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Menopause and Hormones

Prevention

National Center of Health Research

Lower hormone levels in menopause may lead to hot flashes, trouble sleeping, vaginal dryness, and fragile bones.

What is Hormone Therapy for Menopause?

Like all medicines, hormone therapy has advantages and disadvantages. The evidence about risks and benefits is complicated, and some health professionals are more knowledgeable than others, so it’s important to read articles like this one before you talk to your doctor, nurse, or pharmacist about hormones.

What are the Symptoms of Menopause?

  • Thinning of your bones, Bones become more fragile, which may lead to loss of height, and bones are more likely to break (osteoporosis)

What are the Benefits of Using Hormones for Menopause?

  • Hormone therapy is the most effective FDA-approved medicine for the relief of hot flashes, night sweats, or vaginal dryness.
  • While you are taking hormones, they may reduce your chances of your bones becoming fragile and more likely to break (osteoporosis). However, when you stop taking the hormones, your bones will become more fragile, so it is important to improve your bone health through diet (calcium) and exercise.

What are the Risks of Using Hormones for Menopause?

The risks of oral hormones (pills) for menopause tend to be greater for older women (over 60) than for women in their 50s, but regardless of age, on average, long-term hormone use tends to cause harm that outweighs the benefits. The more you know, the more likely you are to make the decision that is best for you. For example, combined hormone therapy has been found to increase the chances of dementia, while estrogen alone increases the chances of developing ovarian cancer and decreases the chances of developing breast cancer. For a woman with a uterus, taking estrogen alone increases her chances of developing endometrial cancer (cancer of the uterine lining), while adding progestin to estrogen lowers the risk of endometrial cancer.

As you can see, the advantages and disadvantages vary depending on which hormones, your age, and your medical history.

Research on combined estrogen and progestin shows it probably can increase the chances of cognitive impairment (early Alzheimer’s or dementia) in women older than 65.

Will Hormone Therapy Protect the Heart and Prevent Strokes?

The evidence is mixed on heart disease, but hormones seem to increase the risk of strokes.

 

All articles are reviewed and approved by Dr. Diana Zuckerman and other senior staff.

The National Center for Health Research is a nonprofit, nonpartisan research, education, and advocacy organization that analyzes and explains the latest medical research and speaks out on policies and programs. We do not accept funding from pharmaceutical companies or medical device manufacturers. Find out how you can support us here. 

The FDA Commissioner Is Missing the Point of Advisory Committees

News Stories & Editorials, We're In the News

Makary’s hand-picked panels lack diversity of opinion, robust evidence reviews, and credibility

by Diana Zuckerman, PhD, November 22, 2025

Zuckerman is the founding president of a nonprofit think tank, and a former Congressional Committee staffer who investigated FDA policies.

The recent controversies about the safety of antidepressants during pregnancy and hormone therapy for menopause were heightened by how decisions are being made. Earlier this month, HHS officials announced that boxed warnings would be removed from hormone therapy drugs to treat symptoms of menopause, several months after a group of 12 experts handpicked by FDA Commissioner Marty Makary, MD, MPH, recommended removal of the warnings.

Makary asserted that traditional FDA advisory committees — which have historically been convened before making such a change — are outdated because they are “bureaucratic, long, often conflicted, and very expensive.” He said he plans to instead rely more on his expert panels, which he described as more “spontaneous” but still “robust.”

There are many differences between advisory committees and the “expert panels” held this year. As someone who has participated in hundreds of FDA advisory committee meetings and watched several of these expert panels, I believe Makary is missing the point and undermining the credibility of FDA decisions.

What Is the Purpose of Advisory Committees?

FDA advisory committee meetings are scheduled for drugs, devices, or tobacco products when there is conflicting evidence or a contentious difference of opinion within the agency or between the agency’s point of view and other interested parties (such as the company that makes the product).

Typically, the meeting focuses on whether a new drug or device merits FDA approval, whether there is persuasive evidence that an approved product is less safe or effective than FDA previously concluded, or if a type of product may require more/less rigorous regulatory standards than currently required.

Most meetings are around 8 hours long (although this varies): approximately 2 hours for the company to provide evidence on safety and efficacy; 1-2 hours for FDA scientists to express their views of the evidence; 1 hour for an “open public hearing” for patients, family members, or health professionals or organizations to express their views; and 3 hours of advisory committee questions, discussion, and voting. A full meeting transcript is made publicly available afterwards and typically the meetings are all livestreamed now as well.

The members typically include about a dozen medical experts (mostly clinicians) who do not work for a federal agency; at least one patient or consumer representative; and one industry representative (non-voting). Many serve on the committee for several years after being nominated and selected based on their medical specialty; at each meeting, a few additional experts are added because of their relevant expertise. FDA staff are not on the committee, but NIH or other agencies may have one or two non-voting members with relevant expertise.

Weeks before the meeting, advisory committee members are provided with the company’s description of their evidence (often 100+ pages long) and the FDA’s detailed critique of that evidence. These documents, the agenda, names and affiliations of committee members, and information about possible conflicts of interest are made publicly available on FDA.gov 48 hours in advance and stay online for years afterwards.

How Are Expert Panels Different?

Compare that to a 2-hour expert panel meeting, comprised of approximately 8 to 12 experts selected by the FDA, each speaking for a few minutes and answering softball questions asked by the FDA commissioner or other official. The list of speakers is not necessarily released in advance (perhaps in part due to the “spontaneous” nature of the panels), no written documentation regarding the evidence has been provided to the public, and the panel members’ presentations appear mostly consistent with the commissioner’s opinion. The public can attend in person or remotely but can’t ask questions or express their views.

One unfortunate trait that the advisory committees and expert panels have in common is that some members are less “expert” than others. Many are clinicians with limited understanding of statistics or the implications of the FDA regulatory process. Meanwhile, the academic physicians participating do not acknowledge that many clinicians who write these prescriptions may rely on drug and device representatives for information rather than regularly reading studies in medical journals or closely studying very long drug labels.

Another unfortunate trait they have in common is conflicts of interest. Financial ties to industry are discouraged but still exist and are not always disclosed. Both panels include clinicians whose quoted statements at these meetings may influence their salaries by generating positive or negative publicity. An additional possible conflict unique to researchers on expert panels is the assumption that pleasing HHS officials could improve their chances of future federal funding or recognition.

Shortcomings of Advisory Committees

To be fair, during advisory committee meetings, some committee members appear to have not read most of the meeting materials provided in advance, and it sometimes seems the FDA has “stacked the deck” by cherry-picking committee members. Also, the votes may at times be unanimous even when numerous members express great concerns about the product. For example, I once heard a committee member share substantial doubts and then say, “I certainly would not want my mother to take it” — but he voted in favor of the product anyway.

