OPDP warns AstraZeneca for misleading Breztri Aerosphere mortality data
The US Food and Drug Administration (FDA) Office of Prescription Drug Promotion (OPDP) has sent a warning letter to AstraZeneca, taking the drugmaker to task over misleading promotional material for its triple-therapy inhaler Breztri Aerosphere (budesonide, glycopyrrolate, and formoterol fumarate).Breztri Aerosphere is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). According to the warning letter, promotional material submitted to the OPDP in FDA Form 2253 implied that Breztri Aerosphere positively impacts all-cause mortality (ACM) and reduces the risk of death in patients with COPD.
The company used data from the Efficacy and Safety of Triple Therapy in Obstructive Lung Disease (ETHOS) trial to support this claim. However, ACM was one of six secondary endpoints in ETHOS and was found to be statistically significant in one comparison in a secondary mortality analysis that appeared 2 years after ETHOS was published.
The primary endpoint in ETHOS was the annual rate of moderate or severe COPD exacerbations. Time to death from any cause was one of six secondary endpoints. The 2019 trial compared both a high and low dose of Breztri Aerosphere (triple therapy) to a long-acting muscarinic antagonist (LAMA), a long-acting beta-agonist (LABA), and two dual therapies: glycopyrrolate/formoterol fumarate (GFF) and budesonide/formoterol fumarate (BFF).
Breztri bested both the LAMA and LABA on the primary endpoint, significantly decreasing both the rate of moderate and severe exacerbations relative to those therapies. But the ACM results, while numerically superior in some comparisons, did not reach statistical significance. The risk of ACM was higher in the lower-dose Breztri Aerosphere group than in the BFF group.
In 2021, a company-sponsored secondary mortality analysis containing previously missing data on 384 of the study’s 8,509 patients appeared in the American Journal of Respiratory and Critical Care Medicine. That analysis concluded that high-dose Breztri Aerosphere conferred a 49% reduced risk of death relative to GFF therapy (unadjusted P = 0.0035) but no significant benefit compared to BFF therapy.
According to the warning letter, AstraZeneca’s advertising material stresses only the 49% difference. Patients also had to withdraw from any inhaled corticosteroid (ICS) before entering the trial, which could have affected the mortality data, the letter noted.
AstraZeneca did include an explanatory note in a supplementary paragraph on its ad, the warning letter pointed out, but it wasn’t enough to clarify the misrepresentation.
“We note the statement below the graph, ‘These results are observational in nature, and any comparisons between treatment arms should be interpreted with caution.’ However, this does not mitigate the misleading impression. To date, no drug has been shown to improve ACM in COPD. The results of the ETHOS trial do not exclude the possibility that the benefits in ACM claimed above may be attributable to chance or to the withdrawal of ICS and not due to Breztri. These claims and presentation are concerning from a public health perspective because they overstate the efficacy of the drug and misleadingly suggest that Breztri will have a positive impact on ACM and reduce the risk of death in COPD patients,” the warning letter said.
A second problem with the ad is its use of a nonsignificant P-value, which OPDP said gives a “misleading impression” of significance.
“The sales aid also includes the following claims: ‘In a 52-week study where patients had a history of exacerbations within the last year, Breztri was the ONLY triple therapy vs. ICS/LABA to show a significant reduction in severe exacerbations [with a] 20% exacerbation reduction vs. ICS/LABA[;] rate ratio: 0.80[;] P=0.02.’
“The presentation of these claims with the associated p-value creates a misleading impression regarding the benefit of the drug by suggesting that Breztri will have a statistically significant reduction in severe exacerbations,” the letter said. “… A p-value is generally understood to indicate statistical significance if it is less than 0.05. Therefore, the inclusion of a p-value of 0.02 in conjunction with the above presentation creates the impression that the reduction in severe exacerbations was statistically significant,” according to the letter.
Again, the letter notes that AstraZeneca attempted to downplay the claim with additional information.
“We acknowledge the footnote, ‘*Based on predefined Type-1 error control plan’ is included following these claims and related presentations. However, this does not mitigate the misleading impression. The presentation is concerning from a public health perspective because it overstates the efficacy of the drug and misleadingly represents that Breztri significantly reduces severe exacerbations.”
These claims make the ad a violation of the FD&C Act. 21 U.S.C. 352(a); 331(a). Cf. 21 CFR 202.1(e)(5) if distributed.
AstraZeneca has 15 working days to reply to the warning letter.
Before this, OPDP’s most recent action was an untitled letter sent on 7 June to Xeris Pharmaceuticals concerning the company’s promotional practices for its high cholesterol treatment Recorlev (levoketoconazole) (RELATED: OPDP hands first untitled letter in twelve months to Xeris, Regulatory Focus, 14 June 2023).
FDA
×
Welcome to the new RAPS Digital Experience
We have completed our migration to a new platform and are pleased to introduce the updated site.
What to expect: If you have an existing login, please RESET YOUR PASSWORD before signing in. After you log in for the first time, you will be prompted to confirm your profile preferences, which will be used to personalize content.
We encourage you to explore the new website and visit your updated My RAPS page. If you need assistance, please review our FAQ page.
We welcome your feedback. Please let us know how we can continue to improve your experience.