How do the new regulations on change management during the review of drug registration applications consider to avoid preemptive positions?

In order to cooperate with the implementation of the "Measures for the Administration of Drug Registration", further standardize the changes during the review of drug registration applications, ensure the safety, effectiveness and quality control of drugs, and strengthen the guidance of applicants' registration applications, on November 11, 2022, the official website of the Center for Drug Evaluation of the State Medical Products Administration released the "Work Procedures for Changes during the Review of Drug Registration Applications (Trial)" (Drug Review Industry [2022] No.
597) (Written: November 09, 2022), effective
from the date of publication.
This article summarizes the key contents of the review of changes during the review of drug registration applications in the guiding principles, and shares
them with you based on your own interpretation.

First, the phases of change

From development, clinical trials, to marketing, drugs usually go through several stages, which will be accompanied by a large number of changes, and the Measures for the Administration of Drug Registration (Order No.
27 of the State Administration for Market Regulation on January 22, 2020) regulators focus on three stages of change, namely clinical period change, review period change and post-marketing change
.

1.
Changes during clinical period

During drug clinical trials, if there are changes in the drug clinical trial protocol, non-clinical or pharmaceutical changes, or new discoveries, the sponsor shall, in accordance with the provisions and refer to the relevant technical guidelines, fully assess the impact
on the safety of subjects.
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 the research and development.
If the safety risk of the subject may be increased, a supplementary application
shall be submitted.
The supplementary application shall be decided whether to agree within 60 days from the date of acceptance, and the applicant shall be notified of the approval result through the website of the Center for Drug Evaluation; If the notice is not given within the time limit, it shall be deemed to have agreed
.
If the sponsor is changed, the changed sponsor shall bear the relevant responsibilities and obligations of the drug clinical trial (Article 29).

2.
Changes during the review period

2.
1 Application for drug clinical trial and supplementary application during drug clinical trial shall not be supplemented with new technical data during the review period; If new research is required, the applicant may resubmit the application after withdrawal (art.
88).

2.
2 During the review of the drug marketing authorization application, if a major change occurs that may affect the safety, efficacy and quality controllability of the drug, the applicant shall withdraw the original registration application and re-declare
it after supplementary research.
Where the change of the applicant's name, the change of the name of the registered address, etc.
does not involve the content of the technical review, the drug evaluation center shall be promptly notified in writing and relevant supporting materials shall be submitted (Article 40).

3.
Changes after listing

3.
1 If the matters or contents specified in the original drug registration approval document and its annexes are changed, the applicant shall, in accordance with the provisions and with reference to the relevant technical guidelines, conduct full research and verification of the drug change, fully assess the impact that the change may have on the safety, efficacy and quality controllability of the drug, and submit a supplementary application, filing or report in accordance with the change procedure (Article 11).

3.
2 Changes after the marketing of drugs shall be classified according to the risk and degree of impact on the safety, efficacy and quality controllability of drugs, and shall be divided into approval changes, filing changes and reporting changes
.
The holder shall, in accordance with relevant provisions and with reference to relevant technical guidelines, comprehensively assess and verify the impact of changes on the safety, efficacy and quality controllability of drugs, and carry out corresponding research work
.
The technical guidelines for post-marketing change research of drugs shall be formulated by the Center for Drug Evaluation and announced to the public (Article 77).

2.
Acceptable changes during the review of drug registration applications under the New Deal

In the process of reviewing a drug registration application, the applicant will inevitably undergo changes related to the application, and the new regulations sort out the various changes that may occur during the review process, adhering to the principle of benefiting the administrative counterparty without affecting the normal review work, the original draft "CDE maintains the principle of fairness and impartiality and consistent scale in the review, in principle, the applicant can only propose one change during the review process, and the proposed change does not affect the evaluability of the original declared matters
.
" 。 "Revised to" In order to ensure the quality and efficiency of the review, the changes proposed by the applicant or the drug marketing authorization holder during the review period shall not affect the technical review
of the original declared matters.
This is to prevent some drug applicants from exploiting loopholes, and avoid the occurrence of applicants declaring in advance and preempting positions due to changes in the review period
.
Changes during the review of drug registration applications (mainly referring to changes during technical review) are mainly divided into the following situations, namely:

1) Scenario 1: Changes during the review period of drug clinical trial application and supplementary application during clinical trial

2) Scenario 2: Changes during the review period of drug marketing authorization applications

3) Scenario 3: Changes during the review period of the post-marketing supplementary application

4) Scenario 4: Changes during the review period of the application for re-registration of drugs produced abroad

3.
Change the strategy during the review of drug registration applications

The working procedures for different changes at each application stage, this paper sorts out the change strategies during the review of drug marketing authorization application in Scenario 2, as follows:

Change Item 1 - Only the applicant body change (no technical changes involved)

Submit a supplementary application to the Center for Drug Evaluation, and submit the application materials with reference to the relevant requirements for the change of holder, and the supplementary application is related to the original marketing authorization application for review and approval, and the review time limit shall be
subject to the longer of the remaining time between the two.

Change 2 - Involves major technical changes

The applicant shall withdraw the original registration application and re-apply after
supplementary research.

Change 3 - Other changes involving technology

1) The applicant shall submit a supplementary application in the professional review status of the original registration application, and the supplementary application shall be reviewed
in connection with the original registration application.

2) If the submitted supplementary application is confirmed to be a major change after review, the supplementary application will not be approved, and the applicant shall withdraw the original registration application and re-apply
after supplementary research.

3) If the evaluation conclusion is inconsistent with the applicant's expectations, the applicant may refer to the "Procedure for Resolving Objections to Drug Registration Review Conclusions (Trial)
".

Change Item 4 - Drug registration approval documents and their annexes that do not involve technical review contain information changes

1) The applicant shall promptly notify the Drug Review Center in writing and submit relevant supporting materials, such as the business license, production license and its change record page before and after the change, and affix the official seal
of the applicant or the registration agent.

2) The change of the registration agency shall also submit the documents of the overseas applicant to terminate the original entrusted agent registration relationship and the new power of attorney documents, and submit the notarized documents and Chinese
translations.

References

[1] www.
cde.
org.
cn, CDE literature, etc