In addition to companies’ hours-long presentations, many recruit and train public comment speakers. Most are patients desperate for a cure who may not realize the product performed no better than placebo. Their stories are often tragic and compelling, and numerous advisory committee members have told me they voted in favor of a product of questionable efficacy because they didn’t want to seem indifferent to the patients’ plight.

As President Biden’s FDA commissioner, Robert Califf, MD, openly expressed concerns about FDA advisory committee meetings. In a meeting with several nonprofit leaders, he made it clear to us that he did not like it when FDA was criticized for approving a product that the advisory committee had voted against. At the end of the day, the advisory committees serve as just that: advisors. They have not been a rubber-stamp; although in the future, FDA may try to take them in a different direction. But the value of this public forum for discussion and transparency cannot be overstated.

Don’t Let Perfect Be the Enemy of Good

Advisory committees are not perfect, but I’ve never seen one that lacks a diversity of opinion. FDA scientists almost always raise important concerns that help committee members consider the risks and benefits of products and strengths and weaknesses of the research evidence.

In contrast, during the expert panel on hormones for menopause, the commissioner and the panel cited studies that, in several cases, were outdated, based on rodents rather than women, or included too few patients or were too short-term to provide meaningful evidence. There were no public speakers and no panel members willing to challenge those flawed research citations, so reporters under tight deadlines had little opportunity to include expert opinions that conflicted with the preordained message of the meeting.

Important FDA decisions deserve scientific scrutiny, challenging questions, differences of opinion, and nuanced summaries. These have, to date, been lacking in the FDA expert panels, making critical information less available to patients and their physicians.

Diana Zuckerman, PhD, is president of the National Center for Health Research in Washington, D.C. She is a former Congressional committee staffer who investigated FDA policies.

You can read the original MedPage Today article here.

Healio: HHS revises hormone therapy black box warning for menopause treatment

In the News, News Stories & Editorials, We're In the News

By Emma Bascom, Michael Monostra, and Andrew Rhoades, November 10, 2025

HHS has announced changes to estrogen hormone therapy black box labeling for menopause treatment in a move that it said corrects misleading warnings.

HHS Secretary Robert F. Kennedy Jr. said in a press conference on Monday that women have been “told to fear the very therapy that could have given them strength, peace and dignity through one of life’s most difficult transitions, menopause,” but “that ends today.”

“We’re challenging outdated thinking and recommitting to evidence-based medicine that empowers rather than restricts,” he added. “When prescribed responsibly and started early, hormone replacement therapy transforms the lives of women.”

The details

The role estrogen replacement should play in menopause treatment has long been controversial. Concerns about menopausal hormonal therapy stem back to the publication of findings from the Women’s Health Initiative in JAMA in 2002.

The study found women receiving estrogen plus progestin had a significantly increased risk for total CVD, stroke and pulmonary embolism, and a nominally increased risk for breast cancer. The trial was stopped early due to “health risks that exceeded health benefits over an average follow-up of 5.2 years,” and its results led to a large decrease in the use of hormone therapy among women.

In July, the FDA convened an expert panel to discuss the safety and efficacy of menopausal hormone therapy, and some members stated the boxed warning should be changed to better reflect the published evidence. In the press conference, FDA commissioner Martin A. Makary, MD, MPH, said the move is based on “a robust review of the latest scientific evidence” and the July panel.

“After 23 years of dogma, the FDA today is announcing that we are going to stop the fear machine steering women away from this life-changing, even life-saving, treatment,” Makary said. “We are also approving two new drugs for the treatment of menopausal symptoms. We are listening to doctors who have been waving the flag in the air saying, ‘Hey, we have this wrong.’”

[….]

In a viewpoint published today in JAMA, Makary and colleagues wrote that the revisions to the labels “signal a meaningful shift toward more nuanced, evidence-based communication of hormone therapy risks — one that prioritizes clinical relevance, distinguishes between different formulations and patient populations, and balances the narrative to reflect both safety and therapeutic value.”

According to the viewpoint, the label updates specifically include:

  • removing boxed warnings for CVD, breast cancer, probable dementia and stroke, but not the warning in systemic estrogen labels for endometrial cancer with unopposed estrogen, since “it is important to remind health care practitioners and patients that this serious risk can be mitigated by adding a progestogen”;
  • removing the recommendation that hormone therapy be prescribed at the lowest effective dose for the shortest possible duration, since “treatment decisions are individualized and fall within the clinical judgment of a clinician in discussion with a patient”;
  • updating timing information to include new guidance on treating women aged younger than 60 years or within 10 years of menopause onset “to optimize the benefit-risk balance”; and
  • tailoring safety information that reflects the risks most relevant to each specific type of hormone therapy product.

[….]

According to Makary and colleagues, current evidence suggests that starting hormone therapy within 10 years of perimenopause onset has long-term health benefits. It has been associated with a reduced risk for fatal cardiovascular events, bone fractures cognitive decline and Alzheimer’s disease, they wrote.

Expert insight

In a statement, Steven J. Fleischman, MD, MBA, FACOG, ACOG president, commended HHS, saying “the modifications to certain warning labels for estrogen products are years in the making, reflecting the dedicated advocacy of physicians and patients across the country.”

[…]

The Menopause Society also released a statement saying it agrees with the decision since “the boxed warning may have been a deterrent to the use of the low-dose vaginal estrogen, which is a safe and effective therapy for a condition that affects most menopausal women.”

“However, systemic estrogen still comes with potential risks that should be reviewed in detail with women initiating therapy,” the organization said. “Risks are greater when initiated in older women and in those who are further from menopause onset. Medical comorbidities, personal and family histories, symptoms, and personal preferences all need to be considered and reviewed with patients considering the use of hormone therapy for management of menopause symptoms or prevention of bone loss.” 

Diana Zuckerman, PhD, the president of National Center for Health Research, told Healio that “the warnings on hormone products for menopause had become outdated and it was time to update them.”

“However, these products still have clear risks, and the benefits are mostly for hot flashes and related symptoms,” Zuckerman said. “They are not the fountain of youth that some people claim, they absolutely are not proven to prevent dementia, and they are definitely not safe for everyone.”

Barbara DePree, MD, NCMP, MMM, director of the Women’s Midlife Services at Holland Hospital in Michigan, told Healio that the decision will likely increase hormone therapy uptake, which is “a win.” Yet she wondered how exactly HHS will tailor the safety information to reflect the most relevant risks for each type of hormone therapy.

“I’m not opposed to that, I’m just curious what data they’ll be using to tailor that information,” she said. “When the FDA panel happened, it felt like some of the benefits were cherry-picked from data.”

DePree was also concerned about claims that hormone therapy can prevent some very serious noncommunicable diseases.

