When do you need to make a protocol amendment for an Investigational New Drug (IND) application?
Once an IND application is in effect, the sponsor of the application may amend the application as needed to ensure that the clinical investigations are conducted according to protocols included in the IND application. The sponsor-investigator may initiate the new protocol once the following two conditions are met:
- The sponsor-investigator has submitted the protocol to FDA for its review; and
- The protocol has been approved by the Institutional Review Board (IRB) with responsibility for review and approval of the protocol in accordance with the requirements of 21CFR56.
The sponsor-investigator may comply with these two conditions in either order. If the IND application sponsor desires FDA to comment on a submission, they should submit a request for such comment and the specific questions that FDA’s response should address. When several submissions with minor amendments are expected within a short period, sponsors are encouraged, to the extent feasible, to include all amendments in a single submission.
Any specific technical information referenced in an IND application amendment as already submitted to FDA in the original IND application is expected to be identified by name, reference number, volume, page number, and date of submission.
Types of protocol amendments, required documents and templates
Click one of the options in the list below to jump to the content you need or scroll down the page to see which amendment applies to your application.
New protocols
This will be identified as “Protocol Amendment: New Protocol”
When to submit a new protocol amendment:
If a sponsor intends to conduct a study not covered by a protocol already contained in their IND application; the sponsor is expected to submit to FDA a protocol amendment containing a copy of the new protocol and a brief description of the most clinically significant differences between it and the previous protocols.
Documents and required information for a new protocol amendment:
- Protocol Amendment Cover Letter (Download Word Template)
- Form 1571 (PDF – 830KB)
- Protocol Amendment Cover Page (Download Word Template)
- Table of Contents
- Protocol Amendment: New Protocol Information Sheet: The information sheet must provide 1) a brief description of the most clinically significant differences between the new protocol and previous protocol(s) and, 2) an outline of the requested information per box 8 of the Form FDA 1572
- Protocol
- Consent form
- IRB approval (if applicable)
- Form 1572 (PDF – 718KB)
- Sponsor-Investigator CV and medical license per box 2 of Form FDA 1572 (if applicable)
- Sub-investigator(s) CV and medical license per box 6 of the Form FDA 1572: A sponsor-investigator is not required to submit sub-investigator’s CV and medical license, but must maintain copies of this documentation in the regulatory binder
- Form 3454 (if applicable): If there are any new investigators or sub-investigators listed on the 1572 (box 1 and box 6) who were not previously reported to the FDA and they do not have any financial interests in the development of the product, then a revised FDA 3454 should be submitted
- Form 3455 (if applicable)
- Form 3674
- Other supporting documentation (if applicable): Submit any additional documentation that is pertinent to the FDA review of the new protocol
Changes to existing protocol(s)
This will be identified as “Protocol Amendment: Change in Protocol”
When to submit a change in protocol amendment:
A sponsor of an IND application is expected to submit a protocol amendment in cases when there are changes in the existing protocol that significantly affect safety of subjects, scope of the investigation, or scientific quality of the study. Such amendment should contain a brief description of the change and reference (date and number) to the submission that contained the original protocol.
For example, changes requiring an amendment to an IND application may include:
- Any increase in drug dosage or duration of exposure of individual subjects to the drug beyond that described in the current protocol, or any significant increase in the number of subjects under study.
- Any significant change in the design of a protocol (such as the addition or elimination of a control group).
- Addition of a new test or procedure intended to improve monitoring for, or reduce the risk of, a side effect or adverse event; or elimination of a test intended to monitor safety.
Note: a protocol change intended to eliminate an apparent immediate hazard to human subjects may be implemented immediately provided the FDA is subsequently notified by protocol amendment, and the reviewing IRB is also notified.
Documents and required information for a change in protocol amendment:
- Protocol Amendment Cover Letter (Download Word Template)
- Information Amendment Cover Page (Download Word Template)
- Form 1571 (PDF – 830KB)
- Table of Contents
- Protocol Amendment: Change in a Protocol Information Sheet: The information sheet must provide 1) a brief description of the change, and 2) reference (date and 1571 serial number) to the submission that contained the original protocol
- Amended Protocol
- Amended Consent form (if applicable)
- IRB approval (if applicable)
- Form 1572 (PDF – 718KB) (if applicable): If any of the changes affect the information provided on the 1572, then a revised 1572 should be submitted with the submission package
- Sponsor-Investigator CV and medical license per box 2 of the Form FDA 1572 (if applicable): If a revised 1572 is being submitted, then a sponsor-investigator’s CV and medical license should be submitted
- Sub-investigator(s) CV and medical license per box 6 of the Form FDA 1572 (if applicable): If a revised 1572 is being submitted and there are changes to the sub-investigators, then the sub-investigator’ CV and medical license can be submitted. Note that a sponsor-investigator is not required to submit sub-investigators’ CV and medical license, but must maintain copies of this documentation in the regulatory binder
- Form 3454 (if applicable): If there are any new investigators or sub-investigators listed on the 1572 (box 1 and box 6) who were not previously reported to the FDA and they do not have any financial interests in the development of the product, then a revised FDA 3454 should be submitted
- Form 3455 (if applicable)
- Other supporting documentation (if applicable): Submit any additional documentation that is pertinent to the FDA review of the changes to the protocol
Addition of a new investigator
This will be identified as “Protocol Amendment: New Investigator”
When to submit a new investigator amendment:
A sponsor of an IND application is expected to submit a protocol amendment when a new investigator is added to carry out a previously submitted protocol. The amendment should include the investigator’s name, the qualifications to conduct the investigation, and any reference to the previously submitted protocol, if relevant. The FDA should be notified within 30 days of the investigator being added.
Documents and required information for a new investigator amendment:
- Protocol Amendment Cover Letter (Download Word Template)
- Protocol Amendment Cover Page (Download Word Template)
- Form 1571 (PDF – 830KB)
- Table of Contents
- Protocol Amendment: New Investigator Information Sheet: The information sheet must provide a brief description of the new investigator and new site (if applicable). It must reference (date and 1571 serial number) to the submission that contained the original protocol that the new investigator is being added
- Form 1572 (PDF – 718KB): The 1572 must be completed by the new investigator listing all of the new investigator’s information per the requirement of the 1572
- Investigator CV and medical license per box 2 of the Form FDA 1572
- Sub-investigator(s) CV and medical license per box 6 of the Form FDA 1572: A sponsor-investigator is not required to submit sub-investigators’ CV and medical license, but must maintain copies of this documentation in the regulatory binder
- Form 3454
- Form 3455
- IRB approval (if applicable)
- Other supporting documentation (if applicable): Submit any additional documentation that is pertinent to the FDA review of the addition of the new investigator and new site