THURSDAY, NOVEMBER 29, 2012 • T HE BULLETIN F S
M EDI C I N E
Asthma
Possidle dangersin asthmadrugs
Continued from F1 Asthma, which affects an estimated 25 million Americans, is caused by inflammation and swelling of the airways in the lungs as well as constriction of those airways. Long-acting beta-agonists, which treat airway constriction, work by relieving routine, day-to-day symptoms. Inhaled corticosteroids treat inflammation. Advair was considered a breakthrough in convenience b ecause i t c o m b ined t h e GlaxoSmithKline b e t a-agonist, Serevent, with an inhaled steroid. Advair and similar drugs are considered appropriate treatment formore severe cases of asthma where the condition can't be controlled with just a steroid. But a 2010 study by Medco Health Solutions found that nearly two-thirds of mild asthma patients were taking the combination drug — often without trying a steroid first. One theory from researchers for why Advair and similar drugs bring increased risk of deadly attacks is that the longacting beta-agonists can mask w orsening inflammation i n the lungs. Patients feel better in the short term, but it may set them up for a catastrophic asthma attack down the road. At a 2008 FDA advisory panel meeting reviewing the
and constriction of airways. Inhaled corticosteroids are the main treatment for many. For some, aseconddrug,known asa long-acting beta-agonist,may beprescribed.Some drugs,suchas market leader, Advair, combine both a steroid and a long-acting beta-agonist. However,
long-acting beta-agonists have been linked to an increased risk of asthma deaths.
The risk involved One theory from researchers for why Advair and similar drugs bring increased risk of deadly attacks is that the long-acting beta-agonists can mask worsening inflammation; patients feel better in the short term, but may suffer a catastrophic asthma attack down the road.
A
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no way or predicting who's going to end up in the cemetery because of Advair." In 2010, when the agency approved mor e l a r ge-scale safety trials of the drugs, some of itsown researchers called doing so unethical because it could put tens of thousands of patients at risk, according to a transcript. Such trials would be especially dangerous for children, agency p hysician A n d r ew Mosholder w a rned, n o ting children "can't give consent themselves and o n e c o uld argue the ethical burden is greater to protect." The trials, which are not expected to yield results until 2017, will involve 46,800 adults and adolescents aged 12 and older. A separate trial involving 6,200 4- to 11-year-olds also is being conducted. FDA spokeswoman Morgan Liscinsky noted in an emailed statement that i n 2 010, the agency instituted new safety requirements for the drugs, including that they should be used foronly the shortest duration necessary to achieve control of symptoms and then discontinued if possible. In addition, the agency has said long-acting beta-agonists should only be used with a steroid. The agency also issued warnings in 2006 about the increased risk of deadly attacks. Liscinsky said the FDA believes the benefits of the drugs outweigh the risks when they are used properly. GlaxoSmithKline s p okeswoman Karen Collins said the company stands by the safety and its promotion of Advair. She said the remarks from the Las Vegas meeting — described infederal court documents — were taken out of context, and do not reflect "the company we are today." " It i s absolutely against GSK's policies and practices to inappropriately influence prescribing decisions," she said.
Criminal allegations In July, GlaxoSmithKline
agreed to pay a record $3 billion to settle criminal and civil allegations filed by the U.S. Department of Justice that it unlawfully promoted several drugs, including Advair. The government a l leged that the company fraudulently pushed Advair as a first-line therapy for mild asthma patients, though it was not approved or medically appropriate for such cases. In addition, the company paid kickbacks to doctors to induce them toprescribe and recommend Advair and other drugs, according to the complaint. The payments included speaking and consulting fees; gifts, travel and entertainment costs; payments for serving on "sham advisory boards;" and continuing medical education
programs.
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drugs known as long-acting beta-agonists goes back
during the 28-week study period, compared with only three
asthma and respiratory causes
to the1990s when a large clinical trial in Great Britain of the GlaxoSmithKline drug Serevent produced disturbing results. In that 16-week trial of 25,000 asthma patients, 12 people getting the drug died
who gota placebo.
of asthma andrespiratory causes, compared with only
are inhaled drugs that are sold
two in the control group who tooka standard medication,
be combined in an inhaler with a steroid.
