Why it took so long for the FDA to address a disputed cold remedy | ET REALITY


Dr. Leslie Hendeles began lobbying the Food and Drug Administration to reject a decongestant in cold medicines when he had a mop of curly red hair and Bill Clinton had just become president.

When opposition to the drug arose, Dr. Hendeles appeared, at age 80, as an expert to testify before agency advisers, with white hair and an overview of the ingredient that spanned 50 years.

His defense culminated in the advisory panel’s unanimous vote Tuesday, when it concluded that the decongestant, a common ingredient in cold and flu remedies, is ineffective.

Spurred by the news, consumers opened their medicine cabinets to learn that the decongestant phenylephrine was listed in more than 250 of their favorite congestion medications, including some versions of DayQuil, Sudafed, Tylenol and Theraflu. And the decision has caused some confusion: Experts say the ingredient still works in nasal sprays, but not when taken orally in pill or liquid form.

Since the drug is considered safe, experts say there is no need to throw away the products, which contain other ingredients that do work.

Nothing will change immediately. FDA officials need to review the panel’s decision, solicit public comment and will most likely give drugmakers some time to adjust or change ingredients rather than face the decision of emptying store shelves of so many products. consumer basics. Further delays could occur if companies challenge the actions in court. And some experts, notably Dr. Scott Gottlieb, a former FDA commissioner, have long maintained that phenylephrine works, to some extent. Some drug advocates may try to oppose any action that banishes the decongestant entirely.

But how phenylephrine remained on the market for so long despite decades of studies and questions is a tangled story involving old drug standards dating back to a law signed by President Kennedy, the proliferation of meth labs that used remedies everyday cold remedies in the 1990s and even the pandemic. .

Like other federal agencies, the FDA can move slowly, sometimes hampered by outdated rules and a thicket of regulatory procedures.

“There’s no question that regulation of over-the-counter drugs was broken for many years,” said Dr. Joshua Sharfstein, a former agency official and vice dean of the Johns Hopkins Bloomberg School of Public Health. The latest moves, he said, indicate that “the agency is only now taking off the handcuffs.”

One could argue that the process of dissecting phenylephrine (a drug used to dilate the eyes and soothe hemorrhoids) took approximately six decades. The Kennedy era ushered in a new law that required the FDA to evaluate a drug’s effectiveness in addition to existing safety standards.

It wasn’t until 1976 that the FDA began reviewing over-the-counter cold medications, such as phenylephrine, as a class of drugs.

But by the early 1990s, the decongestant had not yet received full approval, and long delays had attracted the attention of Dr. Hendeles and a group of pharmacy professors at the University of Florida.

They would become the only constant over the last 30 years of phenylephrine history in pressuring the FDA to do something.

Dr. Hendeles published his first critique of the drug in 1993, noting that the agency had monitored two most popular decongestants that were effective and a third that was not: phenylephrine. The medicine was intended to constrict blood vessels and eliminate congestion in the nose. But it was destroyed in the stomach, he wrote in a medical journal. That meant that most of the medication didn’t reach the bloodstream, much less the nose.

In the 2000s, what might seem like an unrelated problem was emerging: Illegal methamphetamine labs in rural areas of the West Coast were exploding, as was abuse of the illicit drug.

The meth cooks’ preferred ingredient was one of the most common decongestants on the market at the time, pseudoephedrine, which could be found at any pharmacy.

By then, it was one of two decongestants available to relieve congestion; a third had been removed in 2000 after studies linked it to strokes.

The methamphetamine crisis led to the passage of state and federal laws to restrict sales of products containing pseudoephedrine, with consumers having to show identification and sign a ledger to purchase it behind the counter or in a locked cabinet. a drugstore.

Worried about losing sales, companies with drugs containing the popular methamphetamine additive turned to the latest FDA-cleared option: phenylephrine.

Dr Hendeles said he was dismayed to see the ingredient in medicines filling pharmacy shelves, knowing that patients were complaining that the replacement was not helping them at all.

He teamed up with a colleague, Dr. Randall Hatton, and dug deeper, analyzing data used in the 1970s for the drug’s initial approval.

Dr. Hatton unearthed memos to the FDA from the 1960s and 1970s that had not been peer-reviewed. He and his colleagues processed the data in modern analysis software. and concluded that the drug It was no better than a placebo.

