Most clinical trial protocols change mid-study. When patient enrollment stalls, regulators request design revisions, or new safety data emerges, sponsors must formally amend the protocol governing the entire trial. That process has real consequences for sites: According to 2022 Tufts CSDD research tracking 950 protocols, 76% of Phase I to IV studies now carry at least one amendment, up from 57% in 2015. The mean number of amendments per protocol has jumped 60%, from 2.1 to 3.3. Protocols with at least one substantial amendment take an average of three unplanned months longer to complete than those without one. Implementation alone averages 260 days from internal sponsor approval to final ethics committee clearance across all sites. During that window, sites may operate under different protocol versions for an average of 215 days, creating version fragmentation that disrupts enrollment, complicates data collection, and may require patient reconsent. Direct costs to implement a substantial amendment range from $141,000 in Phase II to $535,000 in Phase III. Not all amendments are unavoidable. Roughly 23% were deemed completely avoidable and another 22% somewhat avoidable, pointing directly at protocol design quality as a modifiable risk factor sponsors and CROs can address before site activation.