Investigational New Drug Application: Types, Contents, and Review

An Investigational New Drug application is the submission a sponsor files with the FDA before giving an experimental drug to humans, and once the agency receives it the sponsor must wait 30 calendar days before dosing the first participant. If the FDA raises no objection in that window, the application goes into effect automatically and the trial can begin. There is no filing fee, which is a striking contrast to the $4.68 million user fee attached to a marketing application in fiscal year 2026.¹ The rules live in 21 CFR Part 312, and what you put in the package determines whether that 30-day clock ends with permission to proceed or with a clinical hold.

When You Need an IND

An IND must be in effect before a sponsor ships an experimental drug across state lines for use in a clinical investigation on human subjects.² The same requirement applies when a sponsor wants to study an already-approved drug in a way that significantly changes its risk profile.

A study of a lawfully marketed drug can be exempt from IND requirements, but only if every one of five conditions is met at the same time:

The study is not intended to support a new approved use or any other major labeling change.
For a prescription drug, the study is not intended to support a significant change in advertising.
The study does not involve a new route of administration, dosage level, or patient population that meaningfully increases risk.
The study complies with IRB review and informed consent rules.
The drug is not commercially promoted as part of the investigation.

If any one condition is missing, the full IND requirements apply.³

Types of INDs

A Commercial IND is filed by a pharmaceutical or biotech company aiming to eventually seek marketing approval. It moves through Phase 1, 2, and 3 trials to build the safety and efficacy record a marketing application will need.

An Investigator IND is filed by an individual physician or researcher, often at a university or medical center, who wants to study an unapproved drug or explore a new use for an approved one. The investigator serves as both sponsor and lead researcher, which means carrying all the regulatory obligations that would normally be split between two parties.

Expanded Access lets patients with serious or life-threatening conditions receive an investigational drug outside a clinical trial when no comparable alternative exists. The FDA recognizes three sizes: individual patient access, intermediate-size access for a smaller patient population, and widespread treatment use for a larger group.⁴

Emergency Use covers a genuine emergency where there is no time to prepare a written submission. The treating physician contacts the FDA reviewing official, who can give verbal authorization by telephone to begin treatment. The written application follows once the emergency has been addressed.⁴

Pre-IND Meetings

Before assembling the full package, a sponsor can request a pre-IND meeting with the FDA. The meeting is a chance to present the development plan, ask specific questions about the adequacy of preclinical data, get input on the design of initial clinical trials, and identify potential clinical hold issues before they become actual ones.⁵

The request should include a clear objective, a proposed agenda, and specific questions organized by discipline (toxicology, manufacturing, clinical design, and so on). Propose a date roughly six to eight weeks out, and commit to delivering a detailed background package at least four weeks before the meeting.⁵ Vague or disorganized requests tend to produce unproductive sessions.

What the Application Must Contain

The content requirements are set out in 21 CFR 312.23. The package must convince the FDA that the proposed study will not expose human subjects to unreasonable risk, and it breaks into a few major blocks.

Preclinical Pharmacology and Toxicology

Before any human testing, the sponsor must present animal and laboratory data showing the drug is reasonably safe for initial human exposure. The section summarizes the drug’s pharmacological effects and how it is absorbed, distributed, metabolized, and excreted. The toxicology portion covers acute and long-term toxicity, effects on reproduction and fetal development, and any special testing tied to the drug’s intended route of use.⁶ The application must also identify the scientists who evaluated this data and concluded the proposed human study is safe to start. Reviewers use it to judge whether the starting dose and dosing schedule are justified.

Chemistry, Manufacturing, and Controls

The CMC section describes the drug substance and the finished drug product: what it is made of, how it is manufactured, and how the sponsor ensures it stays pure, potent, and stable throughout the trial. Reviewers look for evidence that the manufacturing process can consistently produce a product of acceptable quality. Contaminated or inconsistent batches can endanger participants and invalidate results, so this section gets close scrutiny.

