Regulatory Toolbox

The definition of the term "drug" in Section 201(g)(1) of the Food, Drug & Cosmetic (FD&C) Act includes:

• "articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease" and
• "articles (other than food) intended to affect the structure or any function of the body of man or other animals."

Biological products are also considered drugs, as defined in Section 351(i)(1) of the Public Health Service Act. A biological product is:

• "a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings."

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According to 21 CFR 312.3, the FDA defines a clinical investigation as any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice.

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FDA defines the Sponsor as any person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual of pharmaceutical company, government 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 (21 CFR 312.3(e)).

Although the FDA 21 CFR 312.3 also provides a definition for Sponsor-Investigator as an individual who both initiates and conducts an investigation and under whose immediate direction the investigational drug is administered or dispense, the NIH Intramural Program no longer accepts NIH Sponsor-Investigator held INDs (except for a type of Expanded Access IND). NIH IRP INDs must be held by the sponsoring IC or partnering entity.

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When a company, institution, or investigator has a drug that they wish to develop or test in human subjects, the FDA is responsible for reviewing the pre-clinical pharmacology and toxicology, chemistry and manufacturing, and previous human data (if available) under an IND application. Drug development under an IND may continue through marketing authorization via a New Drug Application (NDA), or only serve the purpose of conducting clinical trials.

The FDA has two primary objectives in reviewing an IND according to 21 CFR 312.22:

1. To assure the safety and rights of subjects in all phases of an investigation.
2. To help assure that the quality of the scientific evaluation of the drug is adequate to permit an evaluation of the drug's effectiveness and safety in phases 2 and 3 studies.

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INDs fall into two categories:

Commercial, submitted mainly by companies seeking marketing approval for a new drug. Commercial INDs are required to be submitted to the FDA using the electronic Common Technical Document (eCTD) format.

Research (non-commercial), submitted mainly to advance scientific knowledge. These INDs can still be submitted by paper, although many institutes are submitting with eCTD. While the initial determination is up to the Sponsor, please note the FDA may determine a research study is instead commercial, which would require the IND to be submitted in eCTD format.

Many INDs at the NIH IRP are research INDs with an institute as the sponsor and a PI as the investigator. NIH also has studies under Expanded Access INDs, commonly referred to as "compassionate use" INDs. This pathway allows patients with immediate life-threatening conditions or serious disease conditions to gain access to an investigational drug or biologic for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available.

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Please review the FDA guidance for the following specific topics:

Dietary Supplements (falls under Food)

Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), a dietary supplement is defined, in part, as:

• A product taken by mouth that is intended to supplement the diet and that contains one or more dietary ingredients.
• 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, soft gels, liquids, or powders.

Whether an IND is needed for a clinical investigation evaluating a dietary supplement is determined by the intent of the clinical investigation.

• If the clinical investigation is intended only to evaluate the dietary supplement's effect on the structure or function of the body, an IND is not required. For example: studying the effect of guarana on maximal oxygen uptake or the effect of fiber on bowel regularity.
• If the clinical investigation is intended to evaluate the dietary supplement's ability to diagnose, cure, mitigate, treat, or prevent a disease, an IND is required. For example: evaluating a supplement's ability to prevent osteoporosis or treat chronic diarrhea or constipation.

Conventional Foods (falls under Food)

For studies evaluating the effects of a conventional food, the need for an IND depends on the intent of the clinical investigation. As is the case for a dietary supplement, a food is considered to be a drug if it is "intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease," Therefore, a clinical investigation intended to evaluate the effect of a food on a disease requires an IND.

For example, a clinical investigation intended to evaluate the effect of a food on the signs and symptoms of Crohn's disease would require an IND.

