Tagged FDA

A ‘Fountain Of Youth’ Pill? Sure, If You’re A Mouse.

Renowned Harvard University geneticist David Sinclair recently made a startling assertion: Scientific data shows he has knocked more than two decades off his biological age.

What’s the 49-year-old’s secret? He says his daily regimen includes ingesting a molecule his own research found improved the health and lengthened the life span of mice. Sinclair now boasts online that he has the lung capacity, cholesterol and blood pressure of a “young adult” and the “heart rate of an athlete.”

Despite his enthusiasm, published scientific research has not yet demonstrated the molecule works in humans as it does in mice. Sinclair, however, has a considerable financial stake in his claims being proven correct, and has lent his scientific prowess to commercializing possible life extension products such as molecules known as “NAD boosters.”

His financial interests include being listed as an inventor on a patent licensed to Elysium Health, a supplement company that sells a NAD booster in pills for $60 a bottle. He’s also an investor in InsideTracker, the company that he says measured his age.

Discerning hype from reality in the longevity field has become tougher than ever as reputable scientists such as Sinclair and pre-eminent institutions like Harvard align themselves with promising but unproven interventions — and at times promote and profit from them.

Fueling the excitement, investors pour billions of dollars into the field even as many of the products already on the market face fewer regulations and therefore a lower threshold of proof. 

“If you say you’re a terrific scientist and you have a treatment for aging, it gets a lot of attention,” said Jeffrey Flier, a former Harvard Medical School dean who has been critical of the hype. “There is financial incentive and inducement to overpromise before all the research is in.”

Mice frolic in Richard Miller’s pathology and geriatrics lab at the University of Michigan. Miller heads one of the three labs funded by NIH to test anti-aging substances on mice.(Melanie Maxwell for KHN)

Elysium, co-founded in 2014 by a prominent MIT scientist to commercialize the molecule nicotinamide riboside, a type of NAD booster, highlights its “exclusive” licensing agreement with Harvard and the Mayo Clinic and Sinclair’s role as an inventor. According to the company’s press release, the agreement is aimed at supplements that slow “aging and age-related diseases.”

Further adding scientific gravitas to its brand, the website lists eight Nobel laureates and 19 other prominent scientists who sit on its scientific advisory board. The company also advertises research partnerships with Harvard and U.K. universities Cambridge and Oxford.

Some scientists and institutions have grown uneasy with such ties. Cambridge’s Milner Therapeutics Institute announced in 2017 it would receive funding from Elysium, cementing a research “partnership.” But after hearing complaints from faculty that the institute was associating itself with an unproven supplement, it quietly decided not to renew the funding or the company’s membership to its “innovation” board.

“The sale of nutritional supplements of unproven clinical benefit is commonplace,” said Stephen O’Rahilly, the director of Cambridge’s Metabolic Research Laboratories who applauded his university for reassessing the arrangement. “What is unusual in this case is the extent to which institutions and individuals from the highest levels of the academy have been co-opted to provide scientific credibility for a product whose benefits to human health are unproven.”

The bottom line is I don’t try any of these things. Why don’t I? Because I’m not a mouse.

Felipe Sierra, the director of the division of aging biology at the National Institute on Aging at NIH

The Promise

A generation ago, scientists often ignored or debunked claims of a “fountain of youth” pill.

“Until about the early 1990s, it was kind of laughable that you could develop a pill that would slow aging,” said Richard Miller, a biogerontologist at the University of Michigan who heads one of three labs funded by the National Institutes of Health to test such promising substances on mice. “It was sort of a science fiction trope. Recent research has shown that pessimism is wrong.”

Mice given molecules such as rapamycin live as much as 20 percent longer. Other substances such as 17 alpha estradiol and the diabetes drug Acarbose have been shown to be just as effective — in mouse studies. Not only do mice live longer, but, depending on the substance, they avoid cancers, heart ailments and cognitive problems.

“Until about the early 1990s, it was kind of laughable that you could develop a pill that would slow aging,” says University of Michigan biogerontologist Richard Miller. “It was sort of a science fiction trope. Recent research has shown that pessimism is wrong.”(Melanie Maxwell for KHN)

But human metabolism is different from that of rodents. And our existence is unlike a mouse’s life in a cage. What is theoretically possible in the future remains unproven in humans and not ready for sale, experts say.

