Your Clinical Trial Starts Here: IND

What I learned in the Biomedical Regulatory Affairs Program: Topic of the day – IND

So, what is an IND?

1. IND stands for Investigational New Drug. It’s a formal request to the FDA for authorization to start clinical trials in humans.
2. It’s regulated under 21 CFR 312.
3. You’ll need an IND for any study involving a drug or biologic in humans for therapeutic use

Okay, I need to file an IND. But when exactly?

Short answer: After preclinical studies, before you initiate your investigation on first human subject

Do I Qualify for an IND Exemption?

Filing an IND can be a tedious process—I get it. But if your clinical investigation uses a marketed drug in the US, there’s a good chance you may be exempt from submitting an IND, if the following criteria are all met:

• You do not intend to:
• • expand the indication for use, or make any significant change to the labeling.
  • make any significant change in the advertising for the drug.
  • change the route of administration, dosage level, or target population in a way that significantly increases risk *Note: Not only increasing, but also decreasing the dose level could augment the risk profile
• And your investigation must:
• • Follow IRB approval and informed consent requirements (21 CFR Part 50 & 56).
  • Comply with the FDA’s rules against promotion of investigational drugs (21 CFR 312.7).

I think my case is exempt from IND—now what?

Generally, the sponsor can assess whether their study qualifies for an IND exemption.

Some guidance may help with the assessment, for example:

• IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment of Cancer
• Guidance for Clinical Investigators, Sponsors, and IRBs: Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND

If you determine that your study meets the exemption criteria, you may proceed without notifying the FDA.

However, if you're unsure—ASK.

• Consult the FDA through either a formal or informal route:
• • Formal: file an IND but with a request of IND waiver. If the FDA agrees with your exemption request, they will issue an official exemption letter.
  • Informal: Reach out via email, phone, or during a pre-IND meeting. These interactions provide non-binding feedback—helpful but not definite.
• Consult the IRB:
• • All human studies must be reviewed by an IRB, regardless of IND exemption status.
  • The IRB can assist in evaluating exemption eligibility, but only the FDA has the final authority.

Not just any IND—you have to submit the right type:

1. Commercial IND

Your ultimate goal is to get FDA marketing approval for a new drug. This IND supports a NDA or BLA submission.

2. Research IND (also known as non-commercial IND)

Your study aims to improve scientific understanding or medical practice.

If your study doesn't meet the exemption criteria, a research IND is still required. In other words, whether an IND is required depends on your study design, regardless of whether the purpose is commercial or non-commercial.

3. Expanded Access IND (also called “compassionate use”)

For patients with serious or life-threatening conditions with out approved treatment options, an expanded access IND could make a new but unapproved drug available to them.

→ It generally is submitted by the physician.

What to submit? let me introduce you “IND package”

• FDA 1571: the main document of IND
• General Investigational Plan
• Investigator’s Brochure (IB)
• Protocol
• CMC (Chemistry, Manufacturing, and Control): quality
• Drug Substance
• Drug Product
• Label: must state “for investigational use only”
• Environmental analysis: assess potential impact on the environment during manufacturing or after use/metabolism
• Pharmacology & Toxicology: preclinical data
• Clinical experience
• Form 3674: the status of clinical trial registration
• (Form 1572):
• • Commercial IND → not required at submission, but often collected later for inspection
  • Non-commercial IND → required to initiate the IND

IND format

eCTD

1. Stands for: Electronic Common Technical Document
2. Purpose: Standardizes submission format across ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) regions to improve consistency and reduce FDA review burden

• • Original ICH members: US, EU, Japan
  • Taiwan is now also an ICH regulatory member

3. Who uses it?

• • Commercial IND → Required
  • Non-commercial IND → Encouraged, but not mandatory

4. Scope of content:

• • For IND submission, only a few sections of eCTD are needed
  • For NDA/BLA, all modules must be complete

