A small but growing number of doctors prescribe drugs 'off-label' for their possible anti-aging effects, even though there is scant evidence that the practice works.

This story was first published Wednesday, March 6, 2019, by Kaiser Health News.

By Marisa Taylor

Dr. Alan Green's patients travel from around the country to his tiny practice in Queens, N.Y., lured by the prospect of longer lives.

Over the past two years, more than 200 patients have flocked to see Green after learning that two drugs he prescribes could possibly stave off aging. One 95-year-old was so intent on keeping her appointment that she asked her son to drive her from Maryland after a snowstorm had closed the schools.

Green is among a small but growing number of doctors who prescribe drugs "off-label" for their possible anti-aging effects. Metformin is typically prescribed for diabetes, and rapamycin prevents organ rejection after a transplant, but doctors can prescribe drugs off-label for other purposes — in this case, for "aging."

Rapamycin's anti-aging effects on animals and metformin's on people with diabetes have encouraged Green and his patients to experiment with them as anti-aging remedies, even though there's little evidence healthy people could benefit.

"Many of [my patients] have Ph.D.s," said Green, who is 76 and has taken the drugs for three years. "They have read the research and think it's worth a try."

In fact, it's easier for patients to experiment with the drugs — either legally off-label or illegally from a foreign supplier — than it is for researchers to launch clinical trials that would demonstrate they work in humans.

No rigorous large-scale clinical trials have been conducted aimed at aging. The FDA so far has not agreed that a treatment could be approved for delaying the onset of aging or age-related diseases, citing questions about whether research can demonstrate an overall effect on aging rather than just on a specific disease.

Given such reservations, pharmaceutical companies have little incentive to fund costly, large-scale trials. Also, both metformin and rapamycin are generic and relatively cheap.

"There's no profit," said Matt Kaeberlein, a professor of pathology at the University of Washington medical school whose team received a $15 million grant from the National Institutes of Health to study the effects of rapamycin in dogs, but has noted the lack of funds for studies in people. "Without profit, there's no incentive."

Supplements with purported anti-aging effects routinely enter the market with little scrutiny and less evidence.

Yet, late last year, the NIH rejected a $77 million grant proposal by a prominent group of researchers to determine whether metformin could target multiple age-related diseases at once. It was the second rejection of the ambitious but unorthodox bid.

"We’re going to keep trying," said a lead author of the metformin proposal, Stephen Kritchevsky, a co-director of the Sticht Center for Healthy Aging and Alzheimer's Prevention. "These things take time."

Less is known about rapamycin's anti-aging effects and its possible side effects in the general population, including the possibility it could lead to insulin resistance. Yet a litany of studies show that rapamycin extends animal life spans. It also has been shown in such studies to stave off age-related diseases, from cancer to cardiovascular diseases to cognitive diseases.

"There should have been a clinical trial for rapamycin and Alzheimer's disease years ago," said Kaeberlein, who has publicly urged NIH to use a historic boost in Alzheimer's funding to study the drug’s effects. "But the fact is, the clinical trials are really hard and expensive."

Alexander Fleming, a former FDA official and advocate for the metformin proposal, said he believed it was difficult for regulators and funders to grasp that aging can be tackled as a whole — not just one disease at a time.

In fact, NIH reviewers who rejected the metformin proposal cited problems with the project's aim of testing multiple age-related diseases at once. The researchers considered appealing the decision, asserting those reviewers were biased against studying aging as a whole. NIH, which declined to comment, discouraged the attempt.

Dr. Evan Hadley, director of the National Institute on Aging's division of geriatrics and clinical gerontology, told Kaiser Health News that NIH is not ruling out funding projects that target aging, saying such proposals are still "of interest."

The FDA also is open to considering such efforts "based on the scientific evidence presented to us," said FDA spokeswoman Amanda Turney.

Fleming, who oversaw the controversial FDA approval of metformin for Type 2 diabetes, said an argument could be made that it could approve a drug like metformin for preventing age-related diseases instead of just treating them. He points to now widely used statins, which were approved to prevent heart disease.

