Information Supplement Procedure of the Center for Drug Evaluation

　　(Trial Implementation)

　　Chapter I General

　　Article 1 To standardize the management of information supplement required during drug application review, clarify the basis and requirements for information supplement, and improve the quality and efficiency of information supplement by the Applicant, this Procedure is hereby formulated in accordance with Article 87 of the Drug Registration Regulation.

　　Article 2 This Procedure applies to circumstances where the Center for Drug Evaluation of National Medical Products Administration (hereinafter referred to as “CDE”), based on its review needs, notifies the drug registration applicant (“Applicant”) to submit new technical data to supplement the original application materials (“Supplement”) or to make an explanation on the original application materials.

　　Article 3 With the professional review inquiry before the supplement and the information supplement inquiry procedure after the supplement, the CDE is to request the Applicant to make explanations or provide the relevant supporting materials, and to actively communicate with the Applicant in order to improve the quality and efficiency of information supplement.

　　Article 4 The information shall be supplemented in a legitimate, scientific, equitable, fair, timely and accurate manner.

　　Chapter II Professional Review Inquiry

　　Article 5 During the professional review or comprehensive review by the CDE, if the professional chief reviewer or chief reporter, upon full review, considers the application materials doubtful or problematic, they may, upon review by the head of the Evaluation Department, issue a "Letter of Professional Review Inquiry" to the Applicant via the website of the CDE, notifying the Applicant of the specific problematic contents, judgment basis and requirements, and requiring the Applicant to make explanations or give a written reply within five (5) business days.

　　For problems that require supplement, the Evaluation Department shall notify the Applicant in advance by issuing a "Letter of Professional Review Inquiry"; provided however that the "Letter of Professional Review Inquiry" is not a formal written notice of information supplement, nor shall it represent the final review opinion, and the counting of the review period shall not be suspended.

　　Article 6 By issuing the "Letter of Professional Review Inquiry", the CDE is to notify the Applicant to:

　　1) provide supporting materials without study;

　　2) give explanations on the original application materials without the need to submit new technical data; or

　　3) remedy the defects the Evaluation Department considers necessary.

　　Article 7 The Applicant shall make explanations or give a written reply within five (5) business days of the issuance of the “Letter of Professional Review Inquiry”. If a written reply is required, the Applicant shall submit the electronic versions of relevant materials within five (5) business days, and send the paper versions thereof within the prescribed period. The Applicant shall download and print the "Letter of Professional Review Inquiry" from the website of the CDE as the voucher of receiving the additional information and putting them on file.

　　Chapter III Procedure for Formal Supplement, The Procedure of Formal Supplement,Consulting, and Opposition

　　Article 8 If the Applicant is required to submit new technical data to supplement the original application materials during the review, the CDE may, based on the Applicant’s reply to the "Letter of Professional Review Inquiry" and in accordance with the provisions of the Drug Registration Regulation, generally issue a request for one-off information supplement, listing all the problems and notifying the Applicant in writing to submit additional information within eighty (80) business days.

　　Article 9 The Applicant shall submit all the additional information as required once within eighty (80) business days. The time limit for information supplement is not included in the review period.

　　Article 10 Upon receiving all the additional information from the Applicant, the CDE shall immediately initiate the review, and prolong the review period by one third of the initial review period; or if the priority review & approval procedure applies, by one fourth of the initial review period.

　　Article 11 If the Applicant has any doubt about the request for supplement, it may, within ten (10) business days of receiving the written notice of information supplement, submit an application for general technical consultation titled "questions about supplement data" via the website of the CDE. The project managers shall coordinate with the indication team to give a reply in writing or by holding a meeting within fifteen (15) business days. If a meeting is required, it shall, in principle, be held in the form of teleconference.

　　Article 12 If the Applicant still has objections to the reply to the supplement consulting, it may, within ten (10) business days of receiving the reply, raise his objections via the website of the CDE, stating the reasons and basis for the objections.

　　Article 13 The CDE shall, within fifteen (15) business days of receiving the objections from the Applicant, organize a meeting of relevant professional technical committee for comprehensive assessment of the objections.

