The big news in healthcare this week was the end of the six-week government shutdown with Democrats winning none of their demands. Millions of people with Obamacare plans face an immediate, huge increase in their premiums in 2026. Millions more will drop coverage. Every state in the country faces huge reductions in federal support for their Medicaid programs, all because Republicans refuse to reverse the cuts in their one big ugly bill passed last July.
But that’s not what we’re going to talk about on the GoozNews podcast today.
The media’s focus on that larger story overshadowed what is certain to be one of the more consequential decisions by the Food and Drug Administration in recent years, one that could affect millions of women now and for years into the future. I’m talking about the FDA’s decision to remove the black box warning on hormone replacement therapy for menopausal and postmenopausal women.
There’s a lot to unpack in that decision. The science the FDA used to make it; the process it used to make it; the wild claims being made about the benefits of hormone replacement therapies’ use by the new leadership at FDA; and who will be harmed as the FDA encourages wider use of a product whose safety has been hotly debated for more than two decades.
To discuss these issues, I invited onto the podcast someone who has been actively engaged in the debate over hormone replacement therapy or HRT as it’s commonly known. Diana Zuckerman is president of the National Center for Health Research. She has a PhD from Ohio State and did a post-doctoral fellowship in epidemiology and public health at Yale Medical School. Diana served in the Clinton White House working for First Lady Hillary Clinton, and in the Office of Science and Technology Policy. And in 1999, she founded NCHR, seeing the need in Washington for a nonprofit non-partisan think tank focused exclusively on improving the health of adults and children.
I headlined this story with her final words. If you listen, I think you’ll understand why the FDA under Dr. Marty Makary is losing credibility with the general public.
Here’s the transcript (lightly edited in spots for clarity):
GOOZNEWS:
Diana, thanks so much for being with us today.
DIANA ZUCKERMAN:
I’m glad to be here. Thanks for inviting me.
GOOZNEWS:
So, to get us started, give our listeners some history about the use of hormones to treat the symptoms of menopause. And when and why its use became the subject of so much controversy.
DIANA ZUCKERMAN:
Thirty years ago, it wasn’t a controversy. Thirty years ago, women were being told that hormone replacement therapy, as it was then called, would help women be young again. It was virtually described as a fountain of youth. You wouldn’t get heart disease. Your brain would keep functioning as a younger person. You would be sexy and beautiful. It really was a big sell, and it was believed, and women were being told, start taking hormone therapy as soon as you have any signs of menopause, maybe even just before you have any signs of menopause, and then take these hormones for the rest of your life.
So, it was a big story for women and it was considered non-controversial. This was the data. This is what we know. And, so, what happened was a woman (Dr. Bernadine Healy, from 1991-93) became head of the NIH, the National Institutes of Health. She thought it was time to do research that actually looked at hormone replacement therapy. Was it as good as people were being told?
And she got tremendous pushback. She was told by the medical establishment: This is a waste of money. She was told this by Congress as well. This is a terrible waste of money. We know how great these hormones are. There’s no need to study it. But she thought differently. And she said, we’re going to do a large, randomized, double-blind clinical trial.
Women would not know whether they got hormones or a placebo. We’re going to follow them for several years. And we’re going to see what happens to them. And she stuck to her ground, even though she really was pressured to change her mind. And it was a lot of money for a study. And they started the study and it wasn’t talked about very much until suddenly the decision was made to stop the study early.
And they decided that because the results were completely the opposite of what was expected. And not only the opposite of what was expected, but there were some pretty serious danger signs. Women who were getting the hormones were almost twice as likely to develop breast cancer, for example. So they stopped the study.
I was there when they had the announcement at the NIH. I still remember it. There was just tremendous interest and some sense of disbelief that all these women had been taking these hormones for all these years and that perhaps it was causing breast cancer, heart disease, instead of preventing it.
One of the most interesting things that I still remember about that announcement, which was, up in a large venue, everybody was there and they were asking questions as well as listening. And one of the stories was how some of the women in the studies were very upset because they reached out and said: I’ve been in this study, I’ve been doing so great through menopause, it hasn’t been such a problem for me. Please don’t take these hormones away from me. And in some cases, those women were in the placebo group. It was a really important lesson about how when people think they’re getting something that’s going to help them, they really do feel better.
