Millions of Americans want to quit smoking. Critics say drugmakers and the FDA are failing them

WASHINGTON — Of the roughly 15 million Americans who tried to quit smoking in 2022, 5 in 6 failed. It’s a jarring statistic — and an indictment of the treatment options for an addiction that kills 480,000 people in the U.S. each year.

The smoking-cessation drugs on the market don’t work well for the majority of people, and they come with side effects and reputations that keep some smokers from ever trying them. Despite this, there hasn’t been a new class of drug approved for the condition in nearly two decades. 

It’s a situation that in most other areas of medicine would be unacceptable, argued Nora Volkow, the head of the National Institute on Drug Abuse. “We should not be passive about it. We’re not passive about any other condition,” she told STAT. “Look at HIV, how many antiretrovirals do we have? Look at Covid, how many vaccines do we have?”

But the approach in both Washington conference rooms and pharma board rooms has been lackadaisical. Drugmakers have largely written off the expensive and time-consuming work of investigating new ways to treat the addiction for fear that their eventual product wouldn’t be profitable enough to warrant the effort: After all, most adult smokers don’t use the existing approved low-cost drugs when trying to quit, and insurance coverage is spotty. On top of that, the Food and Drug Administration, which is known for its flexibility and willingness to work with drugmakers in other areas of medicine, has been skeptical of new anti-smoking drugs, making the whole endeavor even less enticing.   

Instead, most pharma powerhouses have focused on developing pricier drugs for conditions like rare cancers — though seven times as many Americans attempt to quit smoking every year than the total number diagnosed with any cancer. While the gold standard smoking-cessation drug, Pfizer’s Chantix, once grossed over $1 billion a year, that’s no longer enough to excite drugmakers, who have become accustomed to bringing in $5 billion and even $10 billion a year for blockbuster drugs.

“In this day and age for a big pharmaceutical company, that doesn’t quite cut it,” said John LaMattina, who served as president of Pfizer Global Research and Development during Chantix’s launch.

Advocates, and even former FDA officials, say the FDA’s drug center, known as CDER, deserves a large measure of blame. It’s delayed approval of two potential new treatment options in the last five years alone. The agency’s approval standards for anti-smoking drugs are unreasonably stringent, they argue. In particular, they point to the FDA’s insistence on complete abstinence as the preferred endpoint for studies of new therapies, which ignores people who reduce cigarette use but don’t completely stop. 

“CDER has not been responsive to the need for innovation in this area,” said Dennis Henigan, vice president of legal and regulatory affairs at the Campaign for Tobacco-Free Kids. The campaign, like STAT, receives funding from Bloomberg Philanthropies.

The FDA, for its part, acknowledges that new treatments are needed, and it has scheduled a public meeting in October with the National Institutes of Health to discuss potential new smoking-cessation options. But the agency says it is not solely to blame.

“I understand the disappointment, because we haven’t had an effective treatment for quite a long time, and I understand the frustration,” said Marta Sokolowska, deputy center director for substance use and behavioral health in CDER. “Unfortunately we all have to work on it together.” 

Cigarette smoking is the leading cause of lung cancer globally — but the tremendous progress in treating lung cancer over the last decade stands in stark contrast to the lack of advancement in drugs to help fight the addiction in the first place. 

Since 2020, there have been more than two dozen drugs approved for lung cancer, which strikes about 235,000 Americans annually. The five-year life expectancy for someone with the disease has increased 22% over the last half decade, according to the American Lung Association.

That progress makes the drugs used to prevent cigarette smoking seem archaic. 

Chantix increases smokers’ success at quitting when compared to a placebo — but for every 100 people who use it, just 21 to 25 successfully stop, a recent meta-analysis found. It’s also associated with a raft of side effects, ranging from nausea to vivid dreams. Chantix, also known by its chemical name, varenicline, went generic in 2021 and can be purchased without insurance for roughly $68 for a one month supply, according to GoodRx. 

There is also a 39-year old antidepressant, bupropion, which is believed to help reduce withdrawal symptoms in smokers by mimicking some of the effects of nicotine on the brain, though the drug is considered less effective than Chantix.

