Attorney Marc Ullman explains the significance of two FDA warning letters about homeopathic products and “supplements” containing active pharmaceutical ingredients, and he asks why they have to be so difficult to decipher.

Marc Ullman, Of counsel

March 28, 2024

7 Min Read
Editorial credit: Tada Images / Shutterstock.com

At a Glance

  • FDA isn’t always straightforward with its messages in warning letters.
  • It’s just as important for retailers to track regulatory actions as it is for manufacturers.
  • Companies should regularly check FDA resources, such as warning letters and public health alerts.

by Marc Ullman

During the last quarter of 2023, the U.S. Food and Drug Administration issued two warning letters to Amazon.com Inc. (Amazon) that when viewed in isolation and on their surface seemed quite curious, as well as potentially creating significant burdens for all retailers. 

A closer reading of the letters and some research into the multiple products cited in each suggests FDA’s reasons for issuing the warnings are consistent, straightforward and applicable to all retailers. Why FDA was not equally straightforward in describing the rationale in a manner that provides clear notice to retailers of all regulated products is a question for another day.

Homeopathic drug warning letter

On Nov. 13, 2023, FDA issued a warning letter to Amazon, citing the sale of seven different homeopathic eye drop drugs (“the November warning letter”). On the surface, the letter appears to be an extension of the agency’s December 2022 Homeopathic Drug Products Guidance for FDA Staff and Industry (the homeopathic guidance). In the document, FDA disclosed it expected to increase enforcement against products labeled as homeopathic drugs in the following categories:

● Products with reports of injury that, after evaluation, raise potential safety concerns.

● Products that contain or purport to contain ingredients associated with potentially significant safety concerns.

● Products for routes of administration other than oral and topical.

● Products intended to be used for the prevention or treatment of serious and/or life-threatening diseases or conditions.

● Products for vulnerable populations.

● Products with significant quality issues.

FDA identified the products giving rise to the warning letter:

“Similasan Pink Eye Relief,” “Optique 1 Eye Drops,” “TRP Natural Eyes Floaters Relief,” and “Manzanilla Sophia Chamomile Herbal Eye Drops” are labeled as homeopathic drugs with active ingredient(s) measured in homeopathic strengths. Under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), the term “drug” includes articles recognized in the official Homeopathic Pharmacopeia of the United States (HPUS), or any supplement to it. Homeopathic drug products are subject to the same statutory requirements as other drugs; nothing in the FD&C Act exempts homeopathic drugs from any of the requirements related to adulteration, misbranding, or FDA approval.

Inexplicably, FDA did not point out that each of the products cited in the November warning letter clearly implicated the homeopathic guidance, as they were all for routes of administration other than oral or topical. Non-prescription eye drops also suffered a series of serious quality issues, resulting in consumer injuries and recalls throughout 2023. The notices posted by FDA cited serious consumer health concerns, including eye infections that could result in partial loss of vision, blindness, and bacterial and fungal infections. FDA also noted that ophthalmic drug products pose a potential heightened risk of harm to users because drugs applied to the eyes bypass some of the body’s natural defenses.

At first blush, it might seem unusual for a warning letter like this to be sent to a retailer for issues such as those presented by the homeopathic products cited. The letter raises questions concerning whether FDA expects retailers to be gatekeepers for products they acquire on the wholesale market for resale.

Historically, retailers generally have been held accountable for resale of only the most flagrantly noncompliant product claims, such as those relating to Alzheimer's or Parkinson’s diseases. Interestingly, none of the homeopathic products cited by FDA reach that kind of extreme level of noncompliance.

Some poking around FDA’s website, however, revealed that the brand owners of the products cited in the November warning letter had received their own FDA warning letters announced in a Sept. 12, 2023, press release. This raises another question: whether the real issue for Amazon was the continued sale of products that had been the subject of previous warning letters.

Curiously, FDA never referenced the earlier warning letters to brand owners in its November letter to Amazon. The agency’s failure to do so leaves the impression this was a seemingly random warning letter targeting Amazon for selling homeopathic drugs.

Spiked supplement warning letter

Slightly more than a month later, on Dec. 20, 2023, FDA issued a second warning letter to Amazon, citing the company for the retail sale of seven products spiked with the active pharmaceutical ingredients (API) tadalafil or sildenafil. Each of the products was labeled as a dietary supplement, and the APIs were not listed on any of the labels.

Sildenafil and tadalafil are phosphodiesterase type-5 (PDE-5) inhibitors and the active ingredients in the FDA-approved prescription drugs Viagra and Cialis, respectively, used to treat erectile dysfunction (ED). These undeclared ingredients may interact with nitrates found in some prescription drugs, such as nitroglycerin, and may lower blood pressure to dangerous levels.

