Regulatory background: DSHEA and dietary supplements
- The Dietary Supplement Health and Education Act ( DSHEA) of 1994 defines the FDA’s authority in the regulation of dietary supplement products and dietary ingredients. Under DSHEA, manufacturers are responsible for ensuring their products are safe prior to release to the market. Dietary supplement products may only make “structure/function” claims – claims that the product affects the structure or function of the body – or claims of nutritional support, and may not make any claim that a supplement treats or prevents a specific disease. If a marketed dietary supplement product or dietary ingredient is thought to present a significant or unreasonable risk of illness or injury, or if a product is thought to bear an unsupported claim, the burden of proof lies with the FDA.
- The FDA defines dietary ingredients as “a vitamin; mineral; herb or other botanical; amino acid; dietary substance for use by man to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of the preceding substances.” Dietary supplements are intended for ingestion only, meaning that products that are administered through other routes, such as topically, by injection or by inhalation, do not fall within this definition.
- A dietary supplement is a product “intended to supplement the diet” that contains a dietary ingredient and meets additional qualifications. Dietary supplements must not be “represented for use as a conventional food or as a sole item of a meal or the diet” and should be labeled accordingly. These products are also required to comply with certain labeling expectations and manufacturers are expected to follow a specific set of current good manufacturing practices (a final rule issued in 2007).
- Dietary supplement products do not need approval prior to being marketed – unless they contain a new dietary ingredient (NDI). An NDI is defined as a dietary ingredient not marketed before October 15, 1994. Sponsors of an NDI or a dietary supplement containing an NDI are required to submit what is known as a Premarket Safety Notification to the FDA at least 75 days prior to marketing the product. These applications are more commonly referred to as New Dietary Ingredient Notifications, or NDINs. The application must include the amount of the NDI present in a dietary supplement, the proposed conditions of use, evidence to establish the safety of the product (such as evidence regarding a product’s history of use), and proof of a product’s identity.
- In the 75 days between submitting information and marketing, the FDA’s Office of Dietary Supplement Programs (ODSP) will review the information provided in the premarket safety notification (also called new dietary ingredient notifications, or NDINs). The agency will then respond to the sponsor either with an acknowledgement letter accepting the notification, or with a letter stating that the NDI cannot be used in dietary supplements at this time due to problems with the NDIN in its current form. Letters denying NDIs typically cite one of three main issues: 1) The evidence provided did not adequately show that the NDI could “reasonably be expected to be safe” under the conditions listed, 2) The NDI in question did not meet the statutory definition of a dietary supplement or ingredient; or 3) The NDIN was incomplete.
Despite the language in DSHEA, there are many dietary ingredients currently on the market for which the FDA has never received an NDIN – or for which the NDIN was denied
- In 2022, the FDA called attention to the vast number of dietary ingredients thought to be on the market for which an NDIN was never submitted. In a draft guidance for industry, the FDA stated that it is “aware that some manufacturers and distributors have marketed products for which a premarket NDI notification under section 413(a)(2) of the FD&C Act was required, but never submitted.” According to the FDA’s estimates, this status applies to approximately 3,400 products. [ See AgencyIQ’s analysis of the draft guidance here.]
- At the time, the FDA stated its plan to grant companies 180 days to submit their NDINs – starting on the day that the final guidance is published. “To increase the amount of safety information we have about NDI-containing dietary supplements in the marketplace and to promote risk-based regulation, we are informing manufacturers, distributors, and other interested persons of our intent to exercise enforcement discretion, for a limited time and in limited circumstances, to encourage firms to correct past failures to submit an NDI notification,” wrote the agency
- In some cases, the missing NDINs appear to have been genuine oversights on the part of the sponsors. “A number of firms have told us informally that they realize they should have previously submitted notifications and have the information ready to be submitted, but they are afraid of drawing attention to themselves with a late submission,” FDA wrote in the draft guidance. By taking an amnesty-based approach, the FDA would provide such companies with an opportunity to submit an NDIN without risking regulatory backlash.
