September 18, 2025, Energy & Commerce Subcommittee on Health 

Chairman Griffith, Ranking Member DeGette, Chairman Guthrie, Ranking Member Pallone, and distinguished members of the Committee, thank you for the invitation to testify. I’m Dr. Diana Zuckerman, president of the National Center for Health Research (NCHR), a nonprofit think tank that uses research to improve the quality of medical care in the United States.  

I was previously a faculty member at Vassar and Yale, a research director at Harvard, and most important, a Committee staffer in the House and Senate. 

Both the Breakthrough Devices Act and the Nancy Gardner Sewell Act require Medicare coverage for specific medical devices.  Keep in mind that the standard for Medicare coverage is “reasonable and necessary” for Medicare patients. FDA safety and effectiveness standards are not specific to Medicare-age patients. 

FDA requires prescription drugs be proven safe and effective, almost always based on patients in clinical trials. In contrast, FDA requires less than 5% of medical devices to be tested in clinical trials, while more than 95% go through a less stringent review called the 510(k) pathway. Those devices are cleared for market if the device is “substantially equivalent” to a device that’s already on the market, even though that older device also wasn’t required to be proven safe or effective in a clinical trial. 

Medicare almost always pays for prescription drugs approved by FDA. It does not pay for all medical devices, especially if there are no clinical trials or evidence that they are safe or effective for Medicare patients. 

When I served on CMS’ Advisory Committee that recommends whether products should be covered by Medicare, I saw many devices were not covered because they had never been studied on Medicare-age patients. Age is important for implants and many other devices because the older we are, the more likely we are to have chronic health conditions that make surgery, anesthesia, and other treatments riskier. 

Devices are designated as breakthrough before scientific evidence is available, based on the FDA’s belief that the device will be more effective than any other available devices. But if completed studies show the device is not more effective than other devices, it will still be sold as breakthrough devices.

Most of the 160 breakthrough devices available in the U.S. are therapeutic devices to treat a disease or condition. Thirty-eight percent of these treatment devices cleared the 510(k) review as substantially equivalent to devices already on the market.  Of the 34 distinct 510(k) devices that are relevant to patients 65 and over, 10 (29%) were studied in clinical trials that were listed in ClinicalTrials.gov, although the law requires these types of studies to be listed on that website.  

Most of those 10 devices have not yet publicly reported whether any of the patients studied were 65 and older. It is impossible to determine how many of those 10 devices included studies of sufficient numbers of patients ages 65 and older to be able to conclude that they would be considered reasonable and necessary for Medicare coverage.  

The other 55% of breakthrough 510(k) devices either had nonclinical data such as animal or mechanical data or had some kind of clinical data that was not a clinical trial. While some of those studies may provide very useful information, it will not be possible to conclude the data are relevant to patients over 65, who often have greater risks and fewer benefits from medical interventions. 

59 other breakthrough treatment devices went through the more stringent PMA or De Novo reviews and many were studied in clinical trials. However, numerous studies were small and had no placebo or comparison group.  Many studies did not include Medicare-aged patients or have not yet publicly reported the number of patients studied who were 65 or older. 

Nancy Gardner Sewell Medicare Multi-Cancer Early Detection Screening Coverage Act

As a cancer survivor, I appreciate that the goal of the Nancy Gardner Sewell Screening bill is to save lives. Multi-cancer early detection tests are promising, but they’re not ready for prime time. The most recent research has concluded that the existing tests are subject to bias, miss most early cancers in people who do not have symptoms, and may provide false positives to most patients.[2] In one of the tests, a test result indicating cancer was correct only 4% of the time.

  A test with many false positives, where most patients who are told they may have cancer do not have cancer, causes anxiety and results in additional testing that may be painful, harmful, expensive, time-consuming, and stressful. A test with many false negatives, in which patients are told they do not have cancer when they actually do, is likely to result in patients who ignore signs and symptoms of cancer, thus delaying needed treatment.  

NCI recently launched the Vanguard Study of 24,000 people ages 45-75. The goals are to determine how accurate these tests are and whether any of the tests save lives. As stated in the study in Annals of Internal Medicine, it is unclear whether MCED tests “detect cancer types at later, untreatable stages or whether they detect very early-stage precancerous lesions that might never have developed into cancer.”

If in the future these tests are proven to have benefits that outweigh the risks for Medicare patients, then I strongly urge that the age restrictions be deleted from the bill. Age restrictions set a dangerous precedent for Medicare coverage decisions and would cause an uproar among patients who are excluded from coverage for reasons that are not scientific and will be perceived as unfair.

Conclusions

Both these bills are intended to help Medicare patients by increasing their access to medical devices. However, in both cases there is a lack of evidence that determines which of these devices have benefits that outweigh the risks for Medicare patients.  The goals are wonderful but requiring Medicare to pay for devices not proven to help its beneficiaries is not the best way to help patients. 

