To support the implementation of the “Measures for Drug Registration Management” and further standardize the management of supplementary materials submitted during drug registration review and approval, and in light of research findings on the process-oriented scientific management system for drug review as well as the practical realities of review work, the Center for Drug Evaluation has developed and issued the “Procedures for Handling Supplementary Materials at the Center for Drug Evaluation (Trial Implementation).”

　　This procedure shall take effect as of December 1, 2020. The attachment titled “Written Supplement Standards for Drug Review (Trial)” included in this working procedure will be continuously supplemented and updated in subsequent work.

　　Hereby notified.

　　Center for Drug Evaluation, National Medical Products Administration

　　November 23, 2020

　　Appendix 1: Procedures for Supplemental Data Submission by the Center for Drug Evaluation (Trial).docx

　　Attachment

　　Procedures for Supplementing Data at the Drug Review Center (Trial)

　　Chapter 1 General Provisions

　　Article 1: To standardize the management of supplementary data submissions for drug registration reviews, clarify the basis and requirements for such supplementary data, and enhance the quality and efficiency of applicants’ submissions, this procedure is formulated in accordance with Article 87 of the “Measures for the Administration of Drug Registration.”

　　Article 2: The Drug Review Center of the National Medical Products Administration (hereinafter referred to as the Drug Review Center) shall, based on review needs, notify the drug registration applicant (hereinafter referred to as the applicant) to supplement new technical data on the basis of the originally submitted documentation (hereinafter referred to as “supplementary submission”), or, if only an explanation and clarification of the originally submitted documentation is required, this procedure shall apply.

　　Article 3: The Drug Review Center, through pre-notice professional review inquiries and post-notice supplementary data inquiry procedures, will request applicants to provide explanations or relevant supporting documentation, proactively engage in communication and exchange with applicants, and thereby enhance the quality and efficiency of the supplementary materials.

　　Article 4: In the process of providing supplementary materials, the principles of legality, scientific rigor, impartiality, fairness, timeliness, and accuracy shall be followed.

　　Chapter 2: Professional Review Inquiries

　　Article 5: During the specialized review period or the comprehensive review period, if the lead reviewer or the reporting reviewer, based on a thorough review, has doubts about the submitted documentation or identifies issues with its content, and after review by the head of the review department, they shall issue a “Specialized Review Inquiry Letter” to the applicant via the Drug Review Center’s website. The letter shall specify the exact nature of the identified issues, the supporting evidence, and the required actions, and shall request the applicant to provide explanations or a written response within five working days.

　　During the review process, if the reviewing authority identifies issues requiring supplementary information, it shall send a “Professional Review Inquiry Letter” to the applicant in advance to provide notification. However, the “Professional Review Inquiry Letter” does not constitute an official written notice requesting supplementary materials, nor does it represent the final review decision. The review clock will not be paused.

　　Article 6: The Drug Review Center shall inform the applicant of the following information via a “Professional Review and Inquiry Letter”:

　　1) Supporting documents that can be provided without conducting any research;

　　2) No additional technical documentation is required; only explanations and clarifications of the original submitted materials are needed.

　　3) The review concluded that there may be deficiencies that need to be supplemented and improved.

　　Article 7: The applicant shall provide explanations or a written response within 5 working days of the issuance of the “Professional Review Inquiry Letter.” For those requiring a written response, the applicant shall submit the response electronically within 5 working days and, within the same time frame, mail a hard copy of the document that is identical to the electronic version. The applicant may download and print the “Professional Review Inquiry Letter” from the Center for Drug Evaluation’s website as proof of receipt of the supplementary materials and for inclusion in the dossier.

　　Chapter 3: Formal Supplement Submission, Supplement Consultation, and Objection Procedures

　　Article 8: If, during the review process, the applicant is required to supplement the original submission with new technical data, in conjunction with the responses to the “Specialized Review Inquiry Letter,” and in accordance with the provisions of the “Drug Registration Management Measures,” the Center for Drug Evaluation shall, in principle, issue a single request for supplementary data. After clearly listing all outstanding issues, it shall notify the applicant in writing to submit the supplementary materials within 80 working days.

