Investigational New Drugs

An Investigational New Drug is a new drug or biologic used in a clinical investigation.

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 biological phenomenon or disease process) or evaluation (i.e., for safety and/or effectiveness) of an unapproved drug.

Clarifying the "New" in IND

One of the FDA’s primary mechanisms for ensuring the safety of research subjects is through Investigational New Drug (IND) filing requirements. The term IND can be misinterpreted, leading researchers to inaccurately conclude that if the drug they are studying is already approved by the FDA, it is not a "new" drug needing a IND application to be filed.

There are many other facets to consider whether a drug being investigated is "new". The FDA approves a drug as safe with any or all of the following specifications (these indications are spelled out in the Investigational Brochure or in the PDR):

  • Route of administration
  • Dose/duration
  • Form of the drug (e.g. capsule vs. tablet)
  • For specific medical conditions
  • With concomitant medications or medical conditions

A study that uses a "new" aspect of the drug's use (i.e. different indication, dose, population, etc.) usually requires the filing of an Investigational New Drug Application.  An IND application is a request for authorization to administer an investigational drug or biologic to humans or a marketed drug in a new indication and/or patient population.

General Requirements for Submission of IND Applications for Clinical Research Studies involving Drugs (including biologics) NOT Currently Approved for General Marketing by the U.S. Food and Drug Administration (FDA)

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 biological phenomenon or disease process) or evaluation (i.e., for safety and/or effectiveness) of an unapproved drug.

Exceptions to the General requirements for an IND submission

  • Dietary supplements: Dietary supplements are exempt from FDA regulation as “drugs” provided that they are being evaluated and/or are labeled for intended use in affecting the structure or function of the body (i.e., a structure/function claim). However, the evaluation of a dietary supplement for the diagnosis, prevention, mitigation, treatment or cure of a specific disease or condition (i.e., a disease claim) requires the prior submission of an IND application.
  • Human cells, tissues, and cellular and tissue based products (HCT/Ps): Certain HCT/Ps are exempt from FDA regulation as “drugs” and thus their evaluation or use under a clinical research study does not require the prior submission of an IND application. In order to qualify for such an exemption, the HCT/P must meet each of the following criteria:
  • Minimal manipulation of the HCT/P is required for its clinical or clinical research use;
  • The HCT/P is intended for homologous use (i.e., a use that is the same as its natural use);
  • The HCT/P is not combined with another article; except for water, crystalloids, or a sterilizing, storage or preserving agent that does not, in itself, raise safety concerns; and
  • Either the HCT/P (i) does not have a systemic effect and is not dependent on metabolic activity; or (ii) the HCT/P is for autologous use, for allogeneic use in a 1st or 2nd degree blood relative, or for reproductive use.
  • Radioactive drugs for research use:  Radioactive drugs for certain research uses 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 research study is prior approved by an FDA-approved Radioactive Drug Research Committee (RDRC) in accordance with the provisions of 21 CFR Part 361.1.  In order for the RDRC to approve the clinical research study involving the use of an unapproved radioactive drug:
      • 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
      • The total radiation dose resulting from the administration of the radioactive drug and any other ionizing radiation-emitting procedures performed specifically for the purpose of the research study must be less than (i) 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 (ii) 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.

General Requirements for Submission of IND Applications for Clinical Research Studies involving Drugs (including biologics) CURRENTLY APPROVED for General Marketing by the FDA:

In general, the submission of an IND is not required for any clinical research study that proposes the use or evaluation (i.e., for safety and/or effectiveness) of an approved drug, provided that all 4 of the following criteria are met:

  1. The results of the study are not intended to be reported to the FDA in support of a new labeling indication for the use of the drug or to support any other significant change in the current product labeling;
  2. The results of the study are not intended to support a significant change in the advertising for the drug product;
  3. The study does not involve a route of administration or dosage level, use in a subject population, or other factor that significantly increases the risks (or decreases the acceptability of risks) associated with the use of the drug product; and
  4. The study is conducted in compliance with the FDA’s requirements for IRB review and informed consent.
NOTE:  The use of new drug combinations not supported by literature are generally NOT exempt.

Per FDA guidance: "Unless adequately described in the literature, initial studies involving new drug combinations should be performed under an IND because of the possible occurrence of synergistic toxicity."

Other considerations for exemption status of marketed drugs or biologics:

  • A clinical investigation involving blood grouping serum, reagent red blood cells, or anti-human globulin, is exempt from IND requirements if (a) it is intended to be used in a diagnostic procedure that confirms the diagnosis made by another, medically established, diagnostic product or procedure and ( b ) it is shipped in compliance with 21CFR312.160.
  • A drug intended solely for tests in vitro or in laboratory research animals is exempt from IND requirements if shipped in accordance with 21CFR312.160.
  • A clinical investigation involving use of a placebo is exempt from IND requirements if the investigation does not otherwise require submission of an IND

Not sure if you need an IND?

If you would like to discuss your research project and the potential need for an IND, or request guidance with an IND application, please contact Amanda Wood.

IND Holder Responsibilities: Once submitting an IND, the IND holder is responsible for:

  • Selecting qualified investigators
  • Ongoing monitoring of all studies submitted to the IND
  • The validity of the data from all sites conducting research under the IND
  • Maintaining adequate records of receipt, shipment, and disposition of the investigational drug
  • For multi-site studies, ensuring that all sites are kept informed of adverse events and safety updates

The IND holder must notify the FDA of any of the following:

Protocol Amendments

— Any changes to the protocol or any new protocols using the investigational agent
— Any new sub-investigators or changes to investigators (with a revised FDA Form 1572)

Safety Data

— IND Safety Reports
— IND Annual Reports (includes a summary of all study findings and adverse events to date)

Investigational Drug Updates

— Any changes to the chemistry, manufacturing, and controls
— Changes to the Investigational Brochure

Closing Out the IND

Additional guidance on submitting an IND application