Endogenous Compounds

A common question is whether provocation or challenge studies in which an endogenous compound (e.g., bradykinin, histamine, angiotensin) is administered to subjects to evoke a physiologic response, characterize a disease, or establish the mechanism of action are subject to IND requirements. In these cases, the endogenous compound is plainly not being used for a therapeutic purpose. There is, however, intent to affect the structure or function of the body, so the compound would be considered a drug under these circumstances. Therefore, these types of studies are clinical investigations and require an IND, unless the study meets the criteria for an exemption.

Live Organisms

An IND is required for challenge studies in which a live organism (e.g., virus, bacteria, or fungi, whether modified or wild-type) is administered to subjects to study the pathogenesis of disease or the host response to the organism. Although the challenge organism is not intended to have a therapeutic purpose, there is intent to affect the structure or function of the body. Thus, the organism is both a biological product (see 21 CFR 600.3(h)(1)) and a drug, and an IND is required for the clinical investigation, unless the criteria for exemption are met.

Cosmetics

Studies of ingredients or products marketed as cosmetics require an IND if the ingredient is being studied for use to affect the structure or function of the body or to prevent, treat, mitigate, cure, or diagnose a disease. This is true even if the study is intended to support a cosmetic claim about the ingredient or product's ability to cleanse, beautify, promote attractiveness, or alter the appearance, rather than a structure/function claim.

For example, a study of the effect of a cosmetic product containing human or animal biological material (such as placenta) on skin repair mechanisms would require an IND, even if the study is intended only to support a claim of younger looking skin.

Bioavailability (BA) or Bioequivalence (BE) Studies

A BA/BE study in humans does not require an IND if all of the following conditions are met:

1. The drug product does not contain a new chemical entity (21 CFR 314.108), is not radioactively labeled, and is not cytotoxic.
2. The dose (single dose or total daily dose) does not exceed the dose specified in the labeling of the approved version of the drug product.
3. The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).
4. The sponsor meets the requirements for retention of test article samples (21 CFR 320.31(d)(1)) and safety reporting (21 CFR 320.31(d)(3)).

Radioactive Isotopes

Some studies at NIH utilize positron emission tomography (PET), an imaging technique that uses radioactive substances (radiotracers) injected into participants to provide images of the body using specialized cameras. Some radiotracers can be purchased commercially, however many at NIH, even some that can be purchased commercially, are made at NIH under an IND. This is because the FDA approves manufacturing sites for PET drugs and the NIH is not an approved site for any commercially made radiotracers. The PET Department within the NIH Clinical Center (CC) manufactures the radiotracers below, which all operate under INDs sponsored by the CC:

C-11 Acetate	C-11 Raclopride	F-18 Fluorodopa
C-11 Carbon Monoxide	F-18 Cyclofoxy	F-18 Fluorodopamine
C-11 Flumazenil	F-18 Fallypride	F-18 TZTP
C-11 NNC-112	F-18 FCWAY	Ga-68 DOTATATE*
C-11 Palmitic Acid	F-18 FDG*	N-13 Ammonia
C-11 PBR28	F-18 FLT	O-15 Water
		Tc-94m Sestamibi

*Commercial drug may be provided by the NIH Nuclear Medicine Department

If you seek to include a PET drug in your study, please contact the ORSC Regulatory Support Section for any questions or guidance.

In addition, any radiation used on participants must be approved by the NIH Radiation Safety Committee (RSC).

Human research using a radioactive drug or biological product may be conducted without an IND if:

1. It involves basic research not intended for immediate therapeutic, diagnostic, or similar purposes, or otherwise to determine the safety and efficacy of the product,
2. The use in humans is approved by a Radioactive Drug Research Committee (RDRC), a committee that is approved and regulated by the FDA,
3. The dose to be administered is known not to cause any clinically detectable pharmacological effect in humans, and
4. The total amount of radiation to be administered as part of the study is the smallest radiation dose practical to perform the study without jeopardizing the benefits of the study and is within specified limits.

The RDRC Program is an FDA program that permits basic research using radioactive drugs in humans without an IND when the drug is administered

• to obtain basic information regarding the metabolism of the radioactive drug, or regarding physiology, pathophysiology, or biochemistry;
• is not intended for immediate therapeutic or diagnostic purposes; and
• is not intended to determine safety and effectiveness.

