Investigational New Drugs and Biologics

This guidance is intended to help researchers meet FDA requirements when investigating drugs, biologics, or dietary supplements in clinical research. Federal regulation 21 CFR 312 defines the requirements for clinical investigations of investigational drugs. For a study to fall under the scope of 21 CFR 312, the study must involve a drug(s) and be a clinical investigation of the drug(s).

Definitions

FDA’s Definition of Drug:
  • Intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, OR
  • Intended to affect the structure or any function of the body (other than food), OR
  • Recognized in the official US Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary.

When assessing whether a substance in your study meets the FDA’s definition of a drug, what matters is the intended use of the substance or the purpose of the study. For example, a moisturizing cream (typically regulated as a cosmetic, not a drug) would be considered a drug in a study evaluating its effects on alleviating skin cancer symptoms.

Clinical Investigations of a DrugThe FDA defines a Clinical investigation of a drug/biologic as any experiment in which a drug/biologic is administered to or used on one or more human subjects, except for the use of an approved drug in the course of medical practice.
Clinical Investigations vs. Standard of Care (Course of Medical Practice)

The question of whether a drug is being administered as part of the research or as standard of care (“in the course of medical practice”) can be nuanced in certain circumstances, for example, in research where a drug is merely being used but not studied. 

The provision of standard-of-care palliative care products, such as antiemetics, in an oncology drug study would likely be considered part of the "normal course of medical practice" and not subject to IND regulations, as these are being provided solely for the comfort, safety, or standard care of the participant.

On the other hand, drugs being “used” and not “studied” that are more intimately tied to the main study aims/procedures (e.g., solely used to support a research procedure) may fall outside the “course of medical practice” exception. For example, standard-of-care anesthesia for a research-only biopsy would likely fall under the scope of IND regulations, as the anesthesia use is closely tied to the main research procedure. In this case, the anesthesia is being used to facilitate the conduct of research, not as part of standard medical care for the patient’s benefit.

Active Ingredients:

An active ingredient is defined by the FDA as “any component that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals.”

The active ingredient refers to the component of the investigational product responsible for its intended therapeutic activity or effect. 

It is essential to fully disclose all active ingredients (including proprietary ones) involved in the investigation, as this is a crucial consideration in evaluating the acceptability of risks.

Active ingredients must be listed on the required forms, including the Worksheet: FDA Drugs and IND Requirements.

When an Investigational New Drug (IND) is required

The IND regulations require that human research studies be conducted under an IND if all the following conditions exist:

  1. The research involves a drug.

  2. The research is a clinical investigation.

  3. The clinical investigation is not otherwise exempt from the IND requirements. 

IND Exempt

While all clinical investigations of drugs are FDA-regulated, some may be “Exempt” from IND requirements. To help provide clarity on IND requirements and potential IND exemptions, the FDA has published a guidance document that relays its current thinking on these topics. An investigator who believes their study is eligible for an IND exemption must submit the IRB application along with a supportive rationale and documentation.  The criteria for IND Exempt Category #1, the most common IND Exempt Category, are summarized below.

Category #1: Lawfully Marketed Drugs or Biologics
  1. The drug or biologic is lawfully marketed as a drug product in the United States.

    1. For a drug or biologic to be lawfully marketed, the product must be legally marketed as a drug, meaning it has a New Drug Application (NDA), Abbreviated New Drug Application (ANDA), or Biologics Licensing Application (BLA) that was approved by the FDA, or it conforms to an Over the Counter (OTC) Monograph.

    2. Commercially available products that do not meet the lawfully marketed criteria above do not qualify for this exemption.

  2. The research is not intended to be reported to the 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.

  3. The research is not intended to support a significant change in the advertising for the product.

  4. The research does not involve a route of administration or dosage level or use in a patient population, or other factors that significantly increase the risks (or decrease the acceptability of the risks) associated with the use of the drug product.

    Most on-label use of approved drugs would meet this criterion. For example, an FDA-approved antidepressant (e.g., approved for major depressive disorder) administered orally at the standard labeled dose to eligible patients to evaluate drug–drug interaction potential with a common over-the-counter supplement would meet this criterion as the route, dose, or population used does not significantly increase risk or reduce risk acceptability.  

