1. When is a study of a drug or biologic regulated by the FDA?

All clinical investigations involving a drug or biologic are FDA-regulated and the FDA Informed Consent and IRB (21 CFR 50, 56) regulations apply, even if the study is exempt from IND requirements (see below for additional information). This document is designed to help investigators determine if and what FDA regulations apply to their studies.

2. Definitions:

Biological Product means a virus, therapeutic serum, toxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or other trivalent organic arsenic compound, applicable to the prevention, treatment, or cure of a disease or condition of human beings). [42 U.S.C. 262(i)]

Clinical investigation means any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this definition, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice. [21 CFR 312.3(b)]

Dietary Supplement: A dietary supplement is a product taken by mouth that is intended to supplement the diet and that contains a dietary ingredient. The dietary ingredients in these products can include vitamins, minerals, herbs and other botanicals, amino acids, other dietary substances intended to supplement the diet, and concentrates, metabolites, constituents, extracts, or combinations of the preceding types of ingredients. Dietary supplements can be found in many forms such as tablets, capsules, softgels, liquids, or powders. See section 201(ff) of the FD&C Act [21 U.S.C. 321(ff)]. Please see below for additional information about when a dietary supplement is also considered a drug.

Drug means:

(1) articles recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and

(2) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and

(3) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and

(4) articles intended for use as a component of any article specified above in (1), (2) or (3). Section 201(g)(1) of the FD&C Act [21 U.S.C. 321(g)(1)]

Food is defined as “(1) articles used for food or drink for man or other animals, (2) chewing gum, and (3) articles used for components of any such article.” See section 201(f) of the FD&C Act [21 U.S.C. 321(f)]. Please see below for additional information about when a food is also considered a drug.

Sponsor means a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic Institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-investigator, and the employees are investigators.

Sponsor-Investigator means an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. The term does not include any person other than an individual. The requirements applicable to a sponsor-investigator include both those applicable to an investigator and a sponsor. The PI must indicate in the IRB submission that he/she is aware of his/her regulatory responsibilities in acting as both the investigator and the sponsor for an FDA regulated investigation. For additional information about sponsor-investigator responsibilities, please see this Summary of FDA Requirements for Investigators who are also considered Sponsors of New Drugs. Note: A study initiated by a sponsor-investigator is not required to have an investigator’s brochure [21 CFR 312.55].

3. What are the consent requirements for FDA-regulated studies?

Consent requirements differ slightly for FDA-regulated studies. Consent cannot be waived for FDA-regulated research except for limited circumstances involving life-threatening situations, military operations, public health emergencies or for emergency research [21 CFR 50.23 & 50.24]. All elements of consent must be present as it is not possible to waive elements of consent for FDA-regulated research. This means that deceptive methodologies are not permitted.

A waiver of documentation (signature) of informed consent is permitted only for research that presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside the research context. Note that for greater than minimal risk research, some minimal risk activities may still qualify for this waiver. For example, a minimal risk eligibility screening conducted over the phone may be conducted without collecting a signature, provided that written consent is obtained for the greater than minimal risk activities.

All consent forms for FDA-regulated research must include a statement that the FDA may inspect research records. OSU template language: The FDA, other federal regulatory agencies and the Oregon State University Institutional Review Board (a committee that reviews and approves research studies) may inspect and copy records pertaining to this research.

4. What is an Investigational New Drug (IND) Application and when is it required?

The Investigational New Drug (IND) Application is a formal notification by the study sponsor (or sponsor-investigator) to the FDA that a drug or biologic will be used in a clinical investigation.

All clinical investigations involving drugs or biologics require an IND unless the investigation meets the IND Exemption criteria outlined in 21 CFR 312.2 (see below for additional information). Studies requiring an IND may only begin after the IND becomes effective.

For additional information, please also see:

1. Does my study require an Investigational New Drug (IND) Application from the FDA?

2. How do IRBs Determine Whether Dietary Supplement Studies Require an Investigational New Drug (IND)?

5. When is a study exempt from the IND requirements?

The clinical investigation of a drug product that is lawfully marketed in the United States is exempt from the IND requirements if all the following apply:

  • The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling for the drug;
  • If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the investigation is not intended to support a significant change in the advertising for the product;
  • The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product;
  • The investigation is conducted in compliance with the requirements for IRB review set forth in 21 CFR 56 and with the requirements for informed consent set forth in 21 CFR 50; and
  • The investigation is conducted in compliance with the requirements of 21 CFR 312.7.