History is replete with examples of cures that worked on mice but not in people. Multiple drugs, for instance, have been effective at targeting an Alzheimer’s-like disease in mice yet have failed in humans.

“None of this is ready for prime time. The bottom line is I don’t try any of these things,” said Felipe Sierra, the director of the division of aging biology at the National Institute on Aging at NIH. “Why don’t I? Because I’m not a mouse.”

The Hype

Concerns about whether animal research could translate into human therapy have not stopped scientists from racing into the market, launching startups or lining up investors. Some true believers, including researchers and investors, are taking the substances themselves while promoting them as the next big thing in aging.

“While the buzz encourages investment in worthwhile research, scientists should avoid hyping specific [substances],” said S. Jay Olshansky, a professor who specializes in aging at the School of Public Health at the University of Illinois at Chicago.

Yet some scientific findings are exaggerated to help commercialize them before clinical trials in humans demonstrate both safety and efficacy, he said.

“It’s a great gig if you can convince people to send money and use it to pay exorbitant salaries and do it for 20 years and make claims for 10,” Olshansky said. “You’ve lived the high life and get investors by whipping up excitement and saying the benefits will come sooner than they really are.”

Promising findings in animal studies have stirred much of this enthusiasm.

Research by Sinclair and others helped spark interest in resveratrol, an ingredient in red wine, for its potential anti-aging properties. In 2004, Sinclair co-founded a company, Sirtris, to test resveratrol’s potential benefits and declared in an interview with the journal Science it was “as close to a miraculous molecule as you can find.” GlaxoSmithKline bought the company in 2008 for $720 million. By the time Glaxo halted the research in 2010 because of underwhelming results with possible side effects, Sinclair had already received $8 million from the sale, according to Securities and Exchange Commission documents. He also had earned $297,000 a year in consulting fees from the company, according to The Wall Street Journal.

At the height of the buzz, Sinclair accepted a paid position with Shaklee, which sold a product made out of resveratrol. But he resigned after The Wall Street Journal highlighted positive comments he made about the product that the company had posted online. He said he never gave Shaklee permission to use his statements for marketing.

Harvard University geneticist David Sinclair poses for a portrait in the lab at Harvard Medical School in Boston last year.(Craig F. Walker/The Boston Globe via Getty Images)

Sinclair practices what he preaches — or promotes. On his LinkedIn bio and in media interviews, he describes how he now regularly takes resveratrol; the diabetes drug metformin, which holds promise in slowing aging; and nicotinamide mononucleotide, a substance known as NMN that his own research showed rejuvenated mice.

Of that study, he said in a video produced by Harvard that it “sets the stage for new medicines that will be able to restore blood flow in organs that have lost it, either through a heart attack, a stroke or even in patients with dementia.”

In an interview with KHN, Sinclair said he’s not recommending that others take those substances.

“I’m not claiming I’m actually younger. I’m just giving people the facts,” he said, adding that he’s sharing the test results from InsideTracker’s blood tests, which calculate biological age based on biomarkers in the blood. “They said I was 58, and then one or two blood tests later they said I was 31.4.”

InsideTracker sells an online age-tracking package to consumers for up to about $600. The company’s website highlights Sinclair’s support for the company as a member of its scientific advisory board. It also touts a study that describes the benefits of such tracking, which Sinclair co-authored.

Sinclair is involved either as a founder, an investor, an equity holder, a consultant or a board member with 28 companies, according to a list of his financial interests. At least 18 are involved in anti-aging in some way, including studying or commercializing NAD boosters. The interests range from longevity research startups aimed at humans and even pets to developing a product for a French skin care company to advising a longevity investment fund. He’s also an inventor named in the patent licensed by Harvard and the Mayo Clinic to Elysium, and one of his companies, MetroBiotech, has filed a patent related to nicotinamide mononucleotide, which he says he takes himself.

Sinclair and Harvard declined to release details on how much money he — or the university — is generating from these disclosed outside financial interests. Sinclair estimated in a 2017 interview with Australia’s Financial Review that he raises $3 million a year to fund his Harvard lab.

Liberty Biosecurity, a company he co-founded, estimated in Sinclair’s online bio that he has been involved in ventures that “have attracted more than a billion dollars in investment.” When KHN asked him to detail the characterization, he said it was inaccurate, without elaborating, and the comments later disappeared from the website.

