Well, if you, like many within industry, felt emboldened to disseminate promotional materials that may push the envelope on efficacy (so long as your risk information was tight) think again! OPDP is back in the game, letting all the people know that they are back to run the show.
In what may be the surprise "Warning Letter of the Year" (can you tell this blogger was pretty shocked?) OPDP took issue with
-
The last Warning Letter OPDP issued was in early 2022 to
- Prior to the
CytoDyn letter in 2022, OPDP issued a Warning Letter in 2021 to CooperSurgical for a DTC video entitled "Paragard: Family Planning During the Pandemic" which failed to communicate ANY risk information. - And before CooperSurgical, another 2021 Warning Letter was issued to AcelRx for the infamous "Tongue and Done" tagline used to promote a Schedule II controlled substance subject to a REMS program that requires a healthcare professional's precise placement of the drug using a single-dose applicator into the patient's sublingual space.
Whew! Pretty egregious stuff, right?
In this most recent Warning Letter, however, OPDP did not take issue with ANY of the safety information presented about Breztri in the sales aid; rather, objections were focused solely on false or misleading claims related to efficacy. And those efficacy presentations included disclaimers and context, yet FDA found they were insufficient to "mitigate the misleading impression" caused. Sheesh!
Let's go over some background information relating to Breztri and the OPDP Warning Letter.
Breztri was approved just over 3 years ago in
OPDP first took issue with a headline and graph presented on page 7 of the 12-page brochure. The headline, "Difference Observed in Time to All-Cause Mortality (Over 52 Weeks)" appears above a graph titled "Secondary Endpoint Study 1: Time to all-cause mortality in the ITT population" and includes claims that there is an observed relative difference between Breztri v. LAMA/LABA. The Kaplan Meier graph closely resembles one appearing in the
The second issue raised by OPDP was that the inclusion of a p value in conjunction with a claim suggested statistical significance when the results were not, in fact, statistically significant. OPDP states that a p-value is generally understood to indicate statistical significance if it is less than 0.05. However, in the testing strategy from the trial,
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. 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.
FDA acknowledged a footnote that explained that the analysis was based on predefined Type-1 error control plan however, as above, FDA stated "this does not mitigate the misleading impression."
What does this mean?
While one could argue that these presentations are misleading because they overstate the efficacy of Breztri, the presentations are limited to the middle of a 12-page brochure intended for healthcare professionals and the brochure otherwise describes the studies discussed and includes relevant safety information. The claims are (presumably) not made to patients and each had context that described how the data was interpreted. This certainly doesn't seem like promotion that is prioritized for OPDP enforcement- while the drug has many warnings, it is not a Boxed Warning drug or an opioid, it is not subject to a REMS, nor is it used for COVID-19. As Breztri has been approved for just over 3 years, this is not launch material for a newly approved drug, nor is it a product that has been the subject of previous compliance letters and the promotion is not a "far-reaching" campaign.
In a post-CFL world, these claims walk the line in that they could be "consistent" with the FDA-required labeling in accordance with
Enforcement may also have been triggered by the manner of the presentation. If
But a Warning Letter? This blogger is curious to see what else OPDP has up its sleeve for 2023. At a minimum, this letter gives industry a lot to think about as it considers Rx drug promotional materials.
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