在中国，药物临床试验获准开展后，关于临床试验方案的变更，2022年CDE已发布了相关指导原则，本公众号之前也分享过相关培训资料。

药物临床试验期间方案变更技术指导原则（试行）

下面分享FDA对临床试验方案变更的相关要求。

Once an IND application is in effect, the sponsor of the application may amend the application as needed to ensure that the clinical investigations are conducted according to protocols included in the IND application.Sponsors are expected to submit protocol amendments for new protocols or changes to existing protocols before implementation of the respective changes.New studies may begin when the sponsor has submitted the change to FDA for its review and the new protocol or changes to the existing protocol have been approved by the Institutional Review Board (IRB) with the responsibility for review and approval of the studies. If the IND application sponsor desires FDA to comment on a submission, they should submit a request for such comment and the specific questions that FDA's response should address.

When several submissions with minor amendments are expected within a short period, sponsors are encouraged, to the extent feasible, to include all amendments in a single submission.

Any specific technical information referenced in an IND application amendment as already submitted to FDA in the original IND application is expected to be identified by name, reference number, volume, page number, and date of submission. The general types of protocol amendments are shown below.

FDA把方案变更（Protocol Amendment）分为三种，分别是：1) New  Protocol；2) Change in Protocl；3）New Investigator

1、New protocol should be identified as "Protocol Amendment: New Protocol"

If a sponsor intends to conduct a study that is not covered by a protocol already contained in their IND application, the sponsor is expected to submit to FDA a protocol amendment containing a copy of the new protocol and a brief description of the most clinically significant differences between it and the previous protocols.

第一种情况是指在FDA同一个IND号下递交一个全新的方案（例如I期后递交的II期方案）

2、Changes to existing protocol(s) should be identified as "Protocol Amendment: Change in Protocol"

A sponsor of an IND application is expected to submit a protocol amendment in cases when there are changes in the existing protocol that significantly affect safety of subjects, scope of the investigation, or scientific quality of the study. Such amendment should contain a brief description of the change and reference (date and number) to the submission that contained the original protocol.  

For example, changes requiring an amendment to an IND application may include:

Any increase in drug dosage or duration of exposure of individual subjects to the drug beyond that described in the current protocol, or any significant increase in the number of subjects under study.

Any significant change in the design of a protocol (such as the addition or elimination of a control group).

Addition of a new test or procedure intended to improve monitoring for, or reduce the risk of, a side effect or adverse event; or elimination of a test intended to monitor safety. 

Note: a protocol change intended to eliminate an apparent immediate hazard to human subjects may be implemented immediately, provided that FDA is subsequently notified by protocol amendment and the reviewing IRB is also notified.  

第二种情况是我们中文含义通常所指的临床方案变更

3、Addition of a new investigator should be identified as "Protocol Amendment: New Investigator”   

A sponsor of an IND application is expected to submit a protocol amendment when a new investigator is added to carry out a previously submitted protocol. The amendment should include the investigator's name, the qualifications to conduct the investigation, and any reference to the previously submitted protocol, if relevant. FDA should be notified within 30 days of the investigator being added.   

第三种情况是指新增研究者后，需要将研究者和site的信息递交给FDA（通常递交研究者CV和1572表）。

FDA与CDE不同的是，FDA对于方案变更递交后并没有像首次IND递交那样有30天的固定审评时限和默认许可，也不会发批准通知书等行政类文件，理论上申请人只需要递交新方案给FDA，且IRB伦理通过后即可启动研究。

在实际操作过程中，为了保险起见和防止FDA对方案变更有意见，公司一般会在递交方案变更后等待30天才启动相关研究。但也时常会遇到递交方案变更后，过了2-3个月FDA才会有意见主动提出让申请人修改，或者一直也没有更多反馈。