    By contrast, a dose-escalation study of an FDA-approved antidepressant used off-label at supratherapeutic doses in a patient population, with the goal of evaluating a novel therapeutic effect, would not meet this criterion if the changes in dose and population materially alter the risk profile and significantly increase risk compared with labeled use.

  5. The research is conducted in compliance with the marketing limitations described in 21 CFR §312.7:
    • Sponsor or investigator, shall not represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug.
    • A sponsor or investigator shall not commercially distribute or test market an investigational new drug.
    • A sponsor shall not unduly prolong an investigation after finding that the results of the investigation appear to establish sufficient data to support a marketing application.

If there is uncertainty about whether the exemption criteria above are met, the potential sponsor-investigator (e.g., an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. This individual takes on the dual role of a sponsor and an investigator) can seek advice from FDAConsults or the FDA on the applicability of the IND regulations (§ 312.2(e)).

Legally Marketed versus Commercially Available

It is important to note that there are clear distinctions between drugs that are legally marketed versus those that are commercially available. In order for a drug to meet the definition of legally marketed, the drug must go through the FDA's approval process, which involves demonstrating both safety and effectiveness. 

A product or drug (by FDA definition) may be commercially available (e.g., available at storefronts or in online marketplaces), but this does not mean that the drug has been FDA-approved. Products that are commercially available, but not legally marketed, may require an IND in order for the research to proceed.

Other IND Exemption Categories include:

  • Category #2: Serological Tests (21 CFR 312.2(b)(2)): Includes clinical investigations for an in vitro diagnostic biological product that involves one or more of the following: (1) Blood grouping serum; (2) Reagent red blood cells; or (3) Anti-human globulin. See FDA guidance for criteria.
  • Category #3: Placebos (21 CFR 312.2(b)(5)): A clinical investigation involving the use of a placebo is exempt from IND requirements if the investigation does not otherwise require submission of an IND.
  • Category #4: Bioavailability/Bioequivalence Studies (21 CFR 320.31(b) and (d)): Certain bioavailability or bioequivalence studies using approved drugs are exempt if they comply with specific safety, labeling, and IRB/informed consent criteria as set forth in 21 CFR 50.20. See FDA guidance for criteria.
  • Category #5: Radioactive Drugs for Research Use (21 CFR 361.1): Studies using radiolabeled drugs in amounts generally recognized as safe are exempt if they are approved by a Radioactive Drug Research Committee (RDRC) and meet specific criteria for scientific purpose, dose, and subject risk. See FDA guidance for criteria. Refer to the UCSF RDRC committee website for more information.
  • Category #6: Cold Isotopes for Research Use (FDA enforcement discretion): A study using a non-radioactive (cold) isotope-labeled investigational drug may be IND-exempt if the drug is used in microdoses that do not exert pharmacologic effects, the study is limited to assessing pharmacokinetics or metabolism, and it poses no significant risk to subjects. See FDA guidance for criteria.

How to Determine Whether a Drug is FDA Approved: Drug Approvals and Databases | FDA

The FDA and NIH maintain official, publicly accessible databases of approved drugs and biologics:

For Prescription and Over-the-Counter Drugs Approved through NDAs, ANDAs, and BLAs
For Over-the-Counter (OTC) Drugs Without Approved NDAs (OTC Monograph)
Additional Resources

IRB Review Pathway

drugpathway

Full Committee Review Pathway

Initial review: During the initial review, a convened IRB meeting (full committee) will review the application to determine if all of the criteria for approval are met and whether FDA regulations apply to the study. There are four possible outcomes:

  1. Outright approval: The IRB has enough information to determine whether the criteria are met.
  2. Conditional approval: The IRB believes that the criteria for approval are met IF the research team can verify that certain requirements are met. The study team will receive stipulations about these requirements. If the study team can verify that these conditions are met, the study will be approved. If the study team disagrees with the IRB’s assessment or wishes to make additional changes to the study at this point, the study will have to return to the full committee for additional review.
  3. Deferral: The IRB has determined that more information or substantial changes are needed before it can determine that the criteria for approval are met. The study team will be sent stipulations with the required information and/or changes needed. The study team’s response will be reviewed by the full committee.
  4. Disapproval: The IRB has determined that the criteria for approval cannot be met.
Who is Responsible for Determining when FDA Regulations Apply?

