In accordance with the CFR, a sponsor must submit a protocol amendment to the FDA for which of the following?

According to the U.S. Code of Federal Regulations (CFR), a protocol amendment is required for changes to the clinical investigation protocol itself. The addition of a new test, even to improve safety monitoring, alters the study procedures detailed in the protocol. Per 21 CFR 312.30(b), any change to a protocol that affects the safety of subjects, the scope of the investigation, or the scientific quality of the study must be submitted to the FDA as a protocol amendment. Adding a new monitoring test directly modifies the study procedures and falls under this requirement.

B. A significant change in an investigator's financial interest is reported under financial disclosure regulations (21 CFR Part 54) and is not submitted as a protocol amendment.

C. The addition of a sub-investigator is a personnel change documented via an updated Form FDA 1572 and is not considered a protocol amendment submitted by the sponsor.

D. A change in the manufacturing site is a Chemistry, Manufacturing, and Controls (CMC) change. This requires an information amendment under 21 CFR 312.31, not a protocol amendment.

1. U.S. Code of Federal Regulations, Title 21, Part 312, Subpart B — Investigational New Drug Application (IND).

§ 312.30 Protocol amendments: This section explicitly defines what constitutes a protocol amendment, including "(a) ...whenever a sponsor intends to conduct a study that is different from the study described in the protocol..." and "(b)(1) ...any change... that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study." This directly supports option A.

§ 312.31 Information amendments: This section defines amendments for information not within the scope of a protocol amendment, specifying "(a)(1) New toxicology, chemistry, or other technical information..." A change in manufacturing site falls under this category, making option D incorrect as a protocol amendment.

2. U.S. Code of Federal Regulations, Title 21, Part 54 — Financial Disclosure by Clinical Investigators.

§ 54.4 Certification and disclosure requirements: This part outlines the sponsor's responsibility to collect and disclose financial interest information, which is a separate process from submitting a protocol amendment. This makes option B incorrect.

3. University of California San Francisco (UCSF), Institutional Review Board. Guidance: INDs, IDEs, and Other FDA Submissions. This document clarifies the different types of IND submissions: "Protocol Amendments (21 CFR 312.30) are submitted when there are changes to the protocol... Examples: changes in... study procedures." and "Information Amendments (21 CFR 312.31) are submitted for... new chemistry, manufacturing, and controls (CMC) information." This academic source reinforces the distinction between protocol and information amendments, supporting the rationale for selecting A and rejecting D.