　　Article 9: The applicant shall submit all supplementary materials required in one go within 80 working days. The time taken to submit supplementary materials shall not be counted toward the drug review deadline.

　　Article 10: After the Drug Review Center receives all supplementary materials submitted by the applicant, it shall commence the review process, and the review period shall be extended by one-third. If the priority review and approval procedure applies, the review period shall be extended by one-quarter.

　　Article 11: If the applicant has any questions regarding the request for supplementary information, they may, within 10 working days of receiving the written notice requesting additional materials, submit a general technical inquiry via the Drug Review Center’s website under the category “Questions Related to Supplementary Materials.” Project management personnel will coordinate with the indication-specific team to provide a written or meeting-based response within 15 working days. In cases where a meeting is required, it shall, in principle, be conducted via teleconference.

　　Article 12: If the applicant still has objections to the response received in response to the supplementary consultation, they may submit their objection via the Drug Review Center’s website within 10 working days from the date of receipt of the response. The objection must clearly state the reasons and supporting evidence.

　　Article 13: Upon receiving the applicant’s objection, the Drug Review Center shall, within 15 working days, organize a meeting of relevant technical experts to conduct a comprehensive assessment.

　　Article 14: If the Drug Review Center, after comprehensive assessment, determines that the supplementary requirements need to be adjusted, it shall re-conduct the technical review within 3 working days and notify the applicant of the adjustment results via the Drug Review Center’s website.

　　Article 15: If, after comprehensive evaluation, the Drug Review Center determines that no adjustment to the request for supplementary information is necessary, it shall, within 3 working days, notify the applicant via the Drug Review Center’s website of the reasons and basis for its disagreement with the objection raised regarding the supplementary information request.

　　Chapter 4: Inquiry Regarding Supplementary Materials

　　Article 16: After the Drug Review Center receives all supplementary materials, if the review division has doubts about the supplementary materials or finds that there are issues with their content, it will, in principle, no longer issue additional requests for information. The lead reviewer of each specialty shall draft an “Inquiry Letter Regarding Supplementary Materials,” providing clear explanations and supporting evidence for any items that do not meet the requirements set forth in the original notification of supplementary requests or that have not fully addressed the content of such notifications. If new technical data still need to be submitted, the applicant is advised to voluntarily withdraw the application and state the reasons for doing so. After review and approval by the head of the review division, the “Inquiry Letter Regarding Supplementary Materials” will be posted on the Drug Review Center’s website to notify the applicant; the review deadline will not be suspended.

　　Article 17: Within 5 working days of the issuance of the “Request for Supplementary Information,” the applicant shall either provide explanations or clarifications regarding the supplementary information, or proactively withdraw the application. If the applicant fails to respond to the “Request for Supplementary Information” or does not agree to withdraw the application, the Center for Drug Evaluation will, based on the existing submitted documentation, issue a decision of non-approval and make such decision publicly available. The applicant may file an objection in accordance with the “Procedures for Resolving Disputes over Drug Registration Review Conclusions (Trial).”

　　Article 18: For innovative drugs and new safety indicators not specified in the guiding principles, the Drug Review Center may issue additional requests for information again based on review needs and communication with the applicant.

　　Chapter 5: Reminder of Expiration of Additional Submission Deadline and Termination of Review

　　Article 19: The website of the Drug Review Center will add a reminder function for the expiration of the deadline for supplementary materials. A reminder will be sent on the fifth business day before the deadline specified in the notice requiring supplementary materials, alerting the applicant to submit the supplementary materials on time.

　　Article 20: If the applicant fails to submit the supplementary materials within the prescribed time limit, the Business Management Division of the Drug Review Center will terminate the review procedure in accordance with Item (4) of Article 92 of the “Measures for the Administration of Drug Registration.”

　　Chapter VI Supplementary Provisions

　　Article 21: The Business Management Division of the Drug Review Center shall review the completeness of supplementary materials in accordance with the requirements for additional information and the standards for receiving such materials. Materials that exceed the scope specified in the requirements for additional information and inquiry letters will not be accepted.