Now here we are more than 20 years later, and the controversy never really stopped since that day. There have always been researchers defending hormone therapy. The same people who thought it was great before, many of them were saying, there’s something wrong with this study. No, look at it this way. They did what we call slicing and dicing. You take research and look at everything you can look at to decide, maybe it works better if you’re younger. Or maybe it works better if you are taking it at a different time of day. Or, whatever. Just trying to figure out a way to salvage their reputations. And this belief that hormone replacement therapy really was the answer that was going to help women prevent disease, feel younger and at the same time, of course, not have those side effects.
Most menopausal women know what they are. Hot flashes. Sometimes it’s trouble concentrating. It’s trouble sleeping, waking up in the middle of the night, sweating. These are unpleasant side effects. I’ve been through them and I didn’t like them. They’re worse for some women than others. They’re very manageable for some women, not so manageable for others. There are a lot of things that women learn to do. For example, you stop drinking hot caffeinated beverages because that makes those hot flashes worse. You stop wearing heavy wool sweaters because you could break out in a sweat anytime. You wear layers of clothing. So, if you’re wearing a jacket and doors and you can take it off when you’re sleeping at night, you have light blankets. In addition to the heavy blankets, you use the heavy blankets when you need them. Go to the light blankets when you’re sweating. So there are a lot of things that women have been taught to do that actually work quite well.
GOOZNEWS:
The study you were referring to was the Women’s Health Initiative. It came out in 2002 and less than a year later the FDA put a black box warning on the label, which is the insert that people get with drugs when they received them at the pharmacy that warn them of a number of risks, not just the increased risk of breast cancer.
But also cardiovascular risk, stroke, pulmonary embolism possible dementia was even raised in all of that. I have two questions about all of that. There was controversy from the start by stopping the study and questions raised about the statistical significance of some of those findings. Tell us a little bit about that controversy and your own view on how accurate the criticisms were about what we call statistical significance that were seen in the trial, or not seen as the case may be.
DIANA ZUCKERMAN:
Sure. Let’s start with the breast cancer one. I think that’s the most controversial.
First of all, I would say, nobody expected an increase in breast cancer after just a few years. That seemed surprising. That was very surprising. We think of cancer as taking several years to develop. Why was it that in just a short period of time, women who were taking the hormones were almost twice as likely to develop breast cancer?
And at the same time that it seemed surprising, it was very scary. Most studies, particularly NIH funded studies have what they call a variety of safeguards. There are people who look at the data before it’s released, before anybody else knows. It’s a committee that does this, and they look at data maybe after a year or after two years, depending on the study. They’re responsible for deciding if the study needs to stop. You stop the study if there’s something bad happening, or if there’s something really good happening. So if you’re using an experimental drug and it’s causing problems, potentially cancer, it’s their job to say, we’re going to stop this study early.
And at the same time, if the results look so good, that the experimental treatment is fantastic, they might also stop the study. So that’s their job and that’s what they did. They looked at it and they said, almost twice as likely to get breast cancer, we should stop the study. And I agreed with them. It was not statistically significant at the time because it was just a few years.
Not that many women had already developed breast cancer. It was twice as many, but that doesn’t mean it was. A lot of women (and) I think most people would agree it would be unethical to intentionally expose women to anything that was possibly going to double their chances of breast cancer. So it wasn’t statistically significant, which means it might have happened by chance.
But when you have a large effect like that, almost twice as high, ethically, I’m not sure that there’s anything else you can do.
GOOZNEWS:
There’s been a follow up on the Women’s Health Initiative cohort of women. There were thousands of women in this trial who were followed for years by the same researchers who conducted the study, what have they found in recent years as they followed up?
DIANA ZUCKERMAN:
It’s complicated and I’ll do the best I can to summarize it. The original study did look at women who are quite a few years past menopause for the most part. I believe the average was 60, which is older.
And it made sense at the time to do it because women were being told, take these drugs for the rest of your life. On the other hand, most women are going to take hormone therapy at a younger age. They’re going to take it when they start having hot flashes, not when they’re almost done having hot flashes or are done having hot flashes.
So that was one of the things that other studies have looked at. Looking at the age of the women, did it make a difference? And it does make a difference. So some of the risks that seemed higher for women who were older were not risks for women who started younger, who started at the time or within a few years of starting menopause, women who were 50 instead of 60 or even 65.