It is important to know that if a drug has never been in humans before, it cannot be used under an RDRC and will need to be used under an IND.

More information on the RDRC can be found at the FDA's RDCR website, including the NIH RDRC.

Cold Isotopes

FDA does not intend to object to clinical investigations using cold isotopes of unapproved drugs being conducted without an IND, provided the following conditions are met (the conditions are based on the criteria for studies using radiolabeled drugs [see 21 CFR 361.1])

• The research is intended to obtain basic information regarding the metabolism (including kinetics, distribution, and localization) of a drug labeled with a cold isotope or regarding human physiology, pathophysiology, or biochemistry.
• The research is not intended for immediate therapeutic, diagnostic, or preventive benefit to the study subject.
• The dose to be administered is known not to cause any clinically detectable pharmacologic effect in humans based on clinical data from published literature or other valid human studies.
• The quality of the cold isotope meets relevant quality standards.
• The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR part 56) and the requirements for informed consent (21 CFR part 50).

In Vitro Diagnostic Biological Products

A clinical investigation involving an in vitro diagnostic biological product (i.e., blood grouping serum, reagent red blood cells, or anti-human globulin) is exempt from IND requirements if

1. it is intended to be used in a diagnostic procedure that confirms the diagnosis made by another, medically established, diagnostic product or procedure, and
2. it is shipped in compliance with 21 CFR 312.160.

Use of Placebos and Active Controls

Although the placebo product is considered an inert (inactive) substance with no pharmacologic activity, it will be given to the human subject and should adhere to certain standards of quality and safety. Hence, the FDA will expect to receive certain information describing the quality and safety of the placebo product to be used in the study. The information regarding a placebo is also included in the FDA Guidance document for Phase 2 and Phase 3 studies. A clinical investigation involving use of a placebo is exempt from IND requirements if the investigation does not otherwise require submission of an IND.

Similarly, if an active control (e.g., active comparator treatment) is used as a comparator to the treatment under investigation, sponsors must comply with FDA's IND regulations for both the comparator and the investigational product. An FDA-approved drug without modification is most often used as the comparator. Sponsors should identify the comparator drug, dosage form, strength, and manufacturer, and include a statement that the drug is used without further modification.

Study Drugs Sourced from Non-Approved Manufacturing Sites or Compound Pharmacies

A drug is considered unapproved if it is sourced from a manufacturing site other than the FDA manufacturing site referenced in the approved package insert. For example, if a drug is approved to be manufactured in the U.S., but the clinical study will procure study drug from another country, the study drug is not FDA approved. Likewise, a drug is considered unapproved if it is changed from its approved formulation at a compound pharmacy.

For example, if a drug is FDA approved as a tablet but the study requires the use of suspension or capsule, which are not approved formulations, the conversion of the tablet to another formulation would result in the use of an unapproved drug. In these cases, an IND would be needed to use a drug manufactured at an unapproved manufacturing site or a drug reformulated at a compound pharmacy to an unapproved formulation.

IND Regulations in Title 21 of the Code of Federal Regulations

IND Regulations are found in Title 21 of the Code of Federal Regulations (CFR), Part 312 (21 CFR 312).

Additional regulations that apply to INDs are found in 21 CFR as follows:

21 CFR Part 50	Protection of Human Subjects
21 CFR Part 54	Financial Disclosure by Clinical Investigators
21 CFR Part 56	Institutional Review Boards
21 CFR Part 58	Good Laboratory Practice for Nonclinical Laboratory (Animal) Studies
21 CFR Part 201	Drug Labelling
21 CFR Part 312	Investigational New Drug Application
21 CFR Part 314	ANDA and NDA Applications for FDA Approval to Market a New Drug (New Drug Approval)
21 CFR Part 316	Orphan Drugs

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