IND Submission Checklist (US)
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IND Submission Checklist (US)
A step-by-step guide for Investigational New Drug filings with the FDA — what to include, common pitfalls, and regulatory references
Updated Q4 2025 | BioPharmaWire Editors | Based on 21 CFR Part 312 and FDA Guidance Documents
An Investigational New Drug (IND) application is the regulatory gateway to clinical trials in the United States. Before a sponsor can ship an investigational drug across state lines or administer it to human subjects in a US trial, an IND must be on file with the FDA and the 30-day review period must have elapsed without a clinical hold. This checklist covers all eight sections of a complete IND submission under 21 CFR Part 312, with the specific content requirements and the most common deficiencies that trigger information requests or clinical holds.
IND Basics: What You Need to Know Before You File
Types of IND
Investigator IND: filed by a physician-investigator who both initiates and conducts the study. Commercial IND: filed by a company or institution that will eventually seek marketing approval. Emergency IND: for compassionate use in a life-threatening situation before a formal IND is in place. Treatment IND: provides access to promising therapies for serious conditions while Phase 3 trials are ongoing.
The 30-Day Clock
FDA has 30 calendar days from IND receipt to review the submission and issue a clinical hold if there are safety concerns. If no hold is issued within 30 days, the sponsor may proceed. The clock starts on the date FDA receives the submission — not the date it is mailed. Electronic submissions via the FDA Electronic Submissions Gateway (ESG) are strongly recommended and provide a confirmed receipt date.
Clinical Hold vs. Information Request
A clinical hold prevents the study from proceeding. An information request (IR) does not stop the clock but requires a response. Common clinical hold reasons: insufficient nonclinical data to assess risk, inadequate starting dose justification, unresolved chemistry/manufacturing concerns. Responding promptly and completely to IRs reduces the likelihood of a hold being imposed.
eCTD Format
FDA strongly prefers IND submissions in electronic Common Technical Document (eCTD) format. All commercial INDs should be submitted electronically. Paper submissions are still accepted but create delays. Use eCTD sequence 0000 for the original IND filing.
IND Submission Checklist — 21 CFR Part 312
Note: The checkbox column is for your internal use. CFR references are provided for each item — confirm against the current version of 21 CFR Part 312 and applicable FDA guidance before filing.
| Requirement | What to include / common pitfalls | CFR Reference |
SECTION 1 — COVER SHEET (FORM FDA 1571) | |||
☐ | Form FDA 1571 | The IND cover sheet. Must be signed by the sponsor or sponsor-investigator. Unsigned submissions are a leading cause of IND holds. | 21 CFR 312.23(a)(1) |
☐ | IND type designation | Indicate whether this is an original IND, protocol amendment, information amendment, IND safety report, or annual report. | 21 CFR 312.23(a)(1) |
☐ | Sponsor information | Full legal name and address of sponsor. If sponsor-investigator, include investigator’s name, title, and institution. | 21 CFR 312.23(a)(1) |
☐ | Phase of investigation | Specify Phase 1, 2, or 3. For combination studies, indicate the phase for each component. | 21 CFR 312.23(a)(1) |
☐ | Commitments | Sponsor must commit to IRB review, not commencing trials until 30-day review period expires, and compliance with informed consent regulations. | 21 CFR 312.23(a)(1) |
SECTION 2 — INTRODUCTORY STATEMENT & GENERAL INVESTIGATIONAL PLAN | |||
☐ | Introductory statement | Brief description of drug substance, active ingredient(s), pharmacological class, structural formula, and formulation. | 21 CFR 312.23(a)(2) |
☐ | General investigational plan | Rationale for the drug and the indication. Description of studies planned in the coming year — phases, study types, patient populations. | 21 CFR 312.23(a)(2) |
☐ | Prior human experience | Summary of prior human experience including foreign clinical data, compassionate use, or expanded access if applicable. | 21 CFR 312.23(a)(2) |
SECTION 3 — INVESTIGATOR’S BROCHURE (IB) | |||
☐ | IB cover page | Drug name, chemical/generic name, sponsor name and address, edition number, date of issue, and replacement schedule. | 21 CFR 312.23(a)(5) |
☐ | Summary / table of contents | Concise summary of available nonclinical and clinical data. Should allow an investigator to understand risks and conduct the study safely. | 21 CFR 312.23(a)(5) |
