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Health Affairs' Leslie Erdelack and Jessica Bylander discuss the FDA's efforts to pull the pregnancy drug Makena from the market and the implications for drug policy.
Health Affairs This Week places listeners at the center of health policy’s proverbial water cooler. Join editors from Health Affairs, the leading journal of health policy research, and special guests as they discuss this week’s most pressing health policy news. All in 15 minutes or less.
00;00;37;00 - 00;00;51;18
Leslie Erdelack
Hey everyone, you're listening to Health Affairs This Week, a weekly podcast where we, the editors at Health Affairs, get a chance to dig in to the health policy news and stories that grabbed our attention. I'm Leslie Erdelack.
00;00;52;00 - 00;01;17;03
Jessica Bylander
And I'm Jessica Bylander. Now, before we launch into the episode, we wanted to let our D.C. listeners know about an upcoming in-person networking event for Health Affairs Insiders, which is our membership program that offers access to content beyond the journal. The event is being held on November 17th at Busboys and Poets in Washington and will give attendees the opportunity to network with other health policy professionals.
00;01;17;11 - 00;01;19;22
Jessica Bylander
So we'll put a link in the show notes with more information.
00;01;20;06 - 00;01;23;18
Leslie Erdelack
Yeah, come check it out. I think it should be a great event.
00;01;23;27 - 00;01;24;10
Jessica Bylander
Yeah.
00;01;24;23 - 00;01;53;29
Leslie Erdelack
So on this show today, we are circling back on a topic we've talked about before, which is the accelerated approval program at the FDA that allows for faster approval of drugs to treat serious conditions when no other therapies are available. And, you know, fast tracking certain and, you know, potentially life saving drugs and getting them to patients who needs them seems like a philosophy that, you know, many of us can get behind.
00;01;54;12 - 00;02;23;11
Leslie Erdelack
But approving drugs on an accelerated pathway has produced a lot of controversy, especially recently. And you might remember the Alzheimer's drug that was approved last year over the objections of a panel of FDA advisers who thought its benefits were unproven. And that decision, I think, really sparked this debate around accelerated approval and what it means to rely so much on preliminary evidence on whether these drugs actually work.
00;02;23;27 - 00;02;55;11
Leslie Erdelack
So as part of this process, FDA, of course, can also unilaterally decide to withdraw its approval. And that is looking very likely for one drug currently on the market. So last week, another advisory committee voted to remove a drug called Makena from the market, saying it's not effective at reducing the risk of preterm birth. And Makena's has been on the market, you know, it's been in use for 11 years now and it was initially approved through this accelerated process.
00;02;55;11 - 00;03;09;01
Leslie Erdelack
But FDA has basically said the burden of proof is on the drug maker to show that their product has clinical benefits. And we'll get into that in a minute. But I think just, you know, there have been some really mixed reactions to this decision.
00;03;09;22 - 00;03;36;23
Jessica Bylander
Definitely. And I think to understand those mixed reactions, it helps to know more about the drug. So Makena is a progestin, which is a synthetic hormone that mimics the effects of the hormone progesterone in the body. And so it's currently used to help a pregnancy occur during infertility procedures. And in the case of Makena, it's given to people who've had a preterm birth in the past to try to prevent that from happening again.
00;03;37;10 - 00;04;04;03
Jessica Bylander
So that's a birth that occurs before 37 weeks. And the obvious risks to having a baby before 37 weeks are that the brain and the lungs are still developing in those last weeks of pregnancy and preterm birth and low birth rate contribute to infant deaths, you know, up to 17% of infant deaths, according to the CDC. So right now, there's no other approved treatment for preterm birth.
00;04;04;03 - 00;04;37;20
Jessica Bylander
And an estimated 350,000 people have used Makena in the past decade, according to the company that currently owns the patent to the drug. And that's actually changed over time, kind of as the as it's been sold over the years. So it's also worth noting there's an important disparity element here. Preterm births are most common among black mothers who had a 14.4% preterm birth rate in 2020 compared to a 9.1% preterm birth rate in white mothers that year.
