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
5. Quality and Therapeutic Equivalence Evaluation of Generic Drugs
6. R&D Requirements for Biological Products
8. Administration and Requirements for Changes
9. Others
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.
Q1: According to CDE's Notice of Adjusting the Acceptance Methods and the Application Document Requirements During COVID-19 Pandemic , should the applicant submit electronic application documents if the submission is after Feb. 7, 2022?
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.
Q2: What differences are there between electronic submission and submission in eCTD format?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.
Please don't mix up the two submission methods that are different in application scope and in technical requirements for compact disks.
Q3: Does the applicant need to submit the compact disk for drug registration inspection if the drug application is accepted after Feb. 7, 2022?
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.
Q4: When the overseas originator drug or Chinese-domestically manufactured originator drug has been listed as a reference listed drug (RLD) but unavailable to the drug applicant, the drug applicant can choose the originator drug not imported to China as the RLD. In such a situation, can the applicant's generic drug be classified as a class 4 chemical drug?
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.
Q5: For a chemical drug marketed in China, how to submit the application for adding an indication approved in China and another indication approved overseas but not in China?
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).
Q6: Can the applicant directly submit a marketing authorization application for a generic chemical drug?
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.
Q7: Will the acceptance documents relevant to chemical API (active pharmaceutical ingredient)'s DMF (drug master files) filing be sent to the applicant?
Q8: Should the applicant organize the chemical API filing documents according to the Notice of Chemical Drugs' New Registration Classification and Application Document Requirements (Trial) (No. 80 Announcement in 2016)?
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.
Q9: Can the applicant apply for adding a strength through generic drug marketing authorization application?
A9: No. According to Administrative Measures for Drug Registration and relevant regulations, the applicant should submit a supplemental application to add a strength..
Q10: How to apply for changing the dose, immune procedures, and target group of a marketed vaccine?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.
Q11: Is the applicant permitted to apply for license renewal earlier than six months before the oversea-manufactured drug's marketing authorization license gets expired?
A11: Yes, it is permitted.
Q12: How to continue with the drug application if the registration procedures have been terminated because the applicant fails to pay fees in time?
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.
Q13: Can the applicant apply for priority review for a newly accepted application for a product manufactured on the same production line with another product, or a re-submitted application that has been withdrawn before?
Q14: How to apply for marketing authorization for the combination therapy of two or more new molecular entity drugs whose clinical trials have both/all been approved? Does the applicant need to re-submit the application documents previously submitted for each single drug?
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.
Q15: How to determine the registration classification of a generic chemical drug whose originator drug was marketed in China, and the originator's multiple generic versions have been marketed in China?
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.
Q16: Which is the registration classification for a new dosage form (505b2) approved by FDA and listed as RLD and RS (reference standard) in the Orange Book? Class 5.1 or class 5.2?
A16: According to current regulations, such a drug belongs to class 5.1 chemical drugs.
Q1: Is it mandatory to submit manufacturing and testing standard procedures in the stage of applying for biological product clinical trial?
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.
Q3: Should clinical trials be filed at the filing platform if they are initiated by applicants or researchers themselves?
A3: No, it's not necessary.
The filing platform mainly accepts filing for clinical trials or researches meeting any of the three conditions below:
Q4: When the clinical trial plan/information is public on the filing platform, does it mean that CDE has approved the plan/information?
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.
Q5: Does the applicant need to file the clinical trial result if the trial was completed before the Administrative Rules on Filing and Publishing Drug Clinical Trial Information (Trial) took effect on July 1, 2020?
A5: The applicant can refer to the table below:
Clinical Trial Completion Time
NDA
Filing Requirements
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
Q6: Can the applicant delete the filed information if it decides to terminate the filed international multicenter clinical trial that has started but not yet conducted in China?
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".
Q7: What are China's requirements for the scope of submitting drug safety update reports (DSURs)?A7:（1）Situations where DSUR submission is mandatory:
(2) Situations where DSUR submission is not mandatory:
Q8: What is the scope of regional attachments 4 and 5 of DSUR? Should they cover the global information?
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.
Q9: When drug A's clinical trial has been approved and drug B has obtained marketing authorization in China, does the applicant need to submit clinical trial applications for both drug A and drug B to use them in a combination therapy?
A9: No, it is not mandatory to submit clinical trial applications for both drug A and drug B.
Q10: Is it mandatory for the applicant to apply for pre-IND meeting with CDE before submitting clinical trial applications for chemical drugs and therapeutic biological products?
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:
A11: As the trial is required to be conducted within three years after the applicant receives the clinical trial approval/notification document, what are the conditions for starting a clinical trial?
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.
Q12: For a drug that has obtained marketing authorization outside China to treat acquired immune deficiency syndrome (AIDS), can the applicant directly use the clinical trial data acquired outside China to support the drug's marketing authorization application submitted to China NMPA?
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.
Q14: When the applicant is conducting the international multicenter clinical trials in China for a biological product imported to China, can the applicant conduct phase I clinical trial for the product at the same time?
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.
Q15: According to the Decisions on Affairs relevant to Adjusting the Administration of Imported Drug Registration (former CFDI's No. 35 Announcement in 2017), the registration application for the imported drug can be directly approved if the drug is supported by international multicenter clinical trial data and is exempted from clinical trials in China. For such a drug, when should the applicant submit the application for verifying the drug's generic name?
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.
Q16: When the applicant has completed the approved phase I clinical trial, how should it apply for the subsequent clinical trials?
A16: The applicant should apply for phase II and phase III clinical trials through supplemental applications.
Q17: How should a clinical trial be filed after its approval document's ownership is transferred to another entity?
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.
Q18: Is the certificate of pharmaceutical product (CPP) mandatory for a pplying for conducting international multicenter clinical trials for biosimilars in China?
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.
Q19: Can the applicant use a drug marketed outside China as the reference drug in the international multicenter clinical trial conducted in China?
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.
Q20: When a drug is marketed outside China only, what are the requirements and procedures for using the drug in a clinical trial?
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.
Q21: Can non-clinical researches be exempted for chimeric antigen receptor T cell therapy (CAR T cell therapy) with existing clinical trial data?
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.
China Center for Drug Evaluation Q&A on Drug Application
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