1. Zuckerman D.M., Brown P. & Das A. (2014) Lack of Publicly Available Scientific Evidence on the Safety and Effectiveness of Implanted Medical Devices, JAMA Internal Medicine, 174(11): 1781-1787.  
2. Kahwati, L. C., Avenarius, M., Brouwer, L., Crossnohere, N. L., Doubeni, C. A., Miller, C., Siddiqui, M., Voisin, C., Wines, R. C., & Jonas, D. E. (2025). Multicancer Detection Tests for Screening. Annals of Internal Medicine. https://doi.org/10.7326/ANNALS-25-01877

NCHR Public Comment on Improving the Generic Drug User Fee Act (GDUFA IV), August 11, 2025

Re: Reauthorization of GDUFA Amendments Public Comment from National Center for Health Research [Docket No. FDA-2025-N-0873]

The National Center for Health Research is a nonprofit think tank that scrutinizes the safety and effectiveness of medical products, and we do not accept funding from companies that make those products or have any financial interest in our work.  Since our founding in 1999, we have focused on FDA policies and issues pertaining to the quality of medical care and are pleased to have the opportunity to share our views on improvements needed for GDUFA IV.

Our U.S. healthcare system relies on generic drugs and would be unaffordable without them. We wish Congressional appropriations would be sufficient to support all of the FDA’s essential work, but we know that the FDA needs user fees to ensure getting safe and effective medical products to market in a timely manner. However, speed is not the most important part of that equation.

In its summary of its request for public comments, the FDA stated that GDUFA is designed to facilitate timely access to safe and effective generic drugs for the public, by requiring that generic drug manufacturers and other relevant entities pay user fees to “finance critical and measurable generic drug program enhancements.” As described in the GDUFA III Commitment Letter, FDA committed to achieve certain performance goals, and to provide enhancements “designed to foster the development, assessment, and approval of complex generic products.”

Transparency

We appreciate the accomplishments of GDUFA III, but to achieve its stated goals GDUFA needs to be improved in ways that matter to patients and the U.S. healthcare system. We support recent HHS and FDA statements about transparency and about the need for the FDA to regulate industry, rather than to be influenced by unduly cozy relationships with industry.  An important first step would be for user fee negotiations to include patient, consumer, and public health advocates, instead of only representatives of industry and the FDA negotiating behind closed doors.  Unfortunately, all user fee negotiations have focused on what industry wants and needs and what they are willing to pay for, and not on what patients and consumers want and need. That needs to be improved, and no user fee programs are more important to patients, consumers, and healthcare in the U.S. than GDUFA.

All of us depend on generic drugs, whether taken for headaches or potentially deadly cancer or heart disease.  Patients have been told to trust that generic medications work, but if our experience with a specific generic drug is inferior to what we previously experienced with the brand name version of the drug, our trust in all generic drugs can be harmed. In some cases, problems with specific generic drugs have been well-documented. That has happened too often in recent years, and that is why patients’ and health professionals’ trust in generic drugs has eroded. GDUFA needs to explicitly show that user fees will focus on ensuring that generic drugs are truly equivalent to brand name treatments in all the ways that matter to patients.  Speed should be secondary, because when patients and health professionals realize that some generic drugs are ineffective or unsafe, it harms patients but also harms companies whose products are safe and effective.

Performance Goals

Performance goals need to be improved. Too few have been focused on safety or effectiveness.  We are glad that metrics have included the number of inspections and timeliness of inspections and follow-up warning letters, import alerts, and regulatory meetings, and those metrics should be continued.  However, they are not sufficient.

Last summer, the FDA determined that Synapse (a company in India) “faked and forged” data submitted to the FDA. FDA withdrew the bio-equivalency rating of 400 of their drugs, but they are apparently still on the market.  Neither patients nor pharmacists have access to the names of those drugs.  Why is that?  That decision is terribly unfair to patients, but it is also unfair to companies whose safe and effective generic medications are competing with those 400 drugs.  

More important, it is unfair to all generic companies that make excellent medications when patients don’t know which generic drugs they can trust, and which they can’t trust.

Valisure has also conducted research showing a sizable number of generic drugs are substandard, with doses that are too high, too low, or drugs that are contaminated or have other problems. That’s important information for consumers to know, so the FDA should follow-up on Valisure’s findings to get those drugs off the market.  However, it is equally important that the agency should be on the forefront of conducting that type of research, requiring recalls of those inferior drugs, and warning patients that those medications need to be replaced with those made by a different generic or brand name company. If the FDA does not have sufficient staff to do that, they should hire additional staff, and GDUFA should help to make that possible.

These are just a few examples of why post-market surveillance, pre-market and post-market inspections, and re-inspections are so important and why GDUFA should include funding for staff who will accomplish those quality performance goals.  GDUFA should include relevant metrics in the Commitment Letter that show that these problems are being addressed and that FDA can therefore ensure that generic drugs are truly safe and equivalent to brand name drugs. That’s the promise that GDUFA and the FDA have made to patients, and it needs to be kept.  

Here is an important list of the kinds of metrics that are missing from previous GDUFA Commitment Letters and should be included in FDA monitoring under GDUFA IV.  They are not new ideas; this is the exact same list that the FDA states are criteria for all generic drugs.  The FDA says they must be:

• Pharmaceutically equivalent
• Capable of making the drug correctly
• Capable of making the drug consistently
• The active ingredient is the same as the name brand and the same amount gets in the body
• Inactive ingredients are safe
• Drug does not break down over time

We appreciate the progress that has resulted in reducing the backlog of generic drug applications.  However, many patients and knowledgeable health professionals currently lack confidence in generic drugs, and in some cases their concerns are well-founded. To regain public trust, we respectfully urge the FDA to improve GDUFA by adding performance goals metrics that are focused on ensuring safety and equivalence in GDUFA IV in the ways recommended above.

We would welcome the opportunity to discuss these issues and answer any questions.  We can be contacted at info@center4research.org.

