FDA Advertising and Promotion Enforcement Activities: Update

This e-alert is part of a series of e-alerts summarizing publicly available FDA enforcement letters (i.e., warning letters and untitled letters) relating to the advertising and promotion of prescription drugs, medical devices, and biologics.

In June, the Office of Prescription Drug Promotion (OPDP) posted the following untitled letter on FDA’s website:

• Untitled Letter to Althera Pharmaceuticals, LLC re: ROSZET® (rosuvastatin and ezetimibe) tablets, for oral use, MA 4 (June 2, 2022) (Roszet Untitled Letter)

The Roszet Untitled Letter is the fourth enforcement letter OPDP has issued this year. The Office of Product Evaluation and Quality (OPEQ) at the Center for Devices and Radiological Health (CDRH) and the Office of Medical Device and Radiological Health Operations (OMDRHO) in the Office of Regulatory Affairs (ORA) did not post any enforcement letters related to advertising and promotion in June. FDA’s Advertising and Promotional Labeling Branch (APLB) in the Office of Compliance and Biologics Quality (OCBQ) has not posted any enforcement letters since 2018.

Office of Prescription Drug Promotion (OPDP)

Roszet Untitled Letter (June 2022)

OPDP’s untitled letter to Althera Pharmaceuticals, LLC (Althera) states that a promotional communication directed toward healthcare professionals, which Althera submitted under cover of Form FDA 2253, misbrands Roszet by making false or misleading claims and representations about the drug’s efficacy and risks. Roszet is indicated in adults (1) as an adjunct to diet in patients with primary non-familial hyperlipidemia to reduce low-density lipoprotein cholesterol (LDL-C); and (2) alone or as an adjunct to other LDL-C-lowering therapies in patients with homozygous familial hypercholesterolemia to reduce LDL-C.

False or Misleading Claims about Efficacy

OPDP alleges that the following claims misleadingly attribute specific levels of LDL-C reduction to Roszet at various dosages (emphasis in promotional communication):

• “TOTAL* LDL-C REDUCTIONS
  • Roszet 10 mg/10 mg 64%
  • Roszet 20 mg/10 mg 66%
  • Roszet 40 mg/10 mg 72%”
• “Roszet 5 mg/10 mg total LDL-C reduction is 59%.⃰ ”

OPDP states that these results “are not the findings of any study of Roszet” but instead were retrospectively calculated by combining the results of two, unrelated studies, neither of which evaluated the specific combination of Roszet’s two active ingredients. OPDP states that it “is not aware of a scientific basis for combining study results in this manner,” noting that the studies differed in patient population and the type, dose, and duration of statin therapy. OPDP acknowledges that an asterisk refers to a note explaining how the reductions were calculated, but states that this note “does not mitigate the misleading claims given that they are based on a scientifically unsound analysis.”

OPDP also cites the following claims as misleading with respect to efficacy (emphasis in promotional communication) (citations omitted):

• “Patients Can Get Below 70 mg/dL with One Pill Daily”
• “Mean LDL-C Reductions Achieved in Clinical Trials”
  • “GRAVITY Study
    • Baseline LDL-C 163 mg/dl ® Final LDL-C 65 mg/dl after 12 weeks
      (Dose: rosuvastatin/ezetimibe 10 mg/10 mg)
    • Baseline LDL-C 165 mg/dl ® Final LDL-C 59 mg/dl after 12 weeks
      (Dose: rosuvastatin/ezetimibe 20 mg/10 mg)”
  • “EXPLORER Study
    • Baseline LDL-C 189 mg/dl ® Final LDL-C 57 mg/dl after 6 weeks
      (Dose: rosuvastatin/ezetimibe 40 mg/10 mg)”

OPDP alleges that “multiple limitations” preclude drawing conclusions from the GRAVITY and EXPLORER studies regarding the quantitative treatment effect of Roszet on LDL-C. First, OPDP states that both studies conducted analyses in a modified intent-to-treat population (mITT) that excluded subjects with no post-baseline measurements from the efficacy analyses and only used the last observation carried forward (LOCF) method to impute missing data. Both mITT and LOCF “introduce bias into the study results.” Second, OPDP alleges that claims that patients can get their LDL-C below 70 mg/dL with Roszet were misleading because the primary endpoints in the GRAVITY and EXPLORER studies were mean percent reduction in LDL-C from baseline to week 12 and the proportion of patients who achieved LDL-C below 100 mg/dL at week 6, respectively. OPDP states that the percentage of patients achieving LDL-C levels below 70 mg/dL with Roszet is “only one of numerous secondary endpoints,” and that FDA is not aware of methods taken to control for multiplicity testing. Third, OPDP states that the promotional communication misleading implies that the results for the GRAVITY study represent 12 weeks of treatment when the study was not designed to demonstrate the effect of the combination of rosuvastatin and ezetimibe on LDL-C after 12 weeks.

Finally, OPDP alleges that claims and presentations regarding Roszet’s effect on LDL-C are misleading because they omit material information from the full indication regarding the relative effect of diet for patients with primary non-familial hyperlipidemia. OPDP states that inclusion of the full indication in paragraph format at the bottom of the page “does not mitigate the misleading impression.”

False or Misleading Risk Presentation

In addition, OPDP alleges that the promotional communication “fails to present information relating to the contraindications and warnings and precautions for Roszet with a prominence and readability reasonably comparable with the presentation of information relating to the benefits.” OPDP states that risk information related to contraindications and warnings and precautions is presented at the bottom of the first page and a subsequent page in small font and in paragraph format. Meanwhile, the “Safety and Tolerability” table on the first page includes only the most common adverse reactions associated with Roszet. OPDP concludes that “[t]he overall effect of disclosing risk information in this manner undermines the communication of risk information and thereby misleadingly minimizes the risks associated with the use of Roszet.”

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If you have any questions concerning the material discussed in this client alert, please contact the members of our Food, Drugs, and Devices practice.