00;04;38;01 - 00;04;57;26
Jessica Bylander
So with that in mind, the company is actually arguing that withdrawing the drug could worsen inequities in maternal and infant health. And some black health groups have come out in support of keeping it on the market to continue testing its efficacy. And that's just extremely complicated, too, as others are kind of chiming in, saying it's almost exploiting those.
00;04;58;20 - 00;05;28;25
Jessica Bylander
The calls for racial equity in order to keep this drug on the market and continue making money from it. Obviously, anything that could prevent preterm birth is a good thing. You know, the companies ad has this tagline, help give your baby more time to develop and who wouldn't be moved by that? But as we'll talk about after the drug's initial accelerated approval, which was conditional on conducting more research, there are very clear doubts about whether the drug actually offers any benefit at all.
00;05;28;25 - 00;05;38;22
Jessica Bylander
And it's you know, it's not a cheap drug and it's not without side effects. So, Leslie, this story has layers. Can you tell us more about Makena's journey through FDA?
00;05;39;18 - 00;06;07;18
Leslie Erdelack
Yeah. So like we've been saying, FDA approved it under the accelerated approval program in February of 2011. And that approval was based on the results of a clinical trial that was conducted between 1999 and 2000 to where women who were receiving the drug had a lower rate of preterm birth compared to the placebo group. And FDA determined that it was reasonably likely that the drug would have a clinical benefit.
00;06;07;18 - 00;06;33;26
Leslie Erdelack
And so that's kind of the standard here. So then there was a post-marketing trial that ran for almost a decade. It was completed in 2018. And this trial was actually the basis for FDA's decision to withdraw approval because it failed to show that Makena reduced the risk of complications of preterm birth. And it also failed to show that the drug had any effect on reducing the proportion of women with preterm births.
00;06;34;12 - 00;07;07;15
Leslie Erdelack
So FDA said that when it approved, Makena under accelerated approval, that it was really taking a risk to, you know, make it available earlier in the hope that these trials would eventually show it was effective. FDA also didn't think that the results would be any different if we were to do more clinical trials, you know, saying 10 to 15 years from now, we may very well be in the same position that we are in today, except that Makena would have then been marketed for more than two decades without demonstrating any clinical benefit.
00;07;07;15 - 00;07;41;01
Leslie Erdelack
So that all came out during the hearing. But it was back in 2020 that FDA announced that it would begin the process for withdrawing Makena from the market. But the drug maker, of course, argued against that decision, which led to that, you know, three day hearing and the vote that took place last week. And so it just it feels like we've been here before just with controversy over an accelerated approval drug, not really achieving much in the way of clinical benefits.
00;07;41;13 - 00;07;52;29
Leslie Erdelack
And, you know, is it is it kind of an inherent risk in the process? What do we know about the safety of drugs approved on this fast track kind of more broadly?
00;07;54;10 - 00;08;19;18
Jessica Bylander
Yeah, as you said, we have been here before and we encourage folks to check out our episodes from January 7th of this year and June 11th of last year, which talks about the Alzheimer's drug Aduhelm. And in that case, we had a drug with uncertain clinical benefits and significant costs approved by accelerated approval. And for that drug, the follow up study to determine whether it should stay on the market is still underway.
00;08;20;14 - 00;08;43;22
Jessica Bylander
So, yeah, what's going on with accelerated approval? Well, the pathway began back in 1992 in response to the HIV AIDS epidemic and the need to get treatments to patients quickly and allows certain drugs to be approved on the basis of what's called surrogate endpoints in clinical trials. So those are kind of like stepping stones, I guess, on the way to a potential clinical benefit.
00;08;43;23 - 00;09;07;04
Jessica Bylander
They might show they show up sooner. They don't take as much time. And so therefore, the clinical trials are faster and less expensive to conduct. But they are supposed to, you know, eventually signal that an actual clinical health benefit is happening. So there's meant to be a safety valve and that drug companies have to conduct that confirmatory study to actually show the health benefit.