So the results have been complicated. And at the time there was a lot of money involved. This is less true now in the sense of these drugs are generic and they’re not so expensive. But at the time there were companies like Wyeth and some other companies that were making enormous amounts of money selling these products.
They were sponsoring events for women’s health organizations. They would buy tables costing thousands of dollars that were filled with members of Congress. It was a major kind of promotional campaign for the company and for the products. So there was a lot of incentive for certain researchers who were being paid by the company or other people with a vested interest to to find a way to say, if you look at these particular women, it’s not harmful. And not only that, but if you look at these other particular women, it might even be beneficial.
I do want to say there’s a couple of things that, despite all the controversy, people agree. They agree that estrogen alone, which is one of the very popular types of the hormone therapy, increases the chances of a woman developing endometrial cancer. That’s a type of uterine cancer. And so women are told, if you still have a uterus, which most women do at that age, then you should not take that particular kind of hormone because everyone agrees it does increase the chances of developing endometrial cancer.
GOOZNEWS:
And that’s the one thing that remains on the label. Yes. For the drug, even after this week’s decision.
DIANA ZUCKERMAN:
That’s right. And I would have to say at the time of the announcement, that was not clear because Commissioner Makary was saying, we’re getting rid of the black box warning for over, I don’t know, two dozen products.
And he didn’t specify very clearly which ones. On the positive side of hormone therapy, it is also agreed by everyone that women taking it are less likely to develop osteoporosis. That means they’re less likely to have a bone fracture. Although everyone agrees that is true, is only true while they’re taking the hormones.
So, if they take the hormones for a short period of time, they’re protected during that time. But if they stop taking it, they’re no longer protected. And since most women in their fifties are not having hip fractures, it’s not a big benefit unless they do take it for the rest of their lives.
So, that’s two examples of things that everybody agrees on. Everything else is different, but I know for myself, what really, really bothered me about the commissioner’s announcement (is) the fact that he made it on morning television, his initial announcement, rather than in a scientific venue with scientists talking about it.
Some of the claims he made such as reducing your chances of dementia that was based on one study of a very small number of women with cognitive impairment. And it was actually the follow up of a study on some completely different drug and they just happened to look at who are the women who were happened to be taking hormone therapy and who are the women who happen to develop cognitive impairment.
It’s the kind of study that makes you want to do more research to see if it’s true. But it’s absolutely ridiculous, I’d have to say, a ridiculous study to use as the basis of an FDA announcement about the benefits of hormone therapy. And there are other studies that still show possible cognitive impairment and certainly not cognitive benefit.
GOOZNEWS:
Yes. He made a lot of claims in his announcement. I’m glad you raised that not just reducing the risk of Alzheimer’s disease by 35%, the risk of cardiovascular disease by 50%. And the quality of the studies, if you dig into it, is as you just described. I did this when I reviewed Marty Makary’s book, the commissioner of the FDA, almost a year ago now. And he really seems to cherry pick the literature. And that brings me to a set of questions that I really want to go over because I think it has implications for the future of the FDA and the process they used to arrive at this decision.
They held a meeting back in July. Tell us a little bit about that meeting. I suspect you were there. I was not because I’m here in Chicago but tell us what went on there and the quality of the evidence that they presented to this advisory committee.
DIANA ZUCKERMAN:
I was there, although it wasn’t necessarily automatically going to be true because you had to immediately say you wanted to go. Otherwise you were shut out of it.
One of the things that’s true for most FDA advisory committees is that they’re held in what’s actually called the Great Room at FDA. It’s very large. It holds hundreds of people. It’s one of those big rooms that you can break up into smaller rooms, but it can be really large.
And that’s the process usually. If FDA has a controversial question or decision to make, either it’s a new drug or device that the agency is trying to decide whether to approve or not, or it’s something already on the market that might have risks that people didn’t know about, they have what’s called a public FDA Advisory Committee meeting. It includes people who are experts on that type of disease or that type of treatment. It also may include other people like toxicologists or epidemiologists or other people who are experts in how to look at the data or how to look at certain things like adverse events such as liver damage from a cancer drug, for example.
