2023 End of Year Summary of FDA Advertising and Promotion Enforcement Activity

2023 End-of-Year Summary of FDA Advertising and Promotion Enforcement Activity

July 22, 2024, Covington Alert

This e-alert reviews trends emerging from warning letters and untitled letters concerning product advertising and promotion issued in 2023 by the Office of Prescription Drug Promotion (OPDP) of the Center for Drug Evaluation and Research (CDER), the Office of Product Evaluation and Quality (OPEQ) of 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).^[1] We have summarized the eight advertising and promotion letters and analyzed the most frequently cited allegations.

In 2023, OPDP issued five enforcement letters, including one warning letter and four untitled letters. The limited number of letters is consistent with the longer-term downward trend in OPDP enforcement, which likely reflects continued First Amendment pressure on FDA to permit truthful and non-misleading communications about prescription drugs. OPDP issued four letters in 2022 and six in both 2021 and 2020. By contrast, OPDP issued 52 letters in 2010 and continued to post over 20 letters a year through 2013.

Although it is difficult to draw conclusions from such a limited set of letters, the allegations included therein reflect a focus on the presentation of efficacy data from clinical trials. All five letters included allegations that the sponsor overstated the efficacy of the product by either misrepresenting or drawing unsupported conclusions from clinical trial data. Additionally, consistent with FDA's recent focus on patient communications, four of the five letters-and three of the four letters involving presentation of clinical study data-addressed materials directed at least partially at patients, as opposed to materials intended solely for health care professionals. Two letters included allegations of "false or misleading risk presentation," including one that alleged that the manufacturer did not include any risk information and one that alleged that risk information was minimized. A summary of each letter is provided below.

Recorlev Untitled Letter (June 2023)

OPDP's untitled letter to Xeris Pharmaceuticals, Inc., stated that the Recorlev (levoketoconazole) consumer website misbranded the drug by making false or misleading claims about efficacy and safety. OPDP's letter focused on the presentation of data from the SONICS and LOGICS studies, with OPDP alleging that certain claims "overstat[ed] the efficacy of the product" and "omitt[ed] information necessary to interpret any study results." For example, OPDP cited a claim stating that "67% of patients [in the SONICS study] who moved on to the second part of the study had normal cortisol levels by the end of the study." According to OPDP, the SONICS study included three phases: dose titration, maintenance, and extended evaluation. OPDP stated that, although 67% of the 94 patients enrolled in the SONICS study had normal cortisol levels at the end of the titration phase, of the 77 patients who "moved on" to the subsequent phases, only 38% and 21% had normal cortisol levels at the end of the maintenance and extended evaluation phases, respectively. OPDP also pointed to a statement in the Prescribing Information (PI) that "[b]ecause 51% of patients discontinued treatment prematurely due to adverse reaction, lack of efficacy, or other reasons, these results should be interpreted with caution." In addition, OPDP took issue with Xeris's claim that 52% of patients who were on a stable and steady dose of Recorlev had normal cortisol levels. OPDP stated that these results were "based on a small, select subset of patients enrolled in the [LOGICS] study who had already demonstrated that they were able to tolerate and respond to the drug."

OPDP also alleged that the website minimized the risks associated with the drug, by, among other things, failing to discuss Recorlev's boxed warnings or to provide information regarding specific side effects. OPDP acknowledged that risk information was presented separately on the webpage but stated that the boxed warning was" relegated to the middle of this consolidated risk section" and there was no "significant signal to alert the viewer to them." Untitled Letter (June 7, 2023).

Breztri Warning Letter (August 2023)

OPDP's warning letter to AstraZeneca Pharmaceuticals LP addressed a professional sales aid for Breztri (budesonide, glycopyrrolate, and formoterol fumarate), an inhalation aerosol indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). OPDP alleged that the promotional piece misbranded Breztri by making false and/or misleading claims with respect to the drug's efficacy. Specifically, OPDP asserted that claims citing publications analyzing data from the Efficacy and Safety of Triple Therapy in Obstructive Lung Disease (ETHOS) trial "suggest that Breztri treatment has been shown to have a positive impact on all-cause mortality (ACM) and reduce the risk of death in COPD patients." According to OPDP, the ETHOS trial did not allow for conclusions about ACM to be drawn, because the trial did not show statistically significant results on endpoints higher in the analysis hierarchy, and abrupt withdrawal of patients from inhaled corticosteroids may have been a confounding factor. OPDP acknowledged that a statement below the graph provided that the ACM "results are observational in nature, and any comparisons between treatment arms should be interpreted with caution," but concluded that this "d[id] not mitigate the misleading impression." OPDP also did not agree that the clinical trial data demonstrated a statistically significant reduction in severe exacerbations and, therefore, asserted that the presentation of a claim about exacerbation reduction alongside a p-value of 0.02 created a misleading impression of statistical significance. Warning Letter (Aug. 4, 2023); FDA Advertising and Promotion Enforcement Activities: Update.