　　Article 22: If an applicant wishes to re-submit a registration application after terminating the review, they shall communicate and consult with the Center for Drug Evaluation in advance and clearly state in the submitted documentation the status of any supplementary materials provided and the conclusions reached in the previous review.

　　Article 23: This procedure shall take effect as of December 1, 2020.

　　Attachment: 1. Written Standards for Supplementary Submission in Drug Review (Trial)

　　2. Professional Review Inquiries, Notice of Additional Information, and Inquiries Regarding Additional Information

　　Letter Template

　　Appendix 1

　　Written Supplement Standards for Drug Review (Trial)

　　To standardize and ensure the necessity of supplementary submissions, and to strictly control the number of supplementary submissions during the review process, the Center for Drug Evaluation, after careful study and discussion based on relevant provisions of the "Administrative Measures for Drug Registration" and the practical realities of drug technical review, has now formulated the following standards for supplementary submissions during the review process:

　　1. According to the relevant requirements of the submitted documentation, if the submitted materials contain inconsistencies or discrepancies, are unclear, or do not conform to the prescribed document standards;

　　2. Deficiencies or imperfections exist in the research design, experimental procedures, and data analysis, in accordance with applicable laws, regulations, and technical requirements;

　　3. The research design and data analysis, among other aspects, show discrepancies or uncertainties compared to current scientific understanding and consensus;

　　4. The drafting of key documents such as quality standards, instructions for use, manufacturing and verification procedures, and process information sheets has been reviewed and found to require substantial revisions;

　　5. Supplementary analyses of key safety and efficacy outcomes;

　　6. During the review process, if relevant laws and regulations or technical guidance principles are updated, and the review determines that additional data on drug safety, efficacy, or quality control are required;

　　7. Major issues in the risk control plan;

　　8. The basis for proposing the variety is insufficient and further information needs to be provided, such as when clinical positioning is unclear.

　　9. If the active pharmaceutical ingredients, excipients, and packaging materials have not been submitted for supplementary information as required by the current associated review and approval procedures—for example, if they have not been registered in accordance with the announcement requirements, or if the relevant API and excipient data have not been submitted simultaneously with the drug formulation application; if no authorization letter has been provided to associate these materials with the drug formulation; or if the route of administration of the API and excipients does not meet the route of administration specified for the formulation—then supplementary information will be required.

　　10. It is necessary to conduct sample inspections, on-site inspections, and device-related reviews that have not yet been carried out, or to supplement information if issues are identified during production inspections, on-site inspections, or device-related reviews.

　　11. A major safety accident occurs during the review process, or significant safety risks are identified during the review process;

　　12. Where supplementary materials are required due to a report;

　　13. During the review process, if there are changes to the excipients and packaging materials associated with the product, or if issues identified in the excipients and packaging materials need to be addressed through supplementary submissions during the formulation review;

　　14. During the review process, additional stability data need to be collected to support the product’s shelf life.

　　15. After communicating with the applicant, the review panel determined that a supplementary submission was indeed necessary and that the specific requirements for such a submission were not yet stipulated in the publicly available supplementary submission guidelines. Following deliberation by the department’s technical committee, the proposal shall be submitted to the center’s director in charge for review and approval. Only after the center’s supplementary submission guidelines have been updated and publicly released may the supplementary submission be carried out.

　　Appendix 2

Professional Review Inquiries, Notice of Additional Information, and Inquiries for Additional Information

Template

　　I. Template for Professional Review Inquiries

　　XX Professional Review Inquiries Letter

　　(Third-grade Songti, bold)

　　[Unit Name]: (Xiao Si Songti, line spacing 20 points)

　　Our department has carefully reviewed the application materials submitted by your organization for the product [Drug Name] (application number: [Application Number]). We have identified certain issues that could potentially impact our review and decision-making process. We would like to bring these matters to your attention and urge you to monitor them closely.

　　Content elements (example):

　　1. Please submit the following supporting documents, with specific names and requirements as follows:

　　1) ……

　　2) ……

　　3)……

　　2. Please provide explanations and clarifications regarding … (No need to supplement with new technical data; applicants are only required to explain and clarify the original submitted materials. Reviewers should state their reasons and supporting evidence.)