“I’m fine with maybe taking some of the blinking red lights out of it. That gives women some more ease,” she said. “But I also think we’re not in a position to promote its use to prevent some conditions that we just don’t have the data to support, and I’m worried that it’s headed in that direction. With social media and what’s being overstated, I think this will maybe be another step in that direction, which is a little concerning.”

But she said this will likely give providers more confidence in offering the therapy as a safe alternative.

“We’ve had a whole generation of providers who’ve only grown up with data from the WHI, which basically put it completely in a risk category, and I think this brings it back to the middle for those people who’ve not really had the confidence or the understanding to properly screen women who can very safely and appropriately be using hormone therapy,” De Pree said. “We just don’t want it to say it’s the right option for every woman or just because it’s available everybody should do it because we’re going to save brains and hearts because I just don’t think we have the data to support that.”

Nanette Santoro, MD, professor and the E. Stewart Taylor Chair of OB/GYN at the University of Colorado School of Medicine told Healio that the changes “are a positive step for menopausal women and their physicians,” but was “a bit surprised the black box was completely removed.”

“The changes reflect current data, and it’s great that the route and types of hormones will be dealt with separately as the risks and benefits of estrogen alone compared to estrogen plus progestin are different. These changes should reduce physician anxiety about prescribing hormones, which is important because they are under-prescribed in general,” Santoro said. “And best of all, removing the black box from topical vaginal estrogen is a big relief, because the tiny incremental increase in circulating estradiol that occurs when women use these preparations should not be compared to the systemic dosing regimens and should not be considered to have the same risk.”

However, “some assumptions and statements made here that go way beyond the data that we have available,” which “raise a bunch of red flags for me.”  

“While hormone therapy can indeed be life-changing for symptomatic women, there is not randomized clinical trial evidence that it reduces heart disease, or immune and cognitive decline. There just isn’t,” Santoro said. “And when hormone therapy prescriptions abruptly dropped after the primary WHI publication in 2002, the only population health change that was seen, when hormone therapy went from about 25% of women to less than 2%, was a decrease in breast cancer mortality. There has not been any kind of massive morbidity or mortality as a result of this drop in hormones, although many women suffered with symptoms unnecessarily because of the fear.”

Overall, she said it is “a very good thing that women don’t have to try to decipher the estrogen black box warning (which includes the phrase ‘probable dementia’ and which confuses my patients who read it because they think it means they will probably get dementia if they take estrogen!) and their prescribing clinicians don’t have to have excessive fear of doing harm.”

“[But] the rebirth of the concept that estrogen and hormone therapy are a fountain of youth for women and will extend their lives feels a whole lot like a sharp swing of a pendulum back into the ‘feminine forever’ days.”
[….]

To read the entire article, click here 

Politico Prescription Plus: FDA Removes Black Box HRT Warning

In the News, News Stories & Editorials, We're In the News

Politico Prescription Plus

BY DAVID LIM AND LAUREN GARDNER, OCTOBER 11, 2025

MAKARY’S PRIORITY — In the Hubert H. Humphrey Building’s atrium in front of a crowd of HHS officials, doctors and journalists Monday, FDA Commissioner Marty Makary declared the agency is
urging companies to remove black box warnings for hormone replacement therapy for menopausal women.

[….]

“With few exceptions, there may be no other medication in a modern era that can improve the health outcomes of women on a population level than hormone replacement,” Makary said. “After 23 years of dogma, the FDA today is announcing that we are going to stop the fear machine steering women away from this life-changing, life-saving treatment.”

But the push to remove the warnings of breast cancer, cardiovascular disease and possible dementia isn’t clear-cut, and the process will likely take several months. Makary said the updated package inserts accompanying the treatments will include a nuanced discussion of the recommended ages for HRT use.

An HHS fact sheet released Monday says the FDA will advise women to start hormone replacement therapy within 10 years of menopause or before 60 years old for use of systemic HRT, which delivers the hormone throughout the body instead of a single area. And the FDA is not seeking to change its black box warning for endometrial cancer for systemic estrogen-alone products.

The background: The Women’s Health Initiative — a National Institutes of Health-backed study that looked at the treatments’ benefits and risks — halted a clinical trial in 2002 after researchers said breast cancer, blood clot and stroke risks outweighed the treatments’ benefits in relieving menopausal symptoms. The action prompted many women to stop the therapy.

But Makary slammed the study, saying it was misrepresented and created a “fear machine” around HRT for menopausal women. He argued the study did not show a significant link to breast cancer.

Diana Zuckerman, president of the National Center for Health Research, said it is “well established” that menopausal hormone therapy can increase heart disease and cancer risks in some circumstances.

“I am glad that the Commissioner admitted that there are risks of some types of hormone therapy for some women, but his claim that hormones for menopause is the best way to improve the health of women sounds like a PR statement,
not a scientific one,” Zuckerman said in an email.

Makary dinged advisory committees on Monday as “bureaucratic,
long and often conflicted, and very expensive” when asked why the

FDA did not opt to convene a panel of its outside advisers before making the recommendation.

[….]

To read the entire article, sign up for Politico Pulse Newsletter at politico.com

AFP: US to remove warnings from menopause hormone therapy

In the News, News Stories & Editorials, We're In the News

AFP (Agence France Presse); November 11, 2025

Hormone Replacement Therapy (HRT) replaces estrogen that the female body stops producing during menopause with the aim of alleviating symptoms including hot flashes, brain fog, insomnia, night sweats and joint pain.

Previously used routinely, prescription and use of the therapies have plummeted worldwide since a landmark trial in the early 2000s pointed to risks associated with specific HRT formulations.

Since then “black box warnings” — the strongest warning the US Food and Drug Administration can require on prescription drugs — have sounded alarm over increased HRT risks including of certain cancers, cardiovascular conditions and probable dementia.

But critics have pointed to flaws with the early 2000s Women’s Health Initiative, whose trials were halted as risks appeared: namely it focused on women who were a decade-post-menopause and in their 60s, when cardiovascular risks increase regardless.

Today guidance generally indicates that healthy newly menopausal or perimenopausal women — people broadly in their 40s or 50s — are among potential candidates for treatment.

There also are newer, more localized or lower-dose forms of the therapies available.

“We’re challenging outdated thinking and recommitting to evidence-based medicine that empowers rather than restricts,” US health chief Robert F. Kennedy Jr said in introducing the measure.

Many experts had urged revisiting the black box label, which they say can scare women for whom benefits may outweigh risks.

Others have voiced concern that changes shouldn’t come without a rigorous review process.

“The warnings on hormone products for menopause had become outdated and it was time to update them,” said Diana Zuckerman, president of the nonprofit National Center for Health Research.

But she told AFP “these products still have clear risks and the benefits are mostly for hot flashes and related symptoms of menopause, not for general health.”

FDA head Marty Makary dismissed that notion of an independent review committee, saying they are “bureaucratic, long, often conflicted and very expensive.”

