General Requirements for the Submission of IND Applications for Clinical Research Studies[1]

I. Drugs (including biologics) Not Currently Approved for Commercial Marketing by the U.S. Food and Drug Administration (FDA)[2]

A. General requirements.

In general, the submission of an Investigational New Drug (IND) application is required for any clinical research study that proposes the use (e.g., as a research tool to explore a physiological or pathophysiological process) or evaluation (i.e., for safety and/or effectiveness) of an unapproved drug[3].

B. Exceptions to the g eneral requirements for the submission of an IND application.

1. Dietary supplements:

Under the Dietary Supplement Health and Education Act (DSHEA) of 1994, a dietary supplement is defined, in part, as a product taken by mouth that is intended to supplement the diet and that contains a dietary ingredient. Dietary supplements are not regulated by the FDA as “drugs” provided that they are intended for oral administration and for use in affecting the structure or a function of the body (i.e., a “structure or function” claim). Thus, research studies directed at using or evaluating a marketed dietary supplement (administered orally) for a structure or function claim are exempt from the requirement for submission of an IND application. However, research studies directed at using or evaluating a marketed dietary supplement administered by other than an oral route; or for the diagnosis, cure, mitigation, prevention, or treatment of a specific disease or condition (i.e., a “drug” claim), or symptoms characteristic of a specific disease or condition, must be conducted under a FDA-accepted IND application.

For additional discussion of structure and functional claims for dietary supplements, refer to the FDA’s Guidance for Industry: Structure/Function Claims – Small Entity Compliance Guide (.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/ D ietarySupplements/ucm103340.htm) and the FDA document, Claims That Can be Made for Conventional Foods and Dietary Supplements (an.fd a .gov/~dms/hclaims.html).

2. Human cells, tissues, and cellular and tissue based products (HCT/Ps):

Certain HCT/Ps are regulated solely under section 361 of the Public Health Services (PHS) Act and, as such, are exempt from the FDA’s regulation as a drug, device, or biological product under section 351 of the PHS Act. Hence, the submission of an IND application is not required for clinical research studies involving the use or evaluation of HCT/Ps that meet the criteria for regulation under section 361 of the PHS Act. It must be emphasized, however, that the manufacture of such HCT/Ps remains subject to the facility registration and other requirements addressed under the FDA regulations at 21 CFR Part 1271.

In order to qualify for regulation under section 361 of the PHS Act (and be exempt from the requirement for submission of an IND application), the HCT/P being used or evaluated under the clinical research study must meet each of the following criteria:

· the HCT/P is minimally manipulated;

o Minimal manipulation means (1) for structural tissue, processing that does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement; and (2) for cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of the cells or tissues.

· The HCT/P is intended for homologous use only;

o Homologous use means the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor.

· The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, storage or preserving agent; provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P; and

o Manufacture means, but is not limited to, any or all steps in the recovery, processing, storage, labeling, packaging, or distribution of any HCT/P, and the screening or testing of the cell or tissue donor.

o Crystalloid means an isotonic salt and/or glucose solution used for electrolyte replacement or to increase intravascular volume, such as saline solution, Ringer’s lactate solution, or 5% dextrose in water.

· Either the HCT/P (1) does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or (2) the HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and is (a) for autologous use, (b) for allogeneic use in a first-degree or second-degree blood relative, or (c) for reproductive use.

3. Radioactive drugs for basic research uses:

Clinical investigations involving the use of certain unapproved radioactive drugs for basic research applications do not require the submission of an IND application provided that:

· The research study is intended to obtain basic information regarding the metabolism or kinetics of the radioactive drug or regarding human physiology, pathophysiology, or biochemistry; but not intended for immediate therapeutic, diagnostic or similar purposes or to determine the safety and/or effectiveness of the radioactive drug for such purposes; and

· The radioactive drug and its use in the clinical investigation are approved by a Radioactive Drug Research Com m ittee (RDRC) in accordance with the provisions of the FDA regulations at 21 CFR Part 361.1. In order for the RDRC to approve a clinical investigation under these regulations:

o The mass of the radioactive drug to be administered must be known not to cause any clinically detectable pharmacological effect in human beings based on data available from published literature or other valid human studies; and

o The total radiation dose resulting from the administration of the radioactive drug and from any other procedures that emit ionizing radiation which are performed specifically for the purpose of the clinical investigation must be less than (1) 3 rems (Adult - Single Study) or 5 rems (Adult – Total Annual) to the gonads, lens of the eye, blood-forming organs, and effective dose equivalent; and (2) 5 rems (Adult-Single Study) or 15 rems (Adult – Total Annual) to all other organs. The radiation dose limits for child-subjects are 10% of these adult limits.

4. Unapproved drug substances labeled with stable isotopes.

Based on FDA guidance[4], the submission of an IND application is not required for clinical investigations involving the use of certain unapproved drug substances labeled with stable isotopes provided that each of the following criteria are met:

· The research is intended to obtain basic information regarding the metabolism (including kinetics, distribution, and localization) of the drug labeled with the stable isotope or regarding human physiology, pathophysiology, or biochemistry;

· The research is not intended for immediate therapeutic, diagnostic, or preventative benefit to the study subject;

· The dose of the labeled drug 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 labeled drug meets relevant quality standards; and

o The research protocol should address how the appropriate identity, strength, and purity of the labeled drug will be ascertained (e.g., review of Certificate of Analysis provided with the order of the labeled drug, on-site testing) prior to use.

o If the labeled drug is intended for parenteral administration, there must be verification that the formulation of labeled drug is sterile and apyrogenic.

