Since the start of 2021, the Food and Drug Administration has been busy issuing warning letters. In the first quarter, from January 1 to March 31, the agency issued and posted 166 letters.

The pace appears to be increasing: 43 in January, 60 in February and 63 in March. Moreover, year over year, the FDA has been busier this year as compared to the same time period in 2020, during which only 97 letters were issued.

Perhaps unsurprisingly, a large percentage of warning letters concern adulterated, unapproved or misbranded products related to COVID-19, including purported treatments and preventative products.

The FDA has approved COVID-19-related products through the emergency use authorization process. As a result, there is a limited – and readily identifiable – universe of approved products, making unapproved products easy to spot.  The agency has invited the general public to report companies that are marketing unauthorized treatments. Such reports can lead to regulatory consequences from the agency and  may also increase a company's negative public profile.

Meanwhile, tobacco, another FDA priority, has also received significant attention, and e-cigarette companies continue to be in the agency's crosshairs for selling unapproved products. As use of vaping products by teenagers continues to rise – along with public concern – the agency is looking for products that have not received its explicit clearance or that do not otherwise satisfy an exception to FDA approval.

Below are our observations about the FDA's warning letter activity in the first quarter of 2021, plus some key takeaways.

Products marketed as coronavirus treatment or prevention

The FDA is closely monitoring websites and social media for advertisements about products that, without approval or authorization by the agency, claim to mitigate, prevent, treat, diagnose or cure COVID‐19. 

From January 1 through March 31, 28 of the 166 letters, or nearly 17 percent, went to companies purporting to sell COVID-19 treatments, or products intended to prevent COVID-19. Of those, 12 letters – almost half – came from the agency's Center for Devices and Radiological Health, or CDRH.

Of the remaining letters dealing with COVID-19 treatments or products, eight came from the Center for Drug Evaluation and Research, or CDER, six came from the Center for Food Safety and Applied Nutrition, and two came from the Division of Human and Animal Food Operations.^[1]

Beyond warning letters – to which, in the case of  letters concerning COVID-19-related products, the FDA may request an expedited response within 48 hours – the agency is going a step further, publicly and proactively advising consumers not to purchase or use certain products that have not been approved, cleared or authorized by the FDA, and are being misleadingly represented as safe and/or effective for the mitigation, prevention, treatment, diagnosis or cure of COVID-19.

Companies receiving warning letters are added to a published list on the FDA's website.^[2] Companies can get off that list once they have taken appropriate corrective actions, and the FDA has confirmed such remediation.

Center for Devices and Radiological Health

During the first quarter of 2021, the CDRH sent 12 warning letters to companies related to products purportedly intended to diagnose, or assist with the diagnosis of, COVID-19. Two letters related to serology tests, while the majority – 10 – were directed to companies marketing thermal scanners or other products to measure human body temperature.^[3]

The FDA deemed these products adulterated and misbranded because they did not receive marketing approval, clearance or other authorization from the agency. The Food, Drug and Cosmetic Act, or FDCA, requires such approval or clearance for devices when they are intended for use in the diagnosis of disease or other conditions.

Telethermographic systems are devices that fall within the meaning of this regulation, because they are intended for a medical purpose, such as body temperature measurement, even if used in nonmedical environments.^[4]

The FDA is looking closely at the use of telethermographic devices for assessing human body temperature – and in particular, the risks associated with false positive and false negative results. As the agency stated in a warning letter issued to Thermoteknix System Limited on March 4:

A person with an undetected elevated temperature who was subject to temperature assessment using a telethermographic device may, as a result, be less likely to adhere to infection prevention and control guidelines, such as social distancing and using personal protective equipment.^[5]

The FDA is particularly wary of such risks where telethermographic devices scan multiple individuals simultaneously.

Center for Drug Evaluation and Research

While the CDRH is tasked with monitoring devices, the CDER is keeping tabs on manufacturers and retailers of other products.

