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The JHM IRBs are receiving an increasing number of applications that propose the use of dietary supplements, foods, food-derived products, or other products regulated as dietary ingredients (e.g., spices), (referred to as “nutritional products” for purposes of this document). This guidance, prepared with the advice of Hogan Lovells US LLP, is intended to inform decisions about when to contact FDA and ask for a determination of whether an IND will be required for studies involving nutritional products.
The question of whether IND regulations apply to research involving nutritional products turns on whether the research claim or indication meets the FDA standard of a drug or disease claim. If the nutritional product is being studied to evaluate the nutritional product’s ability to treat a disease or condition, an IND typically will be required unless the product is already approved as a drug and several other exemption criteria apply. This will rarely be the case. The fact that a given research use does not increase risk in comparison to the legally marketed use is not itself relevant to the IND analysis. There are no categorical determinations in this regard; for the same product, INDs may be required for some studies and not for others.
As discussed in more detail, below, regardless of whether a nutritional product is legally marketed as a food or dietary supplement, the researcher must contact FDA for a determination of whether an IND is required if the proposed study involves an indication or evaluates an end point that meets the definition of a drug or disease claim (with narrow exceptions for some nutritional products already approved as drugs, discussed below).
An IND is not required if the studied indication or end point is not intended to evaluate a drug claim or disease claim and instead is focused on the effect of the substance on the structure or function of the body or its mechanism of action.
The definitions of “drug,” “food,” and “dietary supplement” are helpful to understand the situations when INDs are required.
Drug: The FD&C Act defines drugs as “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” and as “articles (other than food) intended to affect the structure or any function of the body of man or other animals.” [FD&C Act, section 201(g)(1), (2)].
Food: The term “food” is defined in the FD&C Act as “articles used for food or drink or man or other animals, chewing gum, and articles used for components of any such article.” [FD&C Act, section 201(f)].
Dietary Supplement: The term “dietary supplement” is defined as a product that contains a “dietary ingredient” and is intended to supplement the diet. [FD&A Act, section 201(ff)]. The “dietary ingredients” in these products may include: (1) vitamins, (2) minerals, (3) herbs or other botanicals, (4) amino acids, (5) substances found in the diet (such as enzymes and edible organ tissues and glandulars), and (6) concentrates, metabolites, constituents, extracts, or combinations of the substances identified in (1)-(5). Dietary supplements may be found in many forms such as tablets, capsules, softgels, gelcaps, liquids, or powders. Dietary supplements are regulated as foods, rather than drugs, for purposes of the FD&C Act and their labeling must identify them as a dietary supplement.
Dietary Supplement Claims: Under the FD&C Act, dietary supplements may bear a claim (1) regarding a benefit related to a classical nutrient deficiency, provided the claim discloses the prevalence of the such disease in the United States, (2) describing the role of a nutrient or dietary ingredient intended to affect the structure of function in humans, (3) characterizing the documented mechanism by which a nutrient or dietary ingredient acts to maintain such structure or function, or (4) describing general well-being from consumption of a nutrient or dietary ingredient. [FD&C Act section 403(r)(6)].
The intended use of a product will determine whether it is regulated as a food, dietary supplement, or a drug. FDA will consider the claims made on product’s label and in its labeling and advertising as well as the end points evaluated in a clinical study when determining intended use. If a claim is made about the impact of a nutritional product on the diagnosis, cure, mitigation, treatment, or prevention of a disease or health related condition, the product will be regulated as a drug. If a study evaluates a drug or disease end point or indication, the substance being studied will be deemed a drug and FDA likely will require an IND.
FDA does not consider the purpose of a study to be therapeutic if the study simply measures the effect of a nutritional product on the structure or function of the body or examines the mechanism by which the product exerts its effect. For example, a study of a dietary supplement’s effect on normal structure or function in humans (e.g., calcium’s effect on bone mass) or a study characterizing the mechanism by which a dietary supplement acts to maintain such structure or function (e.g., fiber’s effect on bowel regularity) would not need an IND. By comparison, a study evaluating a dietary supplement’s ability to prevent osteoporosis, treat diarrhea associated with antibiotic use, chronic constipation, or lower cholesterol, likely would need an IND.