Sinclair cited confidentiality agreements for not disclosing his earnings, but he added that “most of this income has been reinvested into companies developing breakthrough medicines, used to help my lab, or donated to nonprofits.” He said he did not know how much he stood to make off the Elysium patent, saying Harvard negotiated the agreement.

Harvard declined to release Sinclair’s conflict-of-interest statements, which university policy requires faculty at the medical school to file in order to “protect against any faculty bias that could heighten the risk of harm to human research participants or recipients of products resulting from such research.”

“We can only be proud of our collaborations if we can represent confidently that such relationships enhance, and do not detract from, the appropriateness and reliability of our work,” the policy states.

Elysium advertises both Harvard’s and Sinclair’s ties to its company. It was co-founded by Massachusetts Institute of Technology professor Leonard Guarente, Sinclair’s former research adviser and an investor in Sinclair’s Sirtris.

Echoing his earlier statements on resveratrol, Sinclair is quoted on Elysium’s website as describing NAD boosters as “one of the most important molecules for life.”

Supplement Loophole?

The Food and Drug Administration doesn’t categorize aging as a disease, which means potential medicines aimed at longevity generally can’t undergo traditional clinical trials aimed at testing their effects on human aging. In addition, the FDA does not require supplements to undergo the same safety or efficacy testing as pharmaceuticals.

The banner headline on Elysium’s website said that “clinical trial results prove safety and efficacy” of its supplement, Basis, which contains the molecule nicotinamide riboside and pterostilbene. But the company’s research did not demonstrate the supplement was effective at anti-aging in humans, as it may be in mice. It simply showed the pill increased the levels of the substance in blood cells.

“Elysium is selling pills to people online with the assertion that the pills are ‘clinically proven’” said O’Rahilly. “Thus far, however the benefits and risks of this change in chemistry in humans is unknown.”

“Many interventions that seem sensible on the basis of research in animals turn out to have unexpected effects in man,” he added, citing a large clinical trial of beta carotene that showed it increased rather than decreased the risk of lung cancer in smokers.

Elysium’s own research documented a “small but significant increase in cholesterol,” but added more studies were needed to determine whether the changes were “real or due to chance.” One independent study has suggested that a component of NAD may influence the growth of some cancers, but researchers involved in the study warned it was too early to know.

Guarente, Elysium’s co-founder and chief scientist, told KHN he isn’t worried about any side effects from Basis, and he emphasized that his company is dedicated to conducting solid research. He said his company monitors customers’ safety reports and advises customers with health issues to consult with their doctors before using it.

If a substance meets the FDA’s definition of a supplement and is advertised that way, then the agency can’t take action unless it proves a danger, said Alta Charo, a former bioethics policy adviser to the Obama administration. Pharmaceuticals must demonstrate safety and efficacy before being marketed.

“A lot of what goes on here is really, really careful phrasing for what you say the thing is for,” said Charo, a law professor at the University of Wisconsin. “If they’re marketing it as a cure for a disease, then they get in trouble with the FDA. If they’re marketing it as a rejuvenator, then the FDA is hamstrung until a danger to the public is proven.”

“This is a recipe for some really unfortunate problems down the road,” Charo added. “We may be lucky and it may turn out that a lot of this stuff turns out to be benignly useless. But for all we know, it’ll be dangerous.”

The debate about the risks and benefits of substances that have yet to be proven to work in humans has triggered a debate over whether research institutions are scrutinizing the financial interests and involvement of their faculty — or the institution itself — closely enough. It remains to be seen whether Cambridge’s decision not to renew its partnership will prompt others to rethink such ties.

Flier, the former dean of Harvard Medical School, had earlier heard complaints and looked into the relationships between scientists and Elysium after he stepped down as dean. He said he discovered that many of the board members who allowed their names and pictures to be posted on the company website knew little about the scientific basis for use of the company’s supplement.

Flier recalls that one scientist had no real role in advising the company and never attended a company meeting. Even so, Elysium was paying him for his role on the board, Flier said.

Caroline Perry, director of communications for Harvard’s Office of Technology Development, said agreements such as Harvard’s acceptance of research funds from Elysium comply with university policies and “protect the traditional academic independence of the researchers.”

