21 CFR Part 312: IND Application, Phases, and Sponsor Duties

21 CFR Part 312 is the Food and Drug Administration regulation that governs investigational new drug (IND) applications: it sets who may test an unapproved drug in humans, what a sponsor must submit before dosing begins, how the FDA reviews the submission, and the safety, recordkeeping, and reporting duties that continue for as long as the study runs.¹ If a drug is shipped across state lines for a clinical investigation, it needs an active IND, and that IND is what makes the shipment lawful in the first place.

When an IND Is Required

Section 312.1 gives Part 312 broad reach over any procedure for submitting or reviewing an IND. Without an active IND, moving an unapproved drug in interstate commerce for research would violate the Federal Food, Drug, and Cosmetic Act. The IND is the controlled legal channel that permits limited human use under FDA oversight.¹

Not every clinical study requires the full application. Section 312.2 exempts certain studies of already-approved drugs, but only when every one of these conditions holds: the study is not intended to support a new indication or a major labeling change, it does not alter the route of administration or the dose in ways that significantly increase risk, and it complies with IRB and informed consent requirements.¹ Miss any single condition and the full IND process applies. Foreign clinical data can be used in support of an IND or marketing application under Section 312.120, but only if the study was conducted under good clinical practice with independent ethics review and the FDA can validate the data through inspection.²

Three Types of IND Applications

Section 312.3 recognizes three IND types, each meant for a different situation.³

An investigator IND is filed by a physician who both initiates and personally conducts the study. That person functions as a sponsor-investigator and carries the regulatory obligations of both roles. This is the common pathway in academic medicine, where a researcher wants to test a drug in a specific disease without a pharmaceutical company backing the program.

An emergency use IND lets a physician ship and use an experimental drug for a single patient in a life-threatening situation when no approved alternative exists. The FDA can authorize emergency use by telephone through its Emergency Call Center, with the written submission due within 15 working days afterward.⁴

A treatment IND opens access to an investigational drug for broader groups of patients with serious or life-threatening conditions when no satisfactory alternative therapy is available. It sits between formal clinical trials and marketing approval.

Part 312 also draws a line between the sponsor (the entity that initiates and takes responsibility for the investigation) and the investigator (the person who actually administers the drug). When one individual fills both roles, the regulation treats them as a sponsor-investigator subject to the full duties of each.³

The Three Phases of Clinical Investigation

Section 312.21 divides human testing into three phases, each expanding on what the last one showed. No sponsor jumps from animal data to a several-thousand-person trial; the phases enforce a graduated approach to risk.⁵

Phase 1 is the first introduction of the drug into humans. These studies look at how the body metabolizes and responds to the drug, what side effects appear as the dose rises, and whether early signs of effectiveness emerge. Enrollment is usually 20 to 80 participants, often healthy volunteers.

Phase 2 covers controlled studies that assess whether the drug actually works for a specific condition and identify common short-term side effects. Enrollment typically stays under several hundred patients, and comparison groups are common.

Phase 3 involves several hundred to several thousand participants. Preliminary effectiveness has already been shown by this point; Phase 3 gathers the additional safety and efficacy data needed to weigh benefit against risk and to draft the physician labeling. Its results usually form the core of a marketing application.

Phase 1 protocols may be less detailed and more flexible, but they must still specify every element critical to safety, such as vital-sign monitoring and blood testing. Phase 2 and 3 protocols must describe all aspects of the study in detail, including anticipated deviations and the alternatives built in to handle them.⁶

What the IND Application Must Contain

Section 312.23 prescribes both the content and the order of the submission. The package must include Form FDA 1571, a table of contents, an introductory statement, a general investigational plan, an investigator’s brochure, the protocol or protocols, chemistry and manufacturing information, pharmacology and toxicology data, any previous human experience with the drug, and any additional information the FDA needs to assess safety.¹

The pharmacology and toxicology section is where the sponsor shows the drug is reasonably safe for initial human exposure, using animal data on organ-system effects and the doses at which toxicity appears. The chemistry section demonstrates that every batch used in trials is consistent in identity, strength, quality, and purity. Sloppy manufacturing data is one of the fastest ways to trigger an FDA hold.

The clinical protocol must state the study’s objectives, list the qualifications of each investigator, define patient inclusion and exclusion criteria, describe the study design and any control groups, set out the dosing plan and maximum dosage, and explain how the drug’s effects will be monitored. The protocol also has to identify each research facility and each reviewing IRB by name and address.⁶

Form FDA 1571 and Form FDA 1572

Form 1571 is the sponsor’s cover sheet. It captures the sponsor’s contact information, the drug’s name, the proposed indication, the phase or phases to be conducted, and the submission’s serial number, along with the names of the people responsible for monitoring the investigation and for reviewing safety information. Signing it commits the sponsor to conducting the trial in compliance with all applicable regulations.⁷

Form 1572 is the investigator’s counterpart. It is both a signed agreement to run the research in compliance with FDA regulations and a collection of the site and personnel information the sponsor needs to show the FDA that its investigators are qualified. The form requires the investigator’s curriculum vitae, the addresses of all clinical sites, the names of sub-investigators, and the laboratories handling participant testing.⁸ Errors or omissions on either form can hold up review.

The 30-Day Review and Clinical Holds

Once the FDA receives a complete IND, a 30-day clock starts. Under Section 312.40, the IND takes effect 30 days after receipt unless the FDA notifies the sponsor of a clinical hold, or notifies the sponsor earlier that the investigation may begin.¹ No drug may be given to any participant until either the 30 days pass or the FDA grants early clearance.

