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How do you reactivate an IND that FDA has placed on inactive status?
Confirm the inactive-status record, then submit a protocol amendment with the coming year’s general investigational plan and appropriate protocols, referencing relevant prior information. Submit additional supporting information, if any, in an information amendment. Control resumption against FDA’s receipt and communications under §312.45(d), as well as the other requirements for conducting the studies.
Before you begin
Inactive INDs under 21 CFR 312.45. A withdrawn or terminated IND and an unresolved clinical hold require separate analysis.
What you will prepare: An evidence-based inactive-status request or complete reactivation package with a controlled start decision.
Sections covered in this guide (2)
For 1.5.2, establish the inactive-status basis
Section 312.45 addresses INDs with no subjects entered into clinical studies for two years or more, or all investigations on clinical hold for one year or more. FDA may place an IND on inactive status on the sponsor’s request or its own initiative. If FDA proposes that action on its own initiative, the sponsor has the stated 30-day response opportunity. Do not describe every short pause as automatically satisfying these thresholds.
Prepare an identity and chronology record: last subject entry, investigation status, applicable hold dates, sponsor’s reasons and requested disposition. When inactive status is established, investigators must be notified and drug stocks returned or otherwise disposed of under §312.59. Annual reports are not required for an IND on inactive status; a planned request does not establish that the status has already changed.
For 1.5.3, prepare the next year’s actual investigation
Under §312.45(d), resumption requires a protocol amendment containing the proposed general investigational plan for the coming year and appropriate protocols. Reference relevant prior information and submit additional supporting information, if any, in an information amendment. Assess whether old CMC, nonclinical, investigator and safety information still supports the proposed program; do not rely on age alone as evidence of adequacy.
Write the request with the IND/status history, intended studies, proposed start, updated evidence map and references to prior hold issues where relevant. Clinical investigations may resume 30 days after FDA receives the protocol amendment unless placed on hold, or on earlier FDA notification that they may begin. Establish the receipt date and actual agency communications before any start authorization, alongside other applicable clinical requirements.
Worked check: inactive versus still on hold
Fictional exercise: the archived file contains a hold letter, but no evidence that the IND became inactive. Do not start a “reactivation” clock from a new letter merely because there has been no enrollment. Confirm current status with the regulatory owner and FDA record. A clinical hold remains a separate restriction.
If inactive status is confirmed but the new protocol changes dose and duration, the reactivation package needs an evidence assessment supporting those changes. Missing current toxicology or supply information is a real readiness gap, not a reason to reuse the last protocol unchanged.
Separate the status decision, evidence update and start decision
Maintain three linked records. The first establishes that the IND is inactive; the second describes the proposed investigation and its supporting evidence; the third records whether that investigation may start. This prevents an administrative label from becoming an unsupported clinical authorization.
| Record | Minimum useful entries | Decision it supports |
|---|---|---|
| Status chronology | Last subject entry, hold history, FDA inactive-status correspondence | Whether §312.45 is the correct route |
| Investigation package | Coming-year plan, protocol versions and prior-information references | What FDA is being asked to evaluate |
| Evidence assessment | Proposed changes, relevant CMC/nonclinical/safety information and open gaps | Whether the package supports the actual new work |
| Receipt and communications | FDA receipt of the protocol amendment and subsequent communications | Which regulatory timing and restrictions apply |
| Study readiness | Responsible clinical team’s assessment of other applicable requirements | Whether the study is operationally ready to begin |
There are two different 30-day concepts within §312.45. Paragraph (a) gives the sponsor a response opportunity when FDA proposes inactivation on its own initiative. Paragraph (d) governs resumption after FDA receives the reactivation protocol amendment, unless a hold applies, or following earlier FDA notification permitting the investigation. Do not start either period from an internal document-approval date.
Changed-supply exercise: the protocol retains the previous dose, but the intended clinical supply comes from a changed manufacturing process. An unchanged dose does not establish that the prior CMC evidence supports the new supply. Record the change, locate the supporting information and resolve the assessment before declaring the package ready. This is a review question, not a claim that every manufacturing change requires the same studies.
An IND inactive for five years or more may be terminated under §312.44; this is not automatic termination on an anniversary. Recheck the actual record after a long pause. If it shows termination, use the reinstatement guide; if the intended action is to end the IND, use the withdrawal guide.
Your preparation checklist
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Frequently asked questions
Are annual reports required while an IND is inactive?
Section 312.45(c) does not require annual reports for an IND on inactive status. Confirm that status rather than relying on a planned request or an internal pause. Keep the status correspondence and assess other applicable duties separately; the annual-report provision is not a blanket release from record or subject-protection responsibilities.
Does a two-year enrollment gap automatically change an IND to inactive status?
No. The regulation permits FDA to place an IND on inactive status in the stated circumstances, on the sponsor’s request or its own initiative. A qualifying gap supports the status assessment but is not evidence that the agency action has occurred. Obtain and retain the actual status record.
Can an unresolved clinical hold be cleared by sending a reactivation letter?
No. First establish whether the IND is inactive or whether the investigation remains on clinical hold. Section 312.42 requires FDA notification before a held investigation resumes. Do not use the inactive-IND timing provision as a substitute for addressing the actual hold and obtaining its required disposition.
Does an inactive IND terminate automatically after five years?
No. Section 312.45(e) says an IND inactive for five years or more may be terminated under §312.44. Inspect agency correspondence and the applicable termination process. The passage of five years alone does not establish either termination or continued permission to begin a proposed investigation.
Sources and revisions
Requirements, source recommendations and editorial preparation advice have different roles. Review the scope and revision of the source you use.
Regulation
21 CFR Part 312: IND responsibilities and status ↗Current part reopened September 22, 2026; relevant provisions identified in each section. Regulatory requirements, not a marketing-application rule.
Technical specification · placement only
FDA eCTD v4.0 comprehensive hierarchy ↗Version 2.2, February 2025. Section 1.5.2. A heading identifies placement, not mandatory applicability.