A protocol amendment rarely stands alone. By the time it clears IRB review, it has already triggered updates to informed consent forms, statistical analysis plans, site training materials, and sometimes the Investigator's Brochure. This dependency chain is not bureaucracy, it reflects the architecture built into clinical trial documentation from the earliest stages of drug development. Understanding how documents connect is a practical requirement for anyone who designs protocols, writes regulatory submissions, or manages trial operations. When teams handle changes reactively, updating one file at a time, they discover downstream mismatches during monitoring visits or inspections and absorb delays that could have been anticipated. The regulatory framework under ICH E6(R3), adopted by FDA in September 2025, defines essential records as a quality system where documents must be internally consistent with one another. The Investigator's Brochure encodes what is known before the trial begins. The protocol translates that knowledge into testable methods. The ICF communicates key elements to participants. The SAP pre-specifies statistical methods before unblinding. Each document is downstream of at least one other.