By Sarah Owermohle, May 8, 2025

Universities across the country are scrambling to comply with President Donald Trump’s anti-diversity push in an effort to hold on to hundreds of millions of dollars in federal grants that fund critical medical research in areas such as cancer and maternal health.

Last month, the Trump administration threatened to cancel medical research funds and to pull the accreditation for universities that have diversity and inclusion programs and that boycott Israeli companies.

The latest moves broaden the anti-DEI mandate that Trump signed just hours into his second term, declaring diversity, equity and inclusion efforts discriminatory.

The administration is locked in a legal battle with Harvard University that on Monday saw officials cut off future funding, escalating a total freeze on $2.2 billion in federal grants directed to Harvard. The university has sued to unlock those funds, a fight that will likely be expensive, and take months to resolve.

Most universities, particularly public and smaller institutions, lack the resources to take up the fight the way Harvard has. Dozens of schools across the country have publicly ended DEI programs and quietly taken down or rerouted websites referencing diversity and equity. Some have more openly acquiesced to the administration’s demands, banning the use of certain words and phrases such as “equality,” “gender” and “White supremacy,” and laying off dozens of university staff.

But those efforts haven’t spared them from mass funding cuts.

At Columbia University, some $250 million in health research grants remain in limbo even after the university made significant policy changes in late March to placate the administration. Leaders at Ohio State University, Vice President JD Vance’s alma mater, acted early to end DEI programs and eliminate 16 staff positions in February, citing Trump’s mandate and a state bill.

But in March, the administration still canceled 10 grants to Ohio State, clawing back $2.4 million in planned spending on HPV and Covid-19 vaccine uptake and separate studies on substance use, suicide risk and PrEP access among different LGBTQ populations.

Starting in February, the US National Institutes of Health terminated roughly 780 research grants that referenced equity, racial disparities, minority health, LGBTQ populations and Covid-19. The canceled grants spanned the country: Roughly 40% were to organizations in states Trump won in November, according to a KFF analysis.

Those have included cuts to research seemingly squarely in line with the stated goals of the Trump administration and US Health and Human Services Secretary Robert F. Kennedy Jr., such as studies on autism diagnoses, chronic disease improvements and environmental exposures’ intersection with health.

Besides the immediate impact of frozen research and staff layoffs, scientists and public health experts worry about a chilling effect for health care studies overall. The NIH is the world’s largest public funder of biomedical research, issuing roughly 60,000 grants a year to nearly 3,000 universities and hospitals. That accounts for more than 80% of the agency’s current $48 billion annual budget, although the administration aims to slash that spending by a third next year.

“People are frightened,” said Diana Zuckerman, president of the National Center for Health Research, a nonprofit group aimed at improving health care research. “One of the things that I’ve said to people is, you know, ‘how much can you do what you’ve been doing but just call it something else?’”

That can be a tricky prospect for research on health care issues that disproportionately affect certain populations.

Medical researcher: We should be sharing vaccines with developing world

For instance, the US reports persistently high rates of maternal and infant deaths compared with other high-income countries. There are stark disparities within those figures: Black women are three times more likely to die of pregnancy-related causes than White women.

Researchers and state medical boards attribute those statistics to a range of factors including racial bias, health care access, underlying health conditions and socioeconomic status.

That makes it extraordinary difficult to strip equity, race and risks for certain populations from questions about maternal health care and other research, experts say. Whether it’s new mothers’ postpartum survival, HIV prevention in LGBTQ populations or higher risk of aggressive breast cancer in Black women, many studies necessitate a focus on the people most affected, those experts say. The NIH cut research in all those areas.

“There’s real issues here that could be better understood and responded to, and lives could be saved, but only if you study them – and only if you understand what you’re studying,” Zuckerman said.

Beyond hundreds of grants citing words such as equity, disparities, gender, minority, LGBTQ populations or race, the NIH also canceled spending on Covid-19 outreach, vaccination and messaging.

“HHS grants will only go to the most qualified applicants and will not adhere to ideological requirements or discriminatory quotas,” an HHS spokesperson said in response to questions about the canceled grants.

The mass culling of NIH grants has even stoked concern among Republican leaders who argue that the US could slide in medical innovation and world leadership with the combined funding cuts, mass layoffs and agency shakeups.

“We must not lose sight at what is truly at stake here,” Sen. Susan Collins, a Maine Republican, said during a Senate Appropriations hearing last week. “If clinical trials are halted, research is stopped and laboratories are closed, effective treatments and cures for diseases like Alzheimer’s, type 1 diabetes, childhood cancers and Duchenne muscular dystrophy will be delayed or not discovered at all.”

Maternal health and the DEI battle

In 2023, the NIH launched a $168 million initiative across 10 universities to improve maternal health care.

In March, the agency canceled funding to two of them.

Columbia University, one of the 10 maternal health centers in the mass NIH project, was one of the first schools ensnared in grant freezes and a public battle with the Trump administration.

But the broad grant cancellations also caught the Morehouse School of Medicine, part of a historically Black university in Atlanta, Georgia, a state with some of the worst maternal mortality rates in the country.

Along with Georgia’s Emory University, Morehouse stood up a program focused on improving pregnancy and postpartum care for Black women. There was $1.6 million remaining in the $2.9 million grant when the NIH cut funding. Morehouse School of Medicine President Valerie Montgomery Rice stood fast against anti-DEI efforts in February, telling local radio station WABE that “diversity, equity and inclusion, as it relates to health, is not a political term.”