- However, the agency is under no misconception that all 3,400 products marketed without an NDIN were honest mistakes. The FDA notes that its intended enforcement discretion would apply “solely to the failure to file an NDI notification; it will not apply to NDI-containing dietary supplements that would be adulterated (e.g., for safety reasons) even if an NDI notification had been timely submitted, or to any other regulatory requirements that pertain to dietary supplements.” According to an AgencyIQ analysis, the FDA actually denies most of the NDINs received, suggesting that the agency may be anticipating the receipt of a number of notifications which will not be cleared.
It has now been two years since the publication of the draft guidance, and FDA still has not taken its promised action
- As May 20, 2024 – two years since the publication of the draft guidance document – the FDA has yet to finalize the guidance and commence the 180-day amnesty period. Immediately after the release of the draft guidance, the Natural Products Association (NPA) submitted a letter requesting a public hearing to clarify the agency’s “position on new dietary ingredient notification guidance.” However, in July 2022 the agency denied the request for a hearing. In total, the draft guidance received 16 comments, mostly from industry organizations, including a follow-up comment from the NPA and other comments in support of NPA’s request for a hearing. [ See AgencyIQ’s analysis of the FDA’s denial here.]
- None of this discussion touches on the number of dietary ingredients that received an NDIN denial and yet are available on the market. Although it is not possible to know the exact number of substances and products that fall into this category, there are some relatively high-profile examples. One is Prevagen (Apoaequorin; Quincy), a dietary supplement marketed as a memory enhancer, which received a denial in 2012. Although this product has received continued scrutiny because of its advertising claims, its presence on the market despite a denied NDIN has never resulted in action from the FDA. Another relatively well-known example of such a substance is kratom, which has received NDIN denials on multiple occasions and is considered by the FDA to be an unlawfully marketed dietary ingredient. [ See AgencyIQ’s deep dive into kratom research and regulation here.]
- The FDA is also aware of certain substances that are considered to be generally unsafe, and for which an NDIN has not been submitted. Examples of these ingredients include the exercise performance enhancers 5-alpha-hydroxy-laxogenin, higenamine, hordenine and octopamine. While some companies have included these ingredients in their products under the claim that they occur naturally in a variety of herbs, the FDA has questioned the validity of these claims and also expressed concerns about the potential adverse effects from these substances. As a result, the agency has released a number of Warning Letters and some occasional public announcements to alert consumers to the potential dangers of these products.
FDA has also struggled in recent years to regulate some dietary supplements which contain ingredients also marketed in some drug products.
- The FDA requires that dietary supplements meet two legal requirements: 1) The article cannot have previously been approved as a drug substance, and 2) It cannot have previously been studied for use as part of an Investigational New Drug Application (IND) – a type of application which establishes a clinical trial in support of a New Drug Application (NDA) for approval. This latter provision is often referred to as the preclusion provision. However, this means that substances that were already available as dietary ingredients prior to their sponsors submitting an IND or obtaining FDA approval may still be marketed as such.
- Some examples of products available as both drugs and dietary supplements quietly exist in the marketplace without much fanfare. One longstanding example is the laxative senna. Over-the-counter drug formulations of senna contain senna glycoside (sennosides); dietary supplement formulations of senna are derived from Senna alexandrina and also provide senna glycoside. L-glutamine offers an example of a more recently approved drug product. While glutamine has been available as a dietary supplement for decades (and remains available as such today), an L-glutamine product recently received FDA approval as a drug (Endari; Emmaus Medical) for reducing the acute complications of sickle cell disease. Another common example is fish oil; fish oil supplements are ubiquitous in the market and yet there are two prescription products (Lovaza and Vascepa) which provide high doses of fish oil omega-3 fatty acids.
- In recent years, one product that had quietly existed in both categories for decades – N-acetylcysteine (NAC) – became the subject of significant controversy. NAC, a modified amino acid has long been available as both a dietary supplement and a prescription drug product. NAC has been approved by the FDA as a drug in inhaled, injectable and tablet form to treat acetaminophen toxicity as well as conditions with “abnormal, viscid or inspissated mucous secretions” like pneumonia. But in 2020 the FDA issued a trio of Warning Letters that all but explicitly prohibited the sale of NAC, unleashing a number of petitions from industry stakeholders. Ultimately, the FDA released a final guidance declaring its intention to exercise enforcement discretion for certain dietary supplement products containing NAC. [ See AgencyIQ’s analysis of the NAC controversy here.]
