accelerated approval in 2011. But Adam Urato, a maternal fetal medicine specialist in Framingham, Mass., remained skeptical.

He saw that women had been invited to join the trial if they were at risk of preterm birth, meaning they had delivered at least one baby prematurely in the past. But in the placebo group, the percentage of women who ended up having another preterm birth, 54.9%, was really high — roughly double the normal rate among at-risk women.

To Urato, that suggested something had gone wrong in how the women were chosen for the two groups. Upon looking at the details, he saw that prior to the trial, 41.2% of the women getting a placebo had delivered at least two preterm babies, compared with just 27.7% of the women who got the drug.

In other words, the reason the drug appeared effective was not because of the drug, but because women who took it were at lower risk to begin with, relative to those in the placebo group, he said in a phone interview.

“The trial was fatally flawed,” said Urato, who wrote about the issue for STAT, a health and science media outlet.

In the larger, follow-up trial, the drug did not reduce the risk of preterm birth, nor did it improve the health of the babies. The FDA proposed withdrawing its approval in 2020, leading to the hearing that starts Monday.

Urato warned that the drug’s potential side effects on the baby are unknown. In a comment submitted to the FDA, three Temple University physicians expressed similar concerns, citing evidence that the drug might increase the risk of gestational diabetes.

Urato also said it was “deceptive” and “unethical” for the company to claim the drug was especially needed for Black women, when there is no evidence it helps.

Still, some obstetricians and gynecologists, including Shah, say they would still prescribe the drug in certain high-risk cases, pending a discussion with the pregnant patient. Preterm birth can be caused by any of a complex mix of factors, some of which are not fully understood, and it is possible that the drug helps reduce the risk of preterm delivery from some causes but not others, he said.

The American College of Obstetricians and Gynecologists has taken a similarly guarded view, acknowledging the FDA’s analysis while stressing that few other options are available. On Oct. 12, the NAACP joined the debate, urging that the drug remain on the market while further study is conducted.

Greenberg, of the Consumers League, said the patient alliance had been making similar arguments. As for the drug’s cost, she noted that it was well below the cost of treating the complex issues that can occur in preterm babies.

Robert I. Field, a Drexel University professor of law and health policy, said this type of debate will continue to arise so long as the FDA can approve drugs with incomplete evidence.

There are valid policy arguments for approving such drugs if the disease in question is dire, and potential benefits outweigh side effects, he said. On the other hand, Field said, a drug that turns out to be ineffective can fuel false hope — and deliver a blow to the bottom line.

“The question is,” he said, “are we burdening taxpayers or premium payers with paying for a drug that’s worthless?”