21 CFR 312: a map of the IND regulation, subpart by subpart

At a glance

• 21 CFR Part 312 contains the procedures and requirements for using investigational new drugs, including how an IND is submitted to and reviewed by FDA.
• The regulation has eight subparts in use (A to G and I). Subpart H is printed as “[Reserved]” and contains no text.
• A sponsor must not begin a clinical investigation covered by Part 312 until an IND for it is in effect, which happens 30 days after FDA receives the IND unless FDA places it on clinical hold or lets it start earlier.
• Subpart D splits the work: sponsors select investigators, monitor and report to FDA (312.50 to 312.59), and investigators run the study, control the drug, keep records and report to the sponsor (312.60 to 312.69).
• Part 312 leans on Parts 50 and 56: a drug may be used in a clinical investigation only if the sponsor and each investigator comply with Part 312 and Parts 50 and 56.

21 CFR 312 is the FDA regulation for investigational new drug applications (INDs). People usually meet it one section at a time: a monitor cites 312.62(b), a contract mentions 312.52, a regulatory lead asks whether a study needs an IND at all. This page is a map of the whole part. It shows which subpart applies at which point in a drug’s development, who each one binds, and where the section numbers people search for sit.

This page maps the regulation and does not reproduce it. For the wording itself, read the live text on eCFR rather than a saved PDF, which shows the text only as of the day it was printed. This map reflects the eCFR text up to date as of 14 April 2026.

What Part 312 governs

Part 312 contains procedures and requirements governing the use of investigational new drugs, including the submission to, and review by, FDA of INDs (21 CFR 312.1(a)). An investigational drug with an IND in effect is exempt from the premarketing approval requirements that would otherwise apply, and may be shipped lawfully for clinical investigations (312.1(a)). That exemption is the reason the IND exists: without it, shipping an unapproved drug to a study site would be unlawful.

The part applies to all clinical investigations of products subject to section 505 of the Federal Food, Drug, and Cosmetic Act or to the licensing provisions of the Public Health Service Act, except as the section itself provides (312.2(a)). The exceptions are in 312.2(b), covered below. Part 312 does not apply to using an approved drug or licensed biologic for an unlabeled indication in the practice of medicine (312.2(d)).

Two neighbouring regulations are outside this map. Investigational devices are studied under Part 812, which Part 56 names alongside Part 312 as a prior-submission requirement (21 CFR 56.103(a)). Marketing applications for drugs approved under Part 314 are a separate stage, and Part 312 refers to them only as the destination (312.2(d)).

The subparts as a lifecycle

Part 312 reads more easily as a sequence than as a list. Each subpart switches on at a particular moment.

Subpart	Sections	When it switches on	Who it binds	Where we go deeper
A, General provisions	312.1 to 312.10	Before anything else: does this study need an IND?	Sponsors and investigators	Investigator-initiated trials (the sponsor-investigator role)
B, Investigational New Drug Application	312.20 to 312.38	Filing the IND and keeping it current	Sponsors	The IND application, IND safety reporting, IND annual reports and the DSUR
C, Administrative actions	312.40 to 312.48	From the day FDA receives the IND	FDA’s actions on the sponsor	The 30-day clock and IND disclosure
D, Responsibilities of sponsors and investigators	312.50 to 312.70	While the trial runs	Sponsors, CROs, investigators	Sponsor responsibilities, PI responsibilities, Form FDA 1572
E, Drugs for life-threatening and severely debilitating illnesses	312.80 to 312.88	When the drug treats such an illness	Sponsors and FDA
F, Miscellaneous	312.110 to 312.145	Import and export, foreign studies, disclosure, correspondence	Sponsors
G, Drugs for laboratory research animals or in vitro tests	312.160	Shipping drugs for non-human testing	Shippers of such drugs
H	None	Reserved	Nobody
I, Expanded access	312.300 to 312.320	Treating patients outside a clinical trial	Sponsors and licensed physicians

The eCFR table of contents lists Subpart H as “[Reserved]” with no sections under it. That is all the text shows. The section numbering simply jumps from 312.160 in Subpart G to 312.300 in Subpart I.

Subpart A: definitions that decide everything

Most Part 312 questions turn on who counts as whom, and 312.3(b) settles that.