Harvard “enters into research agreements with corporate partners who express a commitment to advancing science by supporting research led by Harvard faculty,” Perry added.

Like Harvard, the Mayo Clinic refused to release details on how much money it would make off the Elysium licensing agreement. Mayo and Harvard engaged in “substantial diligence and extended negotiations” before entering into the agreement, said a Mayo spokeswoman.

“The company provided convincing proof that they are committed to developing products supported by scientific evidence,” said the spokeswoman, Duska Anastasijevic.

Guarente of Elysium refused to say how much he or Elysium was earning off the sale of the supplement Basis. MIT would not release his conflict-of-interest statements.

Private investment funds, meanwhile, continue to pour into longevity research despite questions about whether the substances work in people.

One key Elysium investor is the Morningside Group, a private equity firm run by Harvard’s top donor, Gerald Chan, who also gave $350 million to the Harvard School of Public Health.

Billionaire and WeWork co-founder Adam Neumann has invested in Sinclair’s Life Biosciences.

An investment firm led by engineer and physician Peter Diamandis gave a group of Harvard researchers $5.5 million for their startup company after their research was publicly challenged by several other scientists.

In its announcement of the seed money, the company, Elevian, said its goal was to develop “new medicines” that increase the activity levels of the hormone GDF11 “to potentially prevent and treat age-related diseases.”

It described research by its founders, which include Harvard’s Amy Wagers and Richard Lee, as demonstrating that “replenishing a single circulating factor, GDF11, in old animals mirrors the effects of young blood, repairing the heart, brain, muscle and other tissues.”

Other respected labs in the field have either failed to replicate or contradict key elements of their observations.

Elevian’s CEO, Mark Allen, said the early scientific data on GDF11 is encouraging, but “drug discovery and development is a time-intensive, risky, regulated process requiring many years of research, preclinical [animal] studies, and human clinical trials to successfully bring new drugs to market.”

Flier worries research in the longevity field could be compromised, although he recognizes the importance and promise of the science. He said he’s concerned that alliances between billionaires and scientists could lead to less skepticism.

“A susceptible billionaire meets a very good salesman scientist who looks him deeply in the eyes and says, ‘There’s no reason why we can’t have a therapy that will let you live 400 or 600 years,’” Flier said. “The billionaire will look back and see someone who is at MIT or Harvard and say, ‘Show me what you can do.’”

Despite concerns about the hype, scientists are hopeful of finding a way forward by relying on hard evidence. The consensus: A pill is on the horizon. It’s just a matter of time — and solid research.

“If you want to make money, hiring a sales rep to push something that hasn’t been tested is a really great strategy,” said Miller, who is testing substances on mice. “If instead you want to find drugs that work in people, you take a very different approach. It doesn’t involve sales pitches. It involves the long, laborious, slogging process of actually doing research.”

KHN senior correspondent Jay Hancock contributed to this report.

Former Rep. John Dingell Dies; Longest-Serving Congressman Was A Force In Health Policy

Former Rep. John Dingell, the Michigan Democrat who holds the record as the longest-serving member of the U.S. House, died Thursday night in Michigan. He was 92.

And while his name was not familiar to many, his impact on the nation, and on health care in particular, was immense.

For more than 16 years Dingell led the powerful House Energy and Commerce Committee, which is responsible for overseeing the Medicare and Medicaid programs, the U.S. Public Health Service, the Food and Drug Administration and the National Institutes of Health.

As a young legislator, he presided over the House during the vote to approve Medicare in 1965. As a tribute to his father, who served before him and who introduced the first congressional legislation to establish national health insurance during the New Deal, Dingell introduced his own national health insurance bill at the start of every Congress.

And when the House passed what would become the Affordable Care Act in 2009, leaders named the legislation after him. Dingell sat by the side of President Barack Obama when he signed the bill into law in 2010.

Dingell was “a beloved pillar of the Congress and one of the greatest legislators in American history,” said a statement from House Speaker Nancy Pelosi. “Yet, among the vast array of historic legislative achievements, few hold greater meaning than his tireless commitment to the health of the American people.”

He was not always nice. He had a quick temper and a ferocious demeanor when he was displeased, which was often. Witnesses who testified before him could feel his wrath, as could Republican opponents and even other committee Democrats. And he was fiercely protective of his committee’s territory.

