For frequently asked questions concerning technical issues, China Center for Drug Evaluation (CDE) releases corresponding answers on its website. For further enquiries about drug registration, please contact BaiPharm for professional help.
1. The Submission and Acceptance of Drug Registration Applications;
2. Clinical Trials
3. Bioequivalence (BE) Studies
4. Selection of Reference Listed Drugs
5. Quality and Therapeutic Equivalence Evaluation of Generic Drugs
6. R&D Requirements for Biological Products
7. Associated Review and Approval of APIs, Excipients, and Packaging Materials
8. Administration and Requirements for Changes
This article covers the Q&As on the first two topics.
Read the following two articles on Q&As on other topics:
You can also download the whole Q&A report at the end of this article.
Topic 1: The Submission and Acceptance of Drug Registration Applications
A1: If the applicant has submitted application documents in paper before Feb. 7, 2022, CDE will review the paper documents. If the registration application is found to be deficient in format review, the applicant should submit the supplemental documents in paper in due time according to Article 85 of the Administrative Measures for Drug Registration.
If submitted after Feb. 7, 2022, only application documents in the electronic form will be accepted.
A2: According to National Medical Products Administration (NMPA)'s Announcement on Adopting the eCTD Format for Drug Application (No. 119 Announcement in 2021), only marketing authorization applications for class 1 chemical drugs, class 5.1 chemical drugs, class 1 therapeutic biological products, and class 1 prophylactic biological products can be submitted in eCTD format.
The Notice of Adjusting the Acceptance Methods and the Application Document Requirements During COVID-19 Pandemic applies to all drug applications accepted by NMPA.
Please don't mix up the two submission methods that are different in application scope and in technical requirements for compact disks.
A3: If the applicant has submitted electronic documents in the compact disks according to the Notice of Adjusting the Acceptance Methods and the Application Document Requirements During COVID-19 Pandemic, it doesn't need to submit the documents or an additional compact disk for drug registration inspection.
But if the applicant submitted application documents in paper, it needs to submit the documents and an additional compact disk for drug registration inspection.
A4: If the indication of the generic drug in the marketing authorization application is the same with the indication of the originator drug approved in China, the generic drug can be classified as a class 4 chemical drug for its application.
A5: To add an indication already approved in China, the applicant should submit a supplemental application.
To add an indication approved overseas but not yet in China, the applicant should submit the clinical trial application and the marketing authorization application according to NMPA's Announcement on Chemical Drug Registration Classification and Application Document Requirements (No. 44 Announcement in 2020).
A6: The appendix two to CDE's Notice of Guidance for the Acceptance of Chemical Drug Registration Applications (Trial) (No. 10 in 2020) stipulates that if after evaluation, a generic drug applicant is considered with no need or incapable to apply for clinical trials, and the applicant meets the conditions for clinical trial exemption, the applicant can directly propose marketing authorization for the generic drug and should specify the situation under "Other Items for Special Statement" in the application form.
A7: According to CDE's Notice of Adopting the Electronic Administrative Authorization Documents for Chemical APIs, applicants can print the acceptance documents via the "Applicants' Window" on CDE's website.
A8: The applicant should conduct researches according to NMPA's Notice of Chemical Drug Registration Classification and Application Document Requirements and relevant technical guidelines.
It should organize the application documents with serial numbers according to the existing M4 Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use. The applicant can choose not to submit documents under the inapplicable items by marking them inapplicable, but need to specify the inapplicable reasons.
A9: No. According to Administrative Measures for Drug Registration and relevant regulations, the applicant should submit a supplemental application to add a strength..
A10: According to NMPA's Biological Product Classification and Application Document Requirements (No. 43 Announcement in 2020), a vaccine with a changed dose and immune procedures belongs to class 2.5 improved vaccines, while a vaccine with a changed target group belongs to class 2.6 improved vaccines. To market a vaccine with these changes, the applicant should submit the clinical trial application and the marketing authorization application.
A11: Yes, it is permitted.
A12: According to NMPA's Announcement on New Standards for Drug Registration Fees (No. 75 Announcement in 2020), the registration procedures will be terminated if the drug applicant fails to pay fees accordingly. If the applicant intends to proceed with the application, it should re-submit the application according to the Administrative Measures for Drug Registration.
