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在中國，藥物臨床試驗(yàn)獲準(zhǔn)開展后，關(guān)于臨床試驗(yàn)方案的變更，2022年CDE已發(fā)布了相關(guān)指導(dǎo)原則，本公眾號之前也分享過相關(guān)培訓(xùn)資料。

藥物臨床試驗(yàn)期間方案變更技術(shù)指導(dǎo)原則（試行）

下面分享FDA對臨床試驗(yàn)方案變更的相關(guān)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把方案變更（Protocol Amendment）分為三種，分別是：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.

第一種情況是指在FDA同一個(gè)IND號下遞交一個(gè)全新的方案（例如I期后遞交的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.  

第二種情況是我們中文含義通常所指的臨床方案變更

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.   

第三種情況是指新增研究者后，需要將研究者和site的信息遞交給FDA（通常遞交研究者CV和1572表）。

FDA與CDE不同的是，F(xiàn)DA對于方案變更遞交后并沒有像首次IND遞交那樣有30天的固定審評時(shí)限和默認(rèn)許可，也不會發(fā)批準(zhǔn)通知書等行政類文件，理論上申請人只需要遞交新方案給FDA，且IRB倫理通過后即可啟動(dòng)研究。

在實(shí)際操作過程中，為了保險(xiǎn)起見和防止FDA對方案變更有意見，公司一般會在遞交方案變更后等待30天才啟動(dòng)相關(guān)研究。但也時(shí)常會遇到遞交方案變更后，過了2-3個(gè)月FDA才會有意見主動(dòng)提出讓申請人修改，或者一直也沒有更多反饋。