FDA warns AstraZeneca about false or misleading claims for Breztri

Sales aid gives wrong impression about risk of death, COPD flares with therapy

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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The U.S. Food and Drug Administration (FDA) has issued a warning letter to AstraZeneca for making false or misleading claims about Breztri Aerosphere (budesonide/glycopyrronium/formoterol fumarate), its approved inhalation therapy for chronic obstructive pulmonary disease (COPD).

According to the FDA, promotional material about Breztri distributed by AstraZeneca includes claims about the therapy’s ability to lower a risk of death from any cause, and a risk of severe exacerbations among COPD patients. The claims are not supported by clinical evidence.

“These violations are concerning from a public health perspective because the promotional communication creates a misleading impression regarding the overall benefits a patient may expect as a result of Breztri treatment,” the FDA stated in its warning letter.

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AstraZeneca has 15 days to issue a response to the agency addressing these issues, listing all other promotional communications containing these types of claims, and outlining plans to discontinue use of such communications and provide “truthful, non-misleading, and complete corrective communication(s) about the concern(s) discussed in this letter.”

“Failure to adequately address this matter may lead to regulatory action,” the warning letter states.

Breztri Aerosphere is an inhaled, triple-combination therapy that the FDA approved as a maintenance treatment for COPD in 2020. It contains two medications that help to widen the airways, and a third medicine that reduces inflammation.

Breztri’s approval was based in part on data from the Phase 3 ETHOS clinical trial (NCT02465567). The study tested the therapy against Bevespi Aerosphere (glycopyrronium/formoterol fumarate) and Symbicort (budesonide/formoterol fumarate) — two dual-combination therapies also sold by AstraZeneca — in people with moderate to very severe COPD.

Findings supported Breztri outperforming the older therapies at reducing the risk of exacerbations, or periods when COPD symptoms suddenly worsen.

In a professional sales aid, however, AstraZeneca makes claims about ETHOS trial results that are misleading or not supported by the evidence, the FDA noted, taking issue with two specific claims.

One notes a “49% observed relative difference” in time to all-cause mortality with Breztri as a triple combination therapy, compared with dual-combination therapy. “No conclusions about the effect of Breztri on [all-cause mortality] can be drawn from the ETHOS trial,” the agency wrote.

Statistical analyses of trial data did not support the claim that mortality was lower with Breztri, the FDA stated, and it also noted that patients in the ETHOS trial had to stop treatment with inhaled corticosteroids before entering the study, which may have influenced mortality findings.

“The results of the ETHOS trial do not exclude the possibility that the benefits in [all-cause mortality] claimed above may be attributable to chance or to the withdrawal of [inhaled corticosteroids] and not due to Breztri,” the FDA wrote. “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 [all-cause mortality] and reduce the risk of death in COPD patients.”

Significance at issue in ETHOS trial findings supporting Breztri for COPD

The other issue concerned a part of the promotional material that claims Breztri was the only of the three therapies to lead to a significant reduction in severe exacerbations, and that this drop was 20% greater than the other therapies, with a p-value of 0.02.

A p-value is a mathematical calculation of how likely a finding is due to random chance. Typically, a p-value of 0.05 or lower — meaning the odds of the finding being due to chance are 5% or less — is considered statistically significant, meaning the difference can reasonably be assumed to not be due to chance.

However, in the particular statistical setup for this comparison analysis in the trial, exacerbation differences between the groups would be considered statistically significant only if the p-value was 0.008 or lower.

“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 [dual-combination therapy] by 20% when this has not been demonstrated,” the FDA wrote.

These misleading or false statements mean that the sales aid misbrands Breztri under the Federal Food, Drug, and Cosmetic Act.