Clinical Protocol and Investigator Commitments

The clinical protocol is the study blueprint: the number of participants, the medical condition under study, the dosing plan, how safety will be monitored, and the criteria for stopping the trial if problems emerge. Every investigator who will administer the drug must sign FDA Form 1572, a legally binding commitment to follow the protocol, personally supervise the investigation, obtain informed consent from every participant, report adverse events to the sponsor, and keep accurate records available for FDA inspection.⁷

Form 1572 is not a formality. By signing it, the investigator also agrees to ensure an IRB reviews and approves the study before enrollment begins, to report all unanticipated problems involving risks to subjects, and to make no changes to the research without IRB approval except to eliminate immediate hazards.⁷ Violations can result in FDA enforcement action against the investigator.

FDA Form 1571

Form 1571 is the cover sheet that ties the package together. It identifies the sponsor, the drug name, the proposed indication, the phase of clinical investigation, and every document included in the submission. The form also names the person responsible for monitoring the clinical investigation and the person responsible for evaluating drug safety information. The sponsor or an authorized representative must sign it, certifying accuracy.⁸ Errors or omissions on Form 1571 can trigger an administrative refusal before reviewers even look at the science.

IRB Approval and Informed Consent

No clinical investigation under an IND may begin until an Institutional Review Board has reviewed and approved it. The consequences of ignoring this are severe: the FDA can refuse to consider any data generated from a study that lacked proper IRB oversight.⁹ The board independently evaluates whether the study design minimizes risks and whether the expected benefits justify them, and it must continue reviewing the study at regular intervals for as long as it is active.

Informed consent is equally non-negotiable. Before enrolling, each participant must receive a clear explanation that the study involves research, the purposes and expected duration of participation, the procedures involved, and any reasonably foreseeable risks. The document must also describe potential benefits, alternative treatments, how confidentiality will be handled, and whom to contact with questions or in the event of a research-related injury.¹⁰ The form must state that participation is voluntary and that the participant can withdraw at any time without penalty.

When a study involves more than minimal risk, the consent document must also address whether compensation or medical treatment is available if injury occurs. For applicable clinical trials, a statement directing participants to ClinicalTrials.gov is required.¹⁰

How to Submit

Commercial IND applications must be submitted electronically through the FDA’s Electronic Submissions Gateway (ESG NextGen), the single entry point for all electronic regulatory submissions.¹¹ These submissions must use the Electronic Common Technical Document (eCTD) format, which organizes data into standardized modules. Noncommercial INDs, including investigator-sponsored and expanded-access applications, are encouraged but not required to use eCTD.¹²

Sponsors submitting paper applications send three copies (one original and two duplicates) to the appropriate center’s Document Control Center.¹³ Applications for conventional drugs go to the Center for Drug Evaluation and Research (CDER). Biological products such as vaccines and gene therapies go to the Center for Biologics Evaluation and Research (CBER).⁴

The 30-Day Review and What “In Effect” Means

Once the FDA receives the IND, the sponsor must wait 30 calendar days before starting the trial.² During that window, a team of medical officers, toxicologists, and chemists evaluates whether the proposed study would expose participants to unreasonable risk. If the FDA raises no objection within 30 days, the IND goes into effect automatically. The FDA can also notify the sponsor earlier that the study may begin.¹³

An IND in effect is not an approval of the drug. It is permission to investigate the drug in humans under the conditions described in the application. The sponsor still bears full responsibility for conducting the study safely.