　　Article 14 If the CDE, upon comprehensive assessment, considers it necessary to adjust the request for supplement, it shall conduct a new round of technical review within three (3) business days, and notify the Applicant of the adjustment results via the website of the CDE.

　　Article 15 If the CDE, upon comprehensive assessment, considers it unnecessary to adjust the request for supplement, it shall, within three (3) business days, notify the Applicant via the website of the CDE of the reasons and basis for rejection of the objections raised by the Applicant.

　　Chapter IV Inquiry about Additional information

　　Article 16 After the CDE receives all the additional information, even if the Evaluation Department has doubts about the additional information or considers that there are problems with the contents of the additional information, no supplement shall in principle be required. The professional chief reviewers shall draft the "Additional Information Inquiry Letter", stating the reasons and basis for the failure to meet the requirements of the notice of supplement or to fully respond to the contents of the notice of supplement. If additional technical data is required, it is suggested that the Applicant should withdraw the application and explain the reasons. Upon review by the head of the Evaluation Department, the professional chief reviewers shall send an "Additional Information Inquiry Letter" to the Applicant via the website of the CDE, and the counting of the review period shall not be suspended.

　　Article 17 The Applicant shall explain the additional information or actively withdraw the application within five (5) business days of the issuance of the "Additional Information Inquiry Letter". If the Applicant fails to reply to the "Additional Information Inquiry Letter" or does not agree to withdraw the application for review, the CDE may draw a conclusion of disapproval based on the existing application materials and issue a public notice on the conclusion. The Applicant may raise an objection in accordance with the Procedure for the Handling of Objections to the Conclusion of Drug Registration Review (Trial Implementation).

　　Article 18 For innovative drugs and new safety indicators not specified in the guidelines, the CDE may request for supplement according to the review needs and the communication with the Applicant.

　　Chapter V Supplement Deadline Reminder and Termination of Review

　　Article 19 The website of the CDE will offer a supplement deadline reminder function, which will, on the fifth (5th) business day prior to the expiration of the period stated in the notice of information supplement, issue a deadline reminder to the Applicant, reminding it to timely provide the additional information.

　　Article 20 If the Applicant fails to submit the additional information within the prescribed time limit, the Business Management Office of the CDE may carry out the review termination procedure according to the disapproval circumstances set out in Paragraph (IV) of Article 92 of the Drug Registration Regulation.

　　Chapter VI Supplementary Provisions

　　Article 21 The Business Management Office of the CDE shall review the additional information for integrity according to the request for supplement and the criteria of the required information, and will reject the information beyond the scope of the request for supplement and the Inquiry Letter.

　　Article 22 If the Applicant intends to reapply for registration after the termination of review, it shall communicate with the CDE in advance, and include in the application materials the additional information and the conclusion of the prior review.

　　Article 23 This Procedure comes into effect as of December 1, 2020.

　　Annexes: 1. Written supplement Standard for Drug Review (Trial Implementation)

　　2. Templates of Professional Review Inquiry Letter, Notice of Information supplement and Additional Information Inquiry Letter

　　Annex 1

　　Written Supplement Standard During Drug Techinqual Review (Trial Implementation)

　　With a view to unifying the standardization and necessity of the request for supplement, and strictly controlling the times of supplement during the review, in accordance with the relevant provisions of the Drug Registration Regulation Regulation and the practice in technical review of drugs, and through study and discussion, the CDE hereby formulates the following supplement standard for review:

　　1. According to the relevant requirements for applicationdocument, the document iscontradictory or inconsistent, unclear, or ineligible;

　　2. According to laws, regulations and technical requirements, there are defects or shortcomings in study design, trial conduction and data analysis;

　　3. The study design and data analysis are doubtful or different from the current scientific cognition and consensus;

　　4. The Evaluation Department deems it necessary to do a major modification to the specification, package inserts, manufacturing and testing procedures, manufacturing process information sheet and other key contents;

　　5. The supplemental analysis of important safety and efficacy results;

　　6. Due to the changes in relevant laws and regulations and technical guidelines during the review, the Evaluation Department considers it necessary to supplement the relevant information on the safety, efficacy or quality controllability of drugs;

　　7. Major issues concerning the risk control plan;

　　8. The rationale for the variety is not sufficient, for example, the clinical positioning is unclear, and further information is required;