[….]

“The reason that we knew that we were having disparities in our maternal outcomes is because we started disaggregating the data. We started looking at the outcomes for Black women and White women and Hispanic women,” said one OB/GYN researcher focused on maternal mortality. “If we’re not measuring it, we won’t do anything to improve, because we won’t know. It’s almost like sticking our heads in the sand.”

The researcher asked that their name not be used because they are affiliated with one of the still-funded maternal health programs and are fearful that research could be cut next. Although many of the remaining universities in the program have publicly ended their DEI programs, none feel safe, the person said.

[….]

MAHA priorities amid NIH cuts

Dozens of the cancellations seemingly clash with Kennedy’s vision for a healthier America with fewer chronic illnesses, researchers said. Those include at least two research projects aimed at autism, two focused on diabetes and others on cancer research in rural and underserved areas, and disparities in long-term chronic disease outcomes. In most cases, the grants explicitly mentioned a minority population, equity or disparities in care.

Many of those researchers were years, and thousands to millions of dollars, into their projects: Some were ending soon anyway, and had just a fraction of their grants left to spend.

[….]

Ohio State’s 10 canceled grants include one focused on substance use and associated chronic illnesses across sexual minorities in urban and rural areas. Of the nearly $173,000 grant, just $538.11 was left to be disbursed, according to federal data. The grant was cancelled on March 21; it was scheduled to end 10 days later.

[….]

At the Tulane School of Medicine, the $16 million grant for the maternal health center was untouched in March funding cuts. However, the administration did axe the remaining funding, roughly $279,000, for a $4.2 million grant to study lupus progression in Black Americans. Tulane also lost funding for research on Covid-19 treatment in cancer patients.

The medical school has since quietly removed and rerouted diversity pages on its website. The psychiatry department’s page on equity, diversity and inclusion now says that the content is unavailable: “Some content is currently under review to ensure compliance with the latest federal guidelines and executive orders.”

The president of Tulane University announced in a message to students and faculty on March 13 that it would transition its DEI program into a new “Office of Academic Excellence and Opportunity” to comply with federal law. Diversity pages now reroute to that site.

[….]

Read original article here.

By Sarah Karlin-Smith, May 7, 2025

The US Food and Drug Administration’s announcement of Vinayak “Vinay” Prasad as the new director of the Center for Biologics Evaluation and Research may signal a major philosophical shift in the data required to approve medical products, particularly cell and gene therapies. 

FDA Commissioner Martin Makary announced the pick of Prasad, a hematologist and oncologist, in a 6 May email to staff obtained by Pink Sheet. Prasad most recently worked at the University of California, San Francisco, as a professor of epidemiology and biostatistics. 

Prasad will replace Peter Marks who resigned from FDA rather than be fired in late March

[….] 

Will Prasad Nix Makary’s ‘Provisional’ Pathway? 

Prasad also has a long track record of criticizing the agency for making it too easy to get drugs on the market, raising concerns about the accelerated approval pathway and recent gene therapy approvals, such as Sarepta’s Elevidys (delandistrogene moxeparvovec-rokl). 

He has supported randomized controlled studies with hard clinical outcomes even as the FDA, including Marks, embraced more flexible approaches, particularly for rare diseases. 

Whether Prasad’s views can align with Makary’s recent proposal for a new ‘plausible mechanism’ pathway for rare disease drugs is unclear. 

Prasad’s history, which includes criticism of the FDA and pharma’s close working relationship, worries industry. 

His appointment “seems counter,” to Makary’s discussions in recent weeks about reforming the drug approval process, particularly for rare diseases, said Nicole Paulk, CEO and Founder of Siren Biotechnology, which is developing gene therapies for cancer. 

“Based on [Prasad’s] books that he’s written and the tweets that he has shared, and podcast that he has been on and all of these various public forums, it would seem to be that his position, kind of broadly regardless of modality is pretty anti-FDA, fairly anti-innovation, fairly anti-accelerated anything,” Paulk told Pink Sheet. 

Investor Misunderstanding About CDER, CDER Product Oversight 

The news of Prasad’s appointment sent biotech stocks plummeting. 

A 6 May analyst note from William Blair suggested investors may be confused about the products regulated by CBER and the Center for Drug Evaluation and Research. The analysts said they do not believe there is a risk to the existing development path for most oncology drugs, which are overseen by CDER. 

For cell and gene therapies, “there are clearly outstanding questions and increased uncertainty now as we wait to see whether Dr. Makary or Dr. Prasad will have more impact on the guidelines and regulatory development requirements for these novel therapies, particularly in rare diseases,” the analysts wrote. “Dr. Makary has been vocal since being confirmed as commissioner for more accelerated approval opportunities in the cases of ultrarare diseases or therapies with overwhelming efficacy.” 

Prasad’s appointment also likely will add to the negative sentiment in the vaccine space, they added. 

A Triumph For Evidence Over Hope? 

Many critics of the FDA’s approval standards hope Prasad’s appointment will lead to tougher approval standards. 

“Like us, Vinay has led several impactful research projects raising concerns around surrogate markers and their lack of association with meaningful clinical outcomes, particularly in oncology,” said Reshma Ramachandran, co-director of the Yale Collaboration for Regulatory Rigor, Integrity and Transparency. “He also similarly expressed concerns around the previous CBER Director’s decision to override multiple scientific and technical review teams to approve Elevidys despite lack of evidence of its efficacy. Hopefully, this is a sign that in his new role, he will listen to his scientific review staff in making regulatory decisions.” 