Beyond bupropion and Chantix, which partially blocks the pleasurable effects of nicotine in the brain, most of the options available to smokers simply deliver nicotine in a safer way than cigarettes, staving off withdrawal. 

There are so-called nicotine replacement therapies, which deliver the addiction-driving nicotine without the cornucopia of carcinogens in a cigarette. Those have been around since 1984, but their success long-term is questionable. One study found that smokers who used these products were no more successful long term at kicking the habit than those who went cold turkey. Other research has found that certain nicotine replacement therapies worked better for men than women. 

Researchers insist that it does not have to be this way. They’re teeming with theories on how to treat nicotine addiction, ranging from enzymes that break down nicotine in the body before it ever hits the brain to designing pills to target receptors in the body that can reduce smokers’ “appetite” for nicotine, to repurposing the wildly popular GLP-1 anti-obesity drugs. 

But most of these notions have yet to be tested in humans, and other plausible ideas of how to treat the addiction have previously failed in clinical trials. Pfizer, GSK, and Novartis, for example, all attempted to develop a nicotine vaccine years ago that would block the pleasurable effects of nicotine on the brain. Pre-clinical studies suggested the vaccines worked, but they all failed once injected into humans. 

Most of the large pharmaceutical companies that once had a smoking-cessation program — including Pfizer and Novartis — have since abandoned that work. Pfizer told STAT it discontinued research in this area around 2016, and Novartis said it also has no smoking-cessation drugs or vaccines in its pipeline. Neither explained the decisions. Meanwhile, biotechs pursuing anti-smoking treatments are rare, because venture capital investment is virtually non-existent. 

“I really hope someday … some of the research will be translated to humans,” said Olivier George, a professor of psychology at the University of California, San Diego who worked on the nicotine-blocking enzyme. “However, I’m not delusional and I know that based on the investment from the private sector right now, I don’t see it’s possible.”

George, who himself is a smoker, added: “Maybe after I die, they will pick up some of those ideas.”

Achieve Life Sciences, a Washington-based biotech, is one of the few drugmakers still working on smoking-cessation treatments, and its experience with regulators is a cautionary tale. 

Achieve is hoping to earn FDA approval to sell cytisine, a drug that has been used in Eastern Europe since the 1960s. While it is believed to work like varenicline in the brain, clinical studies have shown users are less likely to experience side effects such as nausea. 

The company’s Phase 3 trial, published in July 2023, found that a quarter of participants who got a six-week course of the drug, and roughly a third of participants who took it for 12 weeks, were not smoking by the last four weeks of treatment. Just 4.4% and 7% of people taking placebo were abstinent over the same time period.  

Achieve has since run head-on into skeptical FDA officials.

The agency requested last year that the company conduct a year-long safety trial for the drug. The need for such a study wasn’t disclosed to Achieve in any of its planning meetings with regulators, forcing the company to scramble and delay the expected filing of an application with the FDA by about a year, according to John Bencich, Achieve’s former CEO who now serves as an adviser. The company is currently enrolling participants for that study and expects to file with the FDA in the first half of 2025, according to a company press release. 

“It’s frustrating to have the goal post moved late in the game,” said Bencich. “If we could have known that they wanted this sooner, we could have already been in a position to file. We would have just built this dataset into our development plan.”

GlaxoSmithKline similarly received a cool reception when it filed an application for approval of a nicotine mouth spray that it argued worked better than other nicotine replacement therapies because it was more quickly absorbed into the bloodstream. The product was already marketed in 45 countries, and was shown in a Phase 3 trial to roughly double smokers’ chances of quitting. However, FDA officials questioned whether the drug was a meaningful advance over similar products already on the market.

While the drug was endorsed by an independent FDA advisory panel in 2019, it was never approved.

Public health advocates argue that the agency’s history of slow-walking new smoking-cessation treatments is not happenstance. Rather, they say that the agency’s drug center has been unnecessarily conservative when reviewing these drugs given the number of deaths caused by cigarette smoking each year.

“What we need is a regulator that brings a genuine public health perspective to this,” said Mitch Zeller, who previously led the FDA’s tobacco center and is now advising a company developing a smoking-cessation device. “It’s not about weakening standards [but] what’s wrong with this picture that there have been no new authorized products in almost 20 years?”