· The research is reviewed and approved by an IRB that functions in compliance with 21 CFR Part 56 and informed consent is obtained from the research subjects in accordance with 21 CFR Part 50.

C. Clinical investigations involving of the use or evaluation of special classes of drug – IND application required[5]

1. Endogenous compounds

Provocation or challenge studies in which an endogenous compound (e.g., bradykinin, histamine, angiotensin) is administered to research subjects to evoke a physiological response, characterize a disease, or establish the mechanism of action require the submission of an IND application; unless the study falls into one of the categories for exemption as discussed under I.B., above. Although the endogenous compound is not being used for a diagnostic or therapeutic purpose, there is intent to affect the structure or function of the body. Thus, the compound would be considered a drug and regulated as such by the FDA.

2. Live Organisms

An IND is required for challenge studies in which a live organism (e.g., virus, bacteria, or fungi that is modified or wild-type) is administered to human subjects to study the pathogenesis of disease or the host response to the organism. Although the challenge organism is not being administered for a diagnostic or therapeutic purpose, there is intent to affect the structure or function of the body. Thus the organism would be considered a drug (i.e. biological product) and regulated as such by the FDA. Similarly, an IND would be required for a clinical investigation designed to evaluate whether a product colonized with a strain of bacteria and administered to subjects can treat or prevent disease in patients with a chronic immune disorder.

II. Drugs (including biologics) Currently Approved for Commercial Marketing by the FDA

A. Clinical investigations involving the use or evaluation of a FDA-approved drug for the clinical indication(s) specified in the FDA-approved product labeling

The submission of an IND application is not required for clinical investigations of an FDA-approved drug being used or evaluated in accordance with its current FDA-approved product labeling.

B. Clinical investigations involving the use or evaluation of a FDA-approved drug for a clinical indication that is not currently specified in the FDA-approved product labeling (i.e., an “off-label” indication)

In accordance with the FDA regulations at 21 CFR Part 312.(b), the clinical investigation of a FDA-approved drug being used or evaluated for an “off-label” indication is exempt from the requirement for the submission of an IND application provided that each of the following criteria are met:

1. The drug product is lawfully marketed in the United States;

2. There is no intent to report the investigation to the FDA as a well-controlled study in support of new labeling indication and no intent to use the investigation to support any other significant change in the labeling of the drug;

3. The investigation is not intended to support a significant change in the advertising for the drug;

4. The investigation does not involve a route of administration, dose, patient population, or other factor that significantly increases the risks (or decreases the acceptability of risks) associated with the use of the drug product;

· Route of administration: A change in the route of administration can introduce a significant new risk. E.g., there could be a significant increase in risk if a marketed drug for oral administration is converted to a dosage form that is to be administered by a parenteral or inhalation route. These other routes of administration introduce concerns regarding sterility, pyrogenicity, hypersensitivity (e.g., airway reactivity), variations in absorption and metabolism, and other issues not present with oral administration.[6]

· Dose: Increases in dose, frequency, or duration of administration, compared to labeled dosing regimens, can significantly increase the risk of the marketed drug. It is possible that a decrease in dose could also significantly increase risk. For example, administering a low dose of a pure polysaccharide vaccine to study subjects can induce hypo-immunologic or non-immunologic responses in the subjects and can also induce tolerance to the vaccine; thus rendering the study subjects at increased risk for the infectious disease that the vaccine is intended to prevent. The significance of changes in dose (in particular increases in dose) can vary across therapeutic areas. For example, the cancer treatment guidance[7] provides some latitude for conducting investigations of high-dose cancer treatments without the requirement for an IND submission, because of the oncologists’ familiarity with the implications of high-dose regimens, in general.[8]

· Patient population: The acceptability of known and unknown risks can vary considerably across different treatment populations. For example, a drug with significant toxicity can be approved for use in a population with a life-threatening or severely debilitating disease because the risk of toxicity is acceptable in that population. Use of that drug in a clinical investigation of a population that is not so ill (e.g., to evaluate the drug for prevention of the disease or symptomatic relief), however, would present a different risk-benefit situation in which the risks would likely not be acceptable. When the acceptability of the risk is significantly decreased, the study would have to be conducted under an IND application.[9]

5. The investigation is conducted in compliance with the requirements for review by an IRB that operates in accordance with 21 CFR Part 56 and with the requirements for informed consent at 21 CFR Part 50; and

6. The investigation is conducted in compliance with the requirements of 21 CFR Section 312.7; i.e., the investigation is not intended to promote or commercialize the drug product by charging the research participant (or his/her insurance provider) for the drug under evaluation.

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[1]Refer also to the FDA’s Guidance for Industry: Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without an IND (.gov/downloads/Drugs/Guida n ceComplianceRegulatoryInformation/Guidances/UCM229175.pdf)

[2] I.e., drugs for which the FDA has not accepted a New Drug Application (NDA) or Abbreviated New Drug Application (ANDA).

[3] The Federal Food Drug and Cosmetic (FD&C) Act defines a “drug” as “any article intended for the diagnosis, cure, mitigation, prevention, or treatment of disease in man or animals. Articles (other than food) intended to affect the structure or function of the body or man or animals.”

[4] Guidance for Industry: Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without an IND, U.S. Food and Drug Administration, 2010 (.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM229175.pdf)

[5] Guidance for Industry: Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without an IND, U.S. Food and Drug Administration, 2010

[6] Guidance for Industry: Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without an IND, U.S. Food and Drug Administration, 2010