Protocol Amendment after IND

In clinical development, filing of IND (Investigational New Drug) is an important milestone. FDA is required by the Modernization Act to respond in writing to an IND sponsor within 30 calendar days of receipt of the sponsor’s IND filing including the clinical study protocol(s). If the clinical study is not put on hold, the sponsor can start all clinical work including the patient enrollment.

After the initial IND is approved, how to oversee the IND if the sponsor makes significant changes to the study protocol?

First of all, any changes in the research protocol (protocol amendment or administrative letter) or patient informed consent form must be approved by the IRB (institutional Review Board) before the investigator or any sub-investigators put those changes into effect

Secondly, the protocol amendment needs to be submitted to FDA (immediately or through IND annual report). According to 21CFR312.30, the following requirements are stated:

"(b) Changes in a protocol. (1) A sponsor shall submit a protocol

amendment describing any change in a Phase 1 protocol that significantly
affects the safety of subjects or any change in a Phase 2 or 3 protocol
that significantly affects the safety of subjects, the scope of the
investigation, or the scientific quality of the study. Examples of
changes requiring an amendment under this paragraph include:
 (i) Any increase in drug dosage or duration of exposure of
individual subjects to the drug beyond that in the current protocol, or
any significant increase in the number of subjects under study.
 (ii) Any significant change in the design of a protocol (such as the
addition or dropping of a control group).
 (iii) The addition of a new test or procedure that is intended to
improve monitoring for, or reduce the risk of, a side effect or adverse
event; or the dropping of a test intended to monitor safety.
 (2)(i) A protocol change under paragraph (b)(1) of this section may
be made provided two conditions are met:
 (a) The sponsor has submitted the change to FDA for its review; and
 (b) The change has been approved by the IRB with responsibility for
review and approval of the study. The sponsor may comply with these two
conditions in either order.
 (ii) Notwithstanding paragraph (b)(2)(i) of this section, a protocol
change intended to eliminate an apparent immediate hazard to subjects
may be implemented immediately provided FDA is subsequently notified by
protocol amendment and the reviewing IRB is notified in accordance with
Sec. 56.104(c)."

IN FDA's compliance program guidance manual on 'clinical investigators and sponsor investigators', 

there are the following statements:

"Protocol changes/amendments. During the course of a study, a protocol may be formally changed 

by the sponsor. Such a change is usually prospectively planned and implemented in a systematic 

fashion through a protocol amendment. Protocol amendments must be reviewed and approved by 

the IRB, prior to implementation, and submitted to FDA. "

Not all protocol changes require the submission of a formal protocol amendment,
however, the sponsor's reporting responsibility depends on the nature of the
change.  In practice, many companies adopt a conservative approach by reporting
virtually all protocol changes.