Drug or Disease Purpose vs. Structure/Function
It is important to carefully assess whether a research study’s purpose is evaluating a drug or disease indication or end point, versus the effect of the nutritional product on the structure or function of the body. To determine whether a study has a drug or disease purpose, we refer to the definition of “disease” promulgated in the FDA regulations for dietary supplements. “Disease” is defined as damage to an organ, part, structure, or system of the body such that the organ, part, structure, or system does not function properly (e.g., cardiovascular disease) or a state of health leading to such dysfunction (e.g., hypertension). [21 C.F.R. § 101.93(g)].
FDA has further defined “disease claims” as including any statement that a product:
- Has an effect on a specific disease or class of diseases;
- Has an effect on the characteristic signs or symptoms of a specific disease or classic diseases;
- Has an effect on an abnormal condition associated with a natural state or process, if the abnormal condition is uncommon or can cause significant or permanent harm;
- Belongs to a class of products that is intended to diagnose, mitigate, treat, cure, or prevent a disease or class of diseases;
- Is a substitute for a product that is a therapy for a disease;
- Augments a particular therapy or drug action that is intended to diagnose, mitigate, treat, cure, or prevent a disease or class of diseases;
- Has a role in the body’s response to a disease or to a vector of a disease;Treats, prevents, or mitigates adverse events associated with a therapy for a disease, if the adverse events constitute diseases; or
- Otherwise suggests an effect on a disease or diseases.
Contact FDA and ask for a decision in writing about whether an IND application is required for any study involving the evaluation of a nutritional product with an end point that falls within the FDA definition of “drug” or “disease.” (1) If the investigator and the regulatory specialist agree that a study is limited to structure or function end points, it is not necessary to contact FDA, unless the study involves a food derivative (see below). Consider the following examples that illustrate the difference between structure/function and disease claims:
Acceptable structure/function claims
Disease or Drug Claims
Mild memory loss associated with aging
Alzheimer’s disease or senile dementias in the elderly
To help manage mild mood changes, cramps, and edema associated with the menstrual cycle
Depression associated with the menstrual cycle
Maintaining cholesterol levels in people with normal levels
Studies Involving Subjects with a Disease or Health-Related Condition
In draft Guidance FDA has taken the position that the clinical condition of study participants (e.g., the presence or absence of disease) has no bearing on whether the study is subject to FDA’s IND requirements. (http://www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/UCM229175.pdf) FDA’s draft guidance on INDs makes no distinction between healthy subjects or those with a disease. In other words, FDA has taken the position that no IND is required for a study involving a patient population with a disease provided the study is evaluating an end point that would not be considered a drug or disease claim (2) . For example, the draft guidance would not require an IND for a study involving the effect of caffeine on metabolism or calcium on bone density in people with AIDs because the end point evaluated is not a disease claim; the end point is evaluating an effect on the nutritional product on the structure or function of the body.
JHM will apply the FDA’s definitions of drug and disease during the review of applications that propose use of a nutritional product regardless of whether the food or product used in the protocol will be purchased over the counter or in a grocery store, or is grown or manufactured for the investigational use.
There are a few narrow circumstances where a study can have a therapeutic intent and an IND is not required. First, due to specific statutory and regulatory language, an IND may not be required for studies involving the impact of a dietary supplement on diseases resulting from essential nutrient deficiencies (e.g., scurvy, pellagra). [FD&C Act section 403(r)(6); 21 C.F.R. section 101.93(g)]. Second, an IND may not be required if the product is already approved as a drug. For example, if the use of the product is off-label and the risks are not significantly altered in the research use or dose of the product, the study may meet criteria for an IND exemption. Legal counsel should be consulted if either of these scenarios is thought to apply for a research study.
Finally, if a study assesses an ingredient derived from a food that is not itself a food, such as a concentrated extract, an IND may be required regardless of whether the study has structure/function intent. Researchers should contact legal counsel if such facts apply for their study.
Further Guidance for Investigators
Investigators are urged to contact pre-IND consultation staff of the JHU Institute for Clinical and Translational Research to discuss the possible IND requirements for proposed research involving nutritional products. The research team should seek this ICTR consultation before an application is submitted to the IRB.
FDA will answer questions from investigators concerning whether an IND application is necessary for a given study. Please see the following IRB guidance for further information: http://www.hopkinsmedicine.org/institutional_review_board/guidelines_policies/guidelines/inquiry_about_ind.html).
(1) FDA must be contacted even if the nutritional product falls within a special product category such as a “medical food,” “food for special dietary use,” or “infant formula.” When contacting FDA and seeking a determination on whether the study should be conducted under an IND, the agency should be told the product is a medical food or falls within some other special product category.