Dietary supplements are easily accessible on store shelves or online marketplaces. These supplements are not classified as drugs under the Dietary Supplement Health and Education Act of 1994 (DSHEA) and, as such, do not require pre-marketing approval from the U.S. Food and Drug Administration (FDA). They are intended to supplement the diet with additional nutrients that have a limited effect on the body’s structure and function, without claiming to have any effect on diseases.
Dietary Supplements in Research Studies
When used as investigational products in a study, dietary supplements may be subject to varying regulations and requirements.
It can be challenging to determine when a protocol is designed to evaluate an investigational supplement’s effect on the body’s structure/function or its mechanism of action, for which an Investigational New Drug (IND) application is not required, or when it aims to diagnose, cure, mitigate, treat, or prevent a disease, for which an IND may be required.
Depending on the ingredients of the product and the objectives of the study, the product may be classified as a drug by the FDA and required to comply with 21 CFR 312. When dietary supplements are classified as drugs, they do not have the same IND exemption pathway as legally marketed drugs, and sponsors may be required to obtain an IND. In the alternative, the product may be classified only as a dietary supplement, and then the requirements under 21 CFR 312 would not be applicable.
In this paper, we will examine what sponsors/investigators need to consider when designing a study with dietary supplements to ensure compliance with the FDA requirements.
Let’s start with identifying what makes a product a dietary supplement
1. What Is a Dietary Supplement? 1
A dietary supplement is a product that is intended to supplement the diet and contains one or more dietary ingredients, such as vitamins, minerals, herbs, or other botanicals, amino acids, or other substances. Dietary supplements come in various forms, including tablets, capsules, soft gels, gel caps, liquids, and powders. (Section 201(ff) of the FD&C Act,)
These products are not intended to cure, diagnose, mitigate, treat, or prevent any disease and are not classified as drugs under the law.
The dietary supplement category also includes:
- Ingredients in a dietary supplement that are already present in the food supply chain as articles used in food in the same chemical form used in the supplement. This is true regardless of whether the product is legally marketed as a food or a dietary supplement.
- Any ingredient already marketed before October 15, 1994, or, if marketed after that date, received pre-market approval from the FDA and is listed in the FDA’s website as a new dietary ingredient notification (NDIN). 2
2. What Is Not a Dietary Supplement?
Even when labeled as a dietary supplement, a product “intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” meets the definition of a drug (FD&C Act, section 201(g)).
The dietary supplement category also excludes:
- Articles approved as new drugs, licensed as biologics, or authorized for clinical investigation under an IND that has gone into effect, unless the article was previously marketed as a dietary supplement or as a food.
- Articles authorized for investigation as a new drug for which substantial clinical investigations have been conducted and made public. This article may not be marketed as or in a dietary supplement unless it was marketed as a dietary supplement or as a food before being authorized for investigation as a new drug.
- Some food ingredients, such as food additives or substances with a modified composition of food ingredients due to chemical processes.
Sponsors and investigators are encouraged to request feedback from the FDA if they are unsure about the classification of a product.
Next, let’s look at considerations for study design:
Study objectives are crucial in defining the specific aim of the research and the intended use of the product. The primary and secondary endpoints of the study are the desired outcomes, and they can be measured through one or more clinical outcome assessments. When planning the study design, the objectives and endpoints must be written in a way that identifies whether the product’s intended use is to treat or prevent a disease (health claim) or to affect the structure and function of the body (structure/function claim) after its use.
1. Structure/Function Claim 3
The DSHEA and the FD&C Act (Section 403) established specific regulatory requirements and procedures for structure/function claims, claims of general well-being, and nutrient deficiency disease claims for dietary supplements. Claims allowed by the regulations include:
- The objective describes the role of a nutrient or dietary ingredient intended to affect the normal structure or function of the human body, for example, “calcium builds strong bones.”
- The objective intends to characterize the documented mechanisms by which a nutrient or dietary ingredient acts to maintain the normal structure or function; for example, “fiber maintains bowel regularity,” or “antioxidants maintain cell integrity.”
Claims of General Well-being
- The objective describes general well-being from consumption of a nutrient or dietary ingredient.
Claims Related to a Nutrient Deficiency Disease
- The objective describes a benefit related to a nutrient deficiency disease (like vitamin C and scurvy), but such claims are allowed only if they also say how widespread such a disease is in the United States.
Examples of Structure /Function Claims
- A clear statement that the claim is referring to structure/function that are already normal: “Maintain cholesterol levels that are already in the normal range.”
