An Investigational New Drug application (IND) is the submission that lets a sponsor start clinical trials of an unapproved drug or biologic in the United States. FDA's own summary of the timing is blunt: "Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials" (FDA, Investigational New Drug Application). In that window FDA decides whether the first study is reasonably safe to start.

For a small biotech, the first IND is often the largest document the company has produced. This guide walks through what goes in it, section by section, using the regulation that defines it, 21 CFR 312.23, and FDA's guidance on the content and format of Phase 1 INDs.

What FDA is looking for

FDA describes three broad content areas in an IND (FDA):

  1. Pharmacology and toxicology: nonclinical data showing the product is reasonably safe for initial testing in humans, plus any previous human experience.
  2. Manufacturing information: composition, manufacturer, stability and controls, so FDA can judge whether the sponsor can make consistent batches.
  3. Clinical protocols and investigator information: whether the first study exposes participants to unnecessary risk, and whether investigators are qualified.

For a first-in-human study, the review question is safety, not efficacy. Every section should be written to help a reviewer answer "is it reasonably safe to give this to these people at this dose?"

The size of a Phase 1 IND

The Phase 1 guidance was written in 1995 partly to stop sponsors over-filing. It says that, if the guidance is followed, Phase 1 INDs "should usually not be larger than two to three, three inch, 3-ring binders." The binders are long gone, but the message holds: a first IND should be complete, not exhaustive. Detail that does not bear on the safety of the proposed study slows the review down.

Section by section

21 CFR 312.23(a) lists the content of an IND in order. Most sponsors now file in eCTD format, so the same content is arranged into CTD modules, but the regulation is still the checklist.

Cover letter and Form FDA 1571

The IND opens with Form FDA 1571, the application form, signed by the sponsor. It commits the sponsor to wait 30 days, to not start a study under a clinical hold, to obtain IRB review, and to follow the IND regulations. Alongside it, most sponsors send a cover letter. The letter is short, but it is the first thing the review division reads. It should say what is being submitted, the product and indication, the proposed first study, the pre-IND meeting reference if there was one, and the contact for questions. If the product is being studied in a way the pre-IND meeting discussed, say so and point to where the advice is addressed.

Other forms travel with the IND: Form FDA 1572 (Statement of Investigator) for each investigator, and Form FDA 3674, the ClinicalTrials.gov certification. These are administrative, but missing ones cause avoidable delays.

Introductory statement and general investigational plan

21 CFR 312.23(a)(3) asks for a brief introduction: the drug's name, active ingredients, pharmacological class, structural formula if known, formulation, route of administration, and the broad objectives of the planned investigation. It also asks for previous human experience, any withdrawal from investigation in another country, and a brief plan for the coming year: the rationale, indications, general approach, the kinds of trials, the estimated number of participants, and any risks of particular severity.

The Phase 1 guidance is direct about length: "Regulations repeatedly describe this section as brief. Ordinarily, two to three pages should suffice." It also tells sponsors not to over-plan. If the first study is simply working out early pharmacokinetics, "sponsors should simply state this in this section and not attempt to develop and write detailed developmental plans that will, in all likelihood, change considerably."

The common mistake is writing this section as a pitch. It is a plan, and FDA reads it to anticipate what the sponsor will need.

Investigator's Brochure

21 CFR 312.23(a)(5) requires an Investigator's Brochure (IB): the compilation of nonclinical and clinical data that lets investigators understand the product and the protocol. The content standard is Appendix A of ICH E6(R3). For a first IND, the IB will be mostly nonclinical. Its reference safety information matters immediately, because it is the basis for deciding whether a serious adverse reaction is expected or needs expedited reporting. See our guide to Investigator's Brochure problems for the common failure points.

Protocol

21 CFR 312.23(a)(6) requires a protocol for each planned study. For Phase 1, the regulation allows a less detailed protocol than later phases: it should give an outline of the investigation, the estimated number of participants, a description of safety exclusions, the dosing plan including duration, dose or method for determining dose, and the elements most critical to safety, such as necessary monitoring of vital signs and blood chemistries.