A13: The applicant should refer to the Administrative Measures for Drug Registration for priority review scope and the Work Procedures for Priority Review of Drug Marketing Authorization Applications for priority review procedures.
Related Article: Expedited Programs for Drug Registration-3.3 Priority Review
A14: As each single drug has not been put on the market, the applicant should submit new clinical trial applications for each drug separately and link the applications together.
Overlapping documents in the combination therapy (except clinically-mixed drugs) application and single drug application can be exempted from submission.
However, the pharmacological and toxicological evaluation of the combination therapy should be combined with each single drug's data. Therefore, all single drugs' pharmacology and toxicology documents should be submitted.
A15: Considering that the finished dosage forms (originator and its generic versions) with the same API already have complete and sufficient safety and efficacy data on Chinese people, the generic chemical drug can be registered as a class 4 chemical drug.
A16: According to current regulations, such a drug belongs to class 5.1 chemical drugs.
Topic 2: Clinical Trials
A1: No, it's not mandatory.
Q2: Researchers usually adopts a seamless design to connect different trials in the clinical research on a new antineoplastic drug. After getting the research data on a single drug, researchers may directly continue to explore the expanded use of the single drug and the combined use of the single drug with other drugs in the same research.
Thus, when the applicant submits the human clinical trial application for the first time, can CDE issue a notification that authorizes the clinical trials of both the single drug and its combination therapy?
A2: In the clinical trial plan submitted for the first time with the application, the applicant can include the single drug's dose escalation & expansion phase, and the exploratory phase of drug combinations.
However, when the plan has no data on the single drugs' pharmacokinetics, pharmacodynamics, safety, and tolerance, CDE can only evaluate the plan's partial content that focuses on the single drug but cannot give a conclusion on the reasonability and risks of the drug combinations.
According to Article 27 of the Administrative Measures for Drug Registration, the applicant should submit the clinical trial application for drug combinations after obtaining the single drug's data.
A3: No, it's not necessary.
The filing platform mainly accepts filing for clinical trials or researches meeting any of the three conditions below:
The applicant has received National Medical Products Administration (NMPA)'s clinical trial authorization document and the trial will be carried out in China.
The applicant has filed the bioequivalence study on the chemical drug and got the filing number for the clinical trial.
The applicant conducts the phase IV clinical trial and/or post-marketing researches according to the drug registration certificate or NMPA's notification.
A4: No. The applicant shall take the primary responsibility for filing drug clinical trial's information according to existing laws and regulations. When necessary, the applicant should submit the clinical trial application & supplemental application, or communicate with CDE.
CDE will review the format and logic of the filed information, but it does not mean that CDE has reached a commitment, recognition, or contract with the applicant on the scientificity and reasonability of the clinical trial plan.
A5: The applicant can refer to the table below:
Clinical Trial Completion Time
After July 1, 2020
Filing is mandatory within 12 months after completing the trial or before submitting NDA
Before July 1, 2020
Filing is mandatory within 12 months after completing the trial or before submitting NDA
Filing is optional
A6: No. The applicant can only delete the filed information when the information is wrong or repeated. The applicant is not allowed to delete the filed information after getting the ethical approval or having filed the subsequent trial information. The applicant should update the information on the filing platform according to the real situation, e.g. to change the status to "terminated voluntarily".
A7:（1）Situations where DSUR submission is mandatory:
The applicant shall submit DSUR if it conducts clinical trials that are permitted in the notification/approval documents for the clinical trial application, supplemental application, re-review application, marketing authorization application, and/or license renewal application.
The applicant shall submit DSUR if it conducts phase IV clinical trial that is permitted in the approval document for the marketing authorization application. The clinical trial includes two specific situations: the applicant assumes it is necessary to file the clinical trial on the Drug Clinical Trial Filing and Information Publicity Platform, and the applicant plans to submit the clinical trial's results as the feedback to the issues in the approval document or as part of the subsequent application.
(2) Situations where DSUR submission is not mandatory:
In principle, the applicant does not need to file the bioequivalence (BE) study for the generic chemical drug's quality and therapeutic equivalence evaluation. But if the BE study meets the conditions in the Article 48 of the Administrative Rules for the Quality of Drug Clinical Trials, the applicant can consider submitting DSUR to CDE.