NOTE: studies that are exempt from the IND requirements are still FDA-regulated studies.

For additional information, please also see the OSU decision tree: Does my study require an Investigational New Drug (IND) Application from the FDA?

6. When is a dietary supplement considered a drug?

A dietary supplement is not considered a drug and is not subject to the premarket approval requirements for drugs if the intended use for which it is marketed is only to affect the structure or any function of the body and is not intended for therapeutic purposes. If there is a clinical investigation intended to evaluate if a dietary supplement has the ability to diagnose, cure, mitigate, treat, or prevent a disease, an IND is required under 21CFR312.

For example, a clinical investigation designed to study the relationship between a dietary supplement’s effect on normal structure or function in humans (e.g. guarana and maximal oxygen uptake) or to characterize the mechanism by which a dietary supplement acts to maintain structure or function (e.g. fiber and bowel regularity) would not need to be conducted under an IND. However, a clinical investigation designed to evaluate a dietary supplement’s ability to prevent osteoporosis or to treat chronic diarrhea or constipation would need to be conducted under an IND.

FDA Informed consent and IRB regulations do not apply for studies involving dietary supplements that are not considered to be drugs. IRB review and approval is still required under 45 CFR 46. Please note, if subjects will be asked to consume dietary supplements, the study will be reviewed at a convened IRB meeting.

NOTE: the FDA issued a stay in October 2015 related to IND Submission requirements for certain types of foods and dietary supplement studies. More information can be found in this FDA Guidance document and on the Federal Register.

Also see guidance related to research involving food or food-derived products, spices/herbs, or dietary supplements.

7. When is a food considered a drug?

A food used as such, (i.e., primarily for taste, aroma, or nutritive value) and not for therapeutic purposes or to affect the structure or function of the body, other than by providing nutrition, is not a drug. For studies intended to evaluate the effects of the food, the analysis for whether an IND is needed turns to the intent of the clinical investigation. A food is considered to be a drug if it is “intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease,” except that a food may bear an authorized health claim about reducing risk of a disease without becoming a drug*. The FDA regulates conventional foods (including baby formula) that are intended to affect the structure or function of the body as foods, not drugs, as long as the intended structure and function effect derives from the product’s character as food – its taste, aroma, or nutritive value.

For example, a clinical investigation intended only to evaluate the nutritional effects of food (including medical foods) would not require an IND, but an investigation intended to evaluate other effects of food on the structure or function of the body would. A study of the effect of iron on hemoglobin levels in which subjects were fed beef or lamb as a source of iron would not require an IND, but a study of the effect of soy isoflavones on bone metabolism would.

*A clinical study designed to evaluate the relationship between a food substance and a disease, and is intended to provide support for such a claim is required to be conducted under an IND, unless the substance-disease relationship being studied is already the subject of an authorized health claim.

FDA Informed consent and IRB regulations do not apply for studies involving foods that are not considered to be drugs. IRB review and approval is still required under 45 CFR 46.

NOTE: the FDA issued a stay in October 2015 related to IND Submission requirements for certain types of foods and dietary supplement studies. More information can be found in this FDA Guidance document and on the Federal Register.

8. When is a study involving a drug eligible for IRB review using expedited procedure?

For a drug study to be eligible for Expedited Review under Expedited Category 1, the drug must present no more than minimal risk to the subject, and meet the criteria in Category 1a:

Expedited Category 1a- Research on drugs for which an IND application (21 CFR Part 312) is not required.

NOTE: Research on marketed drugs that significantly increase the risks or decreases the acceptability of the risks associated with the use of the product is not eligible for expedited review.

For example, a study that uses an already cleared, marketed drug according to its approved indications that is otherwise exempt from the IND requirements AND the study is not more than minimal risk may be reviewed at the expedited level.

9. What if the study information isn’t going to be used for marketing?

Commercial intent is not a factor in the applicability of the regulations pertaining to the requirements for an IND application.

Additional Sources: