Vague FDA guidance fails to provide a roadmap to dietary supplement misbranding minefield

In part one of this series, we presented the current landscape regarding misbranding in the dietary supplement space and FDA enforcement activity. Claims of misbranding related to insignificant levels of impurities and other byproducts put the dietary supplement industry in a difficult position.

However, the notion that products should not contain any impurities or byproducts simply lacks any logical support. In this article, we expand on these concepts by examining how impurities in pharmaceuticals and food products can be acceptable to FDA while the agency inexplicably takes the opposite position with respect to dietary supplements.

By refusing to provide detailed guidance on impurities to the dietary supplement industry, FDA has left open the possibility of enforcement actions against dietary supplement entities predicated on an arbitrary system. If pharmaceuticals are allowed to contain impurities or other byproducts based on FDA’s reasoning that not all levels of impurities pose a risk to consumer health, why is this same standard not applied to dietary supplement products?

Sandoz: Impurities are okay in pharmaceuticals

As seen in the recent Sandoz Inc. v. Becerra decision (57 F.4th 272 [D.C. Cir. 2023]), the potential for arbitrary enforcement related to dietary supplement misbranding contrasts starkly with FDA’s position on impurities in pharmaceutical products.

The federal appeals court in Sandoz sought to determine whether known impurities in an FDA-approved drug would also be considered “approved” by the agency in order to enforce a drug manufacturer’s “new chemical entity exclusivity” rights. In this case, Sandoz Inc., a drug manufacturer, brought an action against the Secretary of Health and Human Services (“HHS”) to challenge FDA’s decision in 2012 that the drug Aubagio was eligible for new chemical entity exclusivity. Sandoz had requested approval for a generic equivalent of Aubagio.

Under the Hatch-Waxman Act, a prescription drug may maintain “new chemical entity exclusivity” for a certain period before generic brands are allowed on the market, if no active ingredient in a drug has been previously approved by FDA. The only active ingredient in Aubagio, which is used to treat patients with relapsing multiple sclerosis, is teriflunomide. Sandoz argued Aubagio did not meet the conditions for new chemical entity exclusivity because teriflunomide was previously “approved” as an impurity in a rheumatoid arthritis drug called Arava that FDA approved in 1998.

Arava is comprised of another ingredient known as leflunomide, which FDA identified as the sole active ingredient in that drug. However, when Arava is manufactured and stored, the leflunomide molecules break down into teriflunomide. FDA even characterized teriflunomide as an “impurity” and allowed Arava to contain up to 3.5 percent teriflunomide.

In deciding for HHS, the court accepted FDA’s argument that teriflunomide was not an “active” ingredient in Arava, and therefore was not considered a previously approved ingredient. However, this case stands for much more than affirming that only active ingredients in a drug product may be considered “approved” in a new drug product.

In this case, FDA openly acknowledged and allowed for certain levels of impurities in drug products, which already face a much higher burden of regulation and testing than dietary supplements. Furthermore, this case shows that FDA allows for known impurities that may be byproducts of chemical breakdowns in a product that were not necessarily included to serve a therapeutic function.

FDA guidance

Hoping to find any source of clarity for avoiding misbranding pitfalls, manufacturers and industry stakeholders have turned to FDA guidance for insight into the agency’s view on enforcement. In May 2023, FDA released a Draft Compliance Policy Guide to provide direction on FDA’s enforcement policy with respect to major food allergen labeling. However, rather than provide clarifying guidance for industry in avoiding misbranding claims for major food allergens, FDA appears to continue to bolster contradictory positions in its non-binding “recommendations.”

In general, major food allergens used as ingredients in packaged foods must be declared by the name of the food source from which the major food allergen is derived either in the ingredient list or the “contains” statement. (21 U.S.C. § 343[w]). A food is therefore considered “misbranded” if the food is formulated to include a food allergen, but the ingredient list does not include that food allergen.

Of note, FDA’s draft guidance states that, with some exceptions, FDA exempts the labeling of incidental additives in the ingredient list. Under FDA regulations, incidental additives that are present in a food at “insignificant levels” that do not have a “technical or functional effect in that food” are exempt from the ingredient declaration requirements. (21 C.F.R. § 101.100[a][3]).

While the above exception is allowed by regulation, neither the statute nor FDA’s draft guidance defines what constitutes “insignificant levels” of incidental additives in a food product. Ultimately, it is up to FDA’s discretion once again to determine the levels it deems problematic in food products without giving manufacturers a clear tool to use in order to ensure industry complies with such regulations.

Indeed, in its draft guidance, FDA even acknowledges there is “no set threshold for any major food allergen.” The guidance goes on to state, “FDA recognizes that published data on population threshold dose responses to various food allergens are becoming available and that these published data are beginning to raise the possibility that some low-level exposures to some major food allergens may not pose a health hazard to the majority of food-allergic individuals.”

Not only does FDA admit to a lack of set standards for impurities or levels of allergens allowed in food products, FDA acknowledges the inclusion of these ingredients may not be harmful at all. Ultimately, rather than providing much needed clarity on impurities and incidental additives in the draft guidance, FDA continues to push back the goalpost for compliance for dietary supplement manufacturers.

Implications for industry

As we have previously noted, FDA needs to issue guidance on permissible threshold levels of impurities in dietary supplements. Without it, dietary supplement companies are forced to either test for every possible impurity, a cost-prohibitive approach, or forgo testing and assume the potential risks that their products will be found to be misbranded if FDA finds impurities.

Furthermore, in the absence of clear thresholds for incidental additives and other major food allergens, manufacturers may end up over-warning consumers of product contaminants or ingredients, which would only confuse them.

Without a clear regulatory standard for enforcement, government agencies have more power to enforce these ambiguous standards unevenly across the industry. Moving forward, the industry urgently requires additional guidance to avoid the misbranding minefield with respect to impurities in dietary supplement products.

Zachary S. Taylor is an associate at Epstein Becker & Green in the health care and life sciences practice who assists dietary supplement companies and health care entities in criminal government investigations, civil litigation and regulatory proceedings. He also helps clients navigate state and federal regulatory issues.

Lauren Petrin is an associate at Epstein Becker & Green in the health care and life sciences practice who assists pharmaceutical, biologic and medical device companies on FDA regulatory compliance issues, including those relating to human subject protections and the conduct of clinical trials, interactions with the FDA, advertising, promotion and labeling, and internal corporate investigations. Lauren also advises FDA-regulated entities in corporate transactions and licensing matters.

Jack Wenik is a member of Epstein Becker & Green in the health care and life sciences and litigation practices who focuses on guiding dietary supplement companies and health care providers to reduce the risks of litigation by the government. He has advised clients dealing with cases from fines to corporate integrity agreements, and Medicare/Medicaid exclusion. Wenik is a regular speaker and commentator to the media on dietary supplement and drug topics.