1）方案违背的定义，可以参考以下文件：

a) 21 CFR 812.150(a)(4) The FDA Center for Device and Radiologic Health  : Deviaitons from the investigational plan .

b) FDA'Compliance Program Guidance Manual": A protocol deviation/violation is generally an unplanned excursion from the protocol that is not implemented or intended as systemetic change.

c) The international Standards Organization" Document 14155: Clinical Investigation of Medical Devices For Human Subjects-Good Glinical Practice: Deviation is instance(s) of failure to follow, intentionally or unintentionally, the requirement of the Clinical Investigational Plan.

d) ICH E3 Guideline for Industry: Structure and Content of Clinical Study Reports, Questions&Answers : A protocal deviation is any change, divergence, or departure from the study design or procedures defined in the protocal.

e) ICH E6 R2 section 3.3.7,4.5.2, 4.5.3, 4.5.4 规定了研究者需要遵循方案和发生方案违背的处理建议

f) 药物临床试验伦理审查工作指导原则

2）方案偏离的分级

首先，明确方案偏离的定义，其次，在FPI之前完成“A trial specific protocol deviations handling plan"( PDHP)，界定Protocol deviation的分类标准和处理措施。如：按照Critical, Major , Minor分类或者按照important/ not important分类。分类标准在于是否对受试者的权益、安全和福祉以及数据的完整性产生影响和影响程度。ICH E3 中规定important Protocol deviation，指入组了违反关键合格性标准的受试者，缺失了对主要终点的解释产生必要影响的数据等等。

申办方通常通过制定相应SOP，来规范公司内部Protocol deviation的管理要求，确保遵守法规要求。