The FDA says that makers of a smoking-cessation drug, like a nicotine-replacement therapy, must demonstrate that more people completely abstain from smoking while taking the drug than abstain while taking a placebo. This means that even smokers who can significantly cut down the number of cigarettes they smoke while taking a drug are viewed as failing therapy — despite the fact that most medical experts acknowledge that smokers often relapse while trying to quit and that reducing smoking is still a major win for their health. 

Critics say it’s a remarkably high bar for an agency that has recently approved drugs, like the muscular dystrophy drug Elevidys and the Alzhimer’s drug Aduhlem, that technically failed in clinical trials because regulators saw a hint of promise for patients desperate for help. 

The approach also is out of step with how it reviews drugs for addictions to substances like cocaine and methamphetamine. In an October 2023 document, the FDA wrote that it would judge a drug treating these conditions not based on how many people stopped using the drugs completely, but instead based on whether users reduced the frequency of their drug use.

FDA’s insistence of abstinence “basically makes no sense,” according to Volkow, the NIH official.

“As a psychiatrist I can tell you … there are very few antidepressants … that completely remove the depression, it reduces the severity. The same thing with analgesics, the FDA is approving drugs that reduce the severity of pain, but they are very rigid when it comes to approving an intervention that will reduce the amount of cigarettes you are taking.”

Several leading tobacco control organizations petitioned the FDA 14 years ago to rethink its standards for nicotine-replacement drugs. The groups complained that the “FDA‘s own stringent limitations” may have “served as an undue disincentive to would-be manufacturers of such products to invest in a new generation of treatments.” The groups also took the unusual step of asking that review of tobacco cessation products be transferred to an entirely different office within FDA.

The FDA rejected the majority of the group’s requests.

In 2019, GlaxoSmithKline wrote to the FDA urging the agency to take several steps that would align its approach toward regulating NRT products with other nations’. Specifically, the drugmaker requested that the agency embrace a “Reduce to Quit” approach, whereby smokers are encouraged to use products like nicotine gum as they gradually reduce their cigarette consumption. 

While the FDA has said it is open to this approach, which is used in countries like Germany, Canada, and the United Kingdom, the agency issued a guidance last year instructing drugmakers they would need to conduct a trial to evaluate the proposed regimen. GSK has warned that the need for another study “will make it less likely for innovator companies to pursue this indication in the U.S.”

Sokolowska, the FDA official, told STAT that the 2023 guidance for industry was intended to make it easier to develop new smoking-cessation drugs, particularly nicotine-replacement therapies, by outlining how to simplify efficacy studies, and highlighting that drugmakers could potentially qualify for FDA fast-track approval pathways.

FDA Commissioner Robert Califf also met with executives from Haleon, which now runs GSK’s smoking-cessation business, in November 2023. The meeting was about “Regulatory Process for Approval of New Nicotine Replacement Therapy Products,” according to public records. Haleon did not respond to requests for comment, and it’s unclear whether the nicotine spray was discussed during the meeting. 

On the ongoing concern about the FDA’s focus on abstinence as the only meaningful endpoint for approval of a smoking-cessation drug, Sokolowska said: “If any other endpoints are being considered, we have to have strong data of the impact, to make sure that it’s impactful for the patients.”

If there was ever a time to propose such a rethink of FDA’s standards, it was earlier this year when the federal health department released a sweeping plan to “Support and Accelerate Smoking Cessation.” 

That plan included delivering smoking-cessation services where people “live, learn, work, play, shop, and worship,” expanding public education campaigns around the dangers of smoking, and working with insurers to remove barriers to smokers accessing anti-smoking drugs. 

While one of the six pillars of the plan was to “Promote Ongoing and Innovative Research to Support and Accelerate Smoking Cessation,” the closest the document got to explicitly calling for new treatments came in a vague proclamation to support “research on new cessation interventions and treatment approaches, including research on culturally appropriate and responsive interventions, interventions for those with non-daily use patterns, and interventions for relapse prevention.”

“It’s disappointing,” said Henigan, regarding the strategy’s lack of focus on new treatments. “And this is after years of advocacy by the public health community.” 

STAT’s coverage of chronic health issues is supported by a grant from Bloomberg Philanthropies. Our financial supporters are not involved in any decisions about our journalism.