“I think very highly of him,” said Diana Zuckerman, president of the National Center for Health Research. She suggested that Prasad’s track record suggests someone who would not allow products on the market simply because patients lack any treatment, unlike Marks. 

“I understand the desire to be responsive to patients’ needs and desire to have hope for a new treatment, but I think it does patients no favor to give them false hope by approving treatments that end up being extremely expensive and not only ineffective, but they don’t follow through with the required post-marketing testing,” Zuckerman said. “So for years they end up on the market with companies that make a lot of money off of them and patients who don’t benefit at all or are harmed financially, physically or both.” 

Ethan Perlstein, CEO Of Perlara, a biotech public benefit corporation developing treatments for rare genetic diseases, said the negative reaction to Prasad comes from “traditional bio” because they dislike a person as outspoken as Prasad who “can’t be controlled in some way or is not beholden to them or to anybody.” 

Perlstein said he understands why many in the industry see Prasad as a “chaos agent,” but added that he appreciates Prasad demonstrating that he is “not beholden to anybody except his principles,” and seems willing to evolve. 

Has Prasad Changed? 

Other medical experts who raised concerns about Prasad’s views on COVID-19 and other vaccine issues in recent years acknowledged that before 2020 they liked many of his stances, such as requiring more rigorous follow up on oncology drugs after accelerated approval. 

But they were not confident that Prasad still existed. 

[….]

“He started out criticizing the COVID vaccines and I think a lot of it is audience capture,” said David Gorski, a professor of surgery and oncology at Wayne State University and editor of the blog Science Based Medicine. “As he drifted into more contrarian positions, he got more likes, clicks praise, as a brave truth teller.” 

[….] 

Gorski suggested Prasad is a victim of what he calls “evidence-based medicine fundamentalism,” which is “if it isn’t a randomized placebo-controlled, double-blind clinical trial, it’s crap,” Gorski said. 

[….]

To read the entire article, click here

April 7, 2025

[Docket No. FDA-2024-D-4245]

Thank you for the opportunity to comment on the FDA’s Draft Guidance for the Study of Sex Differences in the Clinical Evaluation of Medical Products. The National Center for Health Research has conducted research on this issue for decades and our comments today build on the findings of that research.

We strongly support most of the FDA’s proposed guidance, but we note that the agency has attempted to improve the representation of women, older Americans, and racial and ethnic minorities for many years but has fallen short. We have scrutinized this proposed guidance and are providing several suggestions that we respectfully encourage the FDA to implement.

Meaningful Representation of Males and Females and Major Demographic Subgroups

First and foremost, the agency should not focus entirely on increasing females but rather focus on ensuring males and females be substantially represented in all studies of medical products that will be used by males and females. Just as women have historically been underrepresented in studies of treatments for heart disease and several other illnesses, males have been underrepresented in studies of weight loss products and implants that are used by both males and females, for example. We therefore agree with the statement that “For diseases or conditions that can occur in both females and males but rarely occur in one of the sexes in actuality, avoid arbitrary exclusion criteria that prohibit participation based on sex.” It is not sufficient that males and females in the studies be represented in proportion to their likely use of the product; instead, meaningful representation requires that sufficient numbers of patients of the underrepresented sex (or demographic group) be included so that they can be statistically analyzed separately, and the statisticians can draw conclusions about safety and effectiveness for members of each sex.

We agree that sex differences should be the focus, rather than gender differences. We also agree with the importance of enrolling females and males of different ages, races, ethnicities, co-morbidities, and hormonal statuses. For example, when males or females are taking any form of sex hormones for whatever reason (birth control, menopausal symptoms, low testosterone, or due to gender preference), it may be necessary to analyze those groups separately to see if the hormonal treatments affect sex differences. If there are too few to analyze these subgroups separately, the indication on the product label should make it clear that the data may not apply to patients in those subgroups.

We agree with the proposed guidance that companies should analyze and interpret sex-specific data to hormonal and other changes with age, for products used by adults of all ages. Ideally, researchers should first analyze the data separately by sex to see if there are age differences in safety or effectiveness.

Encouraging Rather Than Requiring Meaningful Representation

Unlike other U.S. public health agencies, the FDA merely “encourages representation of females (or other demographic groups) in clinical trials submitted to the FDA” rather than requiring representation. As a result, major demographic groups have often been under-represented in clinical trials submitted to the FDA (Fox-Rawlings et al., 2018). The FDA has justified this lower standard by stating that the studies submitted to the FDA are paid for industry, rather than the U.S taxpayer. However, the U.S. taxpayer pays for the treatments that the FDA approves, even when those treatments are not studied on patients that meaningfully represent the U.S. population. Therefore, encouraging rather than requiring representation is potentially misleading and unsafe for the patients who are not meaningfully represented. At the very least, the FDA should improve the incentives for companies to comply with the recommendations by ensuring that labeling indicates which types of patients were not reliably studied, and limiting the indication to the sex (and age groups, etc.) for whom safety and effectiveness data are reliably provided. 

We support the FDA Draft Guidance statement that sponsors “must submit a diversity action plan with goals for study enrollment, disaggregated by sex, among other demographic characteristics.” Unfortunately, diversity action plans do not always result in achieving the goals intended. We agree with the FDA’s list of ways “to improve the recruitment, enrollment, and retention of females in clinical trials” but believe they are also suitable for improving recruitment of men of all ages as well.

