Opinion: What the Makena vote means about accelerated approval, trust, and the FDA

On Wednesday, the FDA advisory committee that oversees obstetrics, reproductive, and urologic drugs voted 14-1 that the drug Makena was not effective at reducing the risk of preterm birth, and that it should be removed from the market.

We’ve been here before. In 2011, the same year that Makena received accelerated approval from the FDA, I was a member of a similar FDA advisory committee hearing in which we considered withdrawing the breast cancer indication for the drug Avastin. According to an NPR investigation, the FDA has withdrawn at least 28 accelerated approvals, with the process taking an average of more than seven years.

But at a time when many people are expressing doubt in science and the safety of vaccines, and when another vanguard of public health, the U.S. Centers for Disease Control and Prevention, has recently acknowledged its own deficiencies in managing the Covid-19 pandemic, I worry that the FDA’s actions risk sowing further mistrust in medicine and public health. Not because it’s wrong to pull a drug from the market when warranted — that’s absolutely the right thing to do — but because the FDA hasn’t adequately communicated that withdrawing approval is in the public’s best interest.


For the FDA, the coin of the realm is the trust the public holds in the agency — trust that it will safeguard the public’s health while approving the drugs necessary to fight disease safely and effectively. That trust can be bolstered when drugs that are really, really effective are brought to market quickly. One example is the class of chemotherapy drugs known as checkpoint inhibitors, which have extended the lives of people suffering from melanoma, lung cancer, and lymphoma. Another is the rapid approval of Covid-19 vaccines.

Accelerated approval is the FDA’s regulatory mechanism to quickly give a green light to drugs for life-threatening conditions. It was created under the Prescription Drug User Fee Act (PDUFA) of 1992, legislation born from the efforts of HIV/AIDS activists to tear down regulatory hurdles to getting new drugs to people dying of the then-untreatable disease. PDUFA established a system of user fees that pharmaceutical manufacturers paid with any new drug application. In return, the FDA commits to a quicker timetable for drug approval.


To qualify for accelerated approval, a drug must meet three criteria:

  • It must treat a serious medical condition that has an impact on day-to-day functioning, such as HIV/AIDS, cancer, or in the case of Makena, pre-term birth.
  • It must also provide a meaningful advantage over available therapies — no so-called “me too” drugs need apply.
  • It must demonstrate an effect on a surrogate endpoint that is reasonably likely to predict a clinically meaningful benefit such as a reduction in viral load or tumor size or a biomarker for a disease.

But accelerated approval comes with a requirement: that follow-up trials be performed to confirm the results of the studies on which the approval was based.

Since its inception in 1992, the FDA’s accelerated approval mechanism has been used to grant more than 275 marketing approvals for drugs (with some drugs receiving approval for multiple indications).

Accelerated approval can be magical. The drug imatinib, used to treat a subtype of leukemia, transformed survival for people diagnosed with this cancer from an average of about three years to decades. Many of these people were able to live normal lifespans, as if they had never contracted leukemia at all. The FDA ushered imatinib through the accelerated approval process in a record 72 days back in 2001, making it widely available to patients years before they could have received it had it gone through regular approval processes.

But accelerated approval can be problematic when the company that developed the drug fails to conduct the required follow-up studies, or those studies fail to confirm the benefit seen from the trial that led to a drug’s accelerated approval.

Makena received accelerated approval based on results of a trial showing that it reduced the risk of preterm birth by 18%. Unfortunately, a follow-up study conducted in more than 1,700 women, published in 2019, failed to show the same benefit for the drug — thus the need for the hearing.

In the initial trial that led to Avastin’s indication for breast cancer (the drug had already been approved for advanced colon and lung cancers), women receiving Avastin (along with standard chemotherapy) lived without their breast cancers worsening for an average of almost six months longer than women who did not receive Avastin. These early results were promising enough to get the drug approved. But, as with Makena, the follow-up trials fell flat. In those trials, women receiving Avastin didn’t live any longer than women not receiving the drug, and its toxicities were substantial.

When our committee met in 2011, we voted unanimously to withdraw Avastin’s breast cancer indication. It’s never an easy decision to a take a drug away from people with a terminal diagnosis, but we didn’t want to give women false hope in Avastin or expose them to severe side effects. The FDA followed suit a few months after the committee’s vote, and Avastin is longer approved for treating breast cancer.

When the FDA revokes a drug’s approval — as I expect it will do for Makena — it can breed mistrust in the agency for having approved an ineffective, and potentially toxic, drug in the first place. Public reprobation for the decision to remove Avastin was swift, with the FDA accused of everything from “imposing a blanket government abstraction over the individual choices of a patient and her physician,” to rationing access to treatment, and even of imposing a “death sentence” on some women with breast cancer.

Is the FDA pulling a previously approved drug from the market the ultimate demonstration of how its system of checks and balances really works, or how it doesn’t?

I believe it shows that the U.S.’s drug regulatory structure —which is in a constant struggle to quickly get effective drugs to the people who need them while not compromising their safety — functions well.

But for the FDA to not betray the trust Americans hold in it, the agency must do a better job informing the public that drugs approved in an accelerated fashion may not have the robust studies supporting their use as drugs receiving full approval, and that their safety and efficacy may be in question if follow-up studies come up short. Drugs that receive accelerated approval should come with a large asterisk on the drug label, warning patients and prescribers that the approval may be temporary, with additional data on safety and effectiveness yet to come.

The FDA also needs more authority to yank drugs from the market in an expedited fashion when manufacturers fail to conduct the studies to confirm their safety and efficacy in a timely fashion. Legislation requiring that passed in the U.S. House of Representatives earlier this year and awaits action in the Senate.

The FDA should be applauded when it approves safe and effective drugs quickly and improves the lives of people with life-threatening illnesses. It should also be applauded when it removes other drugs to safeguard Americans’ health. But when that happens, the FDA needs to communicate clearly why we’re better off without some drugs, to regain the public’s trust.

Mikkael A. Sekeres is an oncologist, chief of the Division of Hematology and professor of medicine at the University of Miami’s Sylvester Comprehensive Cancer Center, former chair of the FDA’s Oncologic Drugs Advisory Committee, and author of “Drugs and the FDA: Safety, Efficacy, and the Public’s Trust” (MIT Press 2022).

Source: STAT