Bringing new medicine from the laboratory into human testing is one of the most critical steps in drug development. In the United States, this transition requires an Investigational New Drug (IND) application, which is the formal request to the Food and Drug Administration (FDA) for permission to begin clinical trials.
For sponsors and investigators, understanding the IND process is vital. It determines when a study can start and ensures patient safety, product quality, and regulatory compliance. This article explains what an IND application is, who needs to file one, the types of INDs available, and how submissions are reviewed, while also highlighting common pitfalls and practical tips for success.
In Brief
- An IND application is the FDA mechanism that allows an investigational drug to enter or continue human testing in the US.
- The IND submission helps FDA assess whether the nonclinical, CMC and clinical information supports an acceptable initial safety basis.
- Operationally, IND work covers filing, FDA review, protocol amendments, information amendments, annual reports and IND safety reports.
- A common misconception is that an approved product never needs an IND, but study intent, dose, route, population and claims can affect requirements.
- Sponsors should treat IND submission and maintenance as a controlled lifecycle process, not a one-off filing step.
IND Application: What it is and What Filing Means
An IND application is the legal mechanism that allows investigational drugs to be shipped across state lines and administered to humans in clinical trials. Without it, sponsors cannot begin human testing in the US.
When an IND is filed, the FDA acknowledges receipt and assigns an IND number. In practice, ‘filed’ means the submission has been sent to FDA, while ‘received’ means FDA has logged it into its systems for review. From that point, an IND becomes effective 30 days after FDA receipt unless a clinical hold is issued.
Who Needs to File an IND and When is it Required?
An IND is generally required unless the study meets criteria for exemption under 21 CFR 312.2(b).
This requirement can include pharmaceutical or biotech companies developing drugs for commercial use, as well as sponsor-investigators, meaning individual researchers or physicians who both initiate and conduct their own studies. Common triggers include novel compounds, new indications or formulations, or studies intended to support marketing authorisation.
The main decision point around the need for an IND is whether the study involves a drug or biologic that is unapproved, or an approved product being studied in a way that could materially change risk, labelling, or labelling claims. Studies using marketed products may be exempt in narrower circumstances, so teams usually assess intent, route, dose, population, and promotional implications rather than relying on the fact that the product is already approved.
Types of INDs
Common IND categories include:
- Commercial IND: Filed by a commercial Sponsor to study unapproved drugs or new uses of approved drugs
- Research (Investigator) IND: Filed by a physician to study unapproved drugs or new uses of approved drugs, typically in cases such as an academic clinician studying a new indication or dosing approach.
Expanded Access IND (including Emergency Use and Treatment INDs): Typically to provide access for an individual patient when there is no satisfactory standard alternative.
IND vs NDA
An IND application requests FDA permission to start human trials. An NDA (New Drug Application) seeks marketing authorisation after trials are complete. This distinction helps teams plan regulatory timelines effectively, ensuring clarity between early‑stage research and commercialisation. In practical terms, the IND is about whether a product can enter or continue human investigation, while the NDA is about whether the evidence package is sufficient for marketing approval.
What You Need for an IND Submission
Core content areas:
- Nonclinical data: Animal pharmacology and toxicology.
- CMC (Chemistry, Manufacturing, Controls): Composition, stability, and quality assurance.
- Clinical protocols: Study design, investigator qualifications.
Administrative elements: Forms FDA 1571, 1572, 3674, cover letters, financial disclosures, and CVs.
For an initial IND, sponsors typically also need the submission to be organised as a coherent packet, with a clear table of contents, cross-references that are easy to follow, and enough information for FDA to assess whether the investigational product can be studied with an acceptable initial safety basis.
Chemistry, Manufacturing, and Controls (CMC) describes how the investigational product is manufactured, its composition, and the controls in place to ensure quality and consistency. At the IND stage, CMC expectations are phase-appropriate—early-phase submissions (e.g., first-in-human studies) do not require full commercial-scale validation data, but must provide sufficient information to demonstrate that the product can be manufactured reproducibly and administered safely to study participants. As development progresses, the level of detail and control is expected to increase in line with later-phase and marketing requirements.
CDER vs CBER
- CDER (Center for Drug Evaluation and Research): Reviews drugs and small molecules.
- CBER (Center for Biologics Evaluation and Research): Reviews biologics such as vaccines, blood products, and gene therapies.
Correct routing ensures appropriate review expectations. It also affects practical submission planning, because product category influences review context, technical expectations, and the centre-specific materials teams may need to prepare.
How to Submit an IND Application
Electronic submission via the FDA’s Electronic Submissions Gateway (ESG) in eCTD format is the standard and expected approach. Paper submissions remain possible for some research INDs but are less efficient. In practice, teams should think about this less as a filing ‘button’ and more as a submission method with formatting and assembly requirements.
For the majority of sponsors, the operational default is electronic submission through ESG, with eCTD or other FDA-accepted electronic structures depending on the submission type and sponsor context.
After Submission: FDA’s First Review Window
The FDA issues an acknowledgement letter confirming receipt of the IND and assigning an IND number. The agency then has 30 calendar days to review.
If the FDA advises that the study may proceed, trials can begin once the IND is effective and the other study-start requirements, such as IRB approval and site readiness, are in place. In practice, the FDA does not always issue a written approval of an IND. Instead, if the agency does not impose a clinical hold within the 30-day review period, the study may proceed (sometimes referred to as “implicit” or “no-objection” status). The FDA may also notify sponsors prior to day 30 that the study may begin. If the FDA imposes a clinical hold, sponsors must address the cited deficiencies before the study can start or, in some cases, continue.
