Summary:
On June 2, 2022, the FDA’s Office of Prescription Drug Promotion (OPDP) issued an Untitled Letter to Althera Pharmaceuticals, Inc., for an HCP-facing promotional material about their LDL-C reducing combination statin drug, ROSZET (rosuvastatin and ezetimibe).
- The Letter states that Althera made misleading efficacy claims based on improper calculations and unreliable secondary endpoints.
- Althera also made misleading claims regarding the effectiveness of the medication over 12 weeks, rather than the tested 6, and its effectiveness as a standalone medication, rather than as an adjunct to diet.
- Finally, the Letter states that the promotional material did not have the proper equal prominence of risk and benefit information.
Issue 1: False or Misleading Claims about Efficacy
- Calculated the efficacy claims presented by combining data from two unrelated studies of the monotherapies included in the combination product.
- Relied on secondary endpoints for efficacy claims where study design biases limit the conclusions that can be drawn.
- Described the product’s efficacy based on multiplicity testing of secondary endpoints, for which there is a risk of false conclusions due to lack of controls.
- Suggested that combination product was effective as tested over 12 weeks, when in fact the combination product was only tested for 6 weeks.
- Suggested that the product is effective on its own without prominently mentioning the indication is in adjunct to diet.
Issue 2: False or Misleading Risk Presentation
- Contraindications, warnings, and precautions are not given the same prominence or readability compared to the benefits, creating a misleading impression regarding the risk profile of the product.
- Factors impacting prominence and readability include typography, layout, contrast, headlines, paragraphing, white space, and other techniques apt to achieve emphasis.
Detailed Summary:
Background:
- Type of Enforcement: OPDP Untitled Letter
- Company: Althera Pharmaceuticals, LLC
- Product: ROSZET (rosuvastatin and ezetimibe) tablets, for oral use
- Product Type: Prescription drug, statin
- Indication and Usage: To reduce LDL-C in primary non-familial hyperlipidemia and in homozygous familial hypercholesterolemia (HoFH)
- Medium: HCP-facing promotional material
- Bad Ad Program?: No
- Prior OPDP Communications?: No
Issue 1: False or Misleading Claims about Efficacy
Standard of Review: Misleading, among other things, (1) based on the representations made or suggested, (2) the extent to which the ad fails to reveal facts material (a) in light of the representations made, or (b) with respect to consequences from the use of the drug as recommended or suggested.
Findings: The promotional communication are misleading because it:
- Improperly calculated the efficacy claims presented by combining data from two unrelated studies:
- Combining the efficacy from two unrelated studies of each monotherapy drug that the combination drug Roszet is made of
- Using data from studies with different patient populations
- Using data from studies with different durations
- Improperly described the product’s efficacy to reduce LDL-C over a period of time:
- The published studies in the product’s FDA-approved label did not include specific levels for how much LDL-C would be reduced, as the claims in the communication at issue do
- Additionally, the bias introduced in the study designs of the secondary endpoints limit the conclusions that can be drawn regarding the quantitative treatment effect – e.g., the use of the modified intent-to-treat population (mITT) and the last observation carried forward (LOCF) method to impute missing data
- Improperly described the product’s efficacy where there is a risk of false conclusions due to lack of controls for multiplicity testing of secondary endpoints:
- The proportion of patients achieving LDL-C <70 mg/dL was only one of numerous secondary endpoints in the studies that the study publications do not discuss
- The FDA is not aware of any methods taken to control for multiplicity testing of secondary endpoints in these studies
- Improperly suggested that combination product ROSZET was tested over 12 weeks, when in fact the combination product was only tested for 6 weeks, which is misleading as to the longer term effectiveness of the drug
- Improperly suggested that ROSZET is effective on its own without prominently mentioning the indication is in adjunct to diet. The full indication is in the boiler plate language in a much smaller font and with less white space than the product claims
Additional RCL, Commentary: As we continue to see an expansion of Consistent with Label (#CFL) communications that allows for messaging based on studies outside of a label, it’s important to remember that CFL communications must still be adequately substantiated and must not alter the risk-benefit profile of a product.
Issue 2: False or Misleading Risk Presentation
Standard of Review:
- Among other things, (1) the representations made or suggested, (2) the extent to which the ad fails to reveal facts material (a) in light of the representations made, or (b) with respect to consequences from the use of the drug as recommended or suggested.
- Risks and benefits must be given the same prominence or readability. Factors impacting prominence and readability include typography, layout, contrast, headlines, paragraphing, white space, and other techniques apt to achieve emphasis.
Findings:
- Contraindications, warnings, and precautions are not given the same prominence or readability compared to the benefits, creating a misleading impression regarding the risk profile of the product.
- Benefit claims are presented in conjunction with colorful graphics and large bolded headlines, with significant white space
- 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
- Risk information is also presented in small font and in paragraph format
- While the most common adverse events are presented within the primary parts of the promotional material, serious risks (i.e., contraindications and warnings and precautions) are relegated to the bottom of the page and subsequent page in small font and paragraph format