And so the panel usually has about 12 people, and it’s usually an all-day meeting. Sometimes it’s two days where first, the companies or companies whose products are under review, have a chance to talk for several hours about how they think. The evidence is clear that their product is very safe and very effective.
Then the FDA talks usually for about an hour or so about their interpretation of the data and how they do agree or don’t agree. And if they’re going to have a meeting, it usually is because there’s some controversy, something that the agency, or at least some scientists or statisticians think isn’t quite right about the data.
And then the panel asks questions and then what’s really important for this discussion is that there is then an hour or sometimes two hours, I’ve even seen five hours, of what’s called open public hearing. And the open public hearing is an opportunity for anybody, you or me or anyone, to sign up in advance and say, I wanna speak at this meeting and tell you what I think.
And usually those speakers are only given three minutes to talk each, maybe it’s four minutes, maybe it’s five minutes. I have a meeting coming up next week. I get eight minutes. I’m very happy about eight minutes. But it’s a short period of time and most of the people talking now are patients who have been recruited by the company to say how great this product is.
In the old days, that wasn’t true. In the old days, most of the people who came were scientists or physicians or nonprofit leaders. I’ve been doing this for decades. I’ve done hundreds of these public comments. And I can tell you I’m one of the only ones who actually looks at the data and talks about the data.
Most people talk about the disease. This is a terrible disease. We need treatments. We need hope, that kind of thing. And one of the reasons why it’s so lopsided in terms of who’s speaking is because the data that’s going to be discussed is released publicly 48 hours in advance. So, two days before the meeting at eight o’clock in the morning or nine o’clock in the morning, the FDA puts on their website, their summary of the data and the company’s summary of the data, and those summaries can be 40 pages long or they can be 400 pages long, and they’re usually over a hundred pages each. So it’s a lot of information.
GOOZNEWS:
You’ve been describing the process as it existed. What happened in July when they took up hormone replacement therapy?
DIANA ZUCKERMAN:
So this was completely different. And this is something that the FDA this year has started doing, they have what they call expert panels. These are panels, maybe of six people, maybe of 12 people. Could be the same number of people, but they’re handpicked by the commissioner and his staff. And so far at these meetings, and the hormone meeting was typical, they all agree. So instead of having experts in the field with a diversity of opinions, some of whom were committee members for years, and not specifically chosen for that particular meeting, although some are chosen for a particular meeting. Instead of that, you had all these people who basically had one point of view and that was: Get rid of the black box warning.
The only thing that varied in that group was some people were focusing on data. Some people were talking about their patients who, desperately needed hormone therapy because of their hot flashes. And some people were talking about a black box warning only for what’s called topical hormones. Those are things like vaginal creams, because one of the symptoms of menopause is having the vagina gets very dry. That makes sex painful. So instead of taking the pills, which also help with that, it’s possible to use a cream or an ointment, which helps with that. So, some women were really focused on that.
I thought that was a reasonable focus because the data on topical hormones has never shown serious problems. It’s short-term data. Women are studied for a few months of using the product so it’s a little unclear what the long-term risks are. But at least in the short term, at least up to a year or so, it doesn’t seem to cause any health problems.
Therefore, having a black box that says all hormone products are bad, it’s outdated. I think it is outdated. But this meeting, that was the only diversity. Some women were focused on that, and other women were just get rid of all the black boxes. Women deserve these products.
And Commissioner Makary was there. He hosted the meeting and he said a lot of the same things he said in his book about basically the miracle of hormone therapy and how great it was. He told the story of his mother, which he has told several times about how his mother had several broken bones that wouldn’t have happened if only she had been taking hormone therapy, but she was afraid to take hormone therapy. He was a showman. He’s very good at this. He’s very good at being very persuasive. It is not like any other FDA commissioner.
GOOZNEWS:
It should be pointed out that there are other drugs for osteoporosis. You don’t have to take hormone therapy in order to get a treatment for that particular condition. So, I think what I’m hearing you say is that this committee had had a predetermined answer, and this is very far afield from where the FDA has been over the years.
And the staff was cut out of the picture entirely, if I’m not mistaken. Is that correct?
DIANA ZUCKERMAN:
That’s what we’ve heard. We don’t know. The other part of the meeting that was very different was that instead of being held in the great room, it was held in a very small room.
