F.D.A.’s Accelerated Drug Approvals Come Under Scrutiny

By the time Brittany Bonds gave birth to her third son in the back of an ambulance 10 weeks before he was due, she no longer trusted the drug Makena.

The drug was intended to forestall preterm birth and improve the health of a baby. But it did not work for Mrs. Bonds, whose son Phoenix ended up in a NICU for 83 days. At 2, he still has a host of health problems.

Makena is another example — like the controversial Alzheimer’s drug Aduhelm — of a medication fast-tracked by the Food and Drug Administration onto the market even though considerable doubt remained about whether it worked.

The continuing debate over Aduhelm’s approval has renewed attention on the expedited pathway for drugs to reach the market. A bill sponsored by one Republican in Congress would make it even easier for a company to get a drug approved and keep it available. A proposal by a leading Democrat would give the F.D.A. more authority to get definitive answers about fast-tracked drugs and to remove them from the market if they fall short.

But any efforts to impose limits on the fast-track process is likely to draw the ire of the powerful pharmaceutical industry, which was the top U.S. sector in lobbying expenditures last year and spends heavily on political campaigns.

“I think there’s going to be tremendous resistance from the pharmaceutical industry” to tightening the rules on accelerated approvals, said Dr. Michael Carome, a director at Public Citizen, a nonprofit consumer advocacy organization.

Questions had lingered about Makena for a decade before a large study showed the drug had the same effect as a placebo. The F.D.A. proposed taking the drug off the market more than a year ago. It plans to hold a hearing on Makena’s fate that will focus scrutiny on what some critics claim is a speed-over-science drug approval process.

Mrs. Bonds is one of 13 plaintiffs in a lawsuit against the drug’s previous owner, AMAG Pharmaceuticals, and wants the drug taken off the market. “It didn’t work for me and I know it didn’t work for other people,” she said.

Covis Pharma, which now owns the drug, plans to oppose the agency’s decision at the upcoming hearing, arguing that Makena is truly effective for the women it had initially helped: African American women, who face some of the highest preterm birthrates in the developed world.

Premature babies also face elevated risks of being born dead or disabled. “A lot of emotion gets involved in this,” said Dr. Washington Hill, a Black maternal-fetal medicine specialist in Sarasota, Fla. He has prescribed the drug for decades to at-risk women and was paid $1,200 in consulting fees when he testified in its favor in 2019. “I felt this drug was effective in the patients I worked with,” he said in an interview.

Throughout the life of the accelerated approval program that began 30 years ago, the F.D.A. has had to weigh passionate, sometimes desperate pleas for access to drugs against the available science-based evidence.

During those decades, the agency issued 278 approvals under the program as of December. The approvals do not prove that a drug extends survival or improves quality of life. Instead, drugs can be put on the market based on a single study with a positive finding — like tumor shrinkage — and kept on the market if a follow-up study proves a benefit.

This pathway, meant for serious conditions and unmet medical needs, has given patients earlier access to lifesaving drugs, a point of pride for industry groups like BIO, the Biotechnology Innovation Organization. A BIO representative told lawmakers last week that he supported a pending plan for drugmakers to use real-world evidence to more quickly prove that an accelerated approval drug works. PhRMA, which also represents drugmakers, said it supported the program in its current form.

Yet critics and watchdog groups contend that Medicare has spent billions on accelerated approval drugs, even as drugmakers drag their feet to complete the required follow-up studies which, if unfavorable, can lead to withdrawal of the drug. In some cases, fast-tracked drugs that showed little benefit stayed on the market anyway.

Speeding up science has long been fraught: The F.D.A. was heavily criticized for its actions on Vioxx, a pain drug that had been approved under expedited review that was later withdrawn in 2004 over findings that it increased heart attacks and strokes. Even more avenues for expedited reviews were granted under the 21st Century Cures Act in 2016.

On the heels of the Aduhelm approval debate, the F.D.A. faces another round of scrutiny next week when its advisory panel reviews a new drug, Amylyx, for amyotrophic lateral sclerosis, a fatal neurological disorder. While the drug meets one bar for accelerated approval — the addressing a serious disease with unmet needs — its maker is seeking traditional approval.

As for the current state of accelerated approvals, April Grant, a spokeswoman for the F.D.A., said the agency was working to ensure that drugmakers completed follow-up studies of the drugs in a timely manner. If it finds gaps in its authority, “then the agency will work with Congress to close those gaps,” Ms. Grant said.

The accelerated program traces its history to a raucous 1988 protest on the F.D.A.’s front steps, when AIDS activists stormed the agency headquarters, enraged that it had done so little as thousands of young men were dying.

They outlined each other’s bodies with sidewalk chalk. The police cuffed them in zip ties and dragged them away.

Mark Harrington, who helped organize the 1988 demonstration, is executive director of the Treatment Action Group, which advocates access to medical treatments. He said the rowdy protest led to discussions for expediting access to new drugs.

While drugs that initially seemed promising fell short, by the mid-90s, protease inhibitors slashed virus levels and delivered a medical miracle.