Trial Design

We agree with the initial statement of the draft guidance regarding trial design: “For most drugs and devices, males and females should be included in clinical trials in numbers adequate to allow for reliable benefit-risk assessments and to understand any potential sex related differences in medical product response.” 

However, we strongly disagree with the Draft Guidance’s strong focus on determining if a product is safer or more effective for one sex than the other, because that does not matter to patients. What matters to patients is whether the product is statistically significantly safe and effective compared to placebo or other treatments. In other words, there is no reason why a woman would care if a product is more effective for men that for women as long as it is beneficial in a clinically meaningful way for females. Similarly, why would any man care if a product is safer for women than men, if its benefits outweigh the risks for both? Rather than analyze men and women together and separately and then determine if it is safe and effective for both, as the guidance suggests, it would introduce less bias to start with the smaller number of study participants in each sex and if each has statistically significant benefits that outweigh the risks, then it is not necessary to combine males and females. If those benefits are not statistically significant compared to placebo but suggest meaningful benefits, then the men and women can be combined to see if together the results are statistically significant or not. 

We disagree with the draft suggestion that only where sex differences “are anticipated, there should be sufficient numbers to inform reliable benefit-risk assessments in males and females.” Since, it is often unanticipated or unknown whether there will be sex differences, there should always be sufficient numbers of males and females to provide meaningful data. 

Statistical Concepts

We agree that “Analyzing sex differences in medical product performance is an important component of assessing product safety and effectiveness and can inform what goes in the product labeling to improve patient care.” We also agree that “Sex is [only] one of many potential demographic characteristics typically evaluated in subgroup analyses of a clinical trial or non-interventional study.’ We agree that when many subgroup analyses are performed, some will be statistically significant by chance, and that different effects between males and females may be due to other factors associated with sex, such as age and weight. These must be taken into consideration when multiple statistical analyses are performed.

Reporting Results of Analyses 

We support the requirement that sponsors “must include in their annual reports for drug and biological products conducted under an IND, the number of participants entered into the study to date tabulated by age group, sex, and race, and sponsors must present safety and effectiveness data in the clinical data section of an NDA by sex, age, and racial subgroups. Because the enrollment demographics of the clinical study may impact the generalizability of the conclusions, for clinical studies of devices, the FDA recommends that sponsors report the number and proportion of study participants by sex.” We also agree that “Any potential difference by sex should be investigated, explained, and discussed with the Agency.” 

We agree that the labeling should specify the safety and effectiveness of any product separately for males and females of different demographic subgroups when available, and we add that the labeling should specify when those subgroup analyses are not available.

Other General Considerations 

We reiterate that if a product is not proven safe and/or effective compared to placebo or a different treatment, that information should influence the indication. The Draft Guidance suggests that such differences “may potentially be further explored in a study after approval” and that the FDA can require a postmarketing study when applicable criteria are met.” We strongly disagree with this laissez-faire approach, because it can result in years of inappropriate or ineffective treatment for males or females when other treatments might be more beneficial. Therefore, when there is evidence that a product is not safe or not effective for females, or for males, additional research should be conducted before approval.

For example, in our study of high-risk medical devices, we examined publicly available documents for all 22 medical devices that the FDA designated “highest risk” or “novel,” that were reviewed through the premarket approval (PMA) pathway, and were scrutinized at the FDA public meetings from 2014 to 2017 (Fox-Rawlings et al., 2018).1 We evaluated patient demographics and subgroup analyses for all pivotal trials. Although 20 were intended for men and women, the number of patients in the minority gender was only 1 in one study and half the studies included less than 35% of the minority gender. Only 6 (33%) of the devices included subgroup analysis by sex for safety and 13 (72%) included subgroup analysis by sex for effectiveness. One of the devices, the Lutonix drug-coated balloon catheter used to reduce blockage in the leg, was effective for the total patient sample, but that was because it was effective for men. Women assigned to the Lutonix study arm had slightly worse outcomes than women in the control arm of the study; the artery remained sufficiently dilated a year after the procedure for just over half the women. Nevertheless, the FDA approved this high-risk device for women as well as men. The FDA required a post-market randomized study, but the sponsor said it was unable to enroll a sufficient number of patients. Subsequent data continued to indicate female Lutonix patients did not do as well as male patients, but no publicly available studies indicate if non-drug eluting catheters are superior to Lutonix using real life data. Lutonix continues to be approved for female as well as male patients.

Our study indicated that the frequent lack of subgroup analyses makes it impossible to inform patients or physicians as to whether many newly approved medical devices are safe and effective for specific demographic subgroups defined by gender, race, and age. However, even when the analyses indicated that the women did not benefit from a high-risk device, it was approved by the FDA for women and men anyway.

References

¹ Fox-Rawlings, S. R., Gottschalk, L. B., Doamekpor, L. A., & Zuckerman, D. M. (2018). Diversity in Medical Device Clinical Trials: Do We Know What Works for Which Patients?. The Milbank quarterly, 96(3), 499–529. https://doi.org/10.1111/1468-0009.12344

² U.S. Food and Drug Administration. (n.d.). PAS 1 (Extended Follow-up Study) [Post-Approval Studies Database]. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma_pas.cfm?c_id=&t_id=524729

³ Becton, Dickinson and Company. (n.d.). Lutonix™ Drug Coated Balloon PTA Catheters: Clinical Data. BD. Retrieved April 7, 2025, from https://www.bd.com/en-us/products-and-solutions/products/product-families/lutonix-drug-coated-balloon-pta-catheters#clinicaldata

 1. Based on the evidence presented in this draft Recommendation Statement, do you believe that the USPSTF came to the right conclusions?