"There is some kind of belief that the FDA can't approve a therapy to reduce the progress of aging or age-related conditions," said Fleming, an endocrinologist. "It's just not true."

Given the lack of consensus, other researchers have moved ahead with clinical trials focused on specific age-related conditions.

Researchers have shown that a "cousin" of rapamycin boosts the effectiveness of flu shots and lowers the incidence of upper respiratory infections in seniors by up to 30%. This group, led by Dr. Joan Mannick, has licensed it from Novartis and is now working on getting approval to target Parkinson's disease.

"We're trying to be pragmatic," Mannick said of her team's approach.

Some doctors and patients have decided not to wait. At a recent scientific forum on aging, one of the researchers on the NIH proposal asked the 300 or so people in attendance to raise their hands if they were already taking metformin for aging.

"Half the audience raised their hands," recalled the researcher, Dr. Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine, who said a pharmaceutical rep recently estimated that metformin sales are up 20%.

Barzilai is concerned about the off-label trend, although he sees metformin as promising. He contends that researchers in the longevity field first need to set up a framework for testing in clinical trials. Even if metformin doesn't pan out as the most effective drug, he asserts a model like the metformin proposal is needed for any major clinical trial to proceed. His group is now trying to secure about half the amount of funding it requested from NIH from a mix of nonprofit and private investment.

"Much of the aging field is charlatans," Barzilai said. "They tell you take this or that and you'll live forever. But you have to do a clinical trial that is placebo-controlled and only then can you say what it really is and whether it’s safe."

Green nonetheless said he plans to continue prescribing. He estimates about 5% of his patients are doctors themselves. Others have backgrounds in science or are in the upper-income bracket. According to his website, he charges $350 for an initial visit and does not accept insurance.

"They fly to see me on their own planes," he said.

But other doctors who are open to prescribing metformin are holding off on rapamycin, given side effects in higher doses in sick patients.

"I need to see more evidence," said Dr. Garth Denyer, a doctor in The Woodlands, a wealthy Houston suburb, who said he prescribed metformin to a small number of patients but is waiting on rapamycin. "I'm hoping to see more data on safety."

Michael Slattery, who has been HIV-positive since 1983, said he is taking both drugs because the virus is likely to shorten his life expectancy.

So far, he has not noticed any side effects or benefits. His partner, however, who is also HIV-positive, stopped taking rapamycin after getting kidney infections.

"I feel I have nothing left to lose," said Slattery, a retired biotech consultant.

Other patients remain hopeful, even though the evidence is unlikely to be definitive anytime soon.

Linda Mac Dougall, 70, of Port Hueneme, Calif., said she participated in a small study that did not have a placebo control. She’s uncertain whether it had any effect on her.

"I really haven't noticed anything, but that doesn't mean it didn’t work," said Mac Dougall, a massage therapist for seniors. She has slightly more confidence in the wide array of supplements she takes, she said: "If I live until I’m 110, we’ll know."

Marisa Taylor: mtaylor@kff.org, @marisaataylor

More ailments are being treated with medical devices, including implants. And most of these, unlike pharmaceuticals, don't go through human testing before being offered to patients.

This story was first published Tuesday, March 5, 2019, by Kaiser Health News.

By Blake Farmer, Nashville Public Radio

There's no doubt that surgically implanted medical devices can improve lives.

Hip and knee replacements can help people regain their mobility. Drug pumps can deliver doses of pain-relieving medicine on demand. And metal rods can stabilize spines and broken bones.

But implanted devices can also do serious damage, as happened to Mechel Keel, who lives in Owosso, Mich.

To fix her leaky bladder, an OB-GYN stitched a flexible mesh strap inside her pelvis in 2004. But within months, the mesh hardened and started cutting her insides.

The pain kept her from returning to her job as a hairdresser. The injuries and scar tissue that developed required multiple surgeries to correct and also resulted in chronic infections.

Keel said she understands why her doctor in Tennessee thought the high-tech mesh would help. But she also now feels she was treated like "a guinea pig."

"We were the testers," she said. "There was no animal testing done. We were the animals."