Clinical Holds

If the review team identifies serious problems, it can impose a clinical hold, a formal order that prevents a proposed study from starting or stops one already under way. The hold can be communicated by telephone or other rapid means, with a written explanation following within 30 days.¹⁴

For a Phase 1 study, the FDA can impose a hold on any of the following grounds:

Participants would be exposed to a significant and unreasonable risk of illness or injury.
The named investigators lack the scientific training or experience to conduct the study.
The investigator brochure is erroneous, incomplete, or misleading.
The application does not contain enough information to assess the risk to participants.
A study of a life-threatening disease affecting both sexes excludes men or women of reproductive potential solely because of reproductive or developmental toxicity concerns, without adequate justification.¹⁵

A hold can be complete, halting all activity under the IND, or partial, restricting the study in specific ways such as limiting it to certain doses or populations. A sponsor cannot resume any held activity until the FDA formally lifts the hold. To get one lifted, the sponsor submits a written request with a complete response addressing every deficiency identified in the hold order. The FDA then has 30 calendar days from receiving that complete response to either lift or maintain the hold in writing.¹⁴

Obligations After the IND Takes Effect

Getting the IND in effect is not the finish line. The sponsor takes on significant ongoing obligations for the life of the application.

Safety Reporting

When something goes wrong during a trial, the clock starts immediately. If a participant experiences a fatal or life-threatening suspected adverse reaction that is also unexpected, the sponsor must notify the FDA within 7 calendar days of first learning about it. For other serious and unexpected suspected adverse reactions, the deadline is 15 calendar days after the sponsor determines the event qualifies for reporting.¹⁶ These are hard deadlines. Missing them can trigger enforcement action and erode the FDA’s confidence in the sponsor.

Annual Reports

Within 60 days of each anniversary of the IND going into effect, the sponsor must submit an annual report on all studies conducted under the application. The report includes a status summary for each study (enrollment, dropouts, completion rates), a narrative of the most frequent and most serious adverse experiences organized by body system, a list of participants who died during the investigation with causes of death, a summary of safety reports filed during the year, updates on preclinical studies, any significant manufacturing changes, and the general investigational plan for the coming year.¹⁷ The report also covers any significant foreign marketing developments, such as approval or withdrawal of the drug in another country.

Withdrawal

A sponsor can withdraw an active IND at any time without prejudice, meaning the withdrawal does not count against the sponsor in future dealings with the FDA. When an IND is withdrawn, all clinical investigations under it must end, all investigators must be notified, and all remaining drug stocks must be returned to the sponsor or disposed of as directed. If the withdrawal is for a safety reason, the sponsor must promptly inform the FDA, all participating investigators, and all reviewing IRBs, along with the reasons.¹⁸ That transparency protects participants who may still be experiencing effects from the investigational drug and lets IRBs take any necessary follow-up action.

1
Federal Register. Prescription Drug User Fee Rates for Fiscal Year 2026
2
U.S. Food and Drug Administration. Investigational New Drug (IND) Application
3
eCFR. 21 CFR 312.2 – Applicability
4
eCFR. 21 CFR Part 312 – Investigational New Drug Application
5
U.S. Food and Drug Administration. Frequently Asked Questions on the Pre-Investigational New Drug (IND) Meeting
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eCFR. 21 CFR 312.23 – IND Content and Format
7
U.S. Food and Drug Administration. Statement of Investigator (Form FDA 1572)
8
U.S. Food and Drug Administration. IND Forms and Instructions
9
eCFR. 21 CFR Part 56 – Institutional Review Boards
10
eCFR. 21 CFR 50.25 – Elements of Informed Consent
11
U.S. Food and Drug Administration. Electronic Submissions Gateway Next Generation (ESG NextGen)
12
U.S. Food and Drug Administration. Electronic Common Technical Document (eCTD)
13
U.S. Food and Drug Administration. Investigational New Drug (IND) Application Procedures: Overview
14
eCFR. 21 CFR 312.42 – Clinical Holds and Requests for Modification
15
eCFR. 21 CFR 312.42 – Clinical Holds and Requests for Modification
16
eCFR. 21 CFR 312.32 – IND Safety Reporting
17
eCFR. 21 CFR 312.33 – Annual Reports
18
eCFR. 21 CFR 312.38 – Withdrawal of an IND