• Yes; I believe the USPSTF came to the right conclusions.
• Somewhat; I believe the USPSTF came to the right conclusions in some ways but not in others.
• No; I do not believe the USPSTF came to the right conclusions.
• Unsure; I am not sure if the USPSTF came to the right conclusions.
  

Somewhat; I believe the USPSTF came to the right conclusions in some ways but not in others.

2. Please provide additional evidence or viewpoints that you think should have been considered.

Our main disagreement is that our review determined that the data are insufficient to conclude that HPV is superior to cytology for women ages 30-65, taking into consideration all patient outcomes, including diagnosis, overtreatment, survival, psychosocial impact, and costs.

We agree with the USPSTF statements about the high sensitivity of HPV testing, but the USPSTF statement underemphasizes the anxiety and overtreatment for women with a positive HPV test result from a transient infection. The major disadvantage of HPV testing is that a positive HPV result for women from 30-65 years is likely to result in a colposcopy. We therefore question whether HPV testing should be considered preferable to Pap cytology, since the two have comparable effectiveness for many women and Pap cytology avoids diagnosing transient HPV infections. Moreover, while HPV testing can identify more precancerous lesions earlier, its impact on reducing invasive cancer and improving survival is unclear and may depend heavily on follow-up care and screening adherence.

The ARTISTIC trial (Kitchener et al., 2009) found that HPV testing was more sensitive than cytology for detecting CIN3+ lesions in the initial round of screening. However, it did not demonstrate a significant reduction in invasive cervical cancer rates by the second round. Castle et al. (2018) demonstrates that while HPV testing detects more high-grade lesions earlier, it does not significantly reduce invasive cervical cancer rates or improve survival outcomes. Similarly, McCredie et al. (2008) demonstrated that while many high-grade lesions progress to invasive cancer if left untreated, a significant proportion regress spontaneously. These studies suggest that while HPV testing can identify more precancerous lesions earlier, its impact on reducing invasive cancer and improving survival may depend heavily on follow-up care and screening adherence.

In contrast, a pooled analysis looking at the results of 4 studies with a total of more than 170,000 patients, Ronco et al. (2014) found that HPV-based screening significantly reduced the incidence of invasive cervical cancer compared to cytology alone over a 6.5-year period.  The fact that patients enrolled in these 4 studies lived in Europe and Scandinavia could explain why these findings seem to contradict the Kitchener, Castle, and McCredie trials cited in our previous paragraph. It is possible that HPV testing may be more effective than cytology in countries where health care is free and very widely available. Overall, the results suggest that the incremental benefit of HPV testing over cytology is unclear but may be strongest in countries where access to care is not limited. These results do not justify considering it the preferred option for women between the ages of 30 and 65 in the U.S., given the increased costs, uncertain access to follow-up care, psychological stress, and patients’ desire to avoid the cost of potentially unnecessary procedures.

The importance of follow-up care is evident in studies like Dillner et al. (2008), which emphasized the critical need for systems to manage HPV-positive results effectively in order to avoid unnecessary interventions without compromising cancer prevention. Since colposcopies are invasive and more expensive and anxiety-producing than a cytology test, we strongly urge the USPSTF to specify that if HPV is used as the primary test, a positive HPV result should be followed by cytology as the next step before proceeding to colposcopy. This approach is supported by international guidelines such as those in the Netherlands and Australia. Specifically, the Dutch program incorporates cytology as a triage step following a positive HPV test to reduce unnecessary colposcopies, while maintaining sensitivity for clinically significant lesions (Rijkaart et al., 2012). Similarly, Australia’s National Cervical Screening Program transitioned to primary HPV screening with reflex cytology for non-HPV16/18-positive cases to improve cost-effectiveness and patient outcomes (Lew et al., 2017). Similarly, in the four countries studied by Ronco et al, for women whose initial screening was an HPV test, if the results were positive that was followed by cytology rather than colposcopy. If the cytology test was negative despite the positive HPV test, the women underwent a follow-up HPV test approximately one year later. These strategies show that cytology offers a balanced approach to triage, reducing unnecessary referrals after a positive HPV test, while maintaining detection rates.

In addition, the USPSTF draft does not sufficiently address the impact of self-collected HPV samples in real-world settings. Studies like Arbyn et al. (2014) and Polman et al. (2019) highlight logistical barriers, accuracy concerns, and the importance of robust follow-up systems.