• A sponsor is a person who takes responsibility for and initiates a clinical investigation, and can be an individual, a company, a government agency, an academic institution or another organisation (312.3(b)).
• An investigator is the individual who actually conducts a clinical investigation, under whose immediate direction the drug is administered or dispensed, and the responsible leader where a team conducts it (312.3(b)).
• A sponsor-investigator is an individual who both initiates and conducts an investigation, and the requirements on a sponsor-investigator include both those for an investigator and those for a sponsor (312.3(b)).
• A contract research organization is a person that assumes, as an independent contractor with the sponsor, one or more of the sponsor’s obligations (312.3(b)).

One line in the sponsor definition catches companies out. An organisation that uses its own employees to conduct an investigation it initiated is a sponsor, not a sponsor-investigator, and the employees are investigators (312.3(b)). Only an individual can be a sponsor-investigator, which is why an academic PI who files their own IND carries both sets of duties. The investigator-initiated trials guide covers what that means in practice.

Subpart A also holds the exemptions. A clinical investigation of a drug lawfully marketed in the United States is exempt from Part 312 if every condition in 312.2(b)(1) is met, including that it does not support a new indication or significantly increase risk, and that it complies with Parts 50 and 56. On request, FDA will advise on whether Part 312 applies to a planned investigation (312.2(e)). Our guide to IND exemptions walks through each condition.

The rest of Subpart A is short. 312.6 sets the “Caution: New Drug” label, 312.7 bars promoting an investigational drug as safe or effective and bars commercial distribution, 312.8 sets when a sponsor may charge for the drug, and 312.10 lets a sponsor ask FDA to waive a requirement.

Subpart B: filing and keeping the IND current

A sponsor must submit an IND if it intends to conduct a clinical investigation with an investigational new drug subject to 312.2(a) (312.20(a)). A sponsor must not begin such an investigation until it is subject to an IND in effect under 312.40 (312.20(b)).

Subpart B then covers everything the sponsor files over the life of the IND:

Section	What it covers	Where we go deeper
312.21	Phases 1, 2 and 3
312.22	FDA’s review objectives and how much information an IND needs
312.23	IND content and format, in a fixed order starting with the Form FDA 1571 cover sheet	The IND application
312.30	Protocol amendments: new protocol, change in protocol, new investigator
312.31	Information amendments: new technical information not covered elsewhere
312.32	IND safety reports	Expedited safety reporting
312.33	Annual reports	The DSUR
312.38	Withdrawing an IND

The amount of information an IND must contain depends on the novelty of the drug, how far it has been studied, the known or suspected risks, and the phase of development (312.22(b)). Phase 1 typically involves 20 to 80 subjects, Phase 2 no more than several hundred, and Phase 3 several hundred to several thousand (312.21).

Protocol amendments. Once an IND is in effect, the sponsor must amend it as needed so that the investigations follow the protocols in the application (312.30). A new protocol may begin once the sponsor has submitted it to FDA and the IRB has approved it, in either order (312.30(a)). In Phase 1, a change needs a protocol amendment when it significantly affects subject safety. In Phase 2 or 3, a change that significantly affects safety, the scope of the investigation or the scientific quality of the study needs one (312.30(b)(1)). A change to eliminate an apparent immediate hazard to subjects may be made immediately, with FDA notified by protocol amendment afterwards (312.30(b)(2)(ii)). A new investigator added to an existing protocol must be notified to FDA within 30 days of being added (312.30(c)).

Annual reports. A sponsor must submit a brief progress report within 60 days of the anniversary of the date the IND went into effect (312.33).

Every one of these submissions goes in under a Form FDA 1571 cover sheet, the subject of our guide to Form FDA 1571. Product teams who want to test the plan with FDA before filing will find the pre-IND meeting covered in its own guide.

Subpart C: what FDA can do

Subpart C is FDA’s side of the file. It is summarised here because each action has a page of its own.