UCSF IRB Analysts determine whether specific FDA regulations apply to studies based on information in the study application and their interpretation of those regulations. UCSF analysts and researchers may consult with the FDA. The FDA opinion is the ultimate authority regarding FDA regulations.

The sponsor/sponsor-investigator is responsible for determining whether their planned use of a drug is IND-exempt. The IRB reviewer will take this determination into consideration and may request additional information, but the IRB will decide whether to accept the submitted determination.

Timing of FDA and IRB review

When an IND is required, the IND application should be submitted to the FDA concurrently with, or prior to, the IRB application.  The FDA review time for the initial submission of an IND is 30 days from the date the FDA receives the application. The IRB review may begin prior to FDA approval, but the IRB application cannot be fully approved until the IRB receives documentation that the FDA has received the application. The IRB may require confirmation that an IND has been issued. The IND becomes effective 30 days after the stated FDA receipt date unless the FDA sends notification otherwise. Note: A reporting form must be submitted according to the IRB reporting schedule if the FDA places a clinical hold on the study.

When Does a Drug Need to Be Listed in the IRB Application?

The IRB requires that all drugs, biologics, foods, and dietary supplements that will be used in the study be listed in the IRB application. If the study will be conducted under an IND, the IRB application requires that each item’s IND be listed. The application requires that the IND holder be identified and documentation provided for each item. 

What to Submit with the IRB Application
DocumentRequired When:

Investigator brochure and/or package insert

Always
Worksheet: FDA Drugs and IND RequirementsThe sponsor/sponsor investigator believes the use of the drug qualifies for IND Exemption. 
ProtocolThere is a sponsor’s or multicenter protocol
IND confirmation email or letterAn IND is required
When and How to Consult the FDA

After reviewing your complete application, the IRB may require documentation from the FDA that supports the proposed IRB application. 

For example, if the Principal Investigator determines that an IND is not required, yet the IRB determines that it is, the IRB will require that the Principal Investigator contact the FDA to affirm the Principal Investigator’s determination.

The FDA may be contacted by phone 301-796-3400 and by email at [email protected]

Other Considerations for Research Involving Drugs:

Off-Label Use of Drugs

Neither an IND nor UCSF IRB review is required for an off-label use of a legally marketed drug (approved under part 21 CFR 314) or a licensed biologic if such use is strictly for clinical purposes, and the results are not collected for or presented as research.

Over-the-Counter Drug Monographs:

Over-the-counter (OTC) drug monographs are essentially "recipe books" established by the U.S. Food and Drug Administration (FDA) that define the conditions under which a drug product containing specific active ingredients can be marketed without individual FDA approval. These monographs cover aspects like active ingredients, dosages, formulations, labeling, and testing, ensuring that products meeting the monograph's criteria are generally recognized as safe and effective for their intended use. The FDA's website maintains a list of over-the-counter (OTC) drug monographs and includes a specific portal, OTC Monographs@FDA, for viewing and submitting information related to OTC monographs.

If a drug product meets the conditions of a monograph, it can be manufactured and marketed without FDA pre-approval. Additionally, it must meet the “lawfully marketed” requirement for IND Exempt Category #1. For general questions regarding the OTC Drug Review process, email [email protected].

Dietary Supplements

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, softgels, liquids, or powders.

Whether an IND is needed for a clinical investigation evaluating a dietary supplement depends on 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. 
    • Examples: 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

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.

Cosmetics

Studies of ingredients or products marketed as cosmetics require an IND if the ingredient is being studied for its effect on 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.

Endogenous CompoundsA 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 physiological 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.
Example of when an IND is needed: 
  • If a pharmaceutical company is developing a new cancer drug and conducting clinical trials to test its safety and effectiveness, it must submit an IND to the FDA before starting the trials.
  • If a researcher wants to study the use of an existing drug to treat a rare disease for which it is not currently approved, they will likely need to file an IND.
  • If a study is designed to determine whether a particular dietary supplement can help prevent or treat osteoporosis, it would likely require an IND because it involves investigating the supplement's effect on a disease. 
Example of When an IND May Not Be Needed: 
  • If a researcher wants to evaluate a different dosing schedule of an already approved drug for an approved use, provided it doesn't significantly increase risks, they will not likely need an IND.
  • If a researcher is studying the effects of a fiber supplement on bowel regularity, which is a bodily function, an IND would not likely be required because this does not include disease diagnosis, treatment, or prevention.
  • Even with an IND exemption, studies must follow ethical principles, including Institutional Review Board (IRB) approval and informed consent. Investigators must also document the basis for the exemption, and the IRB will verify this documentation. If uncertain about eligibility for an exemption, consulting the FDA is recommended. 

