ProPublica opens up the Advair vault, raises safety and marketing ethics questions
Defining an unmet medical need, and then suggesting an effective way to address that need, is the first step in any well-planned medical marketing campaign. Clearly, there is an unmet medical need around the treatment of asthma. All told, 25 million Americans have asthma, including seven million children. Each year, there are roughly 400,000 asthma-related hospitalizations and 3,500 asthma-related deaths.
When GlaxoSmithKline’s Advair (fluticasone/salmeterol) was approved in 2000, it was considered a breakthrough treatment for patients with moderate-to-severe asthma. As a dual-combo drug, with a metered-dose inhaler, it combined an inhaled corticosteroid (ICS), fluticasone, with the long-acting beta-agonist (LABA), salmeterol. For many patients with severe asthma, who needed multiple medications each day to control their asthma, Advair was a godsend—a first-in-class treatment to address the most intensive needs associated with the pathophysiology of asthma, the need to reduce inflammation, and the need to open the airways.
However, over the last 15 years, over-utilization of Advair in inappropriate patient populations—those with mild asthma or asthma that can actually be sufficiently controlled with an ICS—has become a cautionary tale of too much of a good thing, and the impact of overprescribing in inappropriate populations. According to a recent investigative report by ProPublica, the April 2001 launch of Advair was an all-out extravaganza in which sales reps were exhorted to sell, sell, sell the product. Moreover, according to the article, the gist of the marketing message from GSK was that Advair was an appropriate treatment for most patients with asthma.
Even as GSK was flexing its marketing muscles, a safety issue related to salmeterol, the LABA component of Advair, was lurking in the background. A salmeterol safety trial initiated in 1993 had shown a trend toward an increased risk of death in patients taking the drug. And although by 2000, when the FDA was reviewing Advair, the salmeterol safety data was already out there, GSK presented enough safety and efficacy data to gain approval.
Around this time, experts started to debate potential safety issues around salmeterol. One line of reasoning was that adding an ICS to salmeterol could neutralize the negative effects of salmeterol, while allowing patients to benefit from its airway-opening benefits. Salmeterol safety trials are ongoing, and by 2017, researchers will be able to release even more data detailing the specific risk factors that increase the risk of death.
Another study, the SMART (Salmeterol Multicenter Asthma Research Trial) study, which started in 1996, included more than 26,000 subjects and has become the largest asthma trial ever conducted. This trial, which was designed as a 28-week, placebo-controlled, double-blind, randomized study, was continued for years beyond the original study period. But in 2003, researchers halted the trial when they concluded that asthma-related deaths in salmeterol patients were four times higher than in placebo-treated patients. In fact, Harvard professor and statistician David Schoenfield, MD, reviewed the data and concluded that use of salmeterol resulted in one excess death for every 700 patients with a year of exposure.
The problem of overutilization
In addition to compelling safety data suggesting increased risk, there were heartbreaking reports of sudden asthma-related deaths in Advair-treated patients. In one case detailed in the ProPublica article, a high school student in rural Pennsylvania died several months after starting Advair treatment. Although she did not have severe asthma and only suffered a few attacks per year, this young athlete was prescribed Advair.
In the case of Lisa Wade, convenience was a major deciding factor, but unfortunately she was not an ideal candidate for Advair. In fall 2002, Wade died from an acute asthma attack that killed her within a matter of minutes.
Differentiating a medical need from a marketing goal
While existing unmet medical needs represent a real challenge, the problem of overutilization and inappropriate use can be just as bad as undertreating a medical condition. In fact, overutilization can be fatal.
By 2005, almost five years after Advair was approved, the FDA required that manufacturers of ICS/LABA products change their labels. The updated labeling warned that Advair should only be prescribed for patients whose asthma was not able to be properly controlled with an ICS and where there was clear evidence that more medication was needed.
There were additional efforts to decrease use of Advair in inappropriate populations, including crackdowns in some state Medicaid programs, such as Arkansas, where patients with mild asthma were routinely prescribed Advair.
Suddenly, the battle was on: There were FDA meetings, editorials about Advair overprescribing in peer-reviewed journals, a push by lawyers to uncover internal GSK documents and a spate of legal settlements in which hundreds of thousands, if not millions, of dollars were given to the family of patients who died after taking Advair.
Finally in 2010, an FDA-mandated safety study, which focused on utilization practices, confirmed a decade of Advair overprescribing and misuse. And as Advair sales continued to grow—from $1.4 billion in 2001 to almost $8 billion per year by 2008—the Justice Department closed in. In 2011, the DOJ filed a criminal fraud complaint against GSK regarding overutilization of Advair in inappropriate patients.
All told, Glaxo ended up paying $700 million for illegally marketing Advair to inappropriate patients. Fifteen years post-approval, Advair safety trials are continuing, with study populations segmented by age, asthma severity, genetics, and other factors.
Updated label and responsible marketing
Advair’s label was updated in 2008 with a black-box warning “Risk of Asthma-Related Death.” According to the warning, “LABAs, such as salmeterol, one of the active ingredients in ADVAIR DISKUS, may increase the risk of asthma-related death. Therefore, when treating patients with asthma, physicians should only prescribe ADVAUR DISKUS for patients not adequately controlled on other asthma-controller medications (eg, low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies.”
In reality, effective treatment of severe asthma remains an unmet medical need, with many patients with severe asthma insufficiently controlled either due to lack of access, lack of adherence, or lack of appropriate diagnosis. According to Dr. Peter Barnes, who wrote about the challenges of treating patients with severe asthma in the Journal of Allergy and Clinical Immunology in 2012, “In the future, it will be necessary to find biomarkers that predict response to specific forms of [asthma] therapy.”
Marketing any therapy, including an asthma therapy, requires a responsible approach underscored by sound clinical understanding and an understanding of treatment dynamics in real-world settings. While creativity and the ability to inspire positive action can help create a sense of urgency and drive product uptake, these skill sets must be used in the best interest of patients. Failure to do so can be both expensive and deadly.