☐ | Drug substance & formulation | Physical, chemical, and pharmaceutical properties. Description of formulation(s) used in clinical studies. | 21 CFR 312.23(a)(5) |
☐ | Nonclinical studies summary | In vitro and in vivo pharmacology, toxicology (single dose, repeat dose, genotoxicity, reproductive if available), PK/ADME. | 21 CFR 312.23(a)(5) |
☐ | Clinical experience summary | All prior human exposure including Phase 0/microdosing, foreign trials, published literature. Include safety signals observed. | 21 CFR 312.23(a)(5) |
☐ | Reference list | Full citations for all studies referenced in the IB. Confirm all cited studies are either appended or available for FDA review. | 21 CFR 312.23(a)(5) |
SECTION 4 — CLINICAL PROTOCOL(S) | |||
☐ | Protocol title & number | Full title, protocol number, version number, and date. Must match the Form FDA 1571 exactly. | 21 CFR 312.23(a)(6) |
☐ | Objectives and purpose | Clear primary and secondary objectives. For Phase 1: safety/tolerability and PK. For Phase 2: preliminary efficacy plus safety. | 21 CFR 312.23(a)(6) |
☐ | Investigator list (Form 1572) | Names, addresses, and qualifications of all clinical investigators. FDA Form 1572 required for each investigator. | 21 CFR 312.23(a)(6)(iii)(b) |
☐ | Patient selection criteria | Inclusion and exclusion criteria. FDA expects exclusions to reflect known safety signals from nonclinical data. | 21 CFR 312.23(a)(6)(iii)(c) |
☐ | Study design | Randomisation, blinding, controls, dose rationale, duration. For Phase 1 FIH: MABEL or NOAEL-based starting dose justification required. | 21 CFR 312.23(a)(6)(iii)(d) |
☐ | Dose escalation rules | DLT definitions, cohort size, escalation criteria, stopping rules, de-escalation provisions. DSMB/IDMC charter if applicable. | 21 CFR 312.23(a)(6)(iii)(d) |
☐ | Observations and measurements | Efficacy and safety assessments, schedule of events, PK sampling, biomarker collection plan. | 21 CFR 312.23(a)(6)(iii)(e) |
☐ | Clinical procedures | All procedures to be performed, who performs them, and where. Distinction between standard of care and study-specific procedures. | 21 CFR 312.23(a)(6)(iii)(f) |
☐ | Statistical methods | Primary and secondary endpoints, sample size justification, analysis populations (ITT, PP, safety), interim analysis plan. | 21 CFR 312.23(a)(6)(iii)(g) |
SECTION 5 — CHEMISTRY, MANUFACTURING & CONTROLS (CMC) | |||
☐ | Drug substance description | Chemical name, structural formula, molecular formula/weight, physical and chemical properties. | 21 CFR 312.23(a)(7) |
☐ | Manufacturer information | Name and address of drug substance and drug product manufacturer(s). FDA facility registration numbers. | 21 CFR 312.23(a)(7) |
☐ | Manufacturing method | General description of synthesis or production process. Level of detail appropriate to phase — Phase 1 requires less than Phase 3. | 21 CFR 312.23(a)(7)(iv)(a) |
☐ | Analytical controls | Specifications for drug substance and drug product including identity, purity, potency, and sterility tests. | 21 CFR 312.23(a)(7)(iv)(b) |
☐ | Stability data | Available stability data supporting the proposed shelf life and storage conditions for the investigational period. | 21 CFR 312.23(a)(7)(iv)(c) |
☐ | Placebo description | If applicable: composition and controls for any placebo or vehicle used in the study. | 21 CFR 312.23(a)(7)(iv)(d) |
☐ | Labelling | Draft label for investigational drug including product name, lot number, storage conditions, and “Caution: New Drug — Limited by Federal Law to Investigational Use” statement. | 21 CFR 312.23(a)(7)(iv)(e) |
☐ | Environmental analysis | Statement on environmental impact. Most IND submissions qualify for a categorical exclusion — include signed exclusion claim. | 21 CFR 312.23(a)(7)(iv)(f) |
SECTION 6 — PHARMACOLOGY & TOXICOLOGY (NONCLINICAL) | |||
☐ | Pharmacology summary | Primary pharmacodynamics (mechanism of action, target engagement). Secondary pharmacodynamics and safety pharmacology (hERG, CNS, respiratory). | 21 CFR 312.23(a)(8) |
☐ | Toxicology summary | Single-dose (acute) toxicity, repeat-dose toxicity (species, duration, route, NOAEL, LOAEL), genotoxicity battery. | 21 CFR 312.23(a)(8) |
☐ | Reproductive toxicity | Required if the study population includes women of childbearing potential or if the drug class raises reproductive concerns. | 21 CFR 312.23(a)(8) |
☐ | MABEL/NOAEL starting dose justification | For FIH trials: document MABEL or NOAEL calculation method, species selection rationale, and allometric scaling assumptions. | 21 CFR 312.23(a)(8) |