IND Application

Timing of IND Application

Pre-IND Advice: Investigators considering submitting an IND application to the FDA may request a meeting with the FDA Pre-IND Consultation Program before submitting an IND application. If you think a pre-IND meeting is warranted, please contact FDA Consults or review the OEC website  for assistance with the  IND process.

The IND Submission: When an IND is required, submit the IND application to the FDA prior to submitting the IRB application to the IRB. When you submit the IRB application to the IRB, include the confirmation email from FDA that FDA received the IND application. The IND becomes effective 30 days after the stated FDA receipt date unless the FDA sends notification otherwise. The IRB may require confirmation that an IND has been issued.

IRB Application and Consent Form Requirements

Include the following information in your IRB submission. Note: Do not submit FDA Form 1572 to the IRB; it is used for FDA and sponsor purposes only.

Consent form requirements

Purpose and Background Section:

  • Must include a clear statement that the drug or biologic is investigational and has not been approved or, if studying an approved drug or biologic, that it is approved but not for the use being studied.
  • Should include a brief lay description of what the drug or biologic is and how it is thought to act.
  • Must not state or imply that the issuance of an IND is an approval or endorsement by the FDA.

Confidentiality Section:

Must state that the FDA may review participants’ medical records and research records that identify the participants.

Alternatives Section:

If studying an approved drug or biologic, must explain that subjects can receive drug or biologic without participating in the study. An exception to this may be granted if the off-label prescription of the drug or biologic is unrealistic or unsafe outside of a carefully controlled clinical study.

Costs Section:

Must state how the costs of the study drug or biologic, as well as the administration of the product, will be covered.

IND number verificationThe IND number can be verified either by the IND number being identified in the associated sponsor protocol or by a letter from the FDA attached to the protocol confirming than an IND number has been obtained. The IRB will not issue final approval until the IND number is reported to and verified by the IRB. However, the FDA will review an IND application without IRB approval.
Investigator’s brochureFor any study involving an investigational drug or biologic, the Investigator’s Brochure must be attached to the initial review.
ProtocolIf there is a sponsor’s or multicenter protocol, attach it to the initial submission.

Control of Investigational Drugs and Biologics

Local dispensing policies and regulations

Hospitals or other clinical settings have their own policies regarding the use of investigational drugs and biologics in order to assure patient safety and comply with JCAHO standards, California law, and California Department of Health Services regulations. Investigators conducting research in clinical settings other than those listed below should consult those local policies and the personnel charged with compliance with those policies. Consultation should take place before preparing the budget for the clinical study. 

The UCSF Investigational Drug Services (also known as UCSF IDS or UCSF research pharmacy) page has info on the policies and procedures at UCSF (MyAccess login required).

Investigational drug services at UCSF, ZSFG and SFVAMC
Investigator responsibilities for control of investigational drugs/biologics

Investigators conducting studies in which investigational drugs/biologics will be used must ensure adequate control of the drug or biologic. Adequate control and handling of investigational drug/biologic include all of the following:

  • Ensuring that the investigational drug/biologic is used only in accordance with the IRB-approved protocol.
  • Administering the investigational drug/biologic only to participants under the investigator’s direct personal supervision or under the supervision of a sub-investigator directly responsible to the investigator.
  • Not supplying the investigational drug/biologic to any person not authorized to receive it.
  • Maintaining adequate records of the disposition of the investigational drug/biologic, including dates of dispensing, quantity currently maintained for dispensing, and amount of the investigational product dispensed to participants.
  • Returning any unused supplies of the investigational drug/biologic to the study sponsor, or otherwise provide for disposition of the unused supplies as directed by the sponsor if the investigation is terminated, suspended, discontinued, or completed.
  • If the investigational drug is subject to the Controlled Substances Act, taking adequate precautions, to prevent theft or diversion of the substance into illegal channels of distribution. These precautions include storage of the investigational drug in a securely locked, substantially constructed cabinet, or other securely locked, substantially constructed enclosure to which access is limited.
Sample Investigational Agent Accountability Record

The IRB has a sample Investigational Agent Accountability Record available.