　　9. Supplement is required when the drug substance, excipients and packaging materials fail to meet the requirements for related review and approval, for example, the drug substance, excipients and packaging materials fail to be registered according to the requirements of the announcement or their information is not submitted together with the application for drug product; no power of attorney is provided to related drug products; or the administration route of the drug substance, excipients and packaging materials is inconsistent with that of drug product;

　　10. The sample testing, on-site inspection and device-related review are required but not carried out, or additional information is required due to problems found during production testing, on-site inspection and device-related review;

　　11. Major product safety accidents occur or major safety risks are discovered during the review;

　　12. Additional information is required due to complaints;

　　13. There are changes to drug substance, excipients and packaging materials related to the products during the review, or problems discovered in connection with the drug substance, excipients and packaging materials shall be addressed through Supplement during the drug product review;

　　14. More stability data supporting the products' shelf life shall be collected during the review.

　　15. If the Evaluation Department, upon communication with the Applicant, considers the Supplement indeed necessary, but no relevant provision is stipulated in the published Supplement standard, it may, upon study by its technical committee, submit the request for Supplement to the director in charge of the CDE for review and approval, and update the CDE’s Supplement standard and release to the public before implementation.

　　Annex 2

　　Templates of Professional Review Inquiry Letter, Notice of Information Supplement and Additional Information Inquiry Letter

　　I. Template of Professional Review Inquiry Letter

　　XX Professional Review Inquiry Letter

　　(15pt song typeface; bold)

　　[Company Name:] (12pt song typeface; line spacing: 20pt)

　　We have carefully evaluated the application documentthat submitted by your company for [drug name] (acceptance number: [acceptance number]), and concludes that there are problems which may affect the review decision. We hereby inform you of the relevant matters for your timely attention.

　　Summary (examples):

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

　　1) ……

　　2) ……

　　3) ……

　　2. Please explain....(if the Applicant is required to give explanations on the original application materials without the need to submit new technical data, the reviewers shall explain the reasons and basis); and

　　3. Please note the following matters... (if the reviewers consider it necessary to submit the additional information, the Applicant shall be informed in advance of the defects that the Evaluation Department deems it necessary to be remedied. However, the Applicant is not required to give a reply at the inquiry stage, but shall submit the additional information after the formal notice of Supplement is issued.)

　　[Supplement Requirements]

　　The Applicant shall give explanations or submit the electronic version of supplementary documentthrough the Window of Applicants before DD/MM/YYYY (within five (5) business days of the issuance of this Notice), and shall within the stipulated time limit send two (2) sets of the corresponding paper materials, a letter of commitment stating the consistency of the paper materials with the electronic ones, and a catalog of paper materials.

　　Please give a detailed and clear reply to each content needing Supplement.

　　During the inquiry period, the review clock is not stop. If the reply is overtime, the corresponding inquiry will be closed automatically. The inquiry content only represents our review opinions, and the final opinions shall be subject to the formal notice of Supplement.

　　Professional Department

　　DD/MM/YYYY

　　II. Template of Notice of Information Supplement

　　[Postal code] (font-size: 22pt; bold)    [Acceptance Number] (font-size: 14pt; bold)

　　[Company Address]       (12pt song typeface)

　　To: [Company Name]

　　Supplement Notice (15pt song typeface; bold)

　　Yao Shen Bu Zi [XXX] No. XXXX

　　[Company Name:] (12pt song typeface; line spacing: 20pt)

　　The Center has carefully evaluated the application materials and preliminary additional information submitted by you for the [drug name] (acceptance number: [acceptance number]) and concludes that the following supplement is required to satisfy the requirements for safety, efficacy or/and quality controllability of the drug. The relevant contents are hereby notified as follows:

　　Summary (examples):

　　1. The problems found (indicate the chapters, page numbers and tables and sort them out in orders corresponding to their importance);

　　2. The reason why the problems with the application materials are unable to be fully addressed;

　　3. The scientific grounds supporting the review standing; and

　　4. The additional information to be provided by the Applicant or suggestions on solving the problems;

　　[Supplement Requirements]

　　Please submit all the aforementioned additional information to the Center in triplicate once at a time prior to DD/MM/YYYY. If the Applicant fails to timely submit the additional information, the Center may reject the Applicant’s application in accordance with Paragraph (IV) of Article 92 of the Drug Registration Regulation.