Over the summer Makary convened a panel of experts overwhelmingly in favor of HRT, which included people with ties to pharmaceutical lobbying.

Adriane Fugh-Berman, who directs a project that promotes rational prescribing at Georgetown University, told AFP that Monday’s announcement was “embarrassing” as it was ahead of any consensus and was “not how regulation should happen.”

There could be benefits of HRT for some people, she told AFP, but cautioned that real risks remain, and more high-quality study is needed.

But the president of the American College of Obstetricians and Gynecologists, Steven Fleischman, commended the FDA’s move, saying “the updated labels will better allow patients and clinicians to engage in a shared decision-making process.”

[….]

The FDA said it is not seeking to remove the boxed warning for endometrial cancer for systemic estrogen-alone products.

[….]

To read the entire article, click here 

The FDA removes long-standing warning from hormone-based menopause drugs

In the News, We're In the News

BY  MATTHEW PERRONE, November 10, 2025

Hormone-based drugs used to treat hot flashes and other menopause symptoms will no longer carry a bold warning label about stroke, heart attack, dementia and other serious risks, the Food and Drug Administration announced Monday.

U.S. health officials said they will remove the boxed warning from more than 20 pills, patches and creams containing hormones like estrogen and progestin, which are approved to ease disruptive symptoms like night sweats. The change has been supported by some doctors — including FDA Commissioner Marty Makary, who has called the current label outdated and unnecessary. But some doctors worried that the process which led to the decision was flawed.

Health officials explained the move by pointing to studies suggesting hormone therapy has few risks when started before age 60 and within 10 years of menopause symptoms.

“We’re challenging outdated thinking and recommitting to evidence-based medicine that empowers rather than restricts,” Health Secretary Robert F. Kennedy Jr. said in introducing the update. The 22-year-old FDA warning advised doctors that hormone therapy increases the risk of blood clots, heart problems and other health issues, citing data from an influential study published more than 20 years ago.

[….]

Debate over the health benefits of hormone therapy
continues

 

Medical guidelines generally recommend the drugs for a limited duration in younger women going through menopause who don’t have complicating risks, such as breast cancer. FDA’s updated prescribing information mostly matches
that approach.

But Makary and some other doctors have suggested that hormone therapy’s benefits can go far beyond managing uncomfortable mid-life symptoms. Before becoming FDA commissioner, Makary dedicated a chapter of his most recent book to extolling the overall benefits of hormone therapy and criticizing doctors unwilling to prescribe it.

On Monday he reiterated that viewpoint, citing figures suggesting hormone therapy reduces heart disease, Alzheimer’s and other age-related conditions. “With few exceptions, there may be no other medication in the modern era that can improve the health outcomes of women at a population level more than hormone replacement therapy,” Makary told reporters.

The veracity of those benefits remains the subject of ongoing research and debate— including among the experts whose work led to the original warning.

Dr. JoAnn Manson of Harvard Medical School said the evidence for overall health benefits is not “as conclusive or definitive” as what Makary described. Still, removing the warning is a good step because it could lead to physicians and patients making more personalized decisions, she said.

“The black box is really one size fits all. It scares everyone away,” Manson said. “Without the black box warning there may be more focus on the actual findings, how they differ by age and underlying health factors.”

Hormone therapy was once the norm for American women

 

In the 1990s, more than 1 in 4 U.S. women took estrogen alone or in combination with progestin on the assumption that — in addition to treating menopause — it would reduce rates of heart disease, dementia and other issues.

But a landmark study of more than 26,000 women challenged that idea, linking two different types of hormone pills to higher rates of stroke, blood clots, breast cancer and other serious risks. After the initial findings were published in 2002, prescriptions plummeted among women of all age groups, including younger menopausal women.

Since then, all estrogen drugs have carried the FDA’s boxed warning — the most serious type.

[….]

Continuing analysis has shown a more nuanced picture of the risks.

[….]

Additionally, many newer forms of the drugs have been introduced since the early 2000s, including vaginal creams and tablets that deliver lower hormone
doses than pills, patches and other drugs that circulate throughout the bloodstream.

The original language contained in the boxed warning will still be available to prescribers, but it will appear lower down on the label. The drugs will retain a boxed warning that women who have not had a hysterectomy should receive a combination of estrogen-progestin due to risks of cancer in the lining of the uterus.

FDA sidestepped its usual public process in reviewing warning

 

Rather than convening one of FDA’s standing advisory committees on women’s health or drug safety, Makary earlier this year invited a dozen doctors and researchers who overwhelmingly supported the health benefits of hormone-replacement drugs.

Many of the panelists at the July meeting consult for drugmakers or prescribe the medications in their private practices. Two of the experts also spoke at Monday’s FDA news conference.

Asked Monday why the FDA didn’t convene a formal advisory panel on the issue, Makary said such meetings are “bureaucratic, long, often conflicted and very expensive.”

Diana Zuckerman of the nonprofit National Center for Health Research, which analyzes medical research, accused Makary of undermining the FDA’s credibility by announcing the change “rather than having scientists scrutinize the research at an FDA scientific meeting.”

To read the entire article, click here .

Inside Health Policy: FDA To Proceed With ‘Expert Panels’ Amid HRT Conflict Concerns

In the News, We're In the News

BY Luke Zarzecki , November 10, 2025

FDA will continue to be advised by “expert panels” instead of advisory committees in some cases, FDA Commissioner Marty Makary said as he touted the review method at an HHS event Monday (Nov. 10) announcing the removal of black box warnings from hormone replacement therapy products for menopause. Health research experts told Inside Health Policy the “expert panel” that advised Makary on the decision had conflicts since almost all of its members would benefit financially from the black box warning being eliminated.

Makary said advisory committees governed by the Federal Advisory Committee Act, FDA’s longtime method for consulting outside experts, are bureaucratic, long, often conflicted and very expensive. He added the agency can have spontaneous and more robust discussions with medical experts on the less-formal panels.

“We’re doing both advisory committees following the long, FACA process in the government and we are also convening experts to say ‘speak your mind passionately, state your conflict of interest if you have any, speak your mind passionately about an important topic in medicine that is not being talked about and needs to be talked about ’ and this was one of those panels,” Makary said. “We also had a similar forum on SSRIs in pregnancy, we had one on cell and gene therapies, so we are going to continue to have those it allows us to have a robust debate without all the bureaucratic barriers.”

[….]

The idea has sparked criticism. Inviting experts to temporarily testify on ad-hoc informal panels, rather than convening formal federal advisory committees with a charter and set membership, evades FACA disclosure requirements, critics say. Unlike advisory committee meetings, the expert panels do not require publication of a notice in the Federal Register, the keeping of minutes or a transcript, or disclosures from members about conflicts of interest.

HRT warnings

FDA said in a statement Monday it is removing the HRT warnings after a “comprehensive review of the scientific literature, an expert panel in July, and a public comment period.” The change removes references to risks of cardiovascular disease, breast cancer and probable dementia. The agency is not removing the boxed warnings for endometrial cancer for systemic estrogen-alone products.

“Today, we are standing up for every woman who has symptoms of menopause and is looking to know her options and receive potentially life-changing treatment,” HHS Secretary Robert F. Kennedy Jr. said. “For more than two decades, bad science and bureaucratic inertia have resulted in women and physicians having an incomplete view of HRT. We are returning to evidence-based medicine and giving women control over their health again.”

Conflicts of interest

Diana Zuckerman, president of the National Center for Health Research, told Inside Health Policy in a statement the members of the “expert panel” had conflicts of interest because “virtually all its members would benefit financially from the black box warning being eliminated”

“That’s because they would have more patients seeking their services, and that is a financial conflict of interest as well as a conflict caused by their becoming better known in their field,” she said.

[….]

Adriane Fugh-Berman, a Georgetown professor of pharmacology and physiology, told IHP Makary sought out experts who agreed with him on the topic.

“His handpicked ‘expert’ panels are put together to rubberstamp his preexisting views — they are rife with people with conflicts of interests, include unqualified people, lack any public comment section, and are full of people spouting their often uninformed opinions rather than assessing data,” she alleged.

HHS did not respond to IHP prior to publication on the alleged financial conflicts of interest.

Zuckerman said Makary thinks the only conflict of interests of importance are from pharmaceutical company funding. While the advisory committee system isn’t perfect, she said, FDA’s new format isn’t an improvement.

“In some cases it seems that the FDA designs advisory committee meetings to come to a specific conclusion, and they do that by ‘stacking the deck’ of the committee members as well as the FDA staff presentations,” she said. “Even so, FDA advisory committee meetings are usually much more scientific and nuanced than the recent ‘expert panels’ — a term that should always be in quotation marks because they are very one-sided and some of the ‘experts’ do not seem at all expert.”

Menopause treatment controversy

[….] 

The dispute over hormone therapy for menopause stems from a National Institutes of Health-backed trial of menopausal hormone therapy and its impact on risks of heart disease and other chronic conditions, part of the Women’s Health Initiative, which was halted in 2002 because of patient safety concerns. Researchers said the trial was showing an elevated risk of breast cancer, blood clots and stroke that outweighed the benefits.

Panelists at the FDA event in July said the findings of the Women’s Health Initiative (WHI) study were misinterpreted and the risks of hormone therapy for menopausal women have been overstated, while its benefits have been downplayed. The trial also focused on oral combination drugs, while other options for administration are available now.

Kennedy said Monday hormone replacement therapy reduces the risk of cardiovascular disease and mortality, Alzheimer’s disease, cognitive decline, bone fractures and all-cause mortality. He said the WHI study was not statistically significant.

“It triggered a media frenzy and led to the FDA applying unscientific black box warnings to all hormone replacement therapy products in 2003. The label was designed to frighten women and silence doctors,” he said.

But women’s health professionals urged FDA in August to avoid making changes to its boxed warnings on estrogen hormone therapy products without consulting an independent advisory committee, complaining the July panel included only supporters of hormone therapy.

Fugh-Berman said the WHI study demonstrated hormones do not prevent cardiovascular disease and increased the risk of dementia. She said that the risk of invasive breast cancer was significantly increased for patients who used HRT, and it increased progressively over time.

“Hormones also increase the risk of stroke, pulmonary embolism, gallbladder disease, ovarian cancer, and other conditions,” she said. “Makary’s statements that the breast cancer risk was not significant is entirely wrong.”

Zuckerman said it would be reasonable to revise the black box warning, but not to eliminate it, since some of the hormone products for menopause have scientific evidence that they cause uterine cancer and stroke for some patients, and breast cancer is also a risk for some women.

“In any other product, that would warrant a black box warning. That’s why removing the black box warnings from all hormone products for menopause is a step backwards, despite the FDA commissioner’s statement that these drugs would greatly benefit millions of women,” she said.

[….]

Zuckerman says topical creams have been shown to be safe in the short term, though long-term data is “skimpy.” Systemic hormones have clear risks and some clear benefits, she said.

“The warnings on hormone products for menopause had become outdated and it was time to update them. However, these products still have clear risks and the benefits are mostly for hot flashes and related symptoms of menopause, not for general health,” she said. “Hormones are not the ‘fountain of health’ that Dr. Makary claimed. They absolutely are not proven to prevent dementia and the frequently touted benefit for osteoporosis only lasts while the woman is taking the hormones, not after she stops.”

To read the entire article, click here

FDA ‘serious’ about hormone therapy changes

In the News, News Stories & Editorials, We're In the News

LAUREN GARDNER and DAVID LIM, Politico, October 28, 2025

OUT OF THE BLACK BOX? The FDA could announce as soon as this week a change to the black box warning on estrogen products used to treat menopause symptoms — a policy move that would be the first to stem from Commissioner Marty Makary’s “expert panel” series.

Makary told CNN’s Sanjay Gupta on a podcast earlier this month that the FDA was having “serious discussions” about the warning with changes coming “very soon.” He focused a chapter of his 2024 book “Blind Spots” on an NIH-backed hormone therapy clinical trial that was halted in 2002 amid concerns about cancer and stroke risks, blasting the study’s administrators for misinterpreting the data.

It’s unclear how far the agency will go, according to advocates monitoring the issue. Some of the speakers at Makary’s July panel discussion are medical advisers to a group petitioning the FDA to remove the boxed warning from vaginal estrogen products, arguing that it deters providers and patients from using them.

[….]

At issue: The FDA could opt to remove the warning for topical, nonsystemic estrogen creams or ointments that treat dryness and other genitourinary symptoms that some women experience while going through menopause.

Existing evidence suggests those localized low doses are safe, though Diana Zuckerman, president of the National Center for Health Research, said there’s a dearth of data from long-term controlled trials. Any changes to the black box warning should distinguish between local and systemic therapies, the latter of which she said pose some risks depending on the timing and duration of treatment and the patient’s health profile.

“There’s a lot of nuance in the research,” said Zuckerman, who criticized the July panel as being skewed in favor of hormone therapy. “But when it is presented as if there is no risk here of cancer or heart disease or anything else, that is just completely untrue.”

The opportunity: But Anne Fulenwider, co-founder and co-CEO of telehealth platform Alloy, said removing the warning will help “millions and millions of women” gain greater access to those therapies.

“Even if it is [removed from] just one of them, that is a huge step for all women,” Fulenwider said. “Everyone is afraid of estrogen to their detriment.”

[….]

To read the entire article, click here https://www.politico.com/newsletters/prescription-pulse/2025/10/28/fda-serious-about-hormone-therapy-changes-00623982

Are Playgrounds In Your Community Safe?

Uncategorized

The Well News, October 28, 2025

Many communities are renovating playgrounds using materials that were never proven safe for children’s long-term use. As a scientist and a grandparent, I’m very concerned that young children are being exposed to toxic materials as they play, day after day and year after year. You should be too.

Are these materials being used in your community, perhaps even in your home?  This is what you need to know.

Rubber playground surfaces, tiles and even garden mulch are the surprising culprits. They are often very attractive and colorful, and may cover your community playground, K-12 play area or daycare floor.  You may have seen them advertised online for flooring for a playroom or to use in your backyard under swing sets and other play equipment.

I used to think that rubber is a safe and natural material that comes from a rubber plant, but most rubber is a synthetic product that combines natural rubber (latex) and chemicals from petroleum. Numerous studies show that chemicals found in rubber disrupt our hormones and can cause serious health problems, contributing to obesity, early puberty, and attention problems such as ADHD. They can eventually cause cancer.

…

To read the rest of the article, click here.

We Comment on Coverage of Colorectal Cancer Non-Invasive Biomarker Screening Tests

Policy, Testimony & Briefings

October 10, 2025

Re: National Coverage Analysis (CAG-00440R)
Request for Public Comment on Coverage of Colorectal Cancer Non-Invasive Biomarker Screening Tests

The National Center for Health Research (NCHR) appreciates the opportunity to provide comments in response to the Centers for Medicare & Medicaid Services (CMS) request for input on the coverage of colorectal cancer (CRC) non-invasive biomarker screening tests, including multi-target stool RNA (mt-sRNA) assays, and on the review of sensitivity and specificity cut points.

NCHR is a nonprofit think tank committed to bridging the gap between scientific evidence and public policy with the goal of improving the health and safety of patients and consumers. Our mission is to ensure that medical products and technologies are not sold in the U.S. unless they are proven safe and effective based on rigorous, independent evidence, with particular attention to how benefits and risks differ across diverse patient populations, including older adults who make up the majority of Medicare beneficiaries.

We recognize the need for more convenient CRC screening. However, FDA approval of the multi-target stool RNA (mt-sRNA) screening test ColoSense does not in itself establish clinical effectiveness in Medicare populations. The FDA’s Summary of Safety and Effectiveness Data (P230001) for ColoSense noted uncertainty regarding the test’s sensitivity, requiring a post-market study of 12,500 participants to confirm accuracy. We agree on the need for such a study, but it should be completed and analyzed prior to Medicare making a coverage decision. We describe the research evidence and shortcomings below.

Background and Context

ColoSense, the multi-target stool RNA (mt-sRNA) test, was assessed in the pivotal CRC-PREVENT trial (Barnell et al., 2023) of 8,289 participants, demonstrating analytical validity and 94% sensitivity for colorectal cancer (CRC). However, the FDA’s Summary of Safety and Effectiveness Data (SSED; PMA P230001) identified several limitations in the study design and performance interpretation. According to the SSED, “there is a chance that as many as 24.3% of patients with colorectal cancer may be missed by this test” based on the lower bound of the 95% confidence interval. The FDA therefore required Geneoscopy to conduct a post-approval study of 12,500 participants to confirm real-world sensitivity and specificity. The protocol for this post-market study was originally accepted on May 3, 2024, and the current protocol was accepted on September 9, 2024, but the study appears to have not begun according to fda.gov and there is no NCT registration number for the post-market study posted to ClinicalTrials.gov. 

 

This lack of an active or publicly registered required post-approval study raises substantial concerns about transparency, regulatory compliance, and readiness for coverage in the Medicare population. A study of 12,500 patients followed for 2 years will take years to complete, and yet the company hasn’t even started the research yet. Without post-market validation data, CMS cannot reasonably determine whether ColoSense performs as well as existing CMS-covered tests such as Colorguard, the multi-target stool DNA test.

 

Furthermore, ColoSense’s existing data reported a specificity of 85.6%, which is substantially lower than that of Cologuard Plus (91%), suggesting it would result in an increased false-positive burden and downstream colonoscopy demand (Exact Sciences, 2025). These unresolved issues reinforce the need for the FDA’s required post-market study to be appropriately completed before any national coverage determination is made.

 

The Role of Stool-Based RNA Colorectal Cancer Screening Tests

Stool-based RNA colorectal cancer screening tests expand early-detection options beyond colonoscopy and traditional fecal tests. These assays analyze RNA biomarkers shed by cancer cells into stool, identifying colorectal cancers and precancerous lesions through simple at-home sample collection (Barnell et al., 2023; Barnell et al., 2025).

Unlike other stool-based tests, the mt-sRNA test, ColoSense, eliminates the need for patients to swab or scrape their stool. Instead, the patient deposits a sample into a container and mails it to a lab for technician-handled analysis (Barnell 2025). This could potentially increase adherence among patients who are uncomfortable with other stool-based tests and unwilling or unable to undergo colonoscopy. 

However, the potential for increased adherence is valuable only if verified with real-world data.

Sensitivity and Specificity of Current Non-Invasive CRC Screening Tests

There are several FDA-approved stool-based CRC screening tests that are covered by Medicare.  The goal of stool-based CRC screening tests is to be non-invasive and more convenient than colonoscopies, with the understanding that positive results will require additional testing with a colonoscopy.  They therefore must balance high sensitivity to detect early cancers and advanced adenomas, as well as adequate specificity to prevent unnecessary colonoscopies and associated risks.

The fecal immunochemical test (FIT) is the most widely used stool-based screening tool. It detects hidden (occult) blood in stool by identifying human hemoglobin proteins using specific antibodies. FIT is simple, inexpensive, and can be done annually at home. However, while it is highly specific (~94%), its sensitivity for early cancers (~74%) and advanced adenomas (~23%) is lower than that of multi-target molecular stool tests, leading to more missed precancerous lesions (Imperiale et al., 2014; Lin et al., 2016; Knudsen et al., 2021; US Preventive Services Task Force (JAMA 2021).

The currently approved multi-target stool DNA (mt-sDNA) test, marketed as Cologuard, combines molecular DNA markers with a fecal immunochemical test (FIT) to detect occult blood and DNA mutations associated with colorectal cancer (CRC) and advanced adenomas. In the DeeP-C trial (Imperiale et al., 2014), Cologuard achieved 92.3% sensitivity for CRC, 42.4% for advanced adenomas, and 86.6–89.8% specificity, outperforming FIT alone (73.8% CRC sensitivity, 23.8% advanced adenoma sensitivity, 94% specificity) (Eckmann et al., 2020).

