What is CDE's consideration for the review of changes to drug clinical trial protocols? Here comes the guide!

name

Release date

state

Interpretation of regulations

Announcement on Adjusting the Review and Approval Procedures for Clinical Trials of Drugs (No.
50 of 2018)

July 27, 2018

Promulgation and implementation

The announcement issued by the National Medical Products Administration clearly stipulates for the first time that for major pharmaceutical changes that may increase the safety risk of subjects during clinical trials, the applicant shall submit a supplementary application in a timely manner in accordance with relevant regulations, and CDE may notify the applicant to modify the trial protocol and suspend or terminate the clinical trial according to the
circumstances.
Fills gaps
in change management during clinical trials.
If there are major defects in the application materials, or the clinical trial plan is incomplete, or there is a lack of reliable risk control measures, there are potential clinical risks that cannot guarantee the safety of clinical trial subjects, the Drug Review Center will notify the applicant by means of a notice of suspension of clinical trials, explaining the reasons for
not supporting the conduct of clinical trials at present.
The Drug Review Center shall communicate with the applicant before making a decision to suspend clinical trials
.
Applicants can inquire and download the notice of suspension of clinical trials through the portal of the Drug Review Center
.

Drug Administration Law of the People's Republic of China

July 2019, 8

Promulgation and implementation

Effective from December 1, 2019, if safety problems or other risks are found during drug clinical trials, the clinical trial sponsor shall promptly adjust the clinical trial protocol, suspend or terminate the clinical trial, and report
to the drug regulatory department under the State Council.
When necessary, the drug regulatory department under the State Council may order the adjustment of clinical trial protocols or suspend or terminate clinical trials
.
The importance of pharmacovigilance supervision during clinical trials was once again emphasized, and it was written into the Drug Administration Law to standardize
drug management.

Measures for the Administration of Drug Registration

July 2020, 3

Promulgation and implementation

It came into effect on July 1, 2020, clarifying the procedures and requirements
for changes during drug clinical trials.
Two paths are clearly stipulated, during drug clinical trials, if there is a change in the drug clinical trial protocol, non-clinical or pharmaceutical changes, or new discoveries, the sponsor shall fully assess the impact
on the safety of subjects in accordance with the provisions and with reference to relevant technical guidelines.
If the sponsor evaluates that it does not affect the safety of the subject, it can be directly implemented and reported
in the safety update report during research and development.
Where the safety risk of subjects may be increased, a supplementary application
shall be submitted.
"During the review of a drug marketing authorization application, if major changes occur that may affect the safety, efficacy and quality controllability of drugs, the applicant shall withdraw the original registration application and re-declare after supplementary research"
.
This article mainly discusses the change management during drug clinical trials and the post-market change management of drugs
.

Technical Guidelines for Pharmaceutical Research and Change of Biologics During Clinical Trials

July 2020, 9

Draft for comments

The official website of the Center for Drug Evaluation of the State Medical Products Administration released the "Technical Guidelines for the Research and Change of Biological Products during Clinical Trials" for comments, which broke through the actual declaration requirements for changes during clinical trials, made up for the gaps in the regulation of changes during clinical trials of biological products, helped ensure the safety of subjects, promoted the coordination of the clinical trial and marketing registration process of biological products, and also provided biological product developers with pharmaceutical research and development ideas, methods and stage requirements during clinical trials
。

Technical Guidelines for Pharmaceutical Change During Clinical Trials of Innovative Drugs (Chemical Drugs) (Trial)

July 2021, 3

Promulgation and implementation

The breakthrough puts forward the actual declaration requirements for changes during clinical trials, which helps to ensure the safety of subjects, promotes the coordination of innovative drug (chemical drugs) clinical trials and marketing registration processes, and also provides innovative drug (chemical drugs) developers with pharmaceutical research and development ideas, methods and stage requirements
during clinical trials.

"Working Procedures for Changes During the Review of Drug Registration Applications"

July 2021, 6

Draft for comments

The time limit for the review and approval of drug clinical trial applications and supplementary applications changed during drug clinical trials is 60 days, so during the review period, it is not acceptable for the applicant to provide changes in new technical data, which is also consistent with the concept of the new "Measures" stipulating that no new technical data shall be supplemented during the implied licensing period, which clearly applies to changes during the review of various drug registration applications, and requires the applicant to propose only one change within a limited time in principle, without affecting the evaluability of the original declaration matters, to ensure fairness and justice.
The scale is consistent
.

Technical Guidelines for Protocol Change During Drug Clinical Trials (Trial)

July 2022, 6

Promulgation and implementation

It is clarified that the scope of application of these guidelines is applicable to changes in clinical trial protocols related to registration-related traditional Chinese medicines, chemical drugs, and biological products (including epidemic seedlings
).
These guidelines do not apply to changes in dosage form, route of administration, new indications, and additional combinations with other drugs during clinical trials; Clarifies the sponsor's main responsibility for protocol changes during clinical trials; Referring to and drawing on the regulatory requirements of EMA and FDA, combined with the current situation of China's industry and supervision, the classification of protocol changes during clinical trials in China is formulated into two categories; The classification name of the scheme change is proposed as substantive change, non-material change, or major change or general change, and is proposed as substantive change or non-material change after discussion within the scope of the center; The analysis discusses the general considerations of the plan change, and the technical points of further evaluation, so as to guide the sponsor to analyze the specific problems in the actual work, conduct scientific research and judgment on the nature and impact of the plan change, and carry out the work related to the plan change scientifically and standardly; Examples of substantive changes and non-material changes are provided
.
It is not possible to change all the situations, and it is recommended that difficult and complex problems be further solved
through communication.

Specification for the Evaluation of Drug Clinical Trial Protocols

July 2022, 10

Draft for comments

The time limit for soliciting comments is one month from the date of issuance, which is divided into six parts, the fifth part is the change of the clinical trial protocol, which clarifies that under various circumstances of the change of the clinical trial protocol, the applicant should make a supplementary application, communication or report
.

Protocol changes during clinical trials are divided into the following three situations:

1. Sponsors that evaluate substantive changes that may significantly increase the safety risks of subjects shall submit a supplementary application
   .
   
2. If the sponsor evaluates that it will not significantly increase the safety risk of subjects, but may significantly affect the scientificity of the trial and the reliability of the trial data, if it is a confirmatory (or critical) clinical trial protocol, the applicant should submit an application
   for communication to the Drug Review Center.
   If it is a change in the clinical trial protocol in other stages, the sponsor may also submit an application
   for communication to the Drug Review Center if it deems it necessary.
   
3. If the sponsor assesses that it is a non-material change, it can be directly implemented
   .