How to Maintain and Amend an IND During Phase 2 Clinical Trials

Introduction

After an Investigational New Drug (IND) application is accepted by the U.S. FDA, it must be actively maintained throughout all clinical trial phases. During Phase 2, new data frequently emerge that may require updates to the IND—such as protocol changes, investigator brochures, manufacturing updates, or safety information. This tutorial outlines what constitutes IND maintenance, the types of amendments that apply in Phase 2, submission timelines, and best practices to remain compliant with FDA regulations.

What is IND Maintenance?

IND maintenance refers to the ongoing responsibilities of the sponsor to keep the IND application current and accurate throughout the clinical trial. This includes:

• Submitting amendments (protocol changes, new sites, investigators)
• Reporting safety information
• Updating the Investigator’s Brochure (IB)
• Providing annual reports to the FDA

Types of IND Submissions in Phase 2

1. Protocol Amendments

Required when there are:

• New or revised clinical protocols
• Changes to study design, inclusion/exclusion criteria, dosage, or endpoints
• Addition of new sites or investigators

2. Information Amendments

Submitted to update information not related to the protocol, such as:

• Chemistry, Manufacturing, and Controls (CMC) changes
• Updated pharmacology or toxicology reports
• New preclinical data relevant to human safety

3. Safety Reports

• Must be submitted within 15 days for serious and unexpected adverse events (SAEs)
• 7-day timeline applies for fatal or life-threatening events

4. Annual Reports

• Submitted within 60 days of the IND’s anniversary date
• Includes summary of study status, adverse events, and any new information

Structure of a Protocol Amendment Submission

• Form FDA 1571
• Cover Letter describing changes and rationale
• Revised Protocol Document (highlight changes)
• Updated Investigator’s Brochure (if applicable)
• Supporting data, if required (e.g., new risk assessments)

When Is an Amendment Required?

Type of Change	Amendment Type	Required?
Adding a new clinical site	Protocol Amendment	Yes
Change in formulation or manufacturing site	Information Amendment	Yes
Increased dosing frequency	Protocol Amendment	Yes
Grammar corrections in the protocol	Not required	No

Best Practices for IND Maintenance in Phase 2

• Maintain a central regulatory tracking system for all submissions
• Pre-plan amendments in batches where possible
• Ensure consistent updates to all related documents (IB, ICF, CRFs)
• Include a clear summary of changes and rationale in every amendment

Electronic Submission Requirements

• All IND submissions must follow eCTD format if submitted electronically
• Use FDA Gateway or CDER NextGen Portal
• Module 1: Administrative and product information
• Module 2–5: Summaries, quality, nonclinical, and clinical sections

Global Alignment Considerations

If the Phase 2 trial is part of a global development plan, similar obligations may apply for CTA maintenance in:

• EU: Substantial amendment notifications to local NCA and Ethics Committees
• Japan (PMDA): Submissions via Clinical Trial Notifications (CTNs)
• India (CDSCO): Submit Protocol Amendments to DCGI for approval before implementation

Common Pitfalls and How to Avoid Them

• Delayed amendment filing: Always submit prior to implementation
• Inconsistent documents: Ensure all revisions are reflected across protocol, IB, and consent
• Missing cover letters: Always include a narrative rationale and summary
• Non-compliance with eCTD format: Use correct templates and folders

Conclusion

Maintaining an IND during Phase 2 trials requires more than just annual reporting. With changes to protocols, safety profiles, and manufacturing, sponsors must vigilantly update their IND with well-organized, timely, and complete submissions. By understanding the FDA’s requirements and aligning with global expectations, sponsors can minimize delays, support successful Phase 2 execution, and prepare for seamless Phase 3 transition.