21 CFR 312

21 CFR Part 312 is the core U.S. regulation that determines whether a clinical study involving a drug requires an Investigational New Drug (IND) application. It establishes the rules for initiating, conducting, and overseeing clinical investigations of unapproved drugs, and defines the responsibilities of sponsors, investigators, and the FDA.

Purpose and scope of 21 CFR 312

21 CFR 312 establishes the regulatory framework for the clinical investigation of Investigational New Drugs (IND) in the United States. It defines how sponsors submit IND to the FDA and how the FDA reviews and oversees the use of such drugs in human subjects.

Under U.S. law, a drug generally may not be marketed or shipped without FDA approval. An IND provides a limited regulatory exemption that allows an unapproved drug to be manufactured, shipped, and administered solely for the purpose of conducting clinical investigations. An active IND does not imply that a drug is approved, or that its safety or effectiveness has been established. It indicates only that FDA has permitted the drug to be studied in humans under defined regulatory controls.

The 21 CFR 312 regulation covers

• Submission of IND applications to the FDA
• FDA review of INDs and related amendments
• Conduct of clinical investigations under an active IND
• Responsibilities of sponsors and investigators
• Ongoing FDA oversight during clinical development

2. Applicability (21 CFR 312.2)

As a general rule, 21 CFR 312 applies to any study testing a drug or biologic in humans, unless the study clearly qualifies for a specific regulatory exemption.

a 21 CFR 312 applies to most clinical investigations in humans involving

• Drugs regulated under the Federal Food, Drug, and Cosmetic Act
• Products regulated under the Public Health Service Act

b.1 Exemption for certain studies of marketed drugs

A clinical investigation using a drug already legally marketed in the United States may be exempt only if all conditions for non-promotional, low-risk research are met.

b.1.i No regulatory intent

The study is not intended to be submitted to FDA to:

• Support a new indication
• Support a labeling change

b.1.ii No advertising claims

For prescription drug products:

• The study is not intended to support a significant change in advertising

b.1.iii No increased risk

The study does not:

• Change the route of administration
• Increase or alter dosage
• Expand use to a higher-risk patient population
• Otherwise increase risk compared with approved use

b.1.iv Ethical requirements still apply

The study must comply with:

• Institutional Review Board (IRB) requirements (21 CFR 56)
• Informed consent requirements (21 CFR 50)

b.1.v No promotional use of the drug

• The investigation must not involve promotion or commercialization of the drug (21 CFR 312.7)

If any one of these conditions is not met, the exemption does not apply and an IND is required.

b.2 Certain diagnostic biologics

Some narrowly defined diagnostic biological products are exempt if:

• They are used only to confirm a diagnosis already made by an established method
• They are shipped in accordance with applicable regulatory requirements

Examples include blood grouping sera, reagent red blood cells, and anti-human globulin.

b.3 Laboratory and animal studies

21 CFR 312 does not apply to drugs used solely:

• In vitro (laboratory testing), or
• In laboratory research animals

provided shipping requirements are met.

b.4 INDs for exempt studies

FDA will not accept an IND for a clinical investigation that qualifies for an exemption under this section. This prevents using an IND when one is not legally required.

b.5 Placebo use

The use of a placebo by itself does not trigger IND requirements, unless the overall study otherwise requires an IND.

b.6 Emergency research exception

Clinical investigations conducted under an exception from informed consent (21 CFR 50.24) are not exempt from 21 CFR 312 and must comply with IND requirements.

c. Bioavailability studies

Applicability of 21 CFR 312 to in vivo bioavailability studies in humans is governed by 21 CFR 320.31.

d. Off-label use in medical practice

21 CFR 312 does not apply to:

• Off-label use of an approved drug in routine medical practice

This exclusion does not automatically apply to off-label clinical research, which may still require an IND.

e. FDA guidance and case-by-case advice

FDA may:

• Issue guidance clarifying the applicability of 21 CFR 312
• Provide advice on applicability for a planned clinical investigation upon request

PART 312—INVESTIGATIONAL NEW DRUG APPLICATION
Subpart A—General Provisions
§ 312.1 Scope
§ 312.2 Applicability.
§ 312.3 Definitions and interpretations.
§ 312.6 Labeling of an investigational new drug.
§ 312.7 Promotion of investigational drugs.
§ 312.8 Charging for investigational drugs under an IND.
§ 312.10 Waivers.
Subpart B—Investigational New Drug Application (IND)
§ 312.20 Requirement for an IND.
§ 312.21 Phases of an investigation.
§ 312.22 General principles of the IND submission.
§ 312.23 IND content and format.
§ 312.30 Protocol amendments.
§ 312.31 Information amendments.
§ 312.32 IND safety reporting.
§ 312.33 Annual reports.
§ 312.38 Withdrawal of an IND.
Subpart C—Administrative Actions
§ 312.40 General requirements for use of an investigational new drug in a clinical investigation.
§ 312.41 Comment and advice on an IND.
§ 312.42 Clinical holds and requests for modification.
§ 312.44 Termination.
§ 312.45 Inactive status.
§ 312.47 Meetings.
§ 312.48 Dispute resolution.
Subpart D—Responsibilities of Sponsors and Investigators
§ 312.50 General responsibilities of sponsors.
§ 312.52 Transfer of obligations to a contract research organization.
§ 312.53 Selecting investigators and monitors.
§ 312.54 Emergency research under § 50.24 of this chapter.
§ 312.55 Informing investigators.
§ 312.56 Review of ongoing investigations.§ 312.57 Recordkeeping and record retention.
§ 312.58 Inspection of sponsor's records and reports.
§ 312.59 Disposition of unused supply of investigational drug.
§ 312.60 General responsibilities of investigators.
§ 312.61 Control of the investigational drug.
§ 312.62 Investigator recordkeeping and record retention.
§ 312.64 Investigator reports.
§ 312.66 Assurance of IRB review.
§ 312.68 Inspection of investigator's records and reports.
§ 312.69 Handling of controlled substances.
§ 312.70 Disqualification of a clinical investigator.
Subpart E—Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses
§ 312.80 Purpose.
§ 312.81 Scope.
§ 312.82 Early consultation.
§ 312.83 Treatment protocols.
§ 312.84 Risk-benefit analysis in review of marketing applications for drugs to treat life-threatening and severely-debilitating illnesses.
§ 312.85 Phase 4 studies.
§ 312.86 Focused FDA regulatory research.
§ 312.87 Active monitoring of conduct and evaluation of clinical trials.
§ 312.88 Safeguards for patient safety.
Subpart F—Miscellaneous
§ 312.110 Import and export requirements.
§ 312.120 Foreign clinical studies not conducted under an IND.
§ 312.130 Availability for public disclosure of data and information in an IND.
§ 312.140 Address for correspondence.
§ 312.145 Guidance documents.
Subpart G—Drugs for Investigational Use in Laboratory Research Animals or In Vitro Tests
§ 312.160 Drugs for investigational use in laboratory research animals or in vitro tests.
Subpart H [Reserved]
Subpart I—Expanded Access to Investigational Drugs for Treatment Use
§ 312.300 General.
§ 312.305 Requirements for all expanded access uses.
§ 312.310 Individual patients, including for emergency use.
§ 312.315 Intermediate-size patient populations.
§ 312.320 Treatment IND or treatment protocol.