Section	FDA action	The rule in one line
312.40	IND goes into effect	30 days after FDA receives the IND, unless FDA imposes a clinical hold, or earlier if FDA says so
312.41	Comment and advice	FDA advice without a hold order is advisory only
312.42	Clinical hold	An order to delay a proposed investigation or suspend an ongoing one
312.44	Termination	Preceded by a proposal to terminate and an opportunity to respond, except for immediate danger
312.45	Inactive status	Possible after 2 years with no subjects entered, or 1 year with all investigations on hold
312.47	Meetings	End-of-Phase 2 and pre-NDA meetings, documented in minutes
312.48	Dispute resolution	Administrative disputes go to the division and then the ombudsman

An IND goes into effect 30 days after FDA receives it, unless FDA notifies the sponsor of a clinical hold, or earlier if FDA notifies the sponsor that the investigations may begin (312.40(b)). An investigator may not administer the drug to human subjects until the IND is in effect (312.40(d)). Our article on why there is no public FDA IND database covers how that clock works in practice.

A clinical hold is an order from FDA to delay a proposed investigation or suspend an ongoing one, and it can cover one or more of the studies under an IND (312.42(a)). The grounds differ by phase. For Phase 1 they include unreasonable and significant risk to subjects, unqualified investigators, a misleading or materially incomplete investigator brochure, or too little information under 312.23 to assess the risks (312.42(b)(1)). Phase 2 and 3 add a protocol clearly deficient in design to meet its stated objectives (312.42(b)(2)). Holds, responses and lifting a hold are covered in our guide to FDA clinical holds.

Subpart D: sponsor duties and investigator duties

Subpart D is the part monitors and inspectors read most. Sponsors are responsible for selecting qualified investigators, giving them the information they need, ensuring proper monitoring, keeping the investigations to the plan and protocols, maintaining an effective IND, and ensuring FDA and all investigators are promptly informed of significant new adverse effects or risks (312.50). An investigator is responsible for conducting the investigation according to the signed investigator statement, the investigational plan and applicable regulations, for protecting the rights, safety and welfare of subjects, and for control of the drug (312.60).

Sponsor (312.50 to 312.59)	Investigator (312.60 to 312.69)
312.50 General responsibilities	312.60 General responsibilities, including informed consent under Part 50
312.52 Transfer of obligations to a CRO, in writing	312.61 Give the drug only to subjects under the investigator’s or a subinvestigator’s supervision
312.53 Select qualified investigators and monitors, obtain the signed Form FDA 1572 and other information before an investigator starts	312.62 Drug disposition records, case histories, record retention
312.54 Emergency research under 50.24	312.64 Progress, safety, final and financial disclosure reports to the sponsor
312.55 Give investigators the investigator brochure and keep them informed	312.66 Assure IRB review under Part 56
312.56 Monitor the investigations, secure compliance or end an investigator’s participation	312.68 Give FDA access to records
312.57 Recordkeeping and record retention	312.69 Secure storage of controlled substances
312.58 Give FDA access to records, controlled substance precautions
312.59 Return or dispose of unused drug

Two points the table can’t show. First, a CRO that assumes a sponsor obligation is subject to the same regulatory action as a sponsor for failing to comply with it, and any obligation not covered by the written description is deemed not transferred (312.52). The CRO oversight guide covers how to write that transfer. Second, 312.70 sits at the end of Subpart D but is an FDA action: it sets out how FDA disqualifies an investigator who has repeatedly or deliberately failed to comply with Part 312, Part 50 or Part 56.

For the operational detail, see clinical trial sponsor responsibilities, principal investigator responsibilities, drug accountability (312.59, 312.61, 312.62(a)), record retention and TMF archiving (312.57, 312.62(c)) and BIMO inspection preparation (312.58, 312.68).

Subparts E, F, G and I in brief

Subpart E applies to new drugs and biologics studied for treating life-threatening or severely debilitating diseases (312.81). Its purpose is to expedite the development, evaluation and marketing of such therapies, especially where no satisfactory alternative exists (312.80). Its best-known provision is early consultation: before submitting the initial IND, the sponsor may request a meeting to reach agreement on the animal studies needed to start human testing (312.82(a)).

Subpart F covers import and export of investigational drugs (312.110), foreign studies not conducted under an IND (312.120), public disclosure of IND data (312.130), where to send submissions (312.140) and FDA guidance documents (312.145). FDA will accept a well-designed and well-conducted foreign study not conducted under an IND as support for an IND or marketing application if it was conducted under GCP and FDA can validate the data through an onsite inspection if needed (312.120(a)(1)).

Subpart G lets a drug intended solely for tests in vitro or in laboratory research animals be shipped without an IND if it meets 312.160 (312.2(b)(3)).

