On June 2, 2022, the US Food and Drug Administration (FDA) Office of Prescription Drug Promotion (OPDP) issued an untitled letter [1] to Althera Pharmaceuticals, LLC (Althera) relating to promotional communication for ROSZET® (rosuvastatin and ezetimibe) tablets for oral use (Roszet). The promotional communication was a professional “Roszet Doctor Info Letter Size”. [2] This is the third untitled letter from OPDP this year. In January, OPDP sent an untitled letter to Eli Lilly & Company regarding promotional claims for TRULICITY® on social media. In March, OPDP sent an untitled letter—which we covered in our blog post here —to Bausch Health Companies for misleading statements for DUOBRII™ conveyed in a promotional video and healthcare professional website.
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. Roszet is contraindicated in patients with acute liver failure or decompensated cirrhosis and in patients with hypersensitivity to rosuvastatin, ezetimibe, or any excipients in Roszet. The FDA-approved product labeling (PI) for Roszet includes myopathy, proteinuria and hematuria, and increases in HbA1c and fasting serum glucose levels.
FDA wrote that, for the reasons discussed below, the promotional communication, i) creates a false or misleading impression of the risks and efficacy of Roszet and ii) minimizes the risks associated with the use of Roszet due to a reduced prominence and readability of risks compared to benefits.
False or Misleading Claims About Efficacy
FDA focused on two key areas of the promotional material in determining that the material created a false and/or misleading presentation about the efficacy of Roszet.
FDA’s first concern was the analysis used to make claims about the efficacy of Roszet by attributing specific percentages of LDL-C reduction (ranging from 64%-72%) at various dosages. The promotional communication included the following claims (emphasis in original):
- “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%.”
FDA pointed out that the percentages were not the findings of any study of Roszet but appear to have been retrospectively calculated by combining the results of two separate and unrelated studies. [3],[4] The first study was a monotherapy study that evaluated rosuvastatin and the second was a combination study that evaluated ezetimibe added to ongoing statin therapy.
Importantly, FDA underscored that neither study evaluated the specific combination of rosuvastatin and ezetimibe. Furthermore, the second study did not use rosuvastatin as one of the statins in the evaluation of ezetimibe. Both studies also differed in patient population, type and dose of statin(s), and duration. FDA stated that, under the regulations, Althera’s analysis combining the results of the studies did not support the claims which attributed specific levels of LDL-C reductions to each dose of Roszet, and thus, the promotional communication created a misleading impression of Roszet’s efficacy.
FDA’s second concern regarded limitations in the studies used by Althera to draw conclusions regarding the quantitative treatment effect of Roszet on LDL-C. The promotional communication included the following claims and presentations, based upon two cited references (emphasis in original) [5],[6]:
- “Patients Can Get Below 70 mg/dL with One Pill Daily”
- “Roszet Delivers Powerful LDL-C Reductions”
- “Mean LDL-C Reductions Achieved in Clinical Trials”
- “GRAVITY Study
- Baseline LDL-C 163 mg/dl à Final LDL-C 65 mg/dl after 12 weeks (Dose: rosuvastatin/ezetimibe 10 mg/10 mg)
- Baseline LDL-C 165 mg/dl à Final LDL-C 59 mg/dl after 12 weeks (Dose: rosuvastatin/ezetimibe 20 mg/10 mg)”
- “EXPLORER Study
- Baseline LDL-C 189 mg/dl à Final LDL-C 57 mg/dl after 6 weeks (Dose: rosuvastatin/ezetimibe 40 mg/10 mg)”
- “GRAVITY Study
FDA stated there were multiple limitations to the GRAVITY and EXPLORER studies. Both studies conducted analyses in a modified intent-to-treat population (mITT) that excluded subjects with no post-baseline measurements from the efficacy analyses. The last observation carried forward (LOCF) method was used to impute missing data. As a general matter, FDA noted that the use of mITT and LOCF methodologies introduces bias into study results and limits the conclusions that can be drawn regarding the quantitative treatment effect, increasing the chance of Type I error (i.e., falsely concluding a treatment effect where there is none).
Additionally, the primary endpoints in the studies were mean percent reduction in LDL-C from baseline to week 12 and the proportion of patients who achieved LDL-C <100 mg/dL at week 6, respectively. The proportion of patients achieving <70 mg/dL was only one of many secondary endpoints. The studies do not discuss, and FDA stated it is not aware of, methods to control for multiplicity testing of secondary endpoints in the cited references. [7]
The LDL-C effects seen in Week 12 of the GRAVITY study were based upon six weeks of monotherapy (rosuvastatin only) followed by six weeks of combination therapy (rosuvastatin plus ezetimibe), not twelve weeks of combination therapy. FDA stated that the study design did not support the claimed efficacy of the combination therapy after twelve weeks of treatment as the promotional material purports to show.
FDA also highlighted that the claims “Roszet Delivers Powerful LDL-C Reductions” and “Patients Can Get Below 70 mg/dL with One Pill Daily” were misleading because they omitted material information about the relative effect of diet. One of Roszet’s indications in the PI is as an adjunct to diet, and the omission of this information misleadingly suggested that Roszet alone may provide the stated benefits for that specific indication. FDA did, however, acknowledge that the indication was listed on the material, but given the placement under the ISI header and relegated to a smaller font size with less white space, addition of the indication to the piece alone was not enough to mitigate the misleading impression.
False or Misleading Risk Presentation
FDA’s concern here was that Roszet’s contradictions, warnings and precautions were not presented with the same prominence and readability as its benefits. The following factors were identified as impacting prominence and readability: typography, layout, contrast, headlines, paragraphing, white space, and other techniques apt to achieve emphasis. The benefit claims are presented with colorful graphics, large bolded headlines and significant white space. In contrast, the risk information is in small fonts and paragraph format. Risk information related to some contraindications was placed at the bottom of page one and other contraindications, warnings and precautions were on a subsequent page of the promotional material.
Although the most common adverse reactions were presented in the body of the promotional communication in table format and under the header “Safety and Tolerability”, FDA stated presenting only common adverse reactions in this format while relegating serious risks to the bottom of the page and subsequent page creates a misleading impression of Roszet’s risk profile. [8]
[1] Untitled letter available here: https://www.fda.gov/media/158997/download.
[2] Promotional material available here: https://www.fda.gov/media/158998/download.
[3] Roszet (rosuvastatin and ezetimibe) Prescribing Information, Clinical Studies Section; Morristown, NJ; Althera Pharmaceuticals.
[4] Gagné, Claude, et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. The American journal of cardiology 2002; 90.10:1084-1091.
[5] Ballantyne CM, et al. Efficacy, safety and effect on biomarkers related to cholesterol and lipoprotein metabolism of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg vs. simvastatin 40 or 80 mg plus ezetimibe 10 mg in high risk patients: Results of the GRAVITY randomized study. Atherosclerosis 2014; 232:86-93.
[6] Ballantyne CM, et al. Efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe in patients at high risk of cardiovascular disease (results from the EXPLORER study). Am J Cardiol 2007; 99:673- 80.
[7] Supra note 3, 4.
[8] Event rates for myalgia are prominently presented under the header “Safety and Tolerability,” but the warning and precaution for myopathy and rhabdomyolysis is relegated to the subsequent page in small font and paragraph format.
*Arushi Pandya is a law clerk in the firm's Washington, D.C. location.