A dozen physicians and researchers participating in a US Food and Drug Administration panel last week pleaded with the agency to “stop harming women” and remove the so-called black box warning from packages containing hormone treatments for menopause, reports The New York Times.
Dr Marty Makary, the agency’s commissioner – who has been an outspoken supporter of hormone therapy – said too many women avoid treatment because the risks have been overstated, and the panellists, all selected by him, echoed his belief that the benefits of the therapy outweigh any risks.
One after another, the panellists described patients who suffered from severe menopause symptoms – from hot flushes and painful sex to severe mood swings, forgetting names and even suicidal ideation – yet who were scared away from oestrogen-containing products by the labels.
“We are all begging the FDA: please remove the black box warning,” said Dr JoAnn Pinkerton, Professor of Obstetrics and Gynaecology at the University of Virginia Health System and past President of the Menopause Society.
All menopause treatments containing oestrogen carry a black box warning that the medication should not be used to prevent cardiovascular disease or dementia, and that it increases the risk of strokes, blood clots and probable dementia.
The label, which also warns of the possibility of breast cancer, is found on the packaging of transdermal patches, gels, sprays, vaginal inserts and oral medications, regardless of formulation, so long as they contain oestrogen.
But proponents like Makary say there’s evidence that hormone therapy – approved for the treatment of symptoms like hot flushes – may prevent cognitive decline, heart disease and some cancers with long-term use, in addition to conferring benefits that are not in dispute, like reducing osteoporosis-related fractures.
However, supporters say, the treatment must be initiated within 10 years of the onset of menopause.
Makary has dismissed findings of a heightened risk of breast cancer in women who took combined oestrogen and progestin, saying the research caused a “breast cancer scare” that has deterred women from getting a useful treatment.
“When a woman starts oestrogen or oestrogen and progesterone within 10 years of the onset of menopause, there is somewhere between roughly a 25% and 50% reduction in fatal heart attacks and cardiovascular disease,” he said at the opening of the meeting. “That is comparable to or greater than the risk reduction of a statin.”
Yet women were being denied the treatment, he added: “Fifty-million-plus women have not been offered the incredible potential health benefits of hormone therapy.”
The treatment has become the focus of intense debate. Some researchers argue that a landmark trial carried out more than 20 years ago, called the Women’s Health Initiative, might have exaggerated hormone therapy’s harms, dissuading physicians from prescribing it and leaving patients without relief.
Other advocates for women’s health contend there are risks to long-term use that are now being trivialised.
Several such advocates attended the panel meeting, even though there was no opportunity for members of the public to speak or to question panellists.
In the middle of the meeting, Cindy Pearson, who played a leading role in obtaining funding for the WHI decades ago, asked Makary if there would be any public input on the FDA decision regarding the label.
He was non-committal, saying that public comment sessions take time and that he wanted to act quickly.
After the meeting, Pearson criticised the composition of the panel, saying it was unbalanced and one-sided, with no one voicing any concern or hesitation about removing the label.
There was no scientific presentation by FDA scientists, who typically testify at advisory committee meetings on new drugs and who are expert in analysing drug safety data.
The panel included four physicians who are members of Let’s Talk Menopause, an advocacy group supported by Pfizer, Bayer and other pharmaceutical companies that has called for removing the black box warning from local vaginal oestrogen products used to treat dryness and sexual symptoms.
Several panellists run exclusive private practices that don’t accept insurance and charge high fees.
“This panel was set up by Makary to give him public reason to take the next step forward, using a mix of cherry-picked data, old citations and personal anecdotes to defend his conclusion that hormone therapy would be good for almost every woman who goes through menopause,” Pearson said after the meeting.
Asked about the panel’s makeup, Makary said “others were invited”, but offered no more detail.
He would not say what his next steps were going to be, or whether the black box warning label might be removed from all oestrogen products, including oral products, or only from vaginal creams that are applied locally. “
We need to look at all of it,” he said.
Some of his arguments in favour of hormone therapy are based on observational studies, a weaker form of evidence than randomised controlled clinical trials. But he said, “Observational studies can be very powerful if the effect size is dramatic.”
The Women’s Health Initiative, the largest randomised controlled trial on hormone therapy, was created because observational studies had repeatedly and consistently linked hormone therapy to long-term health benefits for women.
Its findings came as a shock to most medical experts.
The branch of the trial studying combined oestrogen and progesterone was halted abruptly in 2002 because of signs of an increase in breast cancer and overall health risks, though the danger to individual women was very small, especially for women in early menopause.
Two years later, the branch studying menopausal women taking oestrogen alone was halted a year early because participants were at increased risk of stroke. (Combined oestrogen and progestin was also linked to increased stroke risk.)
There was no increase in breast cancer with oestrogen alone, and the hormone lowered heart attack risk in women in their 50s, according to Dr JoAnn Manson, a Professor at Harvard Medical School who was a lead investigator of the Women’s Health Initiative, and who attended remotely.
She said a related study suggested oestrogen alone or with progestin might raise the odds of cognitive impairment and dementia when started after 65.
Critics have raised questions about the design of the WHI, saying that some of the risks it documented were of borderline significance, and that women who wanted to reap the benefits of hormone treatment should initiate it soon after the onset of menopause.
New hormone formulations have come on the market since the WHI trials were halted. Some physicians believe these products are safer, but they have not been tested in large randomised controlled clinical trials.
Oral oestrogen and combined oestrogen and progestin were tested in the WHI because those were the most common forms of hormone therapy in the early 1990s, and “those were the formulations that were showing many benefits in the observational studies”, Manson said.
She added that there are “major differences” between hormone pills and a product that delivers low doses vaginally to relieve dryness or prevent urinary tract infections, and that there are differences between taking oestrogen orally and taking it via transdermal patches, gels or sprays.
“The problem is there are no large-scale randomised trials,” she said, referring to the transdermal and vaginal treatments.
Treatment should be individualised, she added. Oral oestrogen alone may lower the risk of breast cancer, for example, but it should be taken only by women who have undergone hysterectomies because it can cause uterine cancer.
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