During the first quarter, the CDER issued warning letters to a variety of manufacturers for such products as essential oils, tinctures, tea concentrate, reusable hand wipes, mouth spray and CBD products that are purportedly intended to mitigate, prevent, treat, diagnose or cure COVID-19. According to the CDER, the cited oils, tinctures and teas violated a host of FDA regulations, including being unapproved,^[6] misbranded^[7] and illegally offered for sale.^[8]

The CDER also targeted suppliers of FDA-approved medications, such as hydroxychloroquine and azithromycin, that misstated their approved indications and/or overstated their use in patients with COVID-19, even when such medications have not been approved by the FDA for use in the prevention, diagnosis, treatment, mitigation or cure of COVID‐19.

The agency's regulations are intended to protect consumers, because unapproved new drugs do not carry the same assurances of safety and effectiveness as those drugs subject to FDA oversight. Likewise, drugs that have circumvented regulatory safeguards may be contaminated, counterfeit, contain varying amounts of active ingredients or contain different ingredients altogether.

The CDER issued a total of 36 letters between January 1 and March 31.

Beyond the letters discussed above for products specifically advertised for use in treatment or preventing of COVID-19, the CDER also focused on hand sanitizers that failed to meet potency expectations, as well as other current good manufacturing practice, or CGMP, violations by active pharmaceutical ingredient and final drug product manufacturers. The agency also cited clinical investigators for failing to rectify clinical trial and research problems identified during previous FDA inspections.

Consumer purchases of hand sanitizers have increased significantly since the declaration of the global pandemic, and the CDC has issued recommendations about use of hand sanitizers that have also heightened public interest in protection against disease. As a result, the FDA is focusing quality evaluations on hand sanitizer manufacturers.

The agency is monitoring hand sanitizer potency levels, particularly for products manufactured abroad and imported to the US for sale. Indeed, as reflected in many of the warning letters, the agency has been detaining batches of hand sanitizers at the border and conducting testing for overall quality and potency.

During the first quarter of this year, the FDA found that many of the hand sanitizers it inspected fell below effective potency. These products were considered adulterated, because the subpotency demonstrated that quality assurance within the facilities where they were manufactured did not accord with CGMP requirements.

Many of the recipients of the recent warning letters were advised to retain a CGMP consultant to evaluate operations and to assist them in meeting CGMP requirements.

Center for Tobacco

The FDA continues to prioritize protecting consumers from unauthorized tobacco products. In particular, e-cigarette use among children and teenagers is a growing concern, reinforcing the need for FDA to take proactive action.

In 2020, the 139 Center for Tobacco letters comprised 22 percent of all warning letters issued by the FDA. In the first quarter of this year, 77 of the 166 letters, or 46 percent, related to tobacco products. The vast majority of products at issue were e-cigarette or e-liquid products and violated the FDA's requirements for premarket approval before sale in the US.

For background, the FDA's jurisdiction for oversight of this area can be found in a variety of FDCA regulations. The agency regulates products made or derived from tobacco and intended for human consumption.^[9]

FDA jurisdiction extends to and specifically includes e-liquids, which must comply with FDCA requirements.^[10] The FDA's specific oversight of these products, including e-cigarettes and e-liquids, was extended effective August 8, 2016, through a broader definition of a tobacco product.^[11]

Generally, the FDCA requires new tobacco products – defined as any tobacco product that was not commercially marketed in the U.S. as of Feb. 15, 2007 – to have a premarket authorization order to be legally marketed in the U.S.^[12] Excluded from the definition of new tobacco products are modified tobacco products that were commercially marketed after February15, 2007.^[13]

A premarket authorization for a new tobacco product is required absent substantial equivalence to a predicate product, or satisfaction of an exemption to the substantial equivalence requirement.^[14] 

For a product to be deemed substantially equivalent – thus obviating the need for a premarket authorization order – the manufacturer must submit a report to the FDA, and the agency must issue an order finding the product substantially equivalent to a predicate tobacco product.^[15] To be exempt from the substantial equivalence requirement, the manufacturer must submit a report establishing that all modifications are covered by exemptions.^[16]

In virtually every warning letter for a tobacco product issued during the period under consideration, the FDA cited the manufacturer because their e-liquid products were considered new tobacco products but did not have the required premarket authorization and were not subject to an exemption from the rule.  As a result, the products were considered adulterated under Section 902(6)(A) of the FDCA. The agency also flagged many of these products for being misbranded under Section 903(a)(6) of the FDCA, because a notice or other information respecting these products were not provided as required by Section 905(j) of the FDCA. 