Slynd Untitled Letter (August 2023)

OPDP's untitled letter to Exeltis USA, Inc., stated that a social media post misbranded Slynd (drospirenone), a progestin indicated to prevent pregnancy, by making false or misleading claims and representations the drug's risks and efficacy. With respect to risk information, OPDP alleged that the post "present[ed] claims and representations about the benefits of Slynd but fail[ed] to communicate any risk information" (emphasis by OPDP).

OPDP also took issue with the post's description of Slynd as "estrogen-free birth control with periods on a schedule." OPDP alleged that such claims were misleading, stating that, according to the PI, in two studies, the majority of patients experienced decreased "scheduled bleeding" during treatment. Additionally, OPDP asserted that the PI warned that patients may "experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first three months of use." OPDP further alleged that Exeltis did not submit the promotional material to FDA under cover of Form FDA-2253 at the time of initial publication, as required by FDA regulations. Untitled Letter (Aug. 11, 2023); FDA Advertising and Promotion Enforcement Activities: Update.

Phexxi Untitled Letter (October 2023)

OPDP's untitled letter to Evofem Biosciences, Inc., alleged that a direct-to-consumer (DTC) brochure made false or misleading claims and representations about the benefits of Phexxi (lactic acid, citric acid, and potassium bitartrate), a prescription vaginal gel approved to prevent pregnancy. OPDP alleged that claims of a 99% pregnancy prevention rate were based on efficacy "per act of sex," a methodology that "incorrectly assumes that the likelihood of becoming pregnant is the same with each act of sex throughout the menstrual cycle." FDA stated that the endpoints used to evaluate the efficacy of Phexxi in preventing pregnancy, as set forth in the PI, analyze cumulative failure rates over specific lengths of exposure, rather than a failure rate based on individual acts of intercourse. OPDP acknowledged that the claims were accompanied by a statement providing that "[t]hese data are not found in the Product Information and have not undergone the same rigorous evaluation as other data from the study," but OPDP concluded that this disclaimer "d[id] not mitigate the misleading overstatement of efficacy created by these claims." Untitled Letter (Oct. 31, 2023).

Rexulti Untitled Letter (October 2023)

OPDP's untitled letter to Otsuka Pharmaceutical Development and Commercialization, Inc. stated that a DTC television advertisement and DTC banner made false or misleading claims about the efficacy of Rexulti (brexpiprazole), which is indicated for adjunctive treatment of major depressive disorder. OPDP alleged that both promotional pieces included claims that, when added to an antidepressant, Rexulti was proved to reduce depression symptoms 62% more than an antidepressant alone. OPDP calculated reductions of 11.9%, 7.4%, and 4.8% based on studies cited in the PI. OPDP stated that inclusion of superimposed text stating that "[i]ndividual results may vary" "[d]id not mitigate the misleading impression." Untitled Letter (Oct. 31, 2023).

FDA issued eight warning letters related to device advertising and promotion in 2023, each of which was co-signed by CDRH's OPEQ and ORA's OMDRHO. This represented a slight increase from 2022, when these offices issued five warning letters.

