The Problem With the FDA’s Quick-Approval Process for Drugs

(Bloomberg Businessweek) -- One in 10 babies in the U.S. is born premature, with elevated rates of disability and death. For almost a decade, a drug called Makena has been used to reduce the risk of further instances of early delivery for women who’ve previously given birth prematurely. The medicine, approved in 2011 under the Food and Drug Administration’s accelerated process, contributed more than $300 million of annual sales for its manufacturer, Amag Pharmaceuticals Inc.

New research calling into question how well the drug works is now prompting the FDA to consider delisting Makena—a rare step for an approved treatment. For the women in a follow-up study required by the FDA, released last year, Makena did not decrease repeated preterm births. “To see these women and their families have to go through this experience multiple times is heartbreaking,” says Michal Elovitz, a physician and director of the Maternal and Child Health Research Center at the University of Pennsylvania’s Perelman School of Medicine. “They want to know why and why it didn’t work. And the only answer we have for them is we have to figure that out.”

The controversy over Makena has intensified the debate about the FDA’s use of its expedited process, which accounted for 19% of approved drugs in 2019, an increase from 13% from 2015. The FDA has focused especially on stepping up the availability of new cancer drugs and has also approved medicines to treat sickle cell disease and rare inherited disorders like Duchenne muscular dystrophy and Fabry disease. And since the outbreak of the novel coronavirus, the FDA is also under increased pressure from President Trump to green light little tested drugs to treat Covid-19.

The drug industry is counting on the accelerated approvals and other fast-track programs to clear the way for new biomedical therapies. Biogen Inc. may turn to the program to file for U.S. approval of a controversial Alzheimer’s disease therapy that millions of patients could be eligible for. Skeptics say there is slim evidence that the drug, called aducanumab, is effective: Biogen initially declared it a failure but later returned to the results and found support that it worked at a higher dose.

Makena can cost around $16,000 per birth, and cancer drugs can cost more than $10,000 a month. “We as a society end up paying a lot more for drugs that don’t end up working,” says Aaron Kesselheim, a physician and professor of medicine at Harvard Medical School who proposes price concessions for drugs that receive speedy approval.

Among expedited approvals that went wrong were those for the cancer drug Lartruvo, which was pulled voluntarily by Eli Lilly & Co. last year after research found it didn’t help patients live longer, and Roche Holding AG’s Avastin for treatment of metastatic breast cancer, which the FDA withdrew in 2011 over concerns about safety and efficacy. For Makena—the first drug approved by the FDA to reduce preterm birth risk—regulators relied on just one research trial to make their decision. Most therapies are studied in at least two trials before they’re considered.

Amag Pharmaceuticals stands by the efficacy of Makena and wants to keep it on the market while more research is done. The recent trial, which took a decade to complete and release, was complicated by the drug’s U.S. approval, according to Amag. With the treatment widely available, the company says, doctors were hesitant to put prospective mothers in testing where they risked receiving a placebo. It also says that demographic differences among patients may have affected the results.

Until the FDA makes a decision about Makena—it hasn’t indicated when this will happen—doctors and hospital staff will find themselves weighing an older favorable study against a newer damaging one. The two major national professional organizations in this field—the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine—continue to say Makena is an option for at-risk pregnant women. “The jury’s still out on this,” says Mary Norton, a physician who co-wrote the Society for Maternal-Fetal Medicine’s statement about Makena, and noted that the drug is considered safe.

An independent advisory committee that included doctors, scientists, and statisticians recommended in a close vote that the FDA pull Makena’s approval. Adam Urato, chief of maternal-fetal medicine at MetroWest Medical Center in Framingham, Mass., says he had concerns about the medication even before the latest study and has been vocal in urging the FDA to withdraw the drug. “You don’t want to use medications in pregnancy unless you know that they’re safe and effective,” he says.

The FDA acknowledges that accelerated approval inherently creates uncertainty, but it maintains that the risk is worth it. “We would expect every once in a while that we would be wrong,” says Janet Woodcock, director of the Center for Drug Evaluation and Research at the FDA. “Otherwise,” she says, “we’re not taking any chances” and making patients wait too long for new treatments. —With Cristin Flanagan

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