00;09;08;03 - 00;09;35;05
Jessica Bylander
Nowadays, accelerated approval is mostly used for cancer treatments, and there have been some successful examples of the program where after the confirmatory study, the accelerated approval was was just converted to a full approval. So we have Merck's Keytruda, Novartis' Gleevec, and Pfizer's Ibrance cancer drugs. And those all received full FDA approvals after their trials showed survival benefits.
00;09;35;13 - 00;10;12;02
Jessica Bylander
But things don't always go so smoothly. Those confirmatory trials are often delayed, and they may not have good outcomes. As in the case of Makena last April, FDA called for a review of six, quote unquote, dangling accelerated approvals for cancer drugs, which is when the confirmatory trial actually fails. But the drug remains on the market. And also last year, with the approval of Aduhelm, the HHS Office of Inspector General was called on to review FDA's accelerated approval process, kind of to find out what's going on there.
00;10;12;14 - 00;10;39;19
Jessica Bylander
And the first of their findings, which was focused on those confirmatory trials, was released last month. So in a nutshell, OIG found that 278 drug applications have been approved via accelerated approval from 1992 through the end of 2021. And of these, 104 had incomplete confirmatory trials. And maybe a third of the trials, I think, were past the date when they said they would be completed.
00;10;40;08 - 00;11;03;04
Jessica Bylander
They also found that Medicare and Medicaid spend more than or spent more than 18 billion from 2018 to 2021 on 18 drugs who had kind of past the due date for their confirmatory trials to be completed. So yeah, the evidence seems to be really stacking up against accelerated approval and the calls to reform the program are heating up.
00;11;03;13 - 00;11;23;16
Leslie Erdelack
Yeah, I feel like. So the whole time we've been talking, I just really feel like it's hard to look past some of the trade here. So you've got in exchange for quick approval, drug makers have to do these follow up studies and then it can take years to really figure out the true risks and the clinical benefits that come with these therapies.
00;11;23;16 - 00;11;49;11
Leslie Erdelack
And so you have the doctors, you have patients, you have families who are just caught, it seems like, in limbo sometimes hoping for a favorable outcome. And so, you know, there's a lot of emotional intensity that gets factored in. And, you know, that's another reason why I think in a more ideal scenario, you would want these drug sponsors to finish these follow up trials with due diligence.
00;11;50;03 - 00;12;17;29
Leslie Erdelack
So sort of in that vein. FDA has asked Congress for more authority to make sure the drug makers create appropriate post-approval studies and finish them in a timely manner. And there was legislation proposed by House and Senate committees as part of FDA's prescription drug user fee reauthorization bill that would have streamline FDA's ability to withdrawal approval in instances where it's needed.
00;12;18;06 - 00;12;32;22
Leslie Erdelack
But those things didn't end up making it into the final reauthorization bill. And just more recently, the FDA commissioner is publicly calling for reforms for the program as soon as possible.
00;12;33;04 - 00;12;59;26
Jessica Bylander
Yeah, like you said, I do think it just creates this impossible situation for patients and physicians. And as we think ahead to what might happen with Aduhelm, the Makena story just feels like a cautionary tale about how hard it is to withdraw a drug from the market after it's entered common use. And patients and physicians are accustomed to having it as an option and and maybe convinced that it has a benefit for them.
00;12;59;26 - 00;13;24;16
Jessica Bylander
And it's kind of hard to argue against that. So as you noted last year, people are really hoping that the Alzheimer's confirmatory trial actually does show promising clinical results. Otherwise, we'll probably end up back in this kind of a complicated situation. And yeah, what better place to wrap up than another complicated situation? Right, Leslie?
00;13;25;26 - 00;13;34;21
Leslie Erdelack
Yeah as if there were any other way but a good discussion today I think all around.
00;13;35;03 - 00;14;14;25
Jessica Bylander
Yeah. Well, thanks for listening to another episode of Health Affairs This Week. If you like this episode, send us some love by leaving a review, recommending the podcast to a friend and subscribing wherever you listen to podcasts. Thanks, Leslie.