Why it took the FDA so long to take on a cold drug

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

As opposition to the drug formed, Dr. Hendeles was appearing, at age 80, as an expert to testify before agency advisers, his hair white and his insight into the ingredient spanning 50 years .

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

Spurred on by the news, consumers opened their medicine cabinets to learn that the decongestant phenylephrine was listed in more than 250 of their congestion medications of choice, such as some versions of DayQuil, Sudafed, Tylenol and Theraflu. And the move 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 effective ingredients.

Nothing will change immediately. FDA officials must review the committee’s decision, seek public comment and will most likely give drugmakers some time to adjust or swap ingredients rather than having to make the decision to clear store shelves of so many basic consumer products. Further delays could occur if the companies contest the legal actions. And some experts, including Dr. Scott Gottlieb, a former FDA commissioner, have long argued that phenylephrine works, to some extent. Some drug advocates may attempt to oppose any action to ban the decongestant altogether.

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

Like other federal agencies, the FDA can act glacially, sometimes hampered by outdated rules and a jumble of regulatory procedures.

“There is no question that the regulation of over-the-counter drugs has been violated for many years,” said Dr. Joshua Sharfstein, a former agency official and vice dean of the Johns Bloomberg School of Public Health. Hopkins. The latest steps, he said, indicate that “the agency is only beginning to throw off its handcuffs.”

It could be argued that the process of dissecting phenylephrine – a drug used to dilate the eyes and calm hemorrhoids – took around six decades. The Kennedy era had 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, like phenylephrine, as a class of drugs.

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

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

Dr. Hendeles published his first review of the drug in 1993, pointing out that the agency was monitoring two more popular decongestants that were effective and a third that was not: phenylephrine. The medicine was intended to constrict blood vessels and clear nasal congestion. But it was destroyed in the stomach, he wrote in a medical journal. This meant that most drugs did not reach the bloodstream – much less the nose.

By the 2000s, what seemed like an unrelated problem was emerging: Illegal meth labs in rural areas on the West Coast were exploding, as was abuse of the illicit drug.

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

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

The meth crisis resulted in state and federal laws to restrict sales of products containing pseudoephedrine, and consumers had to show identification and sign a register to purchase it behind the counter or in a locked cabinet in a pharmacy.

Fearing losing sales, companies offering drugs containing the popular additive methamphetamine have turned to the latest FDA-authorized option: phenylephrine.

Dr. Hendeles said he was dismayed to see the ingredient in medications lining pharmacy shelves, knowing that patients were complaining that the replacement didn’t help them at all.

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

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

As their research progressed, Dr. Hendeles attempted to reach the FDA, where he had once been a visiting scientist. He couldn’t break through, he said. So he turned to the office of U.S. Rep. Henry Waxman, an activist California lawmaker, for help.

Mr. 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 do not waste their hard-earned dollars on drugs that don’t work,” he wrote in a 2006 letter.

The FDA responded that same year, reiterating the findings 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 it. Dr. Hendeles requested a dosage review and review of the drug’s use in children. That led to an FDA public advisory hearing in 2007. The Consumer Healthcare Products Association, the trade group that represents over-the-counter drug makers, argued that the drug was effective.

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

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

Eight years have passed.

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

But that nagging complaint – congestion – hasn’t budged.

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

Florida pharmacists requested a ban from the agency, using the latest study as ammunition. But their efforts were thwarted by what many former agency officials described as a beleaguered OTC division, which had 31 employees in 2018.

Staff had to follow “a murky process that handcuffed the agency and provided insufficient resources to clear a backlog,” said Dr. Peter Lurie, who served as associate commissioner at the agency until 2017 .

The Florida team has faced other obstacles over the years.

After this week’s vote, in messages onformerly known as Twitter, Dr. Gottlieb, who served as the agency’s commissioner from 2017 to early 2019, called the committee’s decision “shameful.” He recalled that phenylephrine “was considered weakly active when we looked at this issue around 2005/06. Today, there may no longer be good, cheap, accessible options for consumers to obtain graduated relief.

In an interview Friday, Dr. Gottlieb said he thinks more study on the ingredient is needed. “I think it’s premature to say it’s not working,” he said.

Interest in the decongestant was renewed after pandemic legislation expanded the agency’s staff and overhauled the FDA’s procedures for over-the-counter drugs so that decisions were more aligned with those of its Division of Medicines. prescription medications.

Soon after, the FDA team looked into long-standing problems with the decongestant, producing a careful 89-page study of phenylephrine that the advisory committee reviewed to base 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 joy to read,” Dr. Hendeles said.

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

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 negate its effect. A statement from Kenvue, a Johnson & Johnson spinoff, said products containing phenylephrine make up only a small part of its business and that it sells cold products without it.

When the agency’s advisers voted 16-0, Dr. Hendeles was over the moon. “Nothing was as exciting and exhilarating as voting,” he said.

Lawyers representing people who bought cold and flu medications containing phenylephrine have already announced lawsuits against the drugmakers, saying the companies knew the decongestant was useless.

For now, the products remain on the shelves. “We feel vindicated for something we’ve been working on for a long time,” Dr. Hatton said. “But it is not finished.”