- The statement is related to a natural state and not associated to a condition that is a disease (i.e. aging and “mild memory loss associated with aging”).
If the objectives of the study contain only structure /function claims and do not propose to treat a disease, it is likely that the substance will be considered a dietary supplement and will not require an IND.
2. Health Claim 4
A “health claim” refers to a statement about a product that suggests a relationship between the product and a disease or health-related condition. To assess whether the claim meets the criterion of a health claim, the FDA provides a definition of disease claim: a “disease” is damage to an organ, part, structure, or system of the body such that it does not function properly (e.g., cardiovascular disease), or a state of health leading to such dysfunction (e.g., hypertension) (21 U.S.C. 343(r)(6)).
According to the definition, if a supplement is intended to treat, prevent, cure, or alleviate the symptoms of a disease or claims to have an impact on a health-related condition, it is considered a drug.
Examples of Health Claims that Will Likely Be Considered Disease Claim 5
- It mentions a specific disease or class of diseases: product is “protective against the development of cancer” or “reduces the pain and stiffness associated with arthritis.”
- It implies that it affects a specific disease or class of diseases by using descriptions of the disease state:
- “relieves crushing chest pain (angina),””improves joint mobility and reduces inflammation (rheumatoid arthritis),”
- “relief of bronchospasm (asthma).”
- It refers to a condition, to which the signs and symptoms refer, that is related to a disease (i.e. stroke and “reduces cholesterol”).
If the objectives of the study contain a health claim the substance being studied will be considered a drug and the FDA likely will require an IND.
It is important to note that when the intended use of the product is to affect a structure/function of the body that is not in a normal health condition, the study’s objectives play a critical role in determining whether the product is considered a supplement or a drug:
Case 1: the study evaluates the absorption of a product while participants are on antibiotics.
- Although the structure/function of the body is not in a normal state, the product may still be considered a supplement because the objectives of the study focus on its mechanism of action rather than evaluating its ability to prevent, cure, mitigate, or treat a disease or health-related condition.
Case 2: the study evaluates the ability of the product to maintain/improve the gut flora in participants on antibiotics.
- The study’s objectives are focused on determining the product’s impact on a health-related condition rather than evaluating its mechanism of action. Thus, the study intends to evaluate the supplement’s ability to prevent, cure, mitigate or treat a disease, which means that the product is likely to be considered a drug.
Consideration for IRB Review 6
When reviewing a proposed study, the IRB applies the regulations that govern dietary supplements, as well as the regulations that govern drugs. Under current regulations, if the objective(s) of a clinical investigation of products lawfully marketed as dietary supplements meet the FDA’s definition of a health claim, an IND is usually required. However, if the objective(s) of the study are to assess the effect of a dietary supplement on the body’s structure, function, or mechanism of action, then an IND may not be required.
Sponsors and Investigators may contact the FDA before submitting the protocol to the IRB to discuss possible IND requirements and seek advice.
- Questions and Answers on Dietary Supplements. Updated October 26, 2022. Accessed November 6, 2023 https://www.fda.gov/food/information-consumers-using-dietary-supplements/questions-and-answers-dietary-supplements#:~:text=A%20dietary%20supplement%20is%20a,intended%20to%20supplement%20the%20diet.
- Submitted 75-Day Premarket Notifications for New Dietary Ingredients. Updated November 1, 2023. Accessed November 6, 2023 https://www.fda.gov/food/new-dietary-ingredient-ndi-notification-process/submitted-75-day-premarket-notifications-new-dietary-ingredients
- Structure/Function Claims, Updated March 7, 2022. Accessed November 6, 2023 https://www.fda.gov/food/food-labeling-nutrition/structurefunction-claims#:~:text=Structure%2Ffunction%20claims%20may%20describe,to%20maintain%20such%20structure%20or
- Label Claims for Conventional Foods and Dietary Supplements. Updated March 7, 2022. Accessed November 6, 2023 https://www.fda.gov/food/food-labeling-nutrition/label-claims-conventional-foods-and-dietary-supplements
- Small Entity Compliance Guide on Structure/Function Claims. Updated November 10, 2021. Accessed November 6, 2023 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/small-entity-compliance-guide-structurefunction-claims#:~:text=Called%20structure%2Ffunction%20claims%2C%20these,or%20function%20of%20the%20body
- WCG IRB Guide for Researchers. October 17, 2023. Accessed November 6, 2023 https://www.wcgclinical.com/wp-content/uploads/2020/08/Guide_for_Researchers-1.pdf?v=1705950564
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