Thousands of cases of complications from surgical mesh have been reported to the Food and Drug Administration. More and more ailments are being treated these days with medical devices, including implants. And most of these medical devices, unlike pills in a medicine cabinet, don't go through human testing before being offered to patients.

But some devices break down or malfunction in people's bodies, and reports about sometimes debilitating injuries have led the FDA to rethink how it assesses medical devices before allowing them to be sold.

For devices in which failure is obviously life-threatening, regulators have required some sort of human testing as part of the most stringent path — known as premarket approval. But most medical devices enter the market after manufacturers provide technical information and show that the devices are similar to others that have been legally sold previously.

The FDA has acknowledged that some seemingly safe devices have caused major problems, and the agency has elevated the risk level of those products following reports of injuries, as it did with urogynecologic surgical mesh for some uses in 2016. "Unfortunately, the FDA cannot always know the full extent of the benefits and risks of a device before it reaches the market," the agency said in a recent statement.

"We have things like metal-on-metal hips," said health journalist Jeanne Lenzer about a kind of orthopedic implant. "Outside the body, [they] seem to function just fine. They put them in little machines, rock them back and forth — they don't break. [But] put them inside people, and something very different happens."

There have been massive recalls of hip implants, for example, due to devices causing swelling and pain. And there have been problems with weakened bones in patients who received hip implants that contained plastic.

Lenzer wrote a scathing book, "The Danger Within Us," about the device industry and said she was "dumbfounded" to find out how many devices never went through human testing the way drugs do.

That's in part because of a regulatory review process known as 510(k) for a section of the FDA law covering medical devices. Manufacturers typically show their product has "substantial equivalence" to a "predicate device" that has already been legally marketed.

That standard can perpetuate problems. "You just say your device is like an old device, and the old device was never tested, nor was your device," Lenzer said.

In practice, sometimes the basis for a whole family tree of devices turns out to be defective. Pelvic mesh is a relevant example, with much of what's on the market being based on mesh that was around prior to implementation of FDA regulations for medical devices in 1976. One study found that 16% of mesh on the market was designed like products that had been pulled from the market because of safety concerns.

Thousands of women, including Keel, have filed suit — or reached settlements — with medical device companies that manufacture pelvic mesh.

"I would want nothing if you could just give me my life back," said Gloria Jones of Hillsdale, Mich., who is one of thousands who have settled with device manufacturers over faulty mesh. "They could have given me millions, but all I needed was my life back."

Jones, who has struggled to continue working through crippling abdominal pain as a middle school special-education teaching assistant, has had four surgeries to remove pieces and continues to require intravenous drugs to control infections.

"It seems like I get off one antibiotic, and three days later I have another one," she said. "I would beg anybody who is even thinking of putting mesh in their bodies to stop and get a second opinion."

In response to problems reported with mesh, the FDA started requiring human testing for some of these products in recent years. The agency held an advisory committee meeting on Feb. 12 to discuss the safety and effectiveness of mesh and how it should be regulated.

Manufacturers by and large have said they don't oppose what the FDA is trying to do, calling the changes reasonable. But they have pushed back against calls to bring regulation of medical devices in line with that of pharmaceuticals.

"If you're treating someone for high cholesterol, the testing that you go through to ensure safety and effectiveness on a chemical that's going to be used in your body to control your cholesterol is just very different than it would be for the implantation of a heart valve," said Scott Whitaker, CEO of AdvaMed, a trade association for medical device companies. "Honestly, it's apples and oranges."

Whitaker dismisses the idea that devices, which range from tongue depressors to surgical robots, should all go through human trials.

"Testing should be as complete and as thorough and as ethical and as appropriate as possible. But it doesn't all fit the same and can't all fit the same standard," Whitaker said. "And while we always strive for 100%, there are times when something might not go according to plan. It could also be because the surgery didn't go as was planned."

The FDA declined NPR’s request for an interview. But the agency has released some written justification for the regulatory revamp.

"We believe firmly in the merits of the 510(k) process," FDA Commissioner Scott Gottlieb said in a November statement, noting that applications have more than doubled in size to an average of 1,185 pages. "But we also believe that framework needs to be modernized to reflect advances in technology, safety and the capabilities of a new generation of medical devices."