　　3. Please take note of the following matters... (If the reviewers determine that a supplementary submission is required, they shall notify the applicant in advance of any deficiencies or issues that they believe may need to be further supplemented and refined. The applicant does not need to provide additional information during the inquiry stage; instead, such information should be submitted once the formal notice for supplementary submission is issued.)

　　[Supplementary Material Requirements]

　　Please submit the above-mentioned materials via the Applicant’s Portal or electronically by [date], which is within 5 working days from the date of issuance of this notice. At the same time, within the required timeframe, you must also mail two hard copies of the materials that are identical to the electronic version, a commitment letter confirming that the hard copies match the electronic submission, and a table of contents for the hard-copy materials.

　　Please provide a detailed, item-by-item response to each piece of content that requires supplementation. The supplementary information should be thorough and clearly address the issues that need to be explained.

　　During the inquiry period, the review clock will not be paused. If no response is received by the deadline, this inquiry will be automatically closed. The content of the inquiry reflects only the review opinion of this department; the final opinion shall be subject to the official supplementary notification issued.

　　Professional Department

　　Year Month Day

　　II. Template for Notification of Supplementary Materials

　　[Postal Code] (Bold No. 2) [Acceptance Number] (Bold, Number 4)            

　　[Unit Address] (Xiao Si Songti)

　　[Unit Name] Received    (Xiao Si Songti)

　　Supplementary Material Notice (Bold Small Three Song Typeface)

　　Drug Review Supplementary Letter [XXX] No. XXXX

　　[Unit Name]: (Xiao Si Songti, line spacing 20 points)

　　Our center has carefully reviewed the application materials and previously submitted supplementary information for the [Drug Name] (Application Number: [Application Number]) submitted by your organization. We believe that further supplements are still required to fully meet the requirements regarding the safety, efficacy, and/or quality control of this product. We hereby notify you of the relevant details as follows:

　　Content elements (example):

　　1. Identify the issues, indicating the corresponding chapter, page number, table, etc., and rank them according to their level of importance.

　　2. The reason why the current submitted documentation cannot adequately address the issue;

　　3. Clarify the scientific basis that can support the review position;

　　4. Clearly specify the additional information that the applicant needs to provide or suggestions for resolving the issue;

　　[Supplementary Material Requirements]

　　Please submit the above-mentioned materials in triplicate, fully complying with the requirements, to our center by [Month] [Day], [Year]. If the supplementary materials are not submitted by the deadline, our center will, in accordance with Article 92, Paragraph (4) of the “Drug Registration Management Measures,” refuse to approve the application.

　　Please provide a point-by-point response to each item requiring supplementation. Whether it’s supplementary literature or additional experimental work, the supplemented items must be complete and comprehensive. The supplementary content should be detailed and well-organized, clearly addressing the issues that need to be explained. As your organization prepares the aforementioned relevant materials, please be sure to carefully read the “Notes” attached to this notice (see reverse side) and prepare and submit any supplementary materials as required.

　　If your organization has any objections to the supplementary information requested in this notice, please refer to the “General Technical Guidance for Consultation on Drug Registration Review and Approval” and submit a consultation request through the “Applicant’s Window,” providing clear and specific reasons. Your organization’s consultation request will be given due consideration.

　　Hereby notified.

　　Business Chapter

　　Year Month Day

　　Notes and Precautions (No. 3 Songti, bold)

　　(The following text is in Small Four Song typeface, with 1.5-line spacing.)

　　To avoid delays in the progress of your drug registration application due to irregularities in submitting supplementary materials, please ensure that you comply with the requirements outlined in our Center’s notice regarding supplementary materials. Supplement relevant materials At this time, please pay attention to the following matters:

　　I. All supplementary materials must be submitted using: National Standard (Quality 80g) A4-sized paper must be provided by both the declaring entity and the entity that completed the testing. On the seam of the cover Stamp it.

　　2. The three sets of supplementary materials you have submitted should be organized according to the currently required format and placed separately into file folders. At least one set must consist of original documents (with official seals affixed).

