In early June 2022, the United States Food and Drug Administration (FDA) sent an Untitled Letter to Althera Pharmaceuticals, LLC, over its “false or misleading” promotion of ROSZET (rosuvastatin and ezetimibe), a cholesterol drug. The FDA took issue with Althera’s misrepresentation of the efficacy and risk profile of the drug in promotional materials, using a faulty analysis to show the drugs effectiveness and underplay its risks.
False or Misleading Claims About Efficacy
Specifically, the agency notes that Althera made certain claims about how much its pill can lower low-density lipoprotein cholesterol (LDL-C), based on an analysis of two studies. The FDA notes that the problem is the studies do not prove such effectiveness and the company is misrepresenting the data and that the misrepresentation is especially concerning because the drug has “multiple serious and potentially life-threatening risks.”
FDA notes that the analysis used to generate the percentages of LDL-C reductions in the promotion combined the results of “two separate and unrelated studies from the CLINICAL STUDIES section of the Roszet” prescribing information.
FDA notes that one study was a monotherapy study that evaluated rosuvastatin in patients with hyperlipidemia while the other study was a combination study that evaluated ezetimibe added to ongoing statin therapy in patients with primary hyperlipidemia, known coronary heart disease or multiple cardiovascular risk factors, in patients who were already receiving statin monotherapy, but who had not met their target LDL-C goal. The LDL-C reductions that were represented in the promotion by Althera were made from the two unrelated studies and were retrospectively calculated by Althera. In the letter, FDA notes that “The LDL-C reductions claimed in the promotion for each dose of Roszet were calculated by taking the percent change from baseline LDL-C reduction observed in the rosuvastatin monotherapy study and then applying an additional 25% LDL-C reduction which was observed in the separate ezetimibe added to ongoing statin therapy study. FDA is not aware of a scientific basis for combining study results in this manner.”
FDA also notes that the studies had several significant differences, including patient population, type and dose of statins, and the duration of treatment that would preclude someone from making any conclusions based on the combined data. “Such differences between studies limit the interpretability of any cross-study comparisons and any analysis combining the results of these studies,” the FDA said. “Thus, such an analysis does not support these claims that attribute specific levels of LDL-C reductions to each dose of Roszet.”
False or Misleading Risk Presentation
In addition to the efficacy claims, FDA said the company downplayed potential risks and contraindications. The agency notes that 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 PI for Roszet includes warnings and precautions regarding myopathy and rhabdomyolysis, immune-mediated necrotizing myopathy, hepatic dysfunction, proteinuria and hematuria, as well as increases in HbA1c and fasting serum glucose levels. Further, the most common adverse reactions reported with rosuvastatin were headache, nausea, myalgia, arthralgia, dizziness, asthenia, constipation and abdominal pain. The most common adverse reactions reported with ezetimibe were upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza. When ezetimibe is co-administered with a statin, they note the most common side effects include nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, diarrhea, back pain, influenza, pain in extremity, and fatigue.
While the company played up potential benefits of Roszet and its excipients in their promotional material, FDA said Althera did not highlight risks and contraindications to the same degree.
“The promotional communication is misleading because it 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 of Roszet. Factors impacting prominence and readability include typography, layout, contrast, headlines, paragraphing, white space, and other techniques apt to achieve emphasis. Specifically, benefit claims for Roszet are presented in conjunction with colorful graphics and large bolded headlines, with significant white space. However, risk information regarding some of the contraindications is relegated to the bottom of the first page and the remaining contraindications and warnings and precautions are presented on a subsequent page. This risk information is also presented in small font and in paragraph format,” said the Agency.
Third Untitled Letter of 2022
This letter is the third Untitled Letter sent by the FDA Office of Prescription Drug Promotion (OPDP) in 2022.