Manufacturers are responsible for ensuring their tobacco products and all related labeling and/or advertising – including on websites, social media and search engines – comply with each applicable provision of the FDCA and the FDA's implementing regulations. In many of the recent warning letters, the agency notes that the recipient is a registered manufacturer with thousands of products already listed with the FDA.

As is customary in the case of most FDA warning letters, the agency has typically provided 15 working days for companies to respond. Failure to address any violations may lead to regulatory action – including, but not limited to, civil money penalties, seizure and/or injunction.

Because many of these companies already maintain authorizations for other tobacco products, they run the risk of additional regulatory scrutiny and negative action when they are flagged for selling unauthorized products.

Miscellaneous

A handful of other divisions within the FDA issued warning letters during this same time period. For example, the Center for Food Safety and Applied Nutrition flagged manufacturers and retailers for marketing natural and homeopathic remedies and other dietary supplements that have not been approved by the FDA or approved to treat the listed diseases or conditions.

The agency's Division of Northeast Imports and Division of West Coast Imports also warned importers of problems related to food products imported for sale in the US. Finally, the Office of Prescription Drug Promotion warned both a prescription drug and a medical device manufacturer of problems with advertising and marketing materials that failed to adequately convey the risks of products.

Takeaways

The FDA is increasing its scrutiny, most notably, of products making claims about COVID-19 or part of the public health response to COVID-19, and it is also looking closely at vaping products.  Prudent companies are taking these proactive steps:

• Companies which sell products marketed to diagnose or treat any aspect of COVID-19 are being exceptionally cautious about any claims they make for the efficacy of the product.
• Companies that manufacture or sell hand sanitizers are adhering to CGMP and potency standards.
• Companies that manufacture or sell tobacco products – particularly products related to vaping – are similarly taking steps to ensure they are in compliance with applicable provisions of the FDCA and the FDA's implementing regulations

Failure to comply may lead to a warning letter to which FDA typically gives companies 15 days to respond. But in certain circumstances FDA may request an expedited response within 48 hours.  Failure to address any violations may lead to regulatory action – including, but not limited to, civil money penalties, seizure and/or injunction.  For COVID-19 related products, the agency is going a step further and publicly warning consumers not to purchase or use certain products.

An earlier version of this alert appeared on Law360 on April 8, 2021.

^[1] The CFSAN issued five letters to manufacturers or retailers marketing vitamins and teas that purport to be safe and/or effective for the treatment or prevention of COVID-19.

^[2] See https://www.fda.gov/consumers/health-fraud-scams/fraudulent-coronavirus-disease-2019-covid-19-products.

^[3] The CDRH's other three Warning Letters during this period also were directed at manufacturers of telethermographic devices, but those were not specifically marketed for COVID-19 diagnosis.

^[4] 21 U.S.C. § 321(h).

^[5] https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/thermoteknix-system-limited-613565-03042021.

^[6] 21 U.S.C. § 355(a).

^[7] 21 U.S.C. § 352.

^[8] 21 U.S.C. § 331(a) and (d).

^[9] 21 U.S.C. § 321(rr).

^[10] 21 U.S.C. § 387a(b)); 21 C.F.R. § 1100.1.

^[11] See Final Rule, Deeming Tobacco Products To Be Subject to the Federal Food, Drug, and Cosmetic Act, as Amended by the Family Smoking Prevention and Tobacco Control Act; Restrictions on the Sale and Distribution of Tobacco Products and Required Warning Statements for Tobacco Products, 81 Fed. Reg. 28,974 (May 10, 2016), available at https://federalregister.gov/a/2016-10685.

^[12] 21 U.S.C. § 387j(a).

^[13] Id.

^[14] See generally 21 U.S.C. § 387j(c)(1)(A)(i).

^[15] 21 U.S.C. § 387e(j).

^[16] 21 U.S.C. § 387e(j)(1)(A)(ii); 21 U.S.C. § 387e(j)(3)).