Each warning letter emerged out of an FDA inspection and involved allegations that the manufacturer promoted its device or devices beyond the scope of the relevant clearance (seven letters) or premarket exemption (one letter). Six of the eight letters also included allegations pertaining to violations of quality system regulation provisions and regulations, and three of the eight letters included allegations that the manufacturer had made technical changes to its devices or combined cleared devices in a manner that required submission of a new 510(k).^[2]

Sea-Long Medical Systems, LLC Warning Letter (April 2023)

FDA's warning letter to Sea-Long Medical Systems, LLC addressed the Sea-Long Medical Treatment Hood, which was cleared under section 510(k) to be used "any place that a clinician would normally use a mask for medical purposes of supplying gas/oxygen/air." FDA alleged that statements on Sea-Long's website and YouTube channel and in materials collected during the inspection indicated that the device was also intended for noninvasive ventilation, respiratory distress/illness, acute respiratory distress syndrome, pressure support ventilation/positive end-expiratory pressure, COVID-19 treatment, and other additional uses for which Sea-Long lacked clearance or approval. Among other purportedly violative claims, FDA cited excerpts from and links to various media articles and videos on the "Media" page of the company's website, including a link to an NBC news article and video dated March 31, 2020, with the following description: "Sea-Long Medical Systems has drawn huge interest from hospitals and foreign countries seeking alternatives in treating patients suffering with respiratory illness amid a ventilator shortage during the pandemic." Warning Letter (Apr. 4, 2023).

Steiner Biotechnology, LLC Warning Letter (May 2023)

FDA's warning letter to Steiner Biotechnology, LLC included several allegations regarding the promotion of the company's bone grafting materials, including the Socket Graft, Socket Graft Plus, OsseoConduct, OsseoConduct Micron, Ridge Graft Kit, and Immediate Graft devices. For example:

• FDA alleged that the Steiner promoted the Socket Graft for use at an earlier time point than eight weeks for implant placement, even though the device was cleared for implant placement taking place at eight weeks or later. FDA also stated that certain performance claims on Steiner's website were unsupported. These included claims that the Socket Graft was associated with "[n]o allergic reaction" and "[n]o inflammatory response." FDA disagreed with Steiner's position, articulated in a prior response submitted to the agency, that these statements were supported by a bioavailability study. In addition, FDA alleged that Steiner promoted the Socket Graft for use with a local anesthesia (i.e., a drug), even though "[t]his indication was not previously cleared."
• FDA took issue with claims on Steiner's website stating that the OsseoConduct device "prevent[s] bacterial colonization." FDA stated that Steiner had previously acknowledged that this statement was not supported by the relevant 510(k) clearance and agreed to remove it. FDA stated further that Steiner agreed to modify or remove a claim that the OsseoConduct is "significantly resorbed in 3 months" but did not do so.
• FDA alleged that Steiner marketed the Socket Graft Plus, which "appear[ed] to be a combination of [the] Socket Graft and OsseoConduct devices" for use as a "bone graft material appropriate for all socket grafting situations"-a use which allegedly was not covered by either 510(k).

Warning Letter (May 19, 2023).

iRhythm Technologies, Inc. Warning Letter (May 2023)

FDA's warning letter to iRhythm Technologies, Inc. addressed iRhythm's Zio QX ECG Monitoring System, which was cleared "for long-term monitoring of arrhythmia events for non-critical care patients where real-time monitoring is not needed as reporting timeliness is not consistent with life-threatening arrhythmias." FDA alleged that marketing materials promoted the device for non-cleared uses, including for "near real-time monitoring" as a "[m]obile cardiac telemetry monitor." According to FDA, these claims "describ[ed] a new patient population," specifically high-risk patients, and therefore the company was required to submit a new 510(k). After opening several Corrective and Preventative Actions investigations in 2022, iRhythm had proposed labeling changes to the Agency, such as removing the term "high-risk" and replacing the phrase "near real-time monitoring" with "near real time cardiac event monitoring." However, FDA stated that such responses were "inadequate," because such language still "implies that the device provides monitoring for high-risk patients that require clinically actionable, timely notification of life-threatening arrythmias to prevent serious injury or death." Warning Letter (May 25, 2023).

ZYTO Technologies, Inc. Warning Letter (June 2023)

FDA's warning letter to ZYTO Technologies, Inc., stated that the company promoted its Zyto Hand Cradle Galvanic Skin Response (GSR) device and associated proprietary software outside the scope of the device's 510(k) clearance. The device was cleared for "the measurement of [GSR]," meaning it can be used to determine autonomic responses as psychological indicators by measuring the electrical resistance of the skin and the tissue path between two electrodes applied to the skin. FDA alleged that ZYTO impermissibly promoted the device to (1) identify "stressors," including diseases and conditions such as Alzheimer's disease, human immunodeficiency virus (HIV), Parkinson's disease and melanoma and (2) recommend "balancers," including specific treatments or mitigations. FDA also stated that the software was a component of the device, since the two must be used together. According to the warning letter, FDA previously had raised similar concerns with Zyto in a Warning Letter issued in 2015. Warning Letter (June 21, 2023).