- Another ingredient that has recently brought attention to this in-between space is Cannabidiol (CBD). Although the story behind this substance is much more complex than that behind NAC, CBD provides a clear example of the barriers the FDA sometimes encounters in its regulation of dietary supplements. After the passage of the 2018 Farm Bill, certain strains of Cannabis sativa – those containing less than 0.3% tetrahydrocannabinol (THC) – became classified as hemp and were removed from the Controlled Substances Act (CSA). With hemp no longer considered a Schedule I substance, CBD could be derived from hemp without issue, leading many manufacturers to place CBD on the market as a dietary supplement. However, around the same time as the passage of the Farm Bill, the FDA approved the first drug product containing CBD (Epidiolex, Jazz Pharmaceuticals), technically eliminating CBD’s ability to be considered under the preclusion provision and creating a situation in which the FDA recognized CBD as a drug, as opposed to a dietary or food ingredient. [ See AgencyIQ’s in-depth analysis of the FDA’s approach to CBD regulation here.]
FDA’s problems with supplement oversight go well beyond just NDIs. There are also many dietary supplement products which unlawfully contain “hidden” drug ingredients
- Two classes of dietary supplement products are considered to be at particularly high risk for adulteration with unapproved drugs: weight loss and sexual enhancement products. In fact, the FDA maintains dedicated webpages for each of these classes of dietary supplement products, providing extensive lists of products that have been found to be contaminated with drugs. In the case of weight loss supplements, the most common offender is sibutramine, a drug that was previously approved by the FDA for appetite suppression but was removed from the U.S. market in 2010 due to serious safety concerns, including heart attack, stroke, and arrhythmia. As noted by the FDA on its dedicated page, there are a number of other drugs – including those approved in the U.S. and other countries – that have also been found in weight loss supplements. In the case of sexual enhancement products, adulterated products are most likely to contain one of two FDA-approved PDE-5 inhibitors (indicated for erectile dysfunction) – sildenafil (Viagra) and tadalafil (Cialis).
- An important clarification – in these situations, the drugs were not listed on the product label and were only identified via targeted testing. The FDA refers to these types of ingredients as “hidden ingredients,” and provides caveats regarding the limitations of targeted testing. One such caveat reads as follows: “The list below includes only a small fraction of the potentially dangerous products marketed to consumers online and in stores. Even if a product is not included in this list, consumers should exercise caution before using these types of sexual enhancement products.” Another states: “Unfortunately, FDA cannot test and identify all weight loss products on the market that have potentially harmful contaminants in order to assure their safety. Enforcement actions and consumer advisories for unapproved products only cover a small fraction of the potentially hazardous weight loss products marketed to consumers on the internet and at some retail establishments.”
- There are a number of additional examples of unapproved drugs being added to dietary supplements as “hidden ingredients.” One prominent researcher in this area, PIETER COHEN of Harvard Medical School, has published multiple articles revealing hidden substances in dietary supplement products, including methamphetamine analogs, various synthetic stimulants and cognitive enhancers. In many of his publications, Cohen and his research team have identified products that contain both unlisted (hidden) unapproved drugs in combination with listed unapproved drugs, introducing another area of noncompliance with dietary supplements.
Moving beyond “hidden” drug ingredients, another market segment explicitly and openly sells unapproved drugs as supplements
- In some cases, supplement manufacturers have been so brazen as to include foreign drugs in their products and openly disclose them on the label. Prominent examples of these drugs include phenibut and tianeptine, both of which can cause addiction, withdrawal, and serious adverse effects. There are also a number of additional examples of foreign drugs that have found their way into dietary supplement products, including the stimulant adrafinil, the neurologically active drug picamilon (which is sold in Russia), and a wide range of performance enhancement drugs, including anabolic steroids, prohormones, and selective androgen receptor modulators (SARMs).
- Phenibut is a neurologically active drug that is similar in structure to some medications approved for use in the U.S., such as baclofen, pregabalin, and gabapentin. It is available as a prescription drug in Russia, where it is often used as a “nootropic” or brain function enhancer. Reports of use in the U.S. suggest that phenibut has addictive potential, with regular users experiencing tolerance and physical dependence and experiencing withdrawal symptoms on discontinuation. It has also been associated with multiple adverse effects such as confusion, severe sedation, and irregular heart rhythms.