The starting dose and the dose-escalation rules carry most of the weight. Make the link between them and the nonclinical data explicit: which study, which no-observed-adverse-effect level, which safety margin.

Chemistry, manufacturing and controls (CMC)

21 CFR 312.23(a)(7) asks for enough CMC information to assure the identity, quality, purity and strength of the investigational drug. It also recognises that the amount of information depends on the phase. For Phase 1, the guidance focuses on the information needed to evaluate safety: a description of the drug substance and drug product, the manufacturer, the method of manufacture in outline, acceptable limits and analytical methods, and stability information. On stability, it asks for "a brief description of the stability study and the test methods" with preliminary tabular data, and states that neither detailed stability data nor the stability protocol should be submitted.

For sterile products, sterility and non-pyrogenicity matter from the first dose. Placebo composition should be described too.

Pharmacology and toxicology

21 CFR 312.23(a)(8) requires adequate information about pharmacological and toxicological studies, from which the sponsor has concluded that it is reasonably safe to conduct the proposed studies. This is usually the largest section, and it is organised in CTD format as the nonclinical overview (2.4), the written and tabulated summaries (2.6), and the study reports themselves (Module 4).

The Phase 1 guidance made one practical concession that still shapes timelines: FDA will accept "an integrated summary report of toxicology findings based upon the unaudited draft toxicologic reports of completed animal studies" as initial support for human studies, provided the final, audited reports follow. The integrated summary is then updated once the final reports are available. If you rely on draft reports, say so clearly and plan the update.

Each GLP toxicology study also needs a statement that it was conducted in compliance with Good Laboratory Practice, or a reason why not. For what goes in the 2.4 overview and the 2.6 summaries, see our page on nonclinical summaries.

Previous human experience

21 CFR 312.23(a)(9) asks for a summary of any previous human experience with the drug: trials abroad, marketed use elsewhere, or use of a closely related product. For most new molecules this section is short or says there is none. If there is experience, present the safety data in a form a reviewer can compare with the proposed study.

Additional and relevant information

The last parts of 312.23(a) cover special cases: drug dependence and abuse potential, radioactive drugs, paediatric studies, and any other information that would aid evaluation. Use them when they apply, and say "not applicable" when they do not, so the reviewer knows you considered it.

Writing the IND as one document

The IND is several documents written by different people: CMC, toxicology, clinical and regulatory. The most common review problems come from the seams between them.

  • The dose. The starting dose in the protocol, the safety margin in the nonclinical overview, and the dose in the general investigational plan must be the same number, derived the same way.
  • The formulation. The formulation dosed in the toxicology studies, the one described in CMC, and the one in the protocol should match, or the difference should be explained.
  • The safety monitoring. Target organs found in toxicology should show up as specific monitoring in the protocol.
  • The pre-IND advice. Every point FDA raised at the pre-IND meeting should be answered somewhere, and the cover letter should say where.

A short internal consistency check against those four items, done before submission, prevents most clinical hold questions that are about the document rather than the drug.

Where automation helps

Most of the writing in an IND is summarising documents that already exist: study reports into nonclinical summaries, batch data into CMC sections, and both into the general plan. Asthra's IND authoring drafts the cover letter, the introductory statement and general investigational plan, Phase 1 CMC information and the nonclinical summaries from your own reports, with each statement cited to its source. Your regulatory lead still decides the strategy and signs off the submission.

FAQ

How long does FDA take to review an IND? The sponsor must wait 30 calendar days after FDA receives the IND before starting the trial. Within that period FDA can place the study on clinical hold. If it does not, the study can proceed.

Do I need final GLP toxicology reports to file? Not necessarily for Phase 1. FDA's Phase 1 guidance accepts an integrated summary based on unaudited draft reports of completed animal studies, with the final reports and an updated summary to follow.

How long should the general investigational plan be? FDA's Phase 1 guidance says two to three pages should ordinarily suffice.

Is a pre-IND meeting required? No, but it is usually worth it for a first IND, especially for a novel modality. See our guide on how to write an FDA meeting package.

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