In addition, there were 193 hospitalizations or life-
steroid combination product is Advair, sales of which have
in the users of the new drug,
research firm IMS Health.
It is not known why Afri-
can-Americans may bemore vulnerable to the effects of salmeterol. One theory involves genetic variations in cells in
the lungs. Long-acting beta-agonists assingleagents.Theyalsocan The leading beta-agonist/
compared with102 in the other Another long-acting betaagonist, Foradil (formoterolj group. The serious concerns raised also is available as asinglein the first trial of Serevent, agentandasthecombined also known as salmeterol, led product Symbicort, made by to a second large study of the AstraZeneca. drug several years later in the In an email, GlaxoSmithKline United States. spokeswomanKarenCollins
Bronchus
Bronchioles
getting salmeterol, 15 died of
threatening events related to topped $4 billion ayear since asthma and respiratory causes 2007, according to the market
In people with asthma, inflammation can be treated with an inhaled steroid; constriction in those airways can be treated with a long-acting beta-agonist.
Trachea —,' ~
MILWAUKEE — The troubled history of asthma
according to a1993 paper.
4 $ $ 5 5
Reduced airflow
That trial was halted by
said studies consistently have
GlaxoSmithKline, in part beshown that Advair provides cause of excess deaths among better overall asthma control
0
African-Americans.
than just an inhaled corticoste-
Researchers hadhoped to
use ofthe drugs, agency physician David Graham questioned whether it was worth putting an entire population on the drugs just to find that occasional patient who gets better control of hi s or h er asthma, according to a transcript of the meeting. "We have no way of identifying who's going to have that miraculous response to Advair," he said, "just as we have
1990s trial provided early warning signs for asthma drugs
More than 25 million Americans have asthma, a disease that causes inflammation in the lungs
Sources:seekingalpha.com, webmd.com, asthma.com, Journal Sentinel research Graphic: Enrique Rodriguez, Milwaukee Journal Sentinel
Alveoll Air sacs where oxygen and carbon dioxide are exchanged
< ~Ur=
roid, including improvements in lung function, symptom
study 60,000 people in the trial, but only 26,000 people
control and less use ofshortacting rescue inhalers.
had been enrolled when it was
Mucus
stopped in 2003. A 2006 paper that detailed the results of the U.S. trial noted there were 37 asthmaand respiratory-related deaths
Enrique Rodriguez, Milwaukee Journal Sentinel /© 2012 McClatchy-Tribune News Servicc
She said both Advair and
Serevent have improved asthma care. "These medicines areused by millions of people world-
in those receiving salmeterol,
wide and in the vast majority
compared with 14 among
of people treated, they are well tolerated," she said. — John Fauber, Mihvaukee Journal Sentinel
those on usual asthmamedication who also got a placebo.
Collins, o f Gl a x oSmith- the w atchdog o rganization companies. The amount was Among African-Americans Kline, said the company dis- ProPublica. not required to be listed. putes the government's allegaAcademy President Wesley tions and said there was not a Conflicts of interest Burks said the group has been corporate strategy to promote The M ilw a u k ee-based active in disseminating balIn addition to the estimate deaths in other research inAdvair f or ina p p ropriate A merican Academy of A l - anced information about the b y A d verseEvents Inc . o f volving 18,000 Advair patients. patients. lergy, Asthma & Immunology, drugs. On its website, he said, nearly 1,900 deaths between But th e 1 8 ,000 n u mber "The company reached which serves doctors and pa- it clearly mentions the risks 2004 and 2011, long-acting comes from 86 separate clinithis settlement with the gov- tients, has played an advocacy and proper use of the drugs. beta-agonist products were cal trials sponsored by the "As with most medications," the primary suspect in 3,500 company. ernment to avoid the delay, rolefor the drugs. Since 2008, expense, inconvenience and companies that market long- Burks wrote in an email, "there hospitalizations in that period, T he fact t h a t s o m a n y uncertainty o f pro t r acted acting beta-agonists have pro- are risks and benefits which according to the firm. Advair separate, smaller trials were litigation of the government's vided $4.7 million to the group. must be carefully weighed in was the drug used in a vast involved can make a critical claims and to put behind us A bout $2.6 million o f t h at every situation." majority of the cases. difference, especially when these long-standing investiga- came from GlaxoSmithKline. Eric Campbell, an associate The firm uses its own soft- looking