- Tianeptine has recently made headlines due to its potential to cause serious adverse effects and dependence. This drug is actually an antidepressant available by prescription in a number of countries outside of the U.S. In clinical studies, it has been found to exert differing effects at different doses – while at lower doses it exhibits antidepressant activity, at high doses it exhibits opioid-like activity. This latter activity has earned tianeptine the informal nickname of “gas station heroin.” And indeed, a review of one poison control center’s experience showed multiple cases of tianeptine intoxication requiring hospitalization, as well as multiple cases of severe tianeptine withdrawal.
- Anabolic steroids and prohormones – both of which are illegal drug substances – are also a growing segment of the dietary supplement market. While many of these drugs advertise themselves as “legal” performance enhancers, perhaps even going so far as to claim that they contain “legal steroids,” there is nothing legal about the substances found in many of these products. The FDA has released a number of safety alerts regarding these products, notifying consumers that despite the claims that these products contain natural, legal, and/or safe ingredients, many actually contain illegal steroids and steroid-like substances. These ingredients – in addition to being prohibited for use by various sports organizations – can also cause serious health issues, including damage to the heart, liver, and kidneys and changes in personality and mood.
- Unfortunately, steroids and steroid precursors (prohormones) may be nearly impossible to accurately identify on a product label. Many of the steroid substances contained in dietary supplements are novel compounds which have not been evaluated or listed by the U.S. Drug Enforcement Administration (DEA). But this does not alter their legal status in any way. Per the 2014 Designer Anabolic Steroid Control Act (DASCA), any substance that “is derived from, or has a chemical structure substantially similar to, an anabolic steroid that is listed, shall be considered to be an anabolic steroid.” This means that an unsuspecting consumer may purchase a product which claims to contain legal, safe, or natural performance enhancing ingredients, only to be subject to the potential adverse effects and legal implications of taking such a product.
- Under no interpretation would these foreign drugs meet the definition of a dietary supplement as described in DSHEA, and yet they remain available on the market. As a reminder, that definition limits supplements to “a vitamin; mineral; herb or other botanical; amino acid; dietary substance for use by man to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of the preceding substances.” However, these drugs remain readily available via multiple outlets (ranging from gas stations to the internet) and from multiple distributors and manufacturers.
Various branches of the government – from the FDA to the Department of Defense (DoD) – are well aware of these issues
- Fully aware of the existence of these drugs in dietary supplement products, the FDA has delivered warning letters to distributors and safety alerts to consumers. These alerts have spanned all of the products discussed (phenibut, tianeptine, picamilon, steroids, prohormones) and then some. In fact, a dedicated website entitled “Information on Select Dietary Supplement Ingredients and Other Substances” includes an entire list of ingredients which have elicited FDA action or communication for some reason. In many cases, this communication was associated with the illegal nature of the specific substance. Unfortunately, despite these communications, these products still proliferate on the market.
- Because of concern for its service members, the U.S. DoD stood up a program to defend against the use of these products: Operation Supplement Safety (OPSS). Per its website, the program was created in 2012 as a DoD-wide educational campaign on dietary supplements, “to increase awareness within the DoD community about potential health risks and how to choose safe dietary supplements.” This education is intended for service members and their families, as well as healthcare providers and DoD leaders, with the understanding that many service members use dietary supplements for a wide range of purposes. “Unfortunately, some supplements can compromise rather than improve performance. Our goal is to provide the tools and resources to help users make informed decisions about dietary supplements to optimize their health, performance, and careers.”
- Unsurprisingly, the primary focus of OPSS’ work relates to performance enhancing substances. The program offers an entire web hub for information on this topic, informing its audience about SARMs, “legal steroids,” prohormones, stimulants, and nootropics. Knowing that many dietary supplement products now openly disclose that they include these unlawful ingredients, many of these educational materials are focused on helping consumers to identify chemicals which are likely to be prohibited and/or unsafe. However, the threat of hidden ingredients still looms large, and consumers are consistently warned that even careful review of a product label may not be adequate for avoidance of these substances.
