The FDA is removing the ‘black box’ warnings on oestrogen MHT products but the way in which the decision was made is controversial. What precedent does it set, and should Australia follow suit?

The decision to remove the ‘black box’ warning on oestrogen menopausal therapy (MHT) products has been hailed by many as long overdue and necessary, but the way in which it’s been done and the claims that were made about the benefits of MHT have raised collective eyebrows around the globe.

Usually, a multi-disciplinary panel of experts would spend months reviewing the current literature and the manufacturer’s recommendations. They would then come to agreement on what warnings were appropriate to place on the products, and when required, that process would be repeated to ensure the warnings were in line with the risks and benefits.

But in this case, no such process occurred.

Instead, the Trump appointed head of the FDA, Dr Marty Makary, opted to bring together a group of 12 researchers, doctors and menopause experts, many of whom had significant social media followings in the menopause space. They were each given five minutes in a televised session to say why they thought the black box warnings on both topical oestrogen and systemic oestrogen should be changed.

The U.S. Department of Health and Human Services’ press release claimed the decision to remove the black box warnings was a ‘historic action to restore gold-standard science to women’s health’ that would finally end ‘more than two decades of fear and misinformation surrounding hormone replacement therapy (HRT).’

Few would disagree that the labels that were placed on all oestrogen MHT products that cite out-of-date claims from the controversial 2002 Women’s Health Initiative (WHI) study, needed to go. When the study came out women collectively flushed their MHT down the nearest loo for fear of developing breast cancer or cardiovascular disease and prescribing rates plummet globally.

A subsequent reanalysis of the data showed that results from the older women in the trial (average age 63) had been applied to all age groups and that the reporting of the risk was poorly communicated. While women were told it increased their risk of breast cancer by 26%, the relative risk was actually very small, and did not apply at all to vaginal products. Nor do they, it’s argued, apply to the newer forms of transdermal MHT the results only related to conjugated equine oestrogen and medroxyprogesterone acetate.

A question of protocol

There is little argument that change is needed. Many patient groups and clinicians in Australia, the UK and the US have called for a review of the warnings for around a decade, claiming that even when patients are prescribed vaginal oestrogen, they are too scared to use it after reading the warnings. As a result, they are missing out on treatments they need. But was this the best way to go about it?

In an interview with Heathed, Professor Rod Baber, Clinical Professor of Obstetrics and Gynaecology at The University of Sydney and Head of the Menopause and Menstrual disorders clinic at Royal North Shore Hospital, said the process was ‘unusual’ and the choice of experts on the panel was “controversial,” with the interviewer, Terri Foran likening it to “academic speed dating.”

Vocal menopause experts in the US like obstetrician and gynaecologist Dr Jen Gunter, who has likened it to “crowd sourcing pressure,” went further, arguing this approach set a dangerous precedent.

And she’s not alone in that thought. Both Gunter and Professor Lauren Streicher, an obstetrician and gynaecologist based in Chicago, fear that the failure to conduct a proper process means the FDA can now make sweeping changes to further restrict women’s reproductive rights. The FDA has said it will review mifespristone, the so-called ‘abortion pill’ and they are concerned that, like abortion, it too will become harder to access.

A darker agenda?

“What’s really going on?” Professor Streicher said in her podcast on the topic. “Well, this administration has been extremely problematic when it comes to health in general, and specifically women’s health. They’ve taken away reproductive rights, jeopardising the health and lives of countless women. They’ve defunded medical research, including cancer research, and there are many of us that believe that this FDA has another agenda to push this oestrogen label change.”

She said the way this process has been conducted could also be applied to the review of mifepristone, which is the only option for women in states where abortion is restricted to safely terminate an early pregnancy.

“My concern, and the concern of others, is that a review by their hand-picked, anti-choice experts for something that does not need to be reviewed could support their agenda to restrict access to mifepristone so that it can no longer be prescribed virtually or mailed to patients. Removing the oestrogen warning label is an easy win to distract from all the other assaults on health. Give women their oestrogen so they can have better sex, and their bladders will behave and they’ll be happy.”

Dr Gunter concurs. In her Substack video after the November press conference that announced that the label would be changed, she said: “I think it’s part of this whole bigger sort of ‘Trad wife’, ‘women are too hormonal’ message, right? … If your ultimate goal is to take away rights from women, … then it’s very useful to say that women are too hormonal and that they must be on medication, especially, you know, medication that, to some people, is associated with femininity, right? And it sort of reduces your worth to either being a breeder or looking like a breeder. That’s what it says to me.”

But this wasn’t her only beef. The claims that were made about MHT reducing heart attacks by 50% and Alzheimer’s by 35% she said, were simply unfounded. “We have no evidence for that,” she stated.

Mis-stating the risk and benefits

Professor Baber agrees, arguing that Makary was using the same approach as the poorly reported WHI used – presenting relative risk data rather than absolute risk.

“He’s dramatising the risk. And if you go through the WHI’s commentary on the FDA decision, they did observe that none of these changes were actually statistically significant, that any change in cardiovascular or coronary heart disease was associated with oestrogen alone, and only while the hormone was being taken. And that WHI was not a long-term study. They’ve certainly got long-term follow-up. Data only reports on short-term use of hormone therapy for up to about seven and a half years. So, these have just been dragged out of the air to dramatise the justification for change.” These do not justify a change to the management of cardiovascular disease, he said.

And the same applies to claims made by others quoted in the press release, that taking MHT could extend a women’s healthy lifespan by 10 years. “There’s just no evidence at all to support that statement,” Professor Baber said.

Professor Streicher remembers that when the WHI came out, women were angry that they’d been offered a drug that could give them cancer or heart disease, and now she says this televised “PR event” where doctors were invited and asked to wear their white coats to add gravitas, has seen a similar reaction. Women are now angry that they they’ve been denied this potentially life-saving treatment for the past 20 years or so, and that social media has been flooded with women asking “questions about starting hormone therapy in their 60s and 70s, and whether that would save them. What’s the scientific truth? Well, the scientific truth is, it’s individual. Many women benefit from taking hormone therapy, it’s usually safe to do so, but it’s not true that every woman needs to take oestrogen to live a long, healthy life,” she said, adding “did I mention there was no scientific panel behind this decision?”

Australian petition

A petition has been launched here calling on “the Australian Government and the TGA to follow the FDA’s lead and remove or revise the boxed warning on body-identical menopause hormone therapy products so that information reflects the best available evidence.”

So, should Australia follow suit? Only if it’s done properly, Professor Baber argues.

“I think that the FDA and indeed the TGA in Australia, if they do decide to make changes to the black box warnings, should commission a scientific panel which is appropriately staffed. And the International Menopause Society has already made a statement to that effect, saying that if you do this, for goodness sake, get people who know what they’re talking about. … The whole thing desperately needs to be reviewed, but done so properly. We need a calm assessment of the data. And then we do need indeed to share all of that knowledge with our patients. It is completely wrong to selectively pick bits of information to justify your position.”

“We should always remember that the loudest voice is not necessarily the wisest voice,” he adds.

Ultimately, he’d like to see an end to the current divisiveness.

“If I had a magic wand, I’d try to use it to convince the zealots and the sceptics that menopausal hormone therapy is a highly effective treatment for the alleviation of menopausal vasomotor symptoms. And that when we use it appropriately, it’s also associated with very small risks. And no one disputes that.”