So when people tried to sign up to attend in person, it was available remotely as well. Most people that I knew couldn’t get in. They were told the room was was filled. And I happened to be there that day for a different meeting prior to the meeting on hormones. And so I was there for a different meeting, which was held in a very large room that was almost empty.
Nobody was in it. It was part of that great room, and the very small part that was used for the hormone therapy meeting was very small, and it seemed to be filled with the patients of the people who were on the panel, who were mostly physicians talking about their patients’ needs. It felt like, not only was the panel selected to have a certain point of view, even the audience was selected to have that point of view. And oh, we couldn’t even ask a question. We could not ask any questions. We could not make any comments. It was a little over an hour instead of a whole day of debating different issues, asking different questions. The panel members or Commissioner Makary could ask questions of each other. Need, I say softball questions, but there was no public input at all. None.
GOOZNEWS:
So, we only have a few more minutes left. And in this time, when the original black box warning was put on more than two decades ago, there was a tremendous decline in the use of HRT for menopause and menopausal symptoms. Has that recovered in recent years as more topical medicines, as different dosages, there’s been reduced dosages. Has there been a return? If there has been, it would suggest that maybe the removal of the black box warning won’t have a major health impact. But if there hasn’t been a return, maybe there will.
What do you see going forward in the use of these products now that they’ve decided to pull the black box warning?
DIANA ZUCKERMAN:
Keeping in mind that all women were told you should get on. They weren’t told you might want to. They were told you should get on this prior to this study. So yes, it was reduced by about 80% or something that, you know a huge drop.
But then, as I mentioned, there was more and more pushback with researchers, many funded by the company that made it, talking about, “No. That study was bad.” So, yes I’m sure it has gone up since then. I don’t know how much. One of the things that FDA said in their warning was, even though there were all these warnings with a black box around them, which is the one thing that people read on a label. Let me say, that’s why it’s so important. But women were still prescribed hormone therapy, but because they were no longer being prescribed for 20 years of it, they were being prescribed, they were told, take the lowest dosage possible for the shortest period of time.
So most women were taking it for, I’d say, a couple of years instead of 20 years. And so it’s a little hard to know if women going to start taking it for long term because this is what they’re told. On the other hand, obviously the credibility of the FDA and of HHS is not what it used to be. I think that some women are going to say, RFK Junior just said it’s a great product, but then he just said that vaccines are bad, so should I believe him? So I think it’s very unclear what impact it will have. I’m sure it will increase the number of women getting hormone therapy. That was the goal. That is going to be achieved. The only question is how much and we don’t know. And part of the question has to do with whether FDA saying something or HHS saying something is going to convince everyone. Obviously, it’s going to convince some people.
GOOZNEWS:
And, finally, let’s talk about the FDA, you just mentioned it and the trust that the public is going to have in the FDA.
Do you think that when you have Dr. Makary making these claims without even offering scientific evidence or without the FDA scientists being involved, do you think that this is going to impact the credibility that the FDA has with the general public? Or is this just too deep in the weeds for that to happen?
DIANA ZUCKERMAN:
It’s too deep in the weeds for a lot of people. I think there will be researchers and nonprofit leaders, and people like myself, we’re going to be saying, “did you know that one of the studies that Commissioner Makary quoted in his book as evidence on cognitive impairment was actually a study of rodents, not of humans?” We’re going to be talking about that and some people are going to be listening. Some people are not going to be listening. Did you know this study was based on 35 women? These are the kinds of issues some people will understand and say, wow, that is really bad data. But other people will never read it. Or even if they did, they’d say, “35, that’s a pretty good number.” We don’t know. But that’s the issue. Like you, I had read Dr. Makary’s book, Blind Spots. I had read the chapter on hormone therapy. Our center, the National Center for Health Research, had looked at all the data he was quoting, and we were amazed at how bad it was. How many of the studies were 20 years old. Newer studies were showing something different.
So, we don’t know what the impact will be. But the credibility of the FDA, which is the big main issue here, has to be harmed by this. People will say, I just don’t know if I can trust the FDA now.
GOOZNEWS:
We’ve been speaking today with Diana Zuckerman, the President of the National Center for Health Research. Diana, thanks for being with us.
DIANA ZUCKERMAN:
Thanks for having me on.
GOOZNEWS:
This has been a GoozNews podcast.