In the same statement, the agency addressed some specific shortcomings and charted plans to make changes to the process over the next few months:

• Pushing back on manufacturers that base any new device's marketing application on one that's more than 10 years old;
   
• More actively watching how devices perform once they're on the market, rather than relying on patients to report problems;
   
• Scrapping the 510(k) name for something more descriptive, such as the "Safety and Performance Based Pathway."

Dr. Michael Matheny, a Vanderbilt University professor who tracks medical devices, approves of the FDA's incremental approach and calls it thoughtful.

"It would really be unfortunate if patients wouldn't consider any medical devices at all to be used in their bodies," Matheny said. "But I do think being aware that there's nothing without risk is also important."

Matheny notes, though, that in some ways the risks can be more profound for devices than medication. If the FDA recalls pills, a patient can at least stop taking them immediately, he said. With implanted devices, patients are sort of stuck, at least for a while — and that's if surgeons can even safely remove them.

This story is part of a partnership that includes Nashville Public Radio, NPR and Kaiser Health News.

Blake Farmer, Nashville Public Radio: bfarmer@wpln.org, @flakebarmer

The number is the highest since the federal government five years ago launched the Hospital Acquired Conditions Reduction Program, created by the Affordable Care Act.

This story was first published Friday, March 1, 2019, by Kaiser Health News.

By Jordan Rau

Eight hundred hospitals will be paid less by Medicare this year because of high rates of infections and patient injuries, federal records show.

The number is the highest since the federal government five years ago launched the Hospital Acquired Conditions Reduction Program, created by the Affordable Care Act. Under the program, 1,756 hospitals have been penalized at least once, a Kaiser Health News analysis found.

This year, 110 hospitals are being punished for the fifth straight time.

The penalties pit hospitals against one another in a race to prevent the most infections, blood clots, cases of sepsis, bedsores, hip fractures and other complications. Each year, the quarter of general hospitals with the highest rates are punished, even if their records have improved from the previous year.

Under the latest round of sanctions, each hospital will lose 1% of its Medicare payments for patients discharged between last October and this September. That comes on top of other penalties created by the health care law, such as annual payment reductions for hospitals with too many patients being readmitted.

The hospital industry has protested the HAC penalties, saying the program's design creates an arbitrary cutoff for which institutions get punished and which don't. The American Hospital Association calculated that only about 4% of the 768 hospitals penalized in 2017 had HAC scores that were statistically significantly higher than hospitals not being penalized.

"There are not statistical differences that would warrant a quarter of the hospitals in America getting a penalty," said Nancy Foster, the association's vice president for quality and patient safety.

Hospitals also complain that the ones that do the best job testing for infections and other threats to patients appear to be among the worst based on statistics, while their more lackadaisical peers look better than they might be.

Supporters of the punishments argue that the penalties are warranted in prodding hospitals to improve quality. The threat of losing money elevates the issue in many hospitals to the attention of directors and owners, said Missy Danforth, the vice president of health care ratings at the Leapfrog Group, a nonprofit devoted to patient safety.

"The fact that everyone's talking about it, from front-line nurses to boards of directors, is positioning patient safety where it should be, which is at the forefront of everyone's minds," Danforth said.

Danforth dismissed hospital complaints that the penalties are not always fairly applied. "There's a lot of really strong, good best practices to getting to zero on these infections," she said.

Hospital patients suffered an avoidable injury in 9 of every 100 patient stays in 2016, about 2.7 million times, according to a June report from the federal Agency for Healthcare Research and Quality. Those included a bad reaction to medication, an injury from a procedure, a fall or an infection.

The frequency of complications has been dropping in hospitals. The report found an overall 8% decrease from 2014 to 2016. However, the report also found a jump in the numbers of bedsores and urinary tract infections in patients with catheters during that time.

The Hospital Acquired Conditions Reduction Program assesses penalties based on a subsection of the injuries examined in the AHRQ report. For each hospital, Medicare judges infection rates related to colon surgeries, hysterectomies, urinary tract catheters and central lines inserted into veins. Medicare also counts the number of infections of methicillin-resistant Staphylococcus aureus, or MRSA, and Clostridium difficile, known as C. diff.