Outset Medical, Inc. Warning Letter (July 2023)

FDA's warning letter to Outset Medical, Inc., stated that the company was promoting its Tablo Hemodialysis System for non-cleared uses. The device was cleared "for use in patients with acute and/or chronic renal failure, with or without ultrafiltration, in an acute or chronic care facility or in the home." However, FDA alleged that the Outset website promoted the device for continuous renal replacement therapy ("CRRT") treatment by claiming that hospitals converted CRRT programs over to Tablo. Warning Letter (July 5, 2023).

Tesla BioHealing, Inc. Warning Letter (August 2023)

FDA's warning letter to Tesla BioHealing, Inc., addressed the company's Tesla MedBed Generator and Tesla BioHealer devices. FDA cited the Tesla website as stating that "Tesla BioHealing OTC Medical Devices create their own environments of pure Life Force Energy, offering a much higher concentration of this natural healing force than is available in everyday environments" and that "[o]nce the body is given enough Life Force Energy to work with, cellular self-repair mechanisms can begin to activate much faster and more profoundly than previously was possible." By regulation, devices classified under 21 C.F.R. § 890.5500 ("Infrared lamp") "emit[] energy at infrared frequencies . . . to provide topical heating" and are exempt from premarket notification. However, FDA alleged that the Tesla MedBed Generator and Tesla BioHealer devices were intended for different uses, since they "do not have a heating element and are marketed for different intended uses, including treatment of a wide variety of chronic illnesses and diseases, such as terminal cancers, stroke paralysis, Lyme Disease, Alzheimer's/Dementia, and Epilepsy." FDA cited various intended uses and disease claims from the company website, finished product labels, and promotional brochures. Warning Letter (Aug. 10, 2023); FDA Advertising and Promotion Enforcement Activities: Update.

King Systems Corp. Warning Letter (August 2023)

FDA's warning letter to King Systems Corp., dba Ambu, Inc., stated that claims on the company's website promoted the King LTS-D branded supraglottic airway with gastric access lumen with an intended use for pediatric populations, even though the device was cleared for use in adult patients only. Warning Letter (Aug. 16, 2023); FDA Advertising and Promotion Enforcement Activities: Update.

Neurotris, Inc. Warning Letter (October 2023)

FDA's warning letter to Neurotris, Inc., dba A1 Engineering, addressed the company's Class II powered muscle stimulator devices, including the SX2500 (Picowave), SX3800, SX4500, SVX650, PICO Toner, and accessories such as electrodes, conductive gels, and spray. The company's original Body System device (models SX101 and OS2911) was cleared as a power muscle stimulator under 21 C.F.R. 890.5850 "for muscle conditioning to stimulate healthy muscles" and was "not intended to be used in conjunction with therapy or treatment of medical diseases or medical conditions of any kind." FDA stated that the newer muscle stimulator devices had different technological characteristics than the original 510(k) cleared device and that their manuals provided that their intended use was "to stimulate nerves and muscles, causing muscle contraction for esthetic beautification." FDA stated that stimulation of nerves as opposed to muscles "exceed[ed] the intended use definition" for powered muscle stimulators. FDA also asserted that, while the manuals for the original device warned against use on the chest, significant portions of the face, and neck, statements on the company's website, social media, and user manuals promoted the use of the newer devices on these areas. In addition, FDA alleged that the company was marketing additional accessories such as "Probes," "Silver Facial Sculpting Gloves," "Facial Pads," and the "ANMA Lift," with different technological characteristics than the original electrodes cleared for use with the Body System. FDA cited multiple promotional statements from the company's website and social media that differed from the cleared electrode device labeling, including a statement on the Neurotris Facebook that the ANMA Lift "has been called the 'non-surgical facelift.'" Finally, FDA noted that the websites and materials included references to multiple conductive gels and sprays that were not cleared for use with the original Body System device. Warning Letter (Oct. 27, 2023).

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