References

Arbyn M, Verdoodt F, Snijders PJ, et al. Accuracy of human papillomavirus testing on self-collected versus clinician-collected samples: a meta-analysis. Lancet Oncol. 2014;15(2):172-183. doi:10.1016/S1470-2045(13)70570-9

Castle PE, Kinney WK, Xue X, et al. Effect of Several Negative Rounds of Human Papillomavirus and Cytology Co-testing on Safety Against Cervical Cancer: An Observational Cohort Study. Ann Intern Med. 2018;168(1):20-29. doi:10.7326/M17-1609

Dillner J, Rebolj M, Birembaut P, et al. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ. 2008;337:a1754. Published 2008 Oct 13. doi:10.1136/bmj.a1754

Kitchener HC, Almonte M, Gilham C, et al. ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening. Health Technol Assess. 2009;13(51):1-iv. doi:10.3310/hta13510

Lew JB, Simms KT, Smith MA, et al. Primary HPV testing versus cytology-based cervical screening in women in Australia vaccinated for HPV and unvaccinated: effectiveness and economic assessment for the National Cervical Screening Program. Lancet Public Health. 2017;2(2):e96-e107. doi:10.1016/S2468-2667(17)30007-5

McCredie MR, Sharples KJ, Paul C, et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. 2008;9(5):425-434. doi:10.1016/S1470-2045(08)70103-7

Polman NJ, Ebisch RMF, Heideman DAM, et al. Performance of human papillomavirus testing on self-collected versus clinician-collected samples for the detection of cervical intraepithelial neoplasia of grade 2 or worse: a randomised, paired screen-positive, non-inferiority trial. Lancet Oncol. 2019;20(2):229-238. doi:10.1016/S1470-2045(18)30763-0

Rijkaart DC, Berkhof J, Rozendaal L, et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncol.2012;13(1):78-88. doi:10.1016/S1470-2045(11)70296-0

Ronco G, Dillner J, Elfström KM, et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials [published correction appears in Lancet. 2015 Oct 10;386(10002):1446. doi: 10.1016/S0140-6736(15)00411-0]. Lancet. 2014;383(9916):524-532. doi:10.1016/S0140-6736(13)62218-7

3. How could the USPSTF make this draft Recommendation Statement clearer?

• USPSTF’s statement should acknowledge and take into account the psychosocial and economic impacts of unnecessary colposcopies, particularly for low-income and underserved populations.
• UPSTF should review and include well-designed studies on invasive cancer and survival outcomes tied to HPV testing versus cytology, or clearly state that such data are unavailable or inconclusive. Detection alone is not a meaningful endpoint without demonstrated survival benefits.
• USPSTF should provide clearer guidance on triage pathways, emphasizing cytology as the next step after a positive HPV result instead of immediate colposcopy.

4. What information, if any, did you expect to find in this draft Recommendation Statement that was not included?

• A more comprehensive review of comparative data on invasive cancer and survival for HPV testing and cytology as primary screening strategies.
• More nuanced recommendations for women over 65, which consider individual risk factors such as new sexual partners or immunosuppressive conditions.
• Greater detail on the feasibility and cost-effectiveness of implementing self-collected HPV testing in the U.S. in the real world, not just in research or clinical settings, including follow-up protocols to prevent gaps in care.

5. What resources or tools could the USPSTF provide that would make this Recommendation Statement more useful to you in its final form?

The USPSTF could enhance the utility of this Recommendation Statement by providing:

1. Decision-making algorithms or flowcharts for clinicians and patients that clearly outline the steps following various screening outcomes (e.g., HPV-positive, cytology-positive, or combined). This would be particularly helpful in reinforcing the role of cytology as a triage step before colposcopy.
2. Cost-effectiveness analysis summaries comparing different screening strategies (e.g., HPV testing alone, Pap cytology alone, and co-testing) in terms of cancer detection, survival outcomes, and healthcare utilization.
3. Guidance on self-collection implementation, including best practices for ensuring accuracy and follow-up care, particularly for underserved populations.
4. Risk calculators or interactive tools to help patients better understand their individualized risk and the potential benefits or harms of different screening intervals or modalities.

6. The USPSTF is committed to understanding the needs and perspectives of the public it serves. Please share any experiences that you think could further inform the USPSTF on this draft Recommendation Statement.

From a clinical perspective, patients often express significant anxiety about abnormal HPV results, particularly when the next step involves immediate colposcopy. This underscores the need for clear communication about the low risk of invasive cancer in many HPV-positive cases and the rationale for using cytology as an intermediate triage tool. Additionally, underserved populations face barriers such as lack of follow-up after abnormal results or inadequate access to colposcopy services. Unfortunately, when patients are concerned about cost or access associated with a positive HPV test, they may delay follow-up until their condition is much worse. In such cases, the absence of robust systems for patient navigation exacerbates disparities in cervical cancer outcomes.

Based on our experiences with patients, it is especially essential to integrate follow-up protocols into any recommendations involving self-collection or HPV primary screening.

7. Do you have other comments on this draft Recommendation Statement?

Yes, there are additional points to consider:

1. The Recommendation Statement could benefit from a stronger focus on survival outcomes rather than cancer detection alone. Current evidence does not consistently demonstrate that HPV testing translates into better survival outcomes compared to cytology. For example, the ARTISTIC trial found no significant reduction in invasive cancer rates despite increased lesion detection with HPV testing (Kitchener et al., 2009).
2. The USPSTF should provide greater emphasis on individualized screening decisions, especially for women over 65, where risk factors like recent sexual activity or changes in immune status may necessitate continued screening despite adequate prior testing.
3. To ensure equitable care, the Statement should explicitly address the logistical challenges of access to colposcopy and to implementing self-collected HPV testing in real-world settings, including the importance of integrating results into electronic health records (EHRs) and ensuring timely follow-up.
4. Lastly, the draft should clarify the USPSTF’s position on triage pathways for HPV-positive results. Cytology following HPV-positive results should usually serve as an intermediate step before colposcopy, and should be described as the preferred strategy after a positive HPV because it is  more cost-effective and patient-centered.