In citing Amazon for the introduction of unapproved drug products (masquerading as dietary supplements) into the market, FDA noted it had purchased a sample of each from amazon.com, and subsequent laboratory testing confirmed each contained an undeclared and potentially harmful active pharmaceutical ingredient.

Unfortunately, it is not uncommon for FDA warning letters targeting manufacturers and brand owners of dietary supplement products to cite the presence of APIs based on laboratory testing. These companies have specific obligations to test the identity, strength, purity and composition of their products under current good manufacturing practices (cGMPs) incorporated in 21 CFR Part 111.

Retailers face no such obligations. Thus, like the letter about homeopathic products, FDA’s letter to Amazon regarding APIs is perhaps puzzling. Indeed, it could be interpreted as suggesting that to ensure they are not introducing adulterated products into the market, a retailer must adopt some sort of finished product testing program.

Once again, a closer read of the warning letter suggests the real message is something less surprising. A footnote found at the very end of the warning letter refers to seven public health advisories: one relating to the presence of undeclared APIs in each of the products cited in the warning letter to Amazon.

Indeed, it would hardly be surprising for FDA to take the position that a retailer engaged in the sale of products subject to the FD&C Act is responsible for monitoring public health advisories from FDA and acting accordingly. Such an approach by FDA would seem to be a logical, and not overly onerous, application of the Act’s absolute prohibition on the introduction of adulterated products into interstate commerce.

An important message that’s hidden

Read individually, the two warning letters to Amazon are ostensibly puzzling. Why would FDA target Amazon, a retailer selling homeopathic drugs that appear to be labeled properly and do not make the kind of outrageous, flagrantly improper claims like Alzheimer’s disease, cancer and heart disease that are usually cited in FDA warning letters to retailers and others? And why would FDA send a second letter to Amazon, citing it for the sale of unapproved drugs masquerading as dietary supplements, based on laboratory test results showing the presence of undeclared active pharmaceutical ingredients?

In fact, the second letter suggests Amazon must conduct its own laboratory tests to ensure the products it sells as a retailer are not adulterated. This obligation, however, does not exist under the cGMPs.

As it turns out, the two letters have one very significant thing in common: They both directly relate to products that were the subject of significant regulatory action and potentially present a substantial public health risk. It baffles me why FDA would not make crystal clear its underlying enforcement actions and the failure by Amazon to remove the impacted products from the marketplace.

Retailers are frequently the final gatekeeper between the public and potentially dangerous products, and failure to perform this gatekeeping function could result in significant enforcement action. At least, that is the message FDA should be conveying.

For some reason, FDA has chosen not to take this path and missed a considerable opportunity to serve the interests of consumers, whose health the agency is supposed to protect.

Meanwhile, it is prudent for regulated industry — manufacturers, brand owners and retailers — to track FDA actions and follow publicly available information such as warning letters, public health alerts, recalls, market withdrawals and safety alerts, and constituent updates. Much of this information is available via email if a company signs up for automatic delivery from FDA. At a minimum, I advise that companies establish a system to have a responsible person check these resources on a weekly basis.

About the Author(s)

Marc Ullman

Of counsel , Rivkin Radler

Marc S. Ullman represents clients in matters relating to all aspects of Food and Drug Administration regulatory issues with a focus on the dietary supplement/natural products industry; Federal Trade Commission proceedings and litigation concerning consumer protection compliance and response to enforcement actions, concerning advertising practices, privacy and cyber security. Previously, he practiced with one of New York’s leading white collar criminal defense firms for ten years, where he represented clients in both federal and state prosecutions, as well as numerous related civil matters and other litigations.

Marc’s practice as part of Rivkin Radler’s Health Services Practice Group includes representation of clients on issues relating to FDA compliance, including labels, labeling, claims and good manufacturing practices. He has also represented clients in a number of complex adversarial proceedings with the FDA relating to the scope of the agency’s powers under the Dietary Supplement Health and Education Act of 1994 and its ability to seek remedies such as consumer restitution as well as counseling clients on general litigation related issues and most recently on complex legal issues of concern to the emerging hemp trade in the U.S.

He has represented clients in adversarial proceedings involving the FTC, including the negotiation of consent decrees and litigation regarding the adequacy of substantiation of advertising claims. Marc has appeared/testified on behalf of clients before the Food and Drug Administration’s Food Advisory Committee and at the FDA’s 2000 hearing concerning the impact of the First Amendment to the U.S. Constitution on FDA’s regulation of health claims concerning diseases. He has also counseled clients in connection with matters under investigation by the U.S. Congress.

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