In 2010, in response to a prolonged debate over the safety of long-acting beta-agonists (LABAs), the United States Food and Drugs Administration (FDA) issued guidelines for the use of LABAs in asthma,1 and mandated a very large trial examining the safety of LABAs used with concomitant inhaled corticosteroid (ICS).2 Strong voices have called for new safety data,3 ,4 while others have expressed doubt regarding the need for, and likely outcomes of, new trials.5 ,6

Events leading to the FDA-concerns over LABA safety

Controversy regarding safety has surrounded the use of long-acting beta-agonists in asthma virtually since salmeterol (Serevent, GlaxoSmithKline) was introduced into clinical practice in the UK in 1990 (figure 1). Studies showed greater control of asthma with addition of salmeterol to ICS compared with increased doses of ICS7 ,8 and reduced airway responsiveness to allergen challenge, which some interpreted as evidence of anti-inflammatory activity.9 The enthusiasm for salmeterol was dampened in 1993 when Castle et al published results from the large Serevent National Surveillance study showing a statistically insignificant (p=0.10) but worrying threefold increase in mortality in patients prescribed regular salmeterol compared with regular salbutamol therapy.10

When salmeterol was launched in the US in 1994, the FDA required a post-marketing safety study. The Salmeterol Multicentre Asthma Research Trial (SMART) study began in 1996 but was terminated in 2003 with incomplete recruitment because of adverse outcomes on asthma exacerbations and mortality.11 Also in 2003, the FDA expressed concerns about increased exacerbations in adults and children using the Novartis formulation of inhaled formoterol in …