Finally, the government tracks the rate of blood clots, sepsis, post-surgical wounds, bedsores, hip fractures and five other types of in-hospital injuries. Because the penalties will be applied as hospitals submit claims for reimbursement, the total dollar amount of penalties for each hospital will not be known until the federal fiscal year ends in September.

Medicare excludes from consideration a number of specialized hospitals: those serving children, veterans and psychiatric patients. Maryland hospitals are also exempted because the federal government gives that state leeway in how it pays hospitals. And more than 1,000 "critical access" hospitals, which are the only institutions in their area, are also excluded.

For the remaining hospitals, penalties are assigned to the quarter of institutions with the highest HAC rates. That threshold varies slightly from year to year, and is a major reason that the number of hospitals being punished fluctuates annually. Before this, the largest number of hospitals punished was 769, two years ago.

Jordan Rau: jrau@kff.org, @JordanRau

As 'Medicare-for-all' has become a rallying cry for progressive Democrats, several states are looking at offering consumers a government-sponsored plan to provide a more affordable health option.

This story was first published Tuesday, February 26, 2019, by Kaiser Health News.

By Michelle Andrews

Laura Lucero Y Ruiz De Gutierrez has a heart condition and fibromyalgia and is in danger of developing diabetes. She has health insurance through her husband's job. But, between the $800 monthly premium for the couple's coverage and the $2,100 deductible she has to pay down before insurance starts picking up the tab, she doesn't feel she can afford to go to the doctor when she needs to.

She hopes that may soon change. Identical bills proposed in recent weeks in the New Mexico House and Senate would make Gutierrez eligible to buy in to a public health plan modeled on Medicaid. She also could receive state-funded assistance that would save her hundreds of dollars a month on premiums.

As "Medicare-for-all" has become a rallying cry for progressive Democrats, New Mexico is one of several states looking at offering consumers a different government-sponsored plan to provide a more affordable health option.

The proposals, often referred to as "Medicaid buy-in" plans, would typically offer benefits similar to what is available in Medicaid, the state-federal health plan for low-income people.

"Medicare-for-all is not going to happen legislatively in the next couple years. But in the meantime states are saying, 'What about "Medicaid for more"?'" said Heather Howard, who directs Princeton University’s state health and value strategies program and is working closely with some of the states.

A report commissioned by New Mexico projected that up to 16,000 people would enroll in a program like the one originally proposed in the bills, and their premiums would be 15% to 28% lower than plans sold on the individual market.

Gov. Michelle Lujan Grisham favors a Medicaid buy-in option. She doesn't have a position on the current bill, but she is following it closely, said Nora Sackett, the governor's deputy press secretary.

In addition to the governor's and lawmakers' interest, other stakeholders have been deeply involved, increasing the odds of success, Howard said.

Lawmakers in Colorado, Oregon, Washington and Minnesota are among others exploring similar options, said Howard. Nevada lawmakers passed a bill last year that would have set up a Medicaid buy-in plan, but the Republican governor vetoed it.

"The proposals take on different flavors depending on the state" and what officials are trying to accomplish, she said, whether it's increasing the number of people with insurance, making coverage more affordable or helping states avoid "bare" counties where no marketplace plans are offered.

States that want to offer a buy-in option might opt to try to expand Medicaid directly, or offer a plan that builds on but is not part of their Medicaid program, with similar benefits, providers and reimbursement rates. Or they may offer a public option insurance plan that isn't based on Medicaid. Depending on how they structure their plan, states may have to get approval from the federal government to move ahead.

A federal bill that would allow states to open up their Medicaid programs to all residents was reintroduced earlier in February by Sen. Brian Schatz (D-Hawaii) and Rep. Ben Ray Luján (D-N.M.).

In New Mexico, the buy-in plan would be similar to the state's Medicaid program. It would be offered outside the exchange and would not require federal approval to implement. The state would provide financial assistance to help low-income people buy in to it.