　　3. The front of the file folder should clearly indicate: the acceptance number, product name, and submitting organization, and also mark whether each document is an original or a copy. The order of documents within the file folder should be: a copy of the Notice of Supplementary Materials. (If the review by the testing department is involved, the submission voucher stamped with the official seal of the testing department must be provided.) 、 Submission of Supporting Documents and Declaration (with official seal), Table of Contents and Technical Documentation (arranged in the order of comments provided in the Supplementary Information Notice).

　　4. The acceptance period for supplementary materials is Monday through Friday, from 9:00 a.m. to 11:30 a.m.; and on Mondays, Tuesdays, and Thursdays, from 1:00 p.m. to 4:30 p.m. To facilitate applicants, the above-mentioned materials may also be submitted by mail. If you prefer to submit via mail, please... Be sure to pay special attention. Please note the following:

　　(1) Please submit the supplementary materials strictly in accordance with the requirements specified in the supplemental notice. As per general registration management guidelines, we will not accept any additional materials submitted along with the supplementary materials that exceed the scope of the notice. Due to resource constraints, these extra materials will not be returned and will be uniformly destroyed by our center.

　　(2) To ensure the safe and timely delivery of mailed documents to the center, please send them via express courier whenever possible, and clearly indicate “Received by the Business Management Office.” The submission date for supplementary materials shall be determined by the postmark date. Once our center receives the documents and confirms that they meet the relevant requirements, we will promptly initiate the review process.

　　(3) To facilitate timely feedback on receipt, when mailing materials, please accurately include the following information in your email: organization name, contact person, phone number, and fax number.

　　(4) Once the above-mentioned supplementary materials have been officially received by our center, you can check the receipt status in the “Progress Inquiry” section of our center’s website. If necessary, please print the receipt yourself; our center will no longer send out written receipts.

　　V. The 15 calendar days starting from the date of issuance of this notice shall be deemed as the date of receipt.

　　6. If you have any questions about this... Precautions If you have any questions about the content, please feel free to call our Business Management Office for further inquiries.

　　III. Template for the Request for Supplementary Information

　　Supplementary Information Request Letter (Small Three, Bold Songti)

　　[Unit Name]: (Xiao Si Songti, line spacing 20 points)

　　Our department has carefully reviewed the supplementary materials submitted by your organization for the product [Drug Name] (Acceptance Number: [Acceptance Number]). We find that the submitted supplementary materials do not fully address the requirements set forth in the supplementary notice, and further clarification and explanation from your organization are necessary. We hereby provide you with the relevant details as follows:

　　Content elements (example):

　　1. (The review panel has doubts about the content of the supplementary materials.)

　　2. (The review concluded that the supplementary materials did not meet the requirements of the request for additional information or did not fully address the content of the request, and provided reasons and supporting evidence.)

　　3. (If the review finds that additional technical documentation is still required, the applicant is advised to proactively withdraw the application and provide a statement of reasons.)

　　……

　　[Explanation and Requirements]

　　Please provide a written response via the Applicant’s Window by [date—year, month, day] (within 5 working days from the date of issuance of this notice). The Center will no longer accept any supplementary materials.

　　Please provide a detailed, item-by-item response to each item requiring explanation and clarification, ensuring that the content is thorough and clearly addresses the issues at hand. The review timer will not be paused during the inquiry period. If no response is received within the allotted time, this inquiry will be automatically closed.

　　Professional Department

　　Year Month Day

　　Statement (Template)

　　1. The submitted supplementary materials are complete and comprehensive, and do not contain any content beyond the requirements specified in the notice of supplementary materials.

　　2. The supplementary materials submitted are completely consistent with the contents of the table of contents, and the translations are accurate.

　　3. The submitted photocopies are completely identical to the original documents.

　　4. The submitted electronic documents are completely identical in content to the paper documents.

　　5. The supporting documents submitted comply with the provisions of local laws and regulations.

　　6. Ensure that relevant electronic documents are promptly uploaded to the website of the Drug Review Center of the National Medical Products Administration as required.

　　7. If any information provided is false, our organization is willing to assume the corresponding legal responsibilities.

　　Responsible Person/Head of Registration Agency (Signature) Applicant/Head of Registration Agency (Official Seal)

Year Month Day