Asthma Drugs, FDA Under Scrutiny: A Precautionary Tale

Vol. 14 •Issue 10 • Page 24
Drug Data

Asthma Drugs, FDA Under Scrutiny: A Precautionary Tale

Food and Drug Administration officials, still recovering from the Vioxx scandal, proceeded cautiously when they asked an advisory committee to discuss some popular asthma drugs’ safety. This time, the FDA needed to effectively communicate its concerns to a wary public.

A massive finger-pointing mess ensued when Vioxx, a prescription painkiller, was yanked off the market in September 2004 because it caused heart attacks. The FDA faced criticism for not requiring more than a mild warning for Vioxx, not banning the high-dose formulation, and for allowing direct-to-consumer ads that drastically downplayed Vioxx’s side effects.

Two months later, whistle-blower David Graham, MD, who has been with the FDA for more than 20 years, testified at a Senate hearing that the FDA and its Center for Drug Evaluation and Research (CDER) were “broken.” Dr. Graham is associate director for science and medicine in the FDA’s Office of Drug Safety. “The FDA, as currently configured, is incapable of protecting America against another Vioxx,” he said.

Another Vioxx wasn’t just an elusive threat, according to Dr. Graham. He named asthma drug Serevent® (GlaxoSmithKline) and four other FDA-approved drugs that he thought were hazardous to consumers. He alerted the Senate to reports of people “found dead clutching their Serevent inhalers.”


In July 2005, nearly a year after Vioxx was pulled from the market, the FDA assembled an advisory panel of 13 asthma experts to discuss the safety and effectiveness of two long-acting beta2-agonists (LABAs) — salmeterol and formoterol — in treating asthma. Salmeterol is an active ingredient in Serevent and Advair® (GlaxoSmithKline), a combination product that also contains a corticosteroid. Formoterol is the active drug in Foradil® (Novartis).

“In response to some of the concerns expressed last fall about our communicating safety issues to the public, the FDA is taking a more proactive approach,” said Robert Meyer, MD, director of the FDA Office of Drug Evaluation II in the CDER.

“We felt it would be important to discuss in a public setting what is known about the safety of salmeterol and formoterol, to make sure that our approach to the labeling of these products is in accord with the experts.”


Exactly what’s known about the safety of salmeterol and formoterol is up for debate.

Beta2-agonists had a bad rap from their inception. Safety studies from the 1960s, ’70s and ’80s found an association between beta2-agonist use and increased risk of mortality. When salmeterol, the first FDA-approved LABA, became commercially available, a large surveillance study of primary care physicians in the United Kingdom suggested an increase in mortality in patients taking salmeterol.

The FDA asked GlaxoSmithKline to do a long-term safety study for salmeterol, and in 1996, the pharmaceutical manufacturer initiated the Serevent Multi-center Asthma Research Trial (SMART). Meant to compare salmeterol and placebo in the treatment of asthma, GlaxoSmithKline stopped the SMART study prematurely because study participants were dying in statistically significant numbers.

The data showed a small but significant increase in severe exacerbations and asthma-related death in the group taking salmeterol. When GlaxoSmithKline halted the study in 2003, the FDA required it label both Serevent and Advair with a black box, the FDA’s strongest warning, containing the study’s results.

Novartis, Foradil’s maker, conducted trials that found those people taking the higher dose (24 micrograms) of formoterol suffered severe exacerbations. The FDA approved the lower dose (12 micrograms) for use in the U.S., but it still had concerns about formoterol because it belongs to the same drug class as salmeterol.


Critics charge that these studies were inadequate because they didn’t specifically measure the effects of salmeterol when used in combination with corticosteroids.

In the 1960s and 1970s, asthma was regarded as a bronchoconstrictive disease and only treated with bronchodilators. “One of the things we became aware of in the late 1980s is that asthma is primarily an inflammatory disease,” said H. William Kelly, PharmD, professor emeritus at the University of New Mexico, Albuquerque. “So we started treating persistent asthma with anti-inflammatory therapy.” Yet as doctors increased corticosteroid dosages, patients were at risk for systemic toxicity and still had ongoing symptoms.

Landmark research in the mid-’90s suggested that for patients with inadequate symptom control who are receiving low to moderate doses of inhaled corticosteroids, adding a LABA to their treatment provided greater improvement in lung function and symptom control than simply increasing the dose of corticosteroids.