Subpart I governs expanded access: using an investigational drug, or an approved drug whose availability is limited by a REMS, when the primary purpose is to diagnose, monitor or treat a patient’s disease, for patients with serious diseases or conditions and no comparable or satisfactory alternative therapy (312.300(a)). It has three tiers: individual patients including emergency use (312.310), intermediate-size populations (312.315) and treatment INDs or protocols (312.320).

Section lookup: the numbers people search

Section	What it says, in plain words
312.3(b)	The definitions: clinical investigation, CRO, IND, investigator, sponsor, sponsor-investigator, subject and others.
312.23(a)(5)	The investigator’s brochure, if 312.55 requires one: drug description and formulation, pharmacology and toxicology, pharmacokinetics, prior human safety and effectiveness data, and anticipated risks with precautions or monitoring.
312.23(a)(7)	Chemistry, manufacturing and control information: enough to assure the identity, quality, purity and strength of the drug, with the amount varying by phase, duration and dosage form.
312.30	Protocol amendments, submitted before a new or changed protocol is implemented.
312.32	IND safety reports: potential serious risks go to FDA and all participating investigators within 15 calendar days of the sponsor determining they qualify, and unexpected fatal or life-threatening suspected adverse reactions go to FDA within 7 calendar days of first receipt.
312.33	The annual report, due within 60 days of the IND’s anniversary.
312.53(c)(4)	Financial disclosure: before an investigator starts, the sponsor obtains enough financial information to submit the Part 54 certification or disclosure, plus a commitment to update it during the study and for 1 year after.
312.55(b)	Keeping investigators informed: as the investigation proceeds, the sponsor tells each investigator about new observations on the drug, particularly adverse effects and safe use.
312.62(b)	Case histories: the investigator keeps adequate and accurate case histories for every subject, including consent forms and medical records, and they must document that consent was obtained before participation.

A few notes on those rows. Under 312.23(a)(7), the emphasis in an initial Phase 1 submission is generally on identifying and controlling the raw materials and the new drug substance, and final specifications are not expected until the end of the investigational process (312.23(a)(7)(i)). The Phase 1 manufacturing guide picks that up. Under 312.55(a), a sponsor other than a sponsor-investigator must give each participating investigator an investigator brochure before the investigation begins. The brochure itself is the subject of a separate guide. The updates under 312.55(b) may go out as revised brochures, reprints or published studies, or letters to investigators, but important safety information must reach investigators under 312.32 (312.55(b)).

How Part 312 connects to Parts 50 and 56

Part 312 does not repeat the rules on informed consent or IRBs. It points to them, at several places:

• A drug may be used in a clinical investigation only if the sponsor complies with Part 312 and Parts 50 and 56, and each participating investigator conducts the investigation in compliance with Part 312 and Parts 50 and 56 (312.40(a)).
• An investigator must obtain informed consent from each subject under Part 50 (312.60).
• An investigator must assure that an IRB complying with Part 56 is responsible for initial and continuing review and approval of the study (312.66).
• Even an IND-exempt study of a marketed drug must comply with Part 56 IRB review and Part 50 informed consent (312.2(b)(1)(iv)).
• FDA may propose to terminate an IND if the sponsor fails to comply with Part 312, Part 50 or Part 56 (312.44(b)(1)(ix)).

Parts 50 and 56 carry the substance. Part 50 applies to all clinical investigations regulated by FDA under section 505(i) of the Act, among others (21 CFR 50.1(a)). Except as Part 50 provides, no investigator may involve a human being as a subject unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative (21 CFR 50.20). Part 56 says that, with limited exceptions, a clinical investigation that requires prior submission to FDA under Part 312 must not begin until an IRB meeting Part 56 has reviewed and approved it, and it must stay under continuing IRB review (21 CFR 56.103(a)).

The informed consent guide and IRB approval guide cover those parts. For how Part 312 maps onto ICH GCP, see ICH GCP after E6(R3). How Part 312 compares with the Common Rule for federally funded research is covered in a separate guide.

Sources

• 21 CFR Part 312, Investigational New Drug Application, eCFR text up to date as of 14 April 2026
• 21 CFR Part 50, Protection of Human Subjects, April 2024 edition
• 21 CFR Part 56, Institutional Review Boards, April 2024 edition