As his research progressed, Dr. Hendeles attempted to contact the FDA, where he had once been a visiting scientist. He wasn’t breaking through, he said. So he turned to the office of U.S. Rep. Henry Waxman, a campaigning California lawmaker, for help.

Waxman sent four letters, citing the professors’ findings and imploring the agency to act. “The FDA has a duty to provide Americans with the information they need so they don’t waste their hard-earned money on drugs that don’t work.” wrote in a letter in 2006.

He The FDA responded that same year, reaffirming the conclusions of its 1976 decision. The letter suggested that if a consumer did not obtain relief from phenylephrine, “he or she has the option of not purchasing it.”

Dr. Hendeles, the letter said, was free to petition the agency.

And he did. Dr. Hendeles requested a review of dosing and an examination of the drug’s use in children. That led to a public consultation hearing with the FDA in 2007. There, the Consumer Healthcare Products Association, the trade group representing makers of over-the-counter drugs, maintained that the drug worked.

Dr. Hendeles recalled what he considered a spectacular testimony. Representatives of Schering Plow, at the time maker of Claritin-D, which contained the restricted decongestant pseudoephedrine, told their advisers that they had studied its rival, phenylephrine, and found that it had no effect. The company’s newspaper ads touted its “bold move” to maintain Claritin-D’s “powerful formula,” a letter from Mr. Waxman noted.

Still, the advisory committee voted 11 to 1 that “the evidence supports” that phenylephrine “may be effective” and called for more research.

Eight years passed.

Then Dr. Hendeles and his colleagues pounced on a study that came out of Merck, which had acquired Schering Plow. The company tested the drug at the authorized dose and at a dose four times higher, and again found that it did not relieve symptoms. merck also funded a study on a slow release formula.

But that stubborn discomfort in my head (the congestion) did not subside.

(In 2014, Merck sold Claritin-Dwhich still contains pseudoephedrine, to Bayer.)

Florida pharmacists asked the agency for a ban, using the latest study as ammunition. But their efforts were hampered by what many former agency officials described as a beleaguered over-the-counter division, which had 31 employees members in 2018.

Staff had to follow “an arcane process that hamstrung the agency and provided insufficient resources to clear a backlog,” said Dr. Peter Lurie, who was the agency’s associate commissioner until 2017.

The Florida team ran into other obstacles over the years.

After this week’s vote, in posts on XFormerly known as Twitter, Dr. Gottlieb, who was the agency’s commissioner from 2017 to early 2019, called the panel’s decision “a disgrace.” He recalled that “phenylephrine was believed to be weakly active when we looked at this issue around 2005/06. “Now there may not be good, cheap, accessible options for consumers to get incremental relief.”

In an interview Friday, Dr. Gottlieb said he thought more studies were needed on the ingredient. “I think it’s premature to say it doesn’t work,” he said.

Interest in the decongestant was renewed after pandemic legislation expanded the agency’s staffing and revised the FDA’s procedures for over-the-counter drugs so that decisions were more aligned with those of its prescription drug division.

Soon after, the FDA team addressed long-standing problems with the decongestant and produced a thorough and 89 page review of phenylephrine that the advisory panel analyzed as a basis for its decision. (The agency’s report confirmed the findings of Dr. Hendeles and his colleagues, and also noted an apparent bias in some of the data from the 1970s that led to the drug’s initial acceptance.)

“It was a pleasure to read,” Dr. Hendeles said.

When testifying before the panel earlier this week, Dr. Hendeles talked about a 1971 study involving diving masks modified to measure nasal congestion — the first finding that phenylephrine was a failure.

Other organizations, including Public Citizen, the American College of Clinical Pharmacy and the National Center for Health Research, also urged the panel to do without the ingredient. The industry association argued that the ingredient was effective and that low levels in the blood did not nullify its effect. A statement from Kenvue, a subsidiary of Johnson & Johnson, said products with phenylephrine are a small part of its business and it sells cold products without it.

When the agency’s advisers cast their 16-0 vote, Dr. Hendeles was emotional. “Nothing was as exciting and exhilarating as the vote,” he said.

Lawyers representing people who purchased cold and flu medications containing phenylephrine are already announcing lawsuits against the drug makers, alleging that the companies knew the decongestant was useless.

For now, the products remain on the shelves. “We feel vindicated for something we worked on for a long time,” Dr. Hatton said. “But this is not over.”

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