In contrast, ColoSense, a multi-target stool RNA (mt-sRNA) test, uses RNA rather than DNA biomarkers. However, the ColoSense test is not based solely on RNA biomarkers; it combines three components, which are a fecal immunochemical test (FIT) that detects hidden blood in stool, a panel of RNA transcripts shed by tumor or precancerous cells, and a patient factor (smoking status) to generate an overall test score. This means that the mt-sRNA assay, ColoSense, builds upon, rather than replaces, the traditional FIT methodology. However, the FDA’s performance audit identified several limitations in the CRC-PREVENT trial of ColoSense, so the agency required a post-market study to provide real-world accuracy and safety (FDA, 2023; P230001C). 

It is important to note that when the RNA portion of the ColoSense test was analyzed separately, it performed only slightly better than random chance with an Area Under the Receiver Operating Characteristic (AUROC) value of 0.58–0.62 (An AUROC of 0.5 indicates no diagnostic value, while 1.0 indicates perfect accuracy.). This indicates that most of the test’s diagnostic power likely comes from the FIT component rather than the RNA markers themselves. This raises clear questions about the added clinical value of the RNA component and reinforces the importance of continued evidence development before granting full Medicare coverage (Barnell et al., JAMA 2023; Supplement 3, eFigure 3). 

Taken together, these data indicate that while ColoSense is promising, it has not demonstrated that it as effective or superior to the existing CMS-covered mt-sDNA (Cologuard) or FIT tests. 

Patient-Centered Considerations

Expanding coverage for non-invasive colorectal cancer screening options has been found to improve participation among older adults and those with comorbidities who face challenges with colonoscopy preparation, sedation, or access to endoscopy facilities (Cooper et al., 2013; Lin, 2014; Kwok et al., 2023). These at-home stool tests, including the fecal immunochemical test (FIT), multi-target stool DNA (mt-sDNA; Cologuard), and multi-target stool RNA (mt-sRNA; ColoSense) can reduce logistical and procedural barriers to screening. For rural, minority, and socioeconomically disadvantaged populations, mail-based stool tests may help overcome transportation and access barriers (Sepassi et al., 2024; CDC, 2025; Redwood et al., 2023). However, these tests complement, rather than replace colonoscopy, which remains the diagnostic gold standard for detecting and removing precancerous lesions.

Risks, Limitations, Concerns, and Data Gaps

  1. Disproportionate inclusion of smokers may bias the results.
    The ColoSense CRC-PREVENT trial incorporated smoking status as a variable in its composite scoring algorithm, alongside the fecal immunochemical test (FIT) and RNA biomarkers. The FDA’s Summary of Safety and Effectiveness Data (PMA P230001, 2024) reported that 34.3% of participants were classified as current or former smokers, a prevalence nearly three times higher than the U.S. adult current smoking rate average of approximately 12% (CDC, 2024). Because smoking is a known risk factor for colorectal neoplasia, this overrepresentation may have artificially inflated test sensitivity in a high-risk cohort. Moreover, the company does not explain why their study sample included so many smokers, and whether the study participants may not be representative of the general population or of the Medicare population in other ways as well. In addition, since smoking behavior was self-reported and some participants declined to disclose their status, the accuracy of this variable is uncertain and the proportion of smokers may have been even higher. 
  2. False positives increase the downstream burden of colonoscopy.
    While stool-based screening tests aim to reduce unnecessary colonoscopies, their value depends on whether they perform at least as well as existing noninvasive options. ColoSense (mt-sRNA) demonstrated a specificity of 85.6% in the CRC-PREVENT trial, lower than the FDA-approved and CMS-covered Cologuard (mt-sDNA) test, which achieved about 91% specificity and 92% sensitivity for colorectal cancer in the DeeP-C study (Imperiale et al., 2014). Since ColoSense (mt-sRNA) data do not indicate that this RNA-based approach is at least as accurate or that it meaningfully improves real-world adherence, it may not be as beneficial as the ColoGuard test. Moreover, higher false positives increase downstream colonoscopy burden, so any new stool test with more false positives must demonstrate substantial added value to justify coverage. 
  3. Trial performance may not reflect real-world Medicare outcomes.
    Adherence and follow-up rates observed in clinical trials are likely to be substantially higher than those seen in community or Medicare populations. Consequently, real world evidence of ColoSense compared to Cologuard would provide important information that is currently lacking. Continuous monitoring providing real world evidence of adherence, false-positive rates, and follow-up colonoscopy completion is essential to validate test performance.

For all the reasons specified in #1-3, the composite model’s performance may not reflect the accuracy of the test for a representative sample of patients of any age or health status, and certainly not those in the Medicare population. CMS should therefore interpret ColoSense’s published accuracy metrics with caution and require independent validation of the model without the smoking variable before considering coverage.

  1. FDA-Mandated post-approval study is pending; CMS should wait.
    The FDA mandated a post-approval study to confirm the safety and effectiveness of ColoSense, enrolling 12,500 participants to assess performance across diverse populations (FDA PMA P230001C, 2024). Although the protocol was accepted on September 9, 2024, the FDA database currently lists the study as “Study pending” with no posted study information and no NCT number assigned on clinicaltrials.gov. The reporting schedule on the FDA website notes that progress reports have been submitted on time, but no links or public summaries of these reports are available. At present, the only registered clinical trial related to ColoSense is the pivotal CRC-PREVENT study (NCT04739722).

This FDA requirement of a post-approval study for ColoSense and the lack of evidence that the company has started recruited patients adds to the concerns about ColoSense’s trial findings and limits CMS’s ability to assess its performance in Medicare-age populations to make an evidence-based coverage determination. Given ColoSense’s commercial availability, the timely initiation and completion of the required post-approval study may not be a high priority. A NCD could inadvertently reduce the incentive to generate the evidence necessary for regulatory and clinical validation. We strongly encourage CMS to refrain from granting coverage until the required post-market data are available and reviewed by the FDA and/or CMS.

Recommendations

  1. Deferred Coverage Decision Pending Completion of FDA-Mandated Post-Approval Study

Based on results and concerns about the current research and the lack of any useful information about the required post-market study, CMS should not grant coverage for ColoSense, the only multi-target stool RNA (mt-sRNA) test on the market, at this time. As noted above, the FDA mandated a post-approval study enrolling 12,500 participants to confirm the accuracy, safety, and effectiveness of ColoSense (FDA PMA P230001C, 2024). Although the protocol was accepted on September 9, 2024, the FDA database currently lists the study as “pending,” with no NCT registration number and no publicly available results or progress reports. Without completion and publication of this required post-market study, there is insufficient evidence to determine whether ColoSense is as beneficial to Medicare patients as currently covered non-invasive screening options. CMS should therefore withhold national coverage until the FDA-mandated study has been completed on a representative sample and its findings peer-reviewed. This cautious approach ensures scientific integrity, regulatory consistency, and prudence before providing a national Medicare NCD “seal of approval” to a test whose effectiveness and specificity remain unproven outside a potentially biased pivotal trial due to its very large proportion of smokers.