In 1993, during the effort by President Bill Clinton to pass major health reform, as the heads of the three main committees that oversee health issues argued over which would lead the effort, Dingell famously proclaimed of his panel, “We have health.”

Dingell and his health subcommittee chairman, California Democrat Henry Waxman, fought endlessly over energy and environmental issues. The Los Angeles-based Waxman was one of the House’s most active environmentalists. Dingell represented the powerful auto industry in southeastern Michigan and opposed many efforts to require safety equipment and fuel and emission standards.

In 2008, Waxman ousted Dingell from the chairmanship of the full committee.

But the two were of the same mind on most health issues, and together during the 1980s and early 1990s they expanded the Medicaid program, reshaped Medicare and modernized the FDA, NIH and the Centers for Disease Control and Prevention.

“It was always a relief for me to know that when he and I met with the Senate in conference, we were talking from the same page, believed in the same things, and we were going to fight together,” Waxman said in 2009.

Dingell was succeeded in his seat by his wife, Rep. Debbie Dingell, herself a former auto industry lobbyist.

Trump Administration Salutes Parade Of Generic Drug Approvals, But Hundreds Aren’t For Sale

The Trump administration has been trumpeting a huge increase in FDA generic drug approvals the past two years, the result of its actions to streamline a cumbersome process and combat anti-competitive practices. But nearly half of those newly approved drugs aren’t being sold in the United States, Kaiser Health News has found, meaning that many patients are deriving little practical benefit from the administration’s efforts.

The administration’s aggressive push to approve more generics is designed to spur more competition with expensive brand-name drugs, and drive prices lower, President Donald Trump noted at a White House event last month. The Food and Drug Administration has approved more than 1,600 generic drug applications since January 2017 — about a third more than it did in the last two years of the Obama administration.

But more than 700, or about 43 percent, of those generics still weren’t on the market as of early January, a KHN data analysis of FDA and drug list price records shows. Even more noteworthy: 36 percent of generics that would be the first to compete against a branded drug are not yet for sale. That means thousands or even millions of patients have no option beyond buying branded drugs that can cost thousands of dollars per month.

“That’s shockingly high,” said former congressman Henry Waxman, who co-sponsored the 1984 law that paved the way for the generic approval process as we know it today. He said he’d like to know more, but suspects anti-competitive behavior is at least partly to blame and that revisions to the so-called Hatch-Waxman Act might be needed.

The approved generics that haven’t made it to American medicine cabinets include generic versions of expensive medicines like the blood thinner Brilinta and HIV medication Truvada. They also include six different generic versions of Nitropress, a heart failure drug, whose price spiked 310 percent in 2015.

Experts say a variety of factors are to blame. Generics sellers have fought for years against patent litigation and other delay tactics that protect brand-name drugs from competition. In recent years, vast industry consolidation has reduced the ranks of companies willing to purchase and distribute generics. And, in some cases, makers of generics obtain approvals and ultimately make a business decision to sit on them.

“It’s a real problem because we’re not getting all the expected competition,” FDA Commissioner Scott Gottlieb said in an interview, adding that it will be difficult to solve because it has so many causes. It takes five generics on the market to drive prices down to 33 percent of the original brand-name price, according to an FDA analysis.

Without generics to lower drug costs, branded manufacturers can continue to increase their prices, at a rate of roughly 10 percent a year, said Scott Knoer, chief pharmacy officer at the Cleveland Clinic. “It makes health care costs go up across the board.”

Even if hospital patients don’t directly see high drug prices in their bills, the higher costs get passed to insurers, who pass them on as higher premiums, Knoer said. They also get passed to taxpayers, who pay for drugs covered by Medicare and Medicaid.

Consolidation on multiple tiers of the drug supply chain have changed the face of the generic drug market, warping supply and demand.

In some cases, key pharmaceutical ingredients are unavailable or a manufacturer doesn’t have the capacity to launch a product because it’s having difficulty meeting demand for existing products.

Manufacturing consolidation has dramatically reduced the production of injectable drugs, which are typically administered in a doctor’s office. This may be why 157 injectable generics that were approved in the past two years haven’t been brought to market.

Erin Fox, a pharmacist at the University of Utah who tracks drug shortages, said the KHN analysis of stalled generics “highlights that companies often have a lot of products ‘on the books’ but aren’t really making them.” A few generics on the list — like dextrose 10 percent injection, to treat patients with low blood sugar — would have been helpful to combat shortages the past few years. “This comes up with shortages a lot — it looks like there are more suppliers than there really are,” Fox said.

