On August 4, 2023, the FDA’s Office of Prescription Drug Promotion (OPDP) sent a warning letter targeting a sales aid for a drug approved for maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).1 FDA published the letter on August 15, 2023.
The letter reflects several recent developments in FDA enforcement regarding prescription drug promotion, including a general increase in such enforcement and a sustained focus on communications “consistent with” approved labeling (CFL).
- Marked Increase in Enforcement Activity by OPDP in Recent Months
OPDP enforcement of drug promotion requirements has been at a prolonged lull in recent years, a trend noted by many stakeholders.2 For example, OPDP issued only four enforcement letters in all of 2022 and none for over a year between June 2, 2022, and June 7, 2023. Now, in the span of less than two months, OPDP has issued two letters, including its first warning letter since February 2022. If the current pace continues, OPDP could soon reach enforcement levels last seen in 2019.
- Ongoing, and Increasingly Rigorous, Targeting of CFL Communications
A significant proportion of OPDP’s relatively rare enforcement letters in recent years has focused on CFL communications. This letter adds to the trend, representing the fifth out of the past nine OPDP letters to include a citation focused on a CFL presentation.3
In addition, the text of the most recent letter leaves many open questions about the precise nature of OPDP’s concerns here, and its approach to CFL enforcement generally. For example, the letter takes an aggressive stance by focusing on statements that many might view as acceptable under FDA’s CFL guidance, which states that CFL communications “should not overstate the findings of or the conclusions that can be drawn” from the relevant studies or analyses or “fail to disclose their material limitations.”4 For example, the letter targets statements referring to a “difference observed” in all-cause mortality (ACM) for COPD patients. The letter asserts that these statements amounted to “claims” and were misleading because (emphasis added):
[The] 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. In addition, as the ... 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. 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 ... on ACM can be drawn from the ... trial.
This represents an aggressive interpretation of the relevant statements as drawing “conclusions,” even though they referred only to a “difference observed” and were accompanied by a statement that the results “are observational in nature, and any comparisons between treatment arms should be interpreted with caution.” OPDP might have been inclined to find that the statements at issue amounted to “conclusions” or “claims” because they were presented, in the piece cited by the letter, with a 95% confidence interval suggesting that the difference was statistically significant. If this were a key consideration, however, it is odd that the confidence interval is not explicitly referenced in the letter.
Taken on its face, it is also possible that the letter reflects a judgment that, because of the limitations of the trial at issue here, the statements were not supported by “scientifically appropriate and statistically sound” data, and therefore the trial is inadequate to support any representations or suggestions about ACM under the CFL guidance. If that were the case, the letter would be surprising in terms of the level of rigor it appears to require for data to support CFL statements.
Finally, another possibility is that OPDP simply took issue with claims about ACM for COPD given considerations unique to that endpoint in that disease state. The letter does not include text explicitly addressing whether representations or suggestions about ACM would be considered “consistent” with the currently approved labeling for the drug, when evaluated according to the factors of the CFL guidance. But it does state that “no drug has been shown to improve ACM in COPD” to date, and that the letter is not “intend[ed] to convey any views on whether data that did show that Breztri improved ACM in COPD would support a change to the FDA-approved labeling.” This suggests that the letter might reflect a particular concern about any promotional communications addressing ACM in COPD, regardless of the extent to which they might be considered permissible under the analysis called for by the CFL guidance.
At a minimum, this all suggests that OPDP’s approach to enforcement for CFL communications might be significantly more rigorous, and complicated, than either the guidance or FDA’s prior enforcement actions suggest.
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In all events, the new OPDP enforcement letter is in line with other developments suggesting that OPDP is, or may soon be, poised to undertake significant new enforcement activities aimed at prescription drug promotion. For example, new guidance on off-label communications is also under review by the Office of Information and Regulatory Affairs and may articulate significant new expectations that could inform future enforcement activities.5 At a minimum, companies should continue to implement robust processes for multidisciplinary review of promotional communications and monitor OPDP guidance, research initiatives,6 and enforcement activities for signs of what’s to come.
2 See, e.g., OPDP: No More Untitled Letters?, Policy and Medicine (May 29, 2023).
3 The four prior CFL letters were Untitled Letter to Xeris Pharmaceuticals re RECORLEV (levoketoconazole) (June 7, 2023); Untitled Letter to Althera Pharmaceuticals re ROSZET (rosuvastatin, ezetimibe) (June 2, 2022); Untitled Letter to Bausch Health Companies re: DUOBRII (halobetasol propionate, tazarotene) (March 31, 2022); Untitled Letter to Amgen re: NEULASTA (pegfilgrastim) (July 7, 2021).
6 See Office of Prescription Drug Promotion (OPDP) Research (current as of May 19, 2022).
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