for u n usual occurtions of what was, for the most An example: When the FDA professorat Harvard Medical ware to analyze reports of rences such as asthma deaths, part, very old conduct," she held a hearing on the drugs in School, said there is an abun- drug sideeffects to the FDA's said Sanjay Kaul, a physician said. 2008,Stanley Szefler spoke on dant supply of experts without Adverse E v ent R e p orting who has served on FDA adviThe financial links between behalf of the academy, testi- financial conflicts. He said System. Firm President Brian sory panels and is considered the asthma drug companies, fying it would be a disaster if doctors who have worked as Overstreet said the FDA's vol- an expert on drug safety data the medical associations that the drugs were taken offthe speakers for drug companies untary system is known for and clinical trial design. promoted the drugs and the market. should not be allowed to serve capturingas few as 10 percent In large clinical trials, pa"I don't think you want to doctors who wrote treatment on treatment guideline panels. of such cases. tients are t y pically d ivided "Physicians should not be guidelines that recommended walk away from this meeting The estimate of 14,000 ex- into groups with similar risk the drugs followed a pattern and have a headline that this part-time drug salesmen," he cess asthma deaths between factors such as age,the severidentified with other drugs in panel decided to draw back said. 1994 and 2007 came from Gra- ity of their disease and the othearlier investigations by the asthma to 20 years ago," Szeham, the FDA researcher who er drugs they are taking — all Journal Se n t i nel/MedPage fler, a doctor with the National An elusive number warned that Advair might be of which can affect mortality. Today. Jewish Medical and Research Putting a reliable number putting people in the cemetery. That can vary significantly In 2007, the National Heart, Center in Denver, told the pan- on asthma deaths and severe That number is based partly acrossso many trials. "Zero deathsreported from Lung and Blood Institute isel members. attacks caused by Advair and on estimates using findings sued new guidelines for treatSzefler, who did not reply other long-acting beta-agonist from two l arge clinical tri18,000 patients in 86 differing asthma that included this to a request for comment, also drugs has evaded researchers als, both of which looked at ent trials doesn't supply any recommendation: Long-acting was a member of the panel and regulators, in part because Serevent, GlaxoSmithKline's evidence of reassurance," said beta-agonists should be the that issued the asthma treat- overall asthma deaths have beta-agonist drug, as a single Kaul, a Los Angeles physician preferredadd-on treatment to ment guidelines in 2007. At the been declining since the late agent. who alsoserves as director of combine with inhaled steroids, time he listed financial rela1990s to about 3,300 a year. Those estimates were dis- the vascular physiology and both in adults and children tionships as a consultant and Estimates of deaths related puted by Collins, the Glaxo- thrombosis research laboraaged 12 and older. adviser to GlaxoSmithKline to long-acting beta-agonists SmithKline sp o k eswoman, tory at C edars-Sinai Heart Of the 18 members of the and several other asthma drug have varied widely. who said there were no such Institute. panel that wrote the guidelines, 15 had financial ties at the time to GlaxoSmithKline or other companies that market beta-agonists, according to research bythe Journal Sentinel/MedPage Today. The chairman of the panel, William Busse, is a doctor and professor at the University of Wisconsin School of M e dicine and Public Health, whose financial relationships with asthma drug makers include years of work as a paid adviser, speaker and consultant. At the time the guidelines were issued, Busse disclosed that he worked as a speaker and adviser for GlaxoSmithlocg/ go+. Kline and several other drug companies, though specific amounts of money were not listed. Another UW professor who served on the panel, physician Robert Lemanske, also had financial ties to the companies. His financial conflicts required that he get a special waiver from the FDA so that he could speak at it s 2008 hearing on the drugs. In emails, both Busse and Lemanske said they followed the panel's rules for transparency and for managing conflicts of interest. Precisely how much they and the other panel members were paid at the time could not be established. Only recently, in the face of new rules passed by C o ngress, have some drug companies publicly listed their payments to doctors and academics. we're the local dog. we better be good. 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