If the FDA sees a serious problem, it imposes a clinical hold under Section 312.42. The available grounds depend on the phase.⁹

Phase 1 holds can be issued when participants face unreasonable and significant risk of illness or injury, the investigators are not qualified, the investigator’s brochure is misleading or materially incomplete, or the IND lacks enough information to assess risk. The FDA may also hold a study of a life-threatening disease that excludes men or women of reproductive potential solely because of reproductive or developmental toxicity concerns, subject to certain exceptions.

Phase 2 and 3 holds can be issued for any Phase 1 reason and for one more: the protocol is clearly deficient in design to meet its stated objectives.

A hold can cover the entire IND or a single study within it. The FDA sets out the reasons in writing and explains what the sponsor must do to resolve them. Holds that go unaddressed can lead to termination of the IND.

Informed Consent and IRB Review

Part 312 assumes that two other regulations are already being followed: Part 56 governing IRBs and Part 50 governing informed consent. The IRB is the group formally designated to review and monitor human-subjects research, with authority to approve a study, require modifications, or disapprove it, and it must conduct continuing review rather than only signing off at the start.¹⁰

Section 50.25 lists what a participant must be told before enrolling: that the study is research, its purpose and expected duration, and which procedures are experimental; foreseeable risks; reasonably expected benefits; alternative treatments; how records will be kept confidential and the possibility that the FDA may inspect them; whether compensation or medical treatment is available if injury occurs in studies involving more than minimal risk; contact information for questions about the research, participant rights, and research-related injuries; and a statement that participation is voluntary, that refusing carries no penalty, and that the participant may withdraw at any time without losing benefits they are otherwise entitled to.¹¹

Ongoing Duties Once the IND Is Active

Sponsor Duties

Section 312.50 makes sponsors responsible for selecting qualified investigators, giving them the information needed to run the study properly, monitoring the investigation, keeping it aligned with the protocols in the IND, and promptly informing the FDA and every participating investigator of significant new adverse effects or risks.¹² Under Section 312.7, the sponsor cannot promote the drug as safe or effective while it is under investigation, cannot commercially distribute it, and cannot unnecessarily prolong a study after results are sufficient to support a marketing application.¹³

Investigator Duties

Section 312.60 makes investigators responsible for conducting the study per the signed investigator statement and the investigational plan, protecting participants’ rights, safety, and welfare, controlling the investigational drug supply, and obtaining informed consent from every participant as required by Part 50.¹⁴

Section 312.62 adds the recordkeeping. Investigators must document how the drug was used, including dates, quantities, and which participants received it, and must prepare accurate case histories with signed consent forms, progress notes, hospital charts, and lab results. Those records must be kept for two years after a marketing application is approved for the indication studied, or for two years after the investigation is discontinued if no application is filed.¹⁵

Safety Reporting

Section 312.32 is where the urgency lives. Investigators must report all serious adverse events to the sponsor right away, regardless of whether the event appears drug-related. The sponsor evaluates the information, and if it meets the definition of a potential serious risk, must notify the FDA and all participating investigators within 15 calendar days. For unexpected fatal or life-threatening suspected adverse reactions, the deadline is 7 calendar days from the sponsor’s initial receipt of the information.¹⁶ Missing one of these deadlines is one of the clearest paths to a clinical hold.

Annual Reports

Section 312.33 requires the sponsor to submit an annual report within 60 days of the anniversary of the IND’s effective date, with a brief summary of the status of each ongoing study and each study completed in the prior year, identified by title and protocol number.¹⁷

When the FDA Ends an Investigation

Section 312.44 gives the FDA authority to terminate an IND when participants are exposed to unreasonable risk, reports are misleading or fail to disclose known risks, investigators are unqualified, or the drug is being promoted or distributed in violation of the regulations. Termination normally begins with written notice, a 30-day window for the sponsor to respond, and the chance for an informal conference. When immediate action is needed for participant safety, the FDA can terminate first and offer the conference afterward. After termination, the sponsor must end all clinical investigations under the IND and recall or dispose of unused drug supplies.¹⁸

Section 312.70 addresses the individual investigator rather than the IND. The FDA can move to disqualify a clinical investigator who has repeatedly or deliberately failed to comply with the regulations, or who has submitted false information in required reports. The process opens with a written notice, allows the investigator to explain, and, if the explanation is rejected, provides for a formal regulatory hearing. A disqualified investigator becomes ineligible to receive investigational drugs or to conduct any clinical investigation that supports a research or marketing application for FDA-regulated products, and the FDA notifies the sponsor and the relevant IRBs.¹⁹

1
eCFR. 21 CFR Part 312 – Investigational New Drug Application
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eCFR. 21 CFR 312.120 – Foreign Clinical Studies Not Conducted Under an IND
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eCFR. 21 CFR 312.3 – Definitions and Interpretations
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eCFR. 21 CFR 312.310 – Individual Patients, Including for Emergency Use
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eCFR. 21 CFR 312.21 – Phases of an Investigation
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eCFR. 21 CFR 312.23 – IND Content and Format
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Food and Drug Administration. Instructions for Filling Out Form FDA 1571
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Clinical Center. Initial IND Application
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eCFR. 21 CFR 312.42 – Clinical Holds and Requests for Modification
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Food and Drug Administration. Institutional Review Boards Frequently Asked Questions
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eCFR. 21 CFR 50.25 – Elements of Informed Consent
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eCFR. 21 CFR 312.50 – General Responsibilities of Sponsors
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eCFR. 21 CFR 312.7 – Promotion of Investigational Drugs
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eCFR. 21 CFR 312.60 – General Responsibilities of Investigators
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eCFR. 21 CFR 312.62 – Investigator Recordkeeping and Record Retention
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eCFR. 21 CFR 312.32 – IND Safety Reporting
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eCFR. 21 CFR 312.33 – Annual Reports
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eCFR. 21 CFR 312.44 – Termination
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eCFR. 21 CFR 312.70 – Disqualification of a Clinical Investigator