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.

During the second quarter of 2025 FDA’s Office of Prescription Drug Promotion (OPDP) posted one untitled letter and one warning letter.

• Untitled Letter to Mayne Pharma, LLC re NDA 214154 NEXTSTELLIS
  (drospirenone and estetrol tablets), for oral use (April 28, 2025) (Nextstellis Untitled Letter).
• Warning Letter to Sprout Pharmaceuticals, Inc. re NDA 022526 ADDYI (flibanserin) tablets, for oral use (June 10, 2025) (Addyi Warning Letter).

During the same period, the Office of Product Evaluation and Quality (OPEQ) at the Center for Devices and Radiological Health (CDRH) posted one warning letter relating to the advertising and promotion of medical devices.

• Warning Letter to DRG Instruments GmbH re Salivary Cortisol ELISA (REF No. SLV-2930), the Salivary Testosterone ELISA, and the Salivary Cortisol ELISA RUO (March 31, 2025) (DRG Instruments Warning Letter).

The Office of Medical Device and Radiological Health Operations (OMDRHO) in the Office of Regulatory Affairs (ORA) did not post any warning letters relating to the advertising and promotion of medical devices during this period. 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.

This alert merely summarizes the allegations contained in FDA’s letters. It does not contain any analyses, opinions, characterizations, or conclusions by or of Covington & Burling LLP. As a result, the information presented herein does not necessarily reflect the views of Covington & Burling LLP or any of its clients.

Office of Prescription Drug Promotion (OPDP)

Untitled Letter to Mayne Pharma, LLC (Issued April 28, 2025)

OPDP’s Untitled Letter to Mayne Pharma (Mayne) alleges that a professional “presentation for NEXTSTELLIS promotional programs with speaker notes” (“speaker deck”) makes false or misleading claims and presentations about the risks of Nextstellis. Nextstellis is indicated for use by females of reproductive potential to prevent pregnancy.

False or Misleading Claims and Presentations about Risk

OPDP claims the speaker deck misleadingly suggests that Nextstellis is safer than other forms of CHC (Combined Hormonal Contraception), because its active estrogen ingredient is estetrol. OPDP alleges these claims “suggest that estetrol is different from—and lower risk than—other estrogens because of purported native characteristics and a ‘unique pharmacologic profile’ that ‘results in tissue selective actions’ and a ‘low impact.’” Moreover, OPDP alleges the speaker deck misleadingly suggests that estetrol “has differential selectivity in tissues that distinguishes it functionally from other estrogens, when this has not been demonstrated.” OPDP highlights a series of claims, including:

• “NEXTSTELLIS is an FDA-approved, combined oral contraceptive (COC) containing drospirenone (DRSP) and estetrol (E4)—a novel, selective action, low-impact estrogen.”
• “The native characteristics of estetrol have not required any modification for its use in a contraceptive.”
• “The Unique Dual Role of Estetrol (E4) Results in Tissue Selective Actions.”
• “NEXTSTELLIS is the ideal pairing of estetrol and drospirenone, delivering an effective and safe combined oral contraceptive with a unique pharmacologic profile.”

In addition to challenging an “overall misleading impression” OPDP identifies certain individual claims and presentations as allegedly misleading. Specifically, OPDP alleges the speaker deck:

• includes a comparison of pharmacologic profile parameters for “Ethinyl estradiol” and “Estetrol” that misleadingly suggests that estetrol, and therefore, Nextellis, has safety advantages over CHCs with ethinyl estradiol without adequate support for such a claim.
• includes claims that misleadingly suggest Nextellis safer than other CHCs due to a demonstrated statistically significant difference in several observed endocrine and hemostatic parameters as compared to the two reference CHCs. However, this suggestion is not supported by the safety study cited in the speaker deck, which did not prespecify the thresholds for clinically relevant differences in effects of the studied products on the various endocrine and hemostatic parameters.
• includes claims that suggest Nextstellis is a safer option for breast cancer patients despite the fact that it is contraindicated in “patients with a current diagnosis or history of breast cancer, which may be sensitive to female hormones.” The speaker deck cites references for these claims; however, according to OPDP they are inadequate to support such claims.
• includes claims that minimize “serious risks associated with the use of Nextstellis.” Specifically OPDP alleges the claims minimize risks associated with “liver effects” (i.e., “Unlike other estrogens, E4 has a minimal effect on the liver”), reduced glucose tolerance and hypertriglyceridemia (“minimal to no impact on…Cholesterol… Triglycerides…Glucose”), thromboembolic disorders and other vascular problems (“minimal to no impact on . . . clotting factors”). OPDP alleges that these claims are not adequately supported by the references cited.
• includes a misleading statement that the adverse reactions (ARs) presented in the slide deck “include all Adverse Events (AEs) reported…whether drug related or not, thereby “creating a misleading impression that not all of the ARs included in the presentation were related to Nextstellis treatment and suggests that the true AR rates attributable to use of Nextstellis were lower, when this is not the case.”
• omits material facts regarding the risks of hyperkalemia, migraine, and bleeding irregularities, and amenorrhea.” While the slides direct the viewer the prescribing information (PI) for complete safety information, including a hyperlink to the PI, OPDP claims these references “do not mitigate the misleading minimization of risks associated with use of Nextstellis.”
• includes claims and graphical presentations that misleadingly minimize information on bleeding irregularities associated with Nextstellis by relying on an incomplete definition of “unscheduled bleeding.” Similarly, OPDP alleges the deck includes a misleading claim about “consistency of cycle patterns,” which is not adequately supported by the data provided.