  1. Performance Standards: Evidence-Based Benchmarks

Given that CMS already provides coverage for several convenient non-invasive stool-based tests, CMA should determine if future coverage for these or other stool-based CRC screening tests meet clear, evidence-based performance thresholds validated in Medicare-relevant populations. 

These thresholds should include:

  • CRC sensitivity: ≥ 90% preferred, ≥ 70% minimum (Imperiale et al., 2014; 2024; Barnell et al., 2023).
  • Advanced adenoma sensitivity: ≥ 40% minimum, ≥ 50–55% preferred.
  • Specificity: ≥ 85% minimum; ≥ 90% preferred.

However, analytical accuracy alone should not justify coverage. CMS should require demonstration of adherence, follow-up completion, and cancer detection stage shifts prior to any future coverage determination.

  1. Transparency and Post-Market Accountability

Prior to making a coverage determination, CMS should require Geneoscopy and other mt-sRNA screening test companies to make all FDA post-approval study protocols, enrollment progress, and data publicly available. Public dashboards or FDA-linked updates should include adherence rates, positivity rates, specificity, and follow-up colonoscopy completion, stratified by demographics. Such transparency will prevent premature coverage of unproven technologies and support equitable, evidence-based policy.

 

Conclusions 

While multi-target stool RNA (mt sRNA) testing represents a potentially useful approach to colorectal cancer screening, the current evidence is insufficient to support Medicare coverage at this time. The CRC PREVENT trial demonstrates analytical validity but lacks direct comparison with existing stool-based tests such as FIT or mt-sDNA, shows only marginal incremental value of RNA biomarkers beyond FIT, and includes population and methodological biases. Moreover, the FDA’s Summary of Safety and Effectiveness Data (P230001) acknowledges that the test (ColoSense) can miss up to 24 percent of colorectal cancers and mandated a post-approval study of 12,500 participants to confirm real world accuracy and safety. As of October 2025, this study has not been initiated, assigned a ClinicalTrials.gov (NCT) number, or publicly reported.

For Medicare coverage, new tests are reasonable and necessary if they either demonstrate significantly higher sensitivity, specificity, or adherence, or show that they are equally effective and more accessible than existing options. The current data for ColoSense show that the test may be less accurate, especially in a representative Medicare population, and there is no evidence that it meaningfully improves screening uptake.

Given these substantial evidence gaps, CMS should defer national coverage until the FDA mandated post-approval study is completed, independently verified, and vetted by FDA or CMS. Only when it is demonstrated to be at least as beneficial as the mt-sDNA test should CMS reconsider coverage. Taking this cautious, evidence driven approach will uphold CMS’s mission to ensure that coverage determinations are scientifically justified and protective of patient safety and public resources.

Respectfully submitted,
National Center for Health Research

Citations:

 

  1. Barnell EK, Kruse K, Wurtzler EM, Scott MC, Barnell AR, Duncavage EJ. Analytical validation of a scrape-free multitarget stool RNA test for colorectal cancer screening. Pract Lab Med. 2025 Sep 3;47:e00502. doi: 10.1016/j.plabm.2025.e00502. PMID: 40994831; PMCID: PMC12454295.
  2. PMA P230001: FDA Summary of Safety and Effectiveness Data. Accessed October 2025: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230001B.pdf
  3. FDA, 2023; P230001C Summary of Safety and Effectiveness Data. Accessed October 2025 : https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230001C.pdf
  4. Post-Approval Studies (PAS) Database. Accessed October 2025: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma_pas.cfm?t_id=783383&c_id=7964
  5. Exact Sciences. (2025). Cologuard HCP FAQ. Accessed October 2025. https://www.cologuardhcp.com/resources/faq
  6. Santos DAR, Eiras M, Gonzalez-Santos M, Santos M, Pereira C, Santos LL, Dinis-Ribeiro M, Lima L. A preliminary assessment of a stool-based microRNA profile for early colorectal cancer screening. Sci Rep. 2025 Aug 5;15(1):28597. doi: 10.1038/s41598-025-14485-z. PMID: 40764826; PMCID: PMC12325799.
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  9. Lin JS, Perdue LA, Henrikson NB, Bean SI, Blasi PR. Screening for Colorectal Cancer: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2021;325(19):1978–1998. doi:10.1001/jama.2021.4417
  10. Le, Q. A., Greene, M., Gohil, S., Ozbay, A. B., Dore, M., Fendrick, A. M., & Limburg, P. (2025). Adherence to multi-target stool DNA testing for colorectal cancer screening in the United States. International journal of colorectal disease, 40(1), 16. https://doi.org/10.1007/s00384-025-04805-0
  11. Cooper GS, Kou TD, Rex DK. Complications Following Colonoscopy With Anesthesia Assistance: A Population-Based Analysis. JAMA Intern Med. 2013;173(7):551–556. doi:10.1001/jamainternmed.2013.2908
  12. Lin O. S. (2014). Performing colonoscopy in elderly and very elderly patients: Risks, costs and benefits. World journal of gastrointestinal endoscopy, 6(6), 220–226. https://doi.org/10.4253/wjge.v6.i6.220
  13. Kwok, K., Levin, T. R., Dominitz, J. A., Panganamamula, K., Feld, A. D., Bardall, B., … & Day, L. W. (2023). Transportation barriers and endoscopic procedures: barriers, legal challenges, and strategies for GI endoscopy units. Gastrointestinal Endoscopy, 98(4), 475-481.
  14.  Eckmann, J. D., Ebner, D. W., & Kisiel, J. B. (2020). Multi-target stool DNA testing for colorectal cancer screening: emerging learning on real-world performance. Current treatment options in gastroenterology, 18(1), 109-119.
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  17. https://www.cms.gov/medicare/coverage/evidence 
  18. Sepassi, A., Li, M., Zell, J. A., Chan, A., Saunders, I. M., & Mukamel, D. B. (2024). Rural-Urban Disparities in Colorectal Cancer Screening, Diagnosis, Treatment, and Survivorship Care: A Systematic Review and Meta-Analysis. The oncologist, 29(4), e431–e446. https://doi.org/10.1093/oncolo/oyad347
  19. https://www.cdc.gov/pcd/issues/2025/25_0025.htm
  20. Redwood D, Toffolon M, Flanagan C, Kisiel J, Kaur JS, Jeffries L, Zenku M, Lent J, Bachtold J. Provider- and System-Level Barriers and Facilitators to Colonoscopy and Multi-Target Stool DNA for Colorectal Cancer Screening in Rural/Remote Alaska Native Communities. International Journal of Environmental Research and Public Health. 2023; 20(22):7030. https://doi.org/10.3390/ijerph20227030
  21. https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?NCDId=281