New Mexico's bill would target individuals who aren't eligible for Medicaid or Medicare or those who can't get the Affordable Care Act's premium subsidies because their incomes are above 400% of the federal poverty level (about $50,000 for one person or $103,000 for a family of four). It also includes immigrants who are in the country without legal status.

The measure would also help people, like Gutierrez, who are vulnerable to the ACA's so-called family glitch. Her husband's $100 monthly premium for single coverage is considered affordable under the law because it costs less than 9.86% of their family income of about $46,000 a year. That makes her ineligible for premium subsidies on the exchange, even though the $800 premium for the two of them far exceeds that affordability percentage. Their three children already have Medicaid coverage.

"Right now, I pay to have the healthcare, but I can't afford to use it," said Gutierrez, 42.

The bill would provide premium and cost-sharing assistance for people with incomes less than 200% of the federal poverty level, or $60,340 for a family of five. The new coverage would take effect by January 2021.

Gutierrez, whose family lives in Albuquerque, would be eligible for financial assistance to help her buy in to the Medicaid option, while her husband stayed on his employer plan. Because their $46,000 annual income is just above 150% of the federal poverty level, her monthly premium would likely be about $160 per month for a comprehensive plan with a $150 deductible, according to estimates by Manatt Health, which did the original state analyses of buy-in options that were published before the bills were introduced in January.

New Mexico has high levels of poverty, and 40% of all New Mexico residents are already enrolled in the state Medicaid program, compared with about 23% nationwide.

"It's the cornerstone" of our healthcare system, said Colin Baillio, director of policy and communication at Health Action New Mexico, an advocacy group. The legislation would use "those levers that Medicaid has to provide comprehensive coverage and a comprehensive provider network."

The bills were passed by two legislative committees in mid-February, with instructions for further study to examine expanding the buy-in plan to more groups. They now move to two other legislative committees for consideration, Baillio said.

Hospitals and other healthcare providers would be reimbursed at Medicaid rates, which are lower than those for commercial plans. Still, to the extent that people who are uninsured enroll in the new plan, providers stand to gain financially.

"We're obviously very supportive of anything that expands coverage," said Jeff Dye, president of the New Mexico Hospital Association. "It's the issue of getting some payment versus no payment for services rendered."

If the Medicaid buy-in bill passes, Blanca Ivon Rodriguez and her husband, Hugo Montes, could have health insurance for the first time since they moved to New Mexico 14 years ago. The couple and their oldest son, now 18, are immigrants from Mexico who are in the state without proper legal status. Their two younger children, who were born in the United States, are enrolled in Medicaid.

Montes works as a plumber and Rodriguez is studying early childhood development at a community college near their home in Albuquerque. Because they're undocumented, they’re not permitted to buy health insurance on the exchanges, even if they’re willing to pay full price.

Like many people without insurance, they wait until they're really sick before seeking help. When Rodriguez developed pneumonia a few years ago, the waiting lists for an appointment at community clinics that would see her without insurance were long. Finally, when she could no longer breathe comfortably, she went to the emergency department.

"It would bring us peace of mind not having to worry about our healthcare situation," said Rodriguez, 41, through a translator.

Providing healthcare for residents who are undocumented is "an underlying issue with many states that are considering a Medicaid buy-in," said Chiquita Brooks-LaSure, managing director at Manatt Health, who co-authored the reports evaluating Medicaid buy-in options for New Mexico.

The New Mexico bill also would provide some relief for Leah Steimel's family. Neither she nor her husband has employer-sponsored coverage, and with family income of about $100,000 they don’t qualify for ACA premium tax credits. They pay more than $1,900 a month for a silver-level plan with a $10,000 deductible to cover themselves and two of their kids (the third is over age 26).

Buying in to Medicaid would be tempting, said Steimel, 59, who works as a community health consultant with some of the groups advocating for the buy-in. Sure, she said, she wonders if the Medicaid plan would be as easy to use as a regular commercial plan and have access to as many providers.

"But being able to pay into something that would reduce by even a third what I'm paying now, I'd love that," she said.

Michelle Andrews: andrews.khn@gmail.com, @mandrews110