A substantial protocol amendment in a Phase III trial doesn't just change a document. It reopens the startup process at every active site, simultaneously with ongoing enrollment. The average implementation timeline from identification to final ethics approval spans 260 days. During that window, sites routinely operate under different protocol versions for an average of 215 days per amendment. The prevalence is climbing: 76% of Phase I to IV protocols now carry at least one substantial amendment, up from 57% in 2015. The average number of amendments per protocol reached 3.3, a 60% increase over that period. Oncology feels this most acutely, with 91.1% of oncology protocols requiring at least one substantial amendment. The direct median cost ranges from $141,000 for Phase II to $535,000 for Phase III, but the indirect burden is what sites feel most: enrollment days lost during IRB approval cycles, coordinator capacity absorbed by reconsent workflows, EDC form rebuilds, and version fragmentation that creates audit risk. Sites managing amendments alongside routine enrollment often deprioritize screening under the administrative load, and the data confirms it: protocols with substantial amendments see fewer screened and enrolled patients relative to plan, even when the amendment was designed to broaden eligibility.