Subsequent studies showed that if you give an asthma patient the LABA alone, it makes the patient feel better, but the inflammation continues and results in worse exacerbations.

“Now we know that both components are important,” Dr. Kelly explained. “You need to treat the constriction and the inflammation.”

Participants of the U.K. surveillance study weren’t required to take an inhaled steroid at the time, so it may have been that salmeterol was being used as mono-therapy, said Leslie Hendeles, PharmD, professor of pharmacy and pediatrics at the University of Florida, Gainesville.

As for the SMART study, Dr. Hendeles said that the researchers asked patients if they were on an inhaled steroid, and if they said “yes,” the researchers wrote down that the patient was taking an inhaled steroid. “They gave them eight inhalers, sent them on their way, and then telephoned them once a month,” he said. “Poor people who couldn’t afford an inhaled steroid might have taken only the free drug that was given to them.”

It’s unlikely that researchers will ever have a clear-cut answer about the effectiveness and safety of combination therapy with salmeterol and inhaled steroids vs. mono-therapy with salmeterol. It would be unethical for GlaxoSmithKline to conduct such a study, Dr. Hendeles said.

“The sample size you’d need to definitively answer questions about the safety of salmeterol would take tens of thousands of participants,” he said. “You could never again, knowing what we know now, put people on placebo or mono-therapy with salmeterol.”


Without the option of a new study, experts must work with data from the two salmeterol studies and the studies that measured the efficacy of combination therapy. This amalgamation of data is confusing, to say the least.

“It’s a quandary” said Dr. Kelly, who has published more than 80 articles, reviews and book chapters on asthma pharmacotherapy and was co-editor of “Pediatric Asthma.” He was also a pre-meeting consultant to one of the drug companies involved in the July 13 meeting.

On the one hand, Dr. Kelly said, there’s the large SMART study in which patients were given either a placebo or salmeterol, in addition to whatever other therapy they had, and the salmeterol group had an increased risk of dying. On the other hand, there are several small, well-designed trials looking at the effect of combination therapy on asthma, which show a decrease in the risk of severe asthma exacerbations.

“You have this increased risk of death from asthma exacerbations, but you have a decreased risk of having an exacerbation,” Dr. Kelly pointed out. “I think that’s what’s confusing about the whole thing. How do you explain this small, rare, catastrophic event in the face of most of the data showing that you actually decrease the risk of severe asthma exacerbations with combination therapy?”


Though the studies may have been inadequate, and the combined data inconclusive, some of the data indicated a potential danger. “What the FDA calls these are signals,” Dr. Kelly said. “They ask themselves, ‘How important is this signal?'” The FDA heeded these signals and turned to the experts for advice.

During the meeting, the advisory panel listened to presentations by pharmaceutical companies and FDA medical officers, and then the panel answered a series of questions: Should formoterol and salmeterol continue to be marketed in the U.S.? Should formoterol contain a black box or other similar warning? What further investigation is recommended to improve the understanding of risks associated with salmeterol and formoterol?

The panel voted unanimously to keep Serevent, Advair and Foradil on the market. They voted 12 to 1 in favor of making formoterol carry a strong warning; however, the FDA hasn’t yet made an official decision regarding formoterol’s label.

“We’re certainly taking that advice under advisement,” Dr. Meyer said, “and will be moving forward in response to the information we gleaned from the meeting.”

Dr. Hendeles and Dr. Kelly disagreed with the panel’s advice, stating that the data on formoterol were inadequate for the panel to recommend a black box warning.

While the FDA takes the cautious route, asthma patients shouldn’t be discouraged from using salmeterol or formoterol in combination therapy until there’s more conclusive evidence against it, Dr. Kelly said.

“If anything, the SMART study should emphasize the fact that you shouldn’t treat asthma with just beta-agonists and no anti-inflammatory,” Dr. Kelly said. He suggested that the warning should be not to use LABAs as mono-therapy in the treatment asthma.

“Maybe the SMART data are doing something good,” Dr. Hendeles agreed. “Maybe it will get physicians to stop prescribing LABAs as mono-therapy altogether.”

This may all be a lesson in the complexity of medicine management. It’s important that anyone who uses these drugs does so in an informed way, Dr. Meyer said, so that they understand the risks, as well as get the benefits out of the medicine. “Even though this risk has been identified, the overall risk-benefit ratio remains favorable.”

Lauren Constance Everingham is editorial assistant of ADVANCE. She can be reached at [email protected].

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