 

Reporting Requirements

All investigators must report certain adverse events directly to the IRB within certain specified time frames. When an IND is issued, there are additional federal requirements for reporting AEs to the FDA. When the study sponsor holds the IND, investigators must report all AEs to the sponsor, and the sponsor will submit appropriate reports to the FDA. Investigators who hold an IND (investigator-initiated/investigator-sponsor IND) have responsibilities for reporting AEs to the FDA, as described below.

Please see UCSF IRB Adverse Event or Safety Information for information about what, when, and how to report. You can also review the IND Submissions for Sponsor-Investigators information on the UCSF CTSI HUB.

Note: When the study is conducted at the SFVAHCS, additional reporting obligations must be met by the researcher, as described on the Research at the SFVAHCS page.

When study sponsor holds the IND
  • Investigators need to report all adverse events to the sponsor, and the sponsor will submit appropriate reports to the FDA (see timeframe below).
  • Investigators need to understand and comply with the similar but separate reporting requirements for UCSF investigators as described in the UCSF Reporting Requirements Chart.
  • Investigators need to determine if their department or unit has any additional reporting requirements.
When the investigator holds the IND for a specific study protocol (in the case of investigator-initiated/investigator-sponsor INDs)
  • The investigator has responsibilities for reporting adverse events to the FDA (see timeframe below).
  • Investigators need to understand and comply with the similar but separate reporting requirements for UCSF investigators as described in the UCSF Reporting Requirements Chart.
  • Investigators need to determine if their department or unit has any additional reporting requirements.
Investigator-sponsor responsibilities reporting obligation time frames

In addition to reporting to the IRB, an investigator-sponsor must directly report the following AE information to the FDA within the following time frames, which are slightly different than those required for IRB reporting:

  • Within 7 calendar days after the study sponsor’s initial receipt of the information, the sponsor should notify the FDA by telephone or by facsimile transmission of any unexpected fatal or life-threatening experience associated with the use of the drug.
  • Within 15 calendar days after the sponsor’s initial receipt of the information, the sponsor should notify the FDA and all participating investigators in a written IND safety report of: (A) Any adverse experience associated with the use of the drug that is both serious and unexpected; or (B) Any finding from tests in laboratory animals that suggests a significant risk for human participants including reports of mutagenicity, teratogenicity, or carcinogenicity.
  • Additionally, an investigator-sponsor is responsible for reporting safety information to the FDA: "The sponsor shall promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from any source, foreign or domestic, including information derived from any clinical or epidemiological investigations, animal investigations, commercial marketing experience, reports in the scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory authorities that have not already been previously reported to the agency by the sponsor” (21 CFR 321.32(b))."

Additional Reporting Obligations for Investigators-Sponsors

 

When an investigator files an IND, the investigator is considered the sponsor and as such carries all of the FDA regulatory responsibilities and reporting obligations of both the investigator and sponsor as outlined below and described in the FDA regulations (21 CFR 312 (drugs)) and (601 (biologics)). Please refer to the regulations for complete information.

 

Sponsor-Investigator Responsibilities:

When an investigator files an IND, the investigator is considered the sponsor and, as such, carries all of the FDA regulatory responsibilities and reporting obligations of both the investigator and sponsor as outlined below and described in the FDA regulations (21 CFR 312 (drugs)) and (601 (biologics)). Please refer to the regulations for complete information.

Obligations of investigators for reporting to the sponsor (21 CFR 312)
  • Drug disposition
  • Case histories
  • Progress reports
  • Safety reports
  • Final report
  • Financial disclosure report
  • Specific record keeping and record retention
Obligations of sponsors and investigator-sponsors for reporting to FDA under an IND (21 CFR 312)
  • Protocol amendments
  • Information amendments
  • IND Safety Reports
  • Annual Reports
  • Withdrawal of an IND
  • Specific record keeping and retention
  • Notification of Changes to Active Ingredients

FDA Resources

 

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