A lot can change between the time a drugmaker files a generic application with the FDA and the time it’s approved.

Some drugmakers that applied for generic approval years ago switched their attention to more profitable products. Novartis, for instance, recently sold a generics division run by Sandoz so Sandoz could focus on other drugs, including biosimilars, which compete with expensive biologic drugs made from living organisms.

“Some of these [generic] drug applications have been sitting six, seven, eight years,” said Robert Pollock, a former acting deputy director of the FDA’s Office of Generic Drugs who now works for Lachman Consultants. By the time it’s approved, a generic can fall out of favor because patients taking the branded version reported new side effects, or because a more effective branded drug was approved.

For some generic manufacturers, there’s money to be made by waiting. Brand-name drugmakers will pay them to keep their products off the market as part of a tactic sometimes called “pay for delay.” The Federal Trade Commission estimates that such deals cost consumers and taxpayers $3.5 billion a year.

The number of these potentially anti-competitive settlements decreased from fiscal 2014 to fiscal 2015, according to the latest FTC report. Still, Gottlieb said he hopes to crack down on such tactics. The first generic to take on a branded drug is granted 180 days of exclusivity before the second and third generics can be approved, giving those products a clear advantage.

“We don’t like that companies are able to just park [a generic for] 180 days while they cut a deal not to come to market,” Gottlieb said, adding that with help from Congress he hopes to force companies to forfeit exclusivity if they don’t launch on time.

In some cases, Gottlieb said, generic drugmakers wait until they’ve stockpiled a number of newly approved generics and have landed a contract with a purchaser before bringing their medicines to market.

These bundled contracts are secretive, so not much is known about them, but it means companies are filing generic applications just for the option of introducing generics, said health care economist Rena Conti, an associate professor at Boston University. They’ll wait until the most strategic time to launch, which could be after the competition shakes out, leaving them as “the last man standing,” Conti said. Then they can launch and hike the price.

To be sure, the FDA under Gottlieb’s leadership has taken steps to increase generic competition, from shaming brand-name drugmakers for blocking generics to publishing documents to help manufacturers win approval more easily. But approval doesn’t necessarily spur competition.

“We used to say it was all about getting in — once you got approval from the FDA, then you could go to market,” said Chip Davis, CEO of the Association for Accessible Medicines, the trade group for makers of generic drugs. The biggest challenges his members face is that there aren’t enough companies purchasing drugs, Davis said. Consolidation has led to three large buying groups covering 90 percent of the market, according to a Drug Channels Institute report. So, if you’re the fourth or fifth generic, you may have no one left to sell to.

Yet another barrier relates to how drug middlemen select the drugs they’ll cover under industry formularies, which determine what products insurance plans will cover. In some cases, middlemen known as “pharmacy benefit managers” have made it clear they don’t have room on their formularies for another generic. Or they do, but they give branded drugs preferential treatment with lower copays, hurting the generic’s market share.

Barriers to entry are lower under Gottlieb’s FDA than they’ve been in years past, Conti said, and regulations can help foster competition. But, she said, “they can only do so much.”

Methodology

To identify approved drugs that have not reached the market, KHN used the FDA’s Orange Book database — as of Jan. 2 — to identify drug applications approved in 2017 or 2018. We then searched the FDA’s online National Drug Code directory for billing codes for the drugs associated with each application as of the same date. To account for a possible lag, we supplemented this list with a more complete billing code directory that we obtained via a Freedom of Information Act request. It includes codes with expected future launch dates that don’t appear in the online version.

According to experts, a billing code doesn’t necessarily mean a drug is on the market. However, every drug on the market needs a list price for reimbursement. We provided a list of application numbers and billing codes to information technology firm Connecture, which then told us whether each one was active, inactive or had no list price as of Jan. 17.

If an application had at least one billing code with a list price attached, we counted it as on the market, even if other billing codes did not have list prices.

Sometimes, a single generic application can have multiple approval dates. If one of these approval dates occurred in the past two years, we included it in our analysis.

To determine whether a drug was a first generic, KHN used the FDA’s 2017 and 2018 lists of first generics as of Jan 2.