☐ | GLP compliance statement | Confirm whether toxicology studies were conducted under GLP. Non-GLP studies must be flagged; FDA expects GLP tox before Phase 2. | 21 CFR 312.23(a)(8)(iii) |
☐ | Full study reports | Attach complete reports or indicate where they are available. Summaries alone are insufficient for pivotal tox studies. | 21 CFR 312.23(a)(8) |
SECTION 7 — PREVIOUS HUMAN EXPERIENCE (IF APPLICABLE) | |||
☐ | Foreign clinical data | Summary of clinical experience outside the US. If relying on foreign data, confirm ICH E5 bridging considerations addressed. | 21 CFR 312.23(a)(9) |
☐ | Published literature | Relevant published studies on the compound or drug class. Include a critical appraisal — FDA will review citations. | 21 CFR 312.23(a)(9) |
☐ | Prior IND reference | If cross-referencing another sponsor’s IND, include a letter of authorisation. Cannot reference a closed IND without authorisation. | 21 CFR 312.23(a)(9) |
SECTION 8 — ADDITIONAL INFORMATION | |||
☐ | Drug dependence potential | Required if the drug or drug class has known or suspected abuse potential. DEA scheduling consideration. | 21 CFR 312.23(a)(10) |
☐ | Radioactive drugs | If the IND covers a radioactive compound, include radiation safety data and dosimetry calculations. | 21 CFR 312.23(a)(10) |
☐ | Pediatric study plan | If adult indication may extend to pediatric population, include initial pediatric study plan (iPSP) or justification for deferral/waiver. | 21 CFR 312.23(a)(10) |
Common IND Deficiencies and How to Avoid Them
Starting Dose Justification
The most common Phase 1 IND deficiency for novel compounds. FDA expects the starting dose to be derived from nonclinical data using a defined methodology — typically MABEL (Minimum Anticipated Biological Effect Level) for biologics and high-risk small molecules, or NOAEL with a safety factor for conventional small molecules. The calculation must be documented in detail including species selection, PK scaling assumptions, and uncertainty factors applied.
Unsigned Form FDA 1571
A surprisingly common reason for an IND to be placed on administrative hold before review even begins. The 1571 must be signed by an authorised representative of the sponsor. Wet signatures are accepted; electronic signatures under 21 CFR Part 11 are also accepted if the sponsor has an active FDA ESG account.
CMC Gaps for Biological Products
Biological INDs frequently receive information requests related to cell line characterisation, adventitious agent testing, and release specification justification. For Phase 1 biologics, FDA expects identity, purity, potency, and sterility testing at minimum. If a reference standard has not yet been established, document the interim approach and the plan to establish one before Phase 2.
Missing or Incomplete Nonclinical Study Reports
Tabular summaries of nonclinical studies are not sufficient for a complete IND. Full GLP study reports should be included or referenced with a clear statement of availability. For non-GLP studies — common in early discovery — provide a statement explaining why GLP standards were not used and confirm that the data quality is sufficient to support the safety assessment.
Protocol Inconsistencies
The protocol version and date on Form FDA 1571 must match the protocol document exactly. Dose levels referenced in the CMC section must be consistent with the protocol. Inclusion/exclusion criteria must be internally consistent — contradictions (e.g. an exclusion criterion that conflicts with a comorbidity permitted elsewhere in the protocol) are flagged by FDA reviewers.
Key FDA Guidance Documents
The following FDA guidance documents are directly relevant to IND preparation and should be reviewed alongside 21 CFR Part 312:
Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (2005)
M3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (ICH, 2010)
Investigational New Drug Applications for Phase 2 and Phase 3 Studies of Drugs, Including Specified Therapeutic Biotechnology-Derived Products (1992)
Content and Format of an Investigational New Drug Application (IND) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products (1995)
Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions (eCTD) (2023 update)
This checklist is an editorial product of BioPharmaWire intended as a general reference guide based on 21 CFR Part 312 and publicly available FDA guidance as of Q4 2025. It is not legal or regulatory advice. Sponsors should consult qualified regulatory affairs professionals and review current FDA guidance before submitting an IND. Regulatory requirements are subject to change.