A8: DSUR's regional attachment 4 and 5 should include the information related to the clinical trial approved to be conducted in China, as well as the drug marketing authorization application to be submitted to China NMPA in the future.
A9: No, it is not mandatory to submit clinical trial applications for both drug A and drug B.
A10: According to NMPA's Announcement on Adjusting the Review and Approval Procedures for Drug Clinical Trials (No. 50 Announcement in 2018), the applicant should apply for communication with CDE before submitting the clinical trial application for the first time. The specific rules are:
For the drug manufactured outside China, the applicant can submit the drug clinical trial application after a self-evaluation of relevant risks if the clinical trial has been approved in a country or region with a complete drug regulatory system.
For the drug whose applicant has been approved to conduct the clinical trial, the applicant can directly submit a new clinical trial application for adding a new indication. If the drug's previous clinical trial application has been submitted but not approved yet, the applicant needs to evaluate the relevant risks before submitting a new clinical trial application.
NMPA recommends the applicant apply for pre-IND meeting with CDE before submitting the clinical trial application for a biosimilar product.
Applicants of single agents in combination therapies should refer to the rules above.
Q11: According to the Administrative Measures for Drug Registration and NMPA's No. 46 Announcement in 2020, the approved clinical trial's approval document will expire if the trial is not started within three years after the approval. The approved clinical trial can start after the subjects sign the informed consent documents. The rule applies to all clinical trials approved before or after the Administrative Measures for Drug Registration took effect on July 1, 2020.
A12: Such a drug can be reviewed and approved according to Article 2 of NMPA's Announcement on Affairs Relevant to Optimizing the Review and Approval of Drugs (No. 23 Announcement in 2018). If the applicant deems the data free from racial factors after conducting researches, the applicant can directly use overseas clinical trial data for marketing authorization in China.
A13: Yes, it does.
A14: According to the Decisions on Affairs relevant to Adjusting the Administration of Imported Drug Registration (former China Food and Drug Administration, CFDI's No. 35 Announcement in 2017), the applicant is allowed to conduct international multicenter drug clinical trials in China and phase I clinical trials simultaneously. Drugs used in clinical trials are no longer required to be registered overseas, or have entered the phase II or III clinical trial. However, prophylactic biological product should still obey the previous requirement.
A15: For registration applications submitted during the interim period according to the No. 35 Announcement, the applicant can submit the generic name verification application in an official document to CDE in the review process. CDE will transfer the document to the Chinese Pharmacopoeia Commission to verify the generic name.
A16: The applicant should apply for phase II and phase III clinical trials through supplemental applications.
A17: The approval document's original owner should reserve the filing at the Drug Clinical Trial Filing and Information Publicity Platform and change the applicant. Please find out the specific steps at Help and Links on the platform.
A18: According to the Decisions on Affairs relevant to Adjusting the Administration of Imported Drug Registration, unless for prophylactic biological products, the applicant is allowed to conduct international multicenter drug clinical trials in China and phase I clinical trials simultaneously. Drugs used in clinical trials are no longer required to have completed overseas registration (CPP), or have entered the phase II or III clinical trial.
A19: If the overseas-marketed drug has a same type of drug product marketed in China, the applicant can get the overseas-marketed drug via interim import and use it as the reference drug in the clinical trial. Otherwise, in general, the overseas-marketed drug should be registered in China before being used in clinical trials.
A20: According to the Announcement on Affairs Relevant to the Interim Import of Reference Drugs Needed in Researches released in 2016, the applicant can apply for the interim import of drugs marketed outside China only. Only after the imported drugs are tested to be qualified, the applicant can use them in clinical trials.
Reference drugs should be registered and approved in China before they can be used as reference drugs in biological products' clinical trials. In principle, the products approved as biosimilars cannot be used as reference drugs.
A21: Non-clinical trials are for evaluating and controlling the risks of the clinical trial plan to ensure the subjects' safety. If the evaluated clinical trial data shows that the subjects' safety can be ensured, the CAR T cell therapy can be exempted from unnecessary animal tests in the investigational new drug (IND) application according to the principle that specific products should be analyzed based on their specific conditions.
Contact BaiPharm if you'd like to know more about drug regulations in China.