Sponsor-Investigator IND Submission Checklist
- Forms 1571, 1572, 3674, 3454/3455
- Cover letter and table of contents
- Protocols and CVs
- CMC data and toxicology summaries
- Consent forms (recommended)
For sponsor-investigators, the practical aim is a minimum ready-to-file packet that mirrors the main IND content blocks and is easy for FDA to navigate on first review.
Common Pitfalls and How to Avoid Them
- Missing toxicology or CMC data.
- Poor organisation making submissions hard to navigate.
- Slow responses to FDA queries.
Best practices include pre‑IND consultation, clear formatting, and proactive communication. Teams also reduce rework when they make key documents easy to find, keep terminology consistent across modules, and resolve obvious gaps in the safety story before submission rather than after FDA review begins.
Pre-IND Consultation and Regulatory Context
Pre‑IND meetings allow early dialogue with FDA, clarifying data requirements and reducing risk of delays. Regulatory context includes 21 CFR Part 312, Part 50 (informed consent), and Part 56 (IRBs).
In practice, a pre-IND interaction is most useful when there is a real decision to test, such as nonclinical package adequacy, CMC readiness, or first-in-human protocol design. The regulations provide the binding framework, while FDA guidance helps interpret expectations in specific contexts.
Special Situations
Special situations can affect whether an IND is required. For example, studies involving radioactive drugs may fall under 21 CFR 361 rather than IND requirements in specific research settings. Similarly, dietary supplements may require an IND if they are being studied for therapeutic or disease-related claims rather than general wellness use. In such cases, the regulatory pathway depends on study intent, level of risk, and intended claims, rather than product category alone.
These are best treated as watchouts rather than category shortcuts. Borderline situations often turn on what claim the study is intended to support, how the article is being used in the investigation, and whether the planned use changes the regulatory posture of the product.
Global Perspective
While the IND is specific to the US FDA, other regulators have similar frameworks:
- EMA (European Medicines Agency): Requires a Clinical Trial Application (CTA) before human studies.
- MHRA (UK): Oversees CTA submissions under UK law.
- NMPA (China): Requires IND‑style filings for investigational drugs.
- ICH E6(R3): Provides harmonised guidance on Good Clinical Practice across regions.
There are however key differences and differing approaches. Awareness helps sponsors working internationally align submissions with global standards.
IND Lifecycle Management
It is important to note that IND management is an active, controlled lifecycle process. Once an IND is in effect, the sponsor must keep the regulatory file aligned with clinical development activities and must submit amendments and reports as the program evolves. Protocol-driven change control is central. New studies not already covered by the IND, addition of new investigators, and protocol changes that materially affect subject safety (Phase 1) or safety/scope/scientific quality (Phases 2/3) require protocol amendments, generally submitted before implementation (with narrow allowance for immediate hazard elimination followed by notification). In parallel, essential new program information that does not belong in a protocol amendment, safety report, or annual report is submitted as an information amendment.
Ongoing safety surveillance and periodic FDA communication are the other pillar of IND maintenance. Sponsors must submit IND safety reports for potential serious risks, including serious and unexpected suspected adverse reactions, certain risk-signalling findings from other studies, and animal/in vitro findings suggesting significant human risk. Separately, sponsors must file an IND annual report within 60 days of the IND effective-date anniversary, summarizing study status and exposure, cumulative safety (including a summary of IND safety reports submitted that year), key nonclinical and manufacturing changes, and the updated investigational plan (and IB updates as applicable).
IND Safety Reports
Whilst the US FDA is aligned with the EU in many aspects, particularly bearing in mind ICH guidelines, their specific drug safety reporting requirements and routes are different in several ways.
In preparation for submission of expeditable safety reports, the FDA require Sponsors to complete an Analysis of Similar Events. A comprehensive process and template established during study set-up is useful in order to streamline the process throughout the project. Data listings pulled from the global safety database support this analysis, and medical review is important to ensure clinical relevance.
Standard expedited reporting of IND Safety Reports is to be completed no later than 15 calendar days after the sponsor determines the information qualifies, and unexpected fatal or life-threatening suspected adverse reactions are due within 7 calendar days.
Since April 2026, it has become mandatory to electronically submit IND Safety Reports to the FDA in e2b(R3) format (rather than the traditional eCTD format), via the Electronic Submission Gateway (ESG). Registration, set-up and testing of this connection is required, and technical FDA-specific e2b files will need to be generated from the safety database. To note, Annual Safety Reports (accepted in ICH DSUR format, inclusive of FDA-required regional appendices) will still follow the traditional eCTD route.
Conclusion
An IND application is the gateway to human trials in the US. Sponsors must determine whether an IND is required, compile nonclinical, CMC, and clinical data, and submit via the correct FDA centre. IND Safety Reporting follows specific formats and routes, which require some preparation in advance.
About QVigilance
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FAQs
What is an IND application?
It is a formal request to the FDA for authorisation to begin human clinical trials.
What is the difference between NDA and IND applications?
An IND allows human trials to begin; an NDA seeks marketing authorisation after trials are complete.
Who needs to file an IND application?
Sponsors and sponsor‑investigators testing new drugs or new uses of approved drugs in humans.
What does filing an IND mean?
It signals readiness for human testing and triggers the FDA’s 30‑day review window.
What do you need for an IND submission?
Nonclinical data, CMC information, clinical protocols, and administrative forms.
Who needs to submit an IND application?
Pharmaceutical companies, biotech firms, and sponsor investigators conduct clinical trials.
What are the three types of IND?
Commercial IND, Research (Investigator) IND, and Treatment IND / Expanded Access IND and Emergency Use IND (EIND) which is subset of Expanded Access IND.