The FDA’s Office of Prescription Drug Promotion (OPDP) Aug. 4 issued its first Warning Letter in more than a year. The enforcement letter to AstraZeneca Pharmaceuticals LP alleged that a professional sales aid for Breztri Aerosphere made false or misleading claims and/or representations about the efficacy of the drug and requested corrective communications.

Prior to the Aug. 4 Warning Letter, the last Warning Letter issued by OPDP was a February 2022 Letter to CytoDyn Inc., over a video interview posted on the company’s website.

Breztri Aerosphere (budesonide, glycopyrrolate, and formoterol fumarate) inhalation aerosol for oral inhalation use is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD) and is not indicated for the relief of acute bronchospasm or for the treatment of asthma.

OPDP alleged the Breztri safety and efficacy claims were “misleading because they suggest that Breztri treatment has been shown to have a positive impact on all-cause mortality (ACM) and reduce the risk of death in COPD patients.” OPDP contended the claims were not supported by clinical trial findings cited in the aid – the Efficacy and Safety of Triple Therapy in Obstructive Lung Disease (ETHOS) trial.

“The ETHOS trial was designed with ACM as one of multiple secondary endpoints, and due to the failure of the study to show statistically significant results on endpoints higher in the analysis hierarchy, the trial does not allow for any conclusions to be drawn from the ACM data,” the Warning Letter said. “In addition, as the ETHOS study design required removing patients from inhaled corticosteroids (ICS) prior to entering a treatment arm, abrupt withdrawal of ICS may have been a confounding factor when analyzing any positive effect on ACM,” OPDP said.

“Due to the statistical testing hierarchy failure and to the fact that abrupt withdrawal of ICS may have been a confounding factor, no conclusions about the effect of Breztri on ACM can be drawn from the ETHOS trial,” OPDP concluded.

The agency noted the sales aid contained a statement that said: “These results are observational in nature, and any comparisons between treatment arms should be interpreted with caution.” “This does not mitigate the misleading impression,” the Warning Letter said. “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.”

The Warning Letter added the “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.”

OPDP also took issue with two other 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.”
• “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 Warning Letter said. “This suggestion is not supported by the ETHOS trial data analyzed in the cited reference because the reduction in severe exacerbations was not statistically significant for patients treated with Breztri relative to comparator groups. 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. However, for the Breztri to inhaled corticosteroid/long-acting beta agonist (ICS/LABA) comparison (i.e., “20% REDUCTION vs ICS/LABA”), the result was not statistically significant due to the p-value being greater than the significance threshold (critical value) established in the testing strategy.”

OPDP explained that in the ETHOS trial testing strategy the raw p-value of each hypothesis test was compared to the corresponding critical value to determine whether the test was statistically significant. “As the p-value for the Breztri to ICS/LABA comparison (p=0.02) was greater than the critical value (0.008) for that hypothesis test, the result, per the threshold set by the testing strategy, is not statistically significant,” FDA said. “Therefore, the presentation of these claims (i.e., with a p-value of 0.02) creates the misleading impression that Breztri provides a statistically significant reduction in severe exacerbations compared to ICS/LABA by 20% when this has not been demonstrated.”

OPDP acknowledged a footnote – “*Based on predefined Type-1 error control plan” – was included following the 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.”

The FDA requested a written response addressing the concerns in the Warning Letter and listing all other promotional communications for Breztri that contain similar representations, as well as “any plan for discontinuing use of such communications, or for ceasing distribution of Breztri.”

The FDA also requested “a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective communication(s) about the concern(s) discussed in this letter. The corrective communication(s) should be disseminated to the audience(s) that received the promotional communication(s),” the Warning Letter said.

OPDP recommended the corrective communication(s) include a description of the promotional communication(s), a summary of OPDP’s concerns, and information to correct each concern. “Corrective communication(s) should be free of promotional claims and presentations,” the Warning Letter said and “should be distributed using the same media, and generally for the same duration of time and with the same frequency as the promotional communication(s).”

Editor’s Note: FDA Warning and Untitled Letters as well as HHS Office for Human Research Protections (OHRP) Determination Letters are available in Thompson Information Services’ FDA Enforcement Letter Database, which is available to subscribers of Thompson's FDA Compliance Expert.