The FDA-mandated trial of safety of long-acting beta-agonists in asthma: finality or futility?
Bibliographic record
Abstract
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 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 Figure 1 Timeline 1990–2012 of key long-acting beta-agonists (LABA) publications and Food and Drugs Administration (FDA) actions. FDA, Food and Drugs Administration; PAC, Paediatric Advisory Committee; PADAC, Pulmonary, Allergy Drugs Advisory Committee; RCT, randomised controlled trial; SMART, Salmeterol Multicentre Asthma Research Trial; SNS, Serevent National Surveillance. 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 …
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".