Traditional Format

• Paper-based or scanned PDF format
• Only available to non-commercial INDs (no drug-approval intention)

eCTD Module Overview

• Module 1:
• • Administrative and regional documents (not technically part of “eCTD” core)
  • Includes: FDA Form 1571, General Investigational Plan, Investigator’s Brochure (IB), Label, Environmental Assessment, Form 3674, Form 1572
• Module 2:
• • Overviews and summaries
  • Summarizes: Protocol, Pharmacology & Toxicology, Clinical Experience, CMC
• Module 3:
• • Quality
  • Includes: CMC, Drug Substance, Drug Product
• Module 4:
• • Nonclinical study reports
  • Includes: Pharmacology & Toxicology
• Module 5:
• • Clinical study reports
  • Includes: Protocol, Clinical Experience

*Just know: M2=M3+M4+M5

eCTD module overview

Something about Form 3674

It basically certifies that you will register your trial on ClinicalTrials.gov.

Who Needs to Register?

Only “applicable clinical trials” (ACT) need to be registered. Here are the ACT criteria:

1. The trial is interventional

• • Most psychological studies are observational → no need for registration.

1. The trial phase is other than Phase 1
2. The product in the investigation is regulated by the FDA
3. The product is manufactured or exported from the US; or the investigation site is in the U.S.

Since Form 3674 is required to initiate an IND, for those clinical trials that don’t need to be registered, just check “Not Applicable” on the form.

What happens after you submit an IND?

• The FDA has 30 calendar days to review your IND.
• Technically, if the FDA does not respond within 30 days, you may proceed with your clinical trial and ship your product.
• it’s strongly recommended to wait for an official response before step into clinical stage.
• If the IND is acceptable, the FDA will send an acknowledgment letter to the sponsor.

*note: the FDA does not “approve” INDs, they “acknowledges” them.

If the FDA has concerns, the FDA may issue:

• Clinical Hold: Once resolved the concerns, the trial can continue.
• Termination: it requires a new IND submission to proceed.

the IND review process

Clinical Hold / IND Withdrawal / IND Termination

Similarity: All of them can occur at any time.

• Clinical Hold
• • Issued by the FDA
  • Temporarily suspends the investigation(s)
  • Could be due to: Safety concerns, Unqualified investigators, Errors in the Investigator’s Brochure, Inadequate risk assessment, and Potential reproductive impacts
  • Once the issues are resolved and reviewed by FDA, the investigation may proceed.
• IND Withdrawal
• • Initiated by the sponsor
  • Could be due to safety concerns or commercial strategy (e.g., financial reasons)
  • If withdrawal is safety-related → IRB must be notified; If not → IRB does not need to be notified
  • If you want to start the investigation in the future → submit a new IND
• IND Termination
• • Initiated by the FDA
  • Typically due to: Serious safety issues, Fake data or protocol violations, Failure to respond to FDA’s deficiency letters, Conducting the study without FDA authorization
  • The IND is shut down completely → must submit a new IND to proceed again

You think you can leave it behind after submitting it? Nah.

1. IND Annual Report

• Celebrate your IND’s birthday by filing an annual report
• Submit it within 60 days of the IND activation date
• For example: filed on 1/1 → IND goes active on 1/31 → report due by 3/31 next year

2. IND Safety Report

• Use Form 3500A
• Unexpected, fatal or life-threatening adverse reaction → submit it in 7 days
• Other serious, unexpected risks → 15 days

3. Amendment

• Protocol Amendment
• • When do you need one?New protocolProtocol changes that may affect: subject safety, the scope of the investigation, scientific quality (like endpoints)Adding a new investigator
  • If the changes are major, protocol amendment might not be enough → you may need a new IND
• Information Amendment
• • For essential updates that don’t fit under safety reports, protocol amendments, or annual reports

***I’m still figuring things out—but if this piece gave you a little clarity, then we’ve learned together.

Written by Momo, a newbie who just stepped into RA world. 我是Momo，一個在美國讀RA碩士的女森。法規世界無垠，我邊學邊寫，邊迷惘邊理解。