Ultimately, the FDA’s inaction is partly its own fault – and partly the fault of Congress
- In the meantime, the FDA’s plans to bring NDIs into compliance with the law have languished. As noted above, the agency’s proposal to grant a 180-day amnesty period for the submission of NDINs for ingredients already on the market has not been finalized (or subsequently acknowledged) for two years. That being said, the FDA is currently working on overhauling its NDIN guidance and processes. This may have been identified internally as a necessary first step prior to inviting the submission of thousands of NDINs at once; however, this explanation is speculative at best in the context of continued silence from the agency in this space.
- There is reason to believe that FDA is unlikely to begin enforcement soon. The agency is in the midst of a major reorganization, and the FDA’s dietary supplement oversight division, the Office of Dietary Supplement Programs (ODSP), is set to receive a demotion in the reorganization, which will become effective as of October 1 of this year. ODSP will report in to a new Office of Food Chemical Safety, Dietary Supplements and Innovation (FCSDSI), which will have a broad remit over food chemicals. As the agency works to establish new working models and operating procedures, it seems unlikely that it will have the extra resources to crack down on non-compliant NDIs.
- DSHEA – a regulation that is generally focused on retroactive enforcement instead of proactive mitigation – may be mostly to blame for the broader challenges of overseeing the dietary supplement sector. When manufacturers are the responsible party – expected to ensure their products are safe prior to release to the market – no third-party entity is verifying the quality or even regulatory compliance of these products before they become widely available for consumer use. The FDA may only become aware of these violative products once they have been used by consumers. And even then, the burden of proof lies with the FDA.
- As with dietary supplement ingredients, which are listed on labels despite the lack of an NDIN, hidden and explicit drug ingredients fall into an enforcement black hole. Just as the FDA is aware that there may be 3,400 products for which an NDIN should have, but has not, been submitted, it is also aware of the fact that there are unapproved drugs (both in the form of illegal controlled substances such as anabolic steroids and in the form of foreign prescription drugs) available on the market.
- The exponential growth of the dietary supplement market has far surpassed any possibility for enforcement under a retroactive regime. The sheer number of dietary supplement products available today has made the market practicably impossible to effectively police. The Dietary Supplements Label Database (DSLD) – a database funded by the NIH which offers only an incomplete assessment of dietary supplements currently available on the market – contains over 180,000 individual product labels. Because the DSLD is voluntary (manufacturers are not required to participate or provide their labels for inclusion), this extraordinary number of products represents only a fraction of the dietary supplement market, which is currently estimated to be worth approximately $36 billion.
- In fact, this points to another core issue with the U.S. dietary supplement marketplace: its product scope, and even its size, are both largely unknown. When the most comprehensive collection of dietary supplement products is a voluntary database funded by the nation’s research institute, there seems little hope that the agency in charge of enforcement for these products can have a firm handle on the variety of products and bad actors in this space. In fact, the FDA even attests to this in its own Q&A on dietary supplements, stating that “Because FDA does not approve dietary supplements before they are marketed, the agency often does not know when new products come on the market.”
- Awareness of this particular issue has spawned a number of recent Congressional proposals to create a mandatory Dietary Supplement Registry, effectively requiring all dietary supplement manufacturers to list their products (and their ingredients) with the FDA. However, such a proposal comes with some obvious enforcement-related questions. For example, NDINs are already technically required for dietary ingredients, and yet many manufacturers have managed to run afoul of this regulatory step with no clear repercussions.
- Legislators have also recently expressed interest in limiting the presence of unapproved drugs in dietary supplements. This past month, companion bills were introduced to both the House and the Senate with the primary intention of banning tianeptine. However, the bill is written broadly so as to impact the dietary supplement industry as a whole. It would prohibit several actions, including the “introduction or delivery for introduction into interstate commerce of any product marketed as a dietary supplement that does not meet the definition of a dietary supplement,” and the involvement of debarred persons in the packing or preparation of a supplement.
To contact the author of this item, please email Chelsey McIntyre ( cmcintyre@agencyiq.com).
To contact the editors of this item, please email Alexander Gaffney ( agaffney@agencyiq.com) and Kari Oakes ( koakes@agencyiq.com).