“So the bottom line is that the accelerated approval regulations worked,” Mr. Harrington said. “They helped draw more companies into the space. They led to the discovery of effective treatments.”

Yet Mr. Harrington and others have watched with concern as researchers have identified accelerated approval drugs that delivered minimal, if any, gains for patients.

Of the 253 drugs authorized under accelerated approval since 1992, nearly half — 112 — have not been proven to extend survival or improve quality of life, according to an investigation in the The BMJ published last year. Two dozen of the drugs had been on the market for five years or more.

Another study showed that 20 percent of 93 cancer drug treatments cleared since 1992 were proven to extend overall survival, while others remained on the market after follow-up studies showed more modest gains, like delaying tumor growth. The F.D.A. said overall survival improvement can be hard to assess, as it takes years to achieve.

That study reported that one drug, Avastin, got accelerated approval to treat glioblastoma, a brain cancer. Even though a follow-up study did not show extended survival or improved quality of life, Avastin still received full approval for that use in 2017.

The same drug was used to treat breast cancer and is the only example of the F.D.A. revoking accelerated approval for one use of a drug — despite emotional pleas to allow it for cancer patients in 2011.

In 2010, the F.D.A. backed off its decision to withdraw Midodrine for patients with dangerously low blood pressure, just a month after telling the drugmaker it had “not been able to provide evidence of the drug’s benefit.”

In fact, the makers of Makena cited that precedent in arguing that their preterm-birth drug should remain available. The agency altered course on the blood pressure drug “prompted by the outpouring of support for the drug and concern over losing access,” Makena’s maker reminded the F.D.A.

Covis, the drug’s current owner, funded a patient group called the Preterm Birth Prevention Alliance, whose members may testify at the hearing over the drug’s fate.

The story of Makena begins with a medical mystery: Scientists aren’t certain what triggers the process of giving birth in humans. A clue to forestalling it seemed to emerge in 2003 with the results of a study on the drug’s active ingredient, a form of the hormone progesterone.

The study, which included many high-risk Black women, showed that those on the medication saw a 34 percent reduction in their risk of having a preterm birth compared with those in a control group.

An F.D.A. statistical review of the study concluded that the data does “not provide convincing evidence” of effectiveness. Of principal concern, the report said, was that the drug seemed most effective when started at or before 18 weeks of the pregnancy, when the rates of fetal or newborn death was also “most pronounced.”

Still, the F.D.A. granted the drug accelerated approval in 2011, and it remains the only approved drug meant to reduce the risk of recurrent preterm birth. Top medical societies, which have accepted funding from the drug’s maker, endorsed its use, and Makena became so routinely prescribed that it was difficult to study in the United States.

By 2019, though, results of a large study conducted mostly in Europe were in. They suggested that the drug had no effect: The percentage of women who gave birth preterm while on the drug was about the same as those given a placebo.

The F.D.A. examined the data to see if there was a subgroup of patients in the United States, including 113 Black women, who benefited. It couldn’t find one. In October 2020, the F.D.A. announced it wanted to discontinue use of the drug.

The drug’s maker, then AMAG Pharmaceuticals, asked for a hearing, arguing in part that the studies left open the question of whether their drug benefited high-risk Black women. “Our view is that given the results of both of these trials, additional research is merited,” said Francesco Tallarico, general counsel for Covis Pharma.

It’s a concern shared by others who have no financial stake, including Dr. Michael Greene, a professor emeritus at Harvard’s medical school. He and colleagues said the second study was “underpowered” because it included few Black women.

“Is it really fair and equitable to yank the labeled indication for a drug that is helpful to a minority, just because it’s not helpful to the majority?” said Dr. Greene, who is an associate editor of the New England Journal of Medicine. “That didn’t really seem fair to us.”

Debate over the drug has divided the maternal-fetal medical care community, Dr. Hill, the maternal-fetal specialist in Sarasota, said. He wants the drug to remain approved, but is uncertain that will happen. “My gut reaction would be it’s going to take a lot of convincing.”

Even those who are skeptical of the drug want to know more. “I think there should be more study,” said Olivette Bennett, a pregnant Baltimore woman, who is Black, who recently stopped taking the drug because she didn’t think it was working. “Where is the voice for the African American women who said it worked for them?”

In the federal lawsuit against AMAG Pharmaceuticals, Mrs. Bonds of Missouri, who is white, and other plaintiffs claim the company leaders did periodic reviews of the 2019 study, but continued to market the drug as something that could help women. AMAG said the lawsuit should be dismissed, arguing it amounted to an attack on a drugmaker’s right to advertise an F.D.A.-approved drug.

In an interview, Mrs. Bonds said she began taking Makena during each of three pregnancies after a stillbirth in 2011. Her first two sons were born at 36 weeks, several weeks short of full-term.

She said she reluctantly took the drug while pregnant with her third son. She was dispirited that his birth came earliest of all. She said the drug should have been studied more before approval. “I think it would have helped prevent a lot of false hope,” Mrs. Bonds said.