Warning Letter to Sprout Pharmaceuticals, Inc. (Issued May 29, 2025, Posted June 10, 2025)

OPDP’s warning letter to Sprout Pharmaceuticals, Inc. (Sprout) alleges that a social media post by Sprout’s Chief Executive Officer for Addyi is false or misleading “in that it makes representations about the benefits of Addyi but fails to include any risk information about the drug and omits material information regarding the full indication, including the limitations of its use.” OPDP notes that it sent Sprout a warning letter in August 2020 addressing “presentation of Addyi with certain similarities to the post addressed in this letter” and that “OPDP is concerned that, despite receiving this previous Warning Letter, Sprout continues to promote Addyi in a similarly misleading manner.”

Addyi is indicated for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD), as characterized by low sexual desire that causes marked distress or interpersonal difficulty and is NOT due to a co-existing medical or psychiatric condition, problems within the relationship, or the effects of a medication or other drug substance. Addyi is not indicated for the treatment of HSDD in postmenopausal women or in men and is not indicated to enhance sexual performance.

False or Misleading Risk Presentation

OPDP alleges “[t]he post is misleading because it includes representations about the benefits of Addyi but fails to communicate any risk information,” thereby creating a misleading impression about the drug’s safety. OPDP suggests “[t]his omission is especially problematic from a public health perspective given the serious risks associated with the drug.” OPDP references the specific claims:

• “The first articles on @addyi a decade ago questioned the women struggling, told them it was normal, debated how many more satisfying sexual events were enough for them to deserve a pill…”
• “…Addyi, the Sex Pill for Women…”
• “Addyi is the first FDA-approved treatment for women’s sexual dysfunction.”

Omission of Material Facts

OPDP also alleges that by “failing to disclose the full indication and limitations of use associated with Addyi, the post creates a misleading suggestion about the FDA-approved indication and use for Addyi.”  OPDP states that “[t]his broad claim suggests that Addyi is indicated, among other things, to enhance sexual performance, which is particularly concerning given the limitations of use and serious risks of this product.”

Failure to Submit Under Form FDA-2253

OPDP also alleges that Sprout failed to submit the FDA transmittal form (Form FDA-2253) and a copy of the post at the time of initial dissemination or publication as required by FDA regulations at 21 CFR 314.81(b)(3)(i).

Office of Product Evaluation and Quality (OPEQ) at the Center for Devices and Radiological Health (CDRH)

Warning Letter to DRG Instruments GmbH (Issued March 31, 2025, Posted May 27, 2025)

OPEQ’s warning letter to DRG Instruments GmbH (DRG), regarding the company’s in vitro diagnostic devices, including the Salivary Cortisol ELISA RUO test, arose out of an inspection of the company November 4 through 7, 2024, and a review of DRG’s website.

OPEQ alleges­ that the Salivary Cortisol ELISA RUO is misbranded because the test is intended for clinical diagnostic use and lacks 510(k) clearance, notwithstanding the product’s labeling for research use only. OPEQ alleges that the evidence obtained during the inspection and DRG’s website are inconsistent with the company’s assertion that the test is intended for research use only.  For example, OPEQ alleges that DRG’s website describes the test as having advantages for “clinical applications such as: Diagnosis of systemic/local conditions,” that the test instructions describe how to collect samples from individuals (e.g., “Eating, drinking, chewing gums or brushing teeth should be avoided for 30 minutes before sampling.”), and that customer records demonstrate the company shipped the test to companies in the business of performing clinical analysis that do not perform research. OPEQ notes DRG’s website compares the Salivary Cortisol ELISA RUO to a reference test and “states it provides ‘Industry Leading Accuracy with Kit Components Calibrated to Mass Spectrometry,’” thereby implying the Salivary Cortisol ELISA RUO is intended for clinical diagnostic use. In addition to concerns with marketing claims, OPEQ alleges that “during the inspection, [DRG] provided to the FDA investigator copies of certification letters from certain customers of the Salivary Cortisol ELISA RUO as evidence that these customers were aware that they were only supposed to use these products for research purposes. However, . . . a review of these customers’ websites strongly suggests that these customers are engaged in clinical diagnostic testing.”

Separately, OPEQ alleges the DRG’s website includes a tab called “FDA Cleared Tests” and lists several devices, such as a Thyroid Stimulating Hormone (TSH) assay for in vitro diagnostic use, for which there is no record of a 510(k) clearance held by DRG. Additionally, OPEQ claims the DRG’s website include misleading language indicating that a class I 510(k) exempt product, the DRG Hybrid XL, has been reviewed and approved by FDA. Specifically, the claim states it is “Now FDA Approved.”

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