　　Please give a reply to each content needing Supplement. All items to be supplemented, whether they are literatures or experimental tasks, shall be complete, sufficient and orderly and can clearly state the problems to be explained. When preparing the aforementioned materials, you are required to carefully read the "dos and don'ts" (please see the back page) attached to this Notice, and prepare and submit the additional information as required.

　　If you have any objection to the content of the additional information required by this Notice, please apply for consulting via the Window of Applicants in accordance with the Regulations on the Administration of Consulting on General Technical Issues concerning Drug Registration Review, and provide clear and specific reasons. Your application for consulting will be given full attention.

　　It is hereby notified.

　　Business Seal

　　DD/MM/YYYY

　　Dos and Don'ts (16pt song typeface; bold)

　　(The body content below is written in 12pt song typeface with a line spacing of 23.4pt.)

　　In order to prevent your application for drug registration from being delayed due to the submission of ineligible additional information, please pay attention to the following matters when you supplement the relevant information according to the notice of information Supplement issued by the Center:

　　I. All additional information shall be prepared on A4 papers of national standard (mass: 80 g), and shall be sealed by the Applicant and the trial completion entity on the cross-page of the cover.

　　II. The three (3) sets of additional information submitted by you shall be sorted out in the style and form as required and put into the file packets respectively, including at least one (1) set of originals (physical copies affixed with seal).

　　III. The front of the file packet shall be marked with the acceptance number, drug name, applicant, and whether the materials are originals or photocopies. The materials in the file packet shall be placed in the order of: photocopy of notice of information Supplement (if review is required by the Inspection Department, the inspection certificate affixed with the Inspection Department’s official seal shall be submitted), the explanations and statements on submissions (affixed with the official seal), table of contents of materials, and technical data (placed in the order of the opinions stated in the notice of information Supplement).

　　IV. The additional information will be received from 9:00 a.m.-11:30 a.m. from Monday to Friday, and 13:00 p.m.-16:30 p.m. on Monday, Tuesday and Thursday. For the convenience of the Applicant, the above information may also be submitted by mail. If you are willing to submit the information by mail, please pay special attention to the following matters:

　　(1) Please submit the additional information in strict accordance with the requirements of the notice of information Supplement. Other materials beyond the scope of the notice that are submitted together with the additional information will be rejected by us according to the general requirements for registration management, and due to the limitation of manpower, these materials will not be returned and will be uniformly destroyed by the Center.

　　(2) In order to ensure the safety and timely delivery of the mailing materials to the Center, please send them by express mail service whenever possible, and mark the Business Management Office as the recipient. The additional information shall be deemed submitted on the date shown on the postmark. The Center will initiate the review task after receiving the additional information and confirming that it meets the relevant requirements.

　　(3) In order to facilitate the timely feedback on whether the additional information has been received or not, please accurately indicate the following information in the mail: company name, contact, telephone, fax, etc.

　　(4) Once the above additional information is officially received by the Center, you may inquire about the receipt in the progress query column of the Center’s website. You may print the receipt if you deem it necessary, and the Center will not send any written receipt.

　　V. This Notice shall be deemed to have been received on the 15th calendar day of the issuance thereof.

　　VI. If you have any questions about these dos and don'ts, please call the Center’s Business Management Office.

　　III. Additional Information Inquiry Letter (Template)

　　Additional Information Inquiry Letter (15pt song typeface; bold)

　　[Company Name:] (12pt song typeface; line spacing: 20pt)

　　We have carefully evaluated the additional information submitted by you for the [drug name] (acceptance number: [acceptance number]) and concludes that the additional information submitted fails to fully meet the requirements of the notice of information Supplement, which requires your further explanations. The relevant matters are hereby notified as follows:

　　Summary (examples):

　　1. (The Evaluation Department has doubts about the content of the additional information)

　　2. (The Evaluation Department concludes that the additional information fails to meet the requirements or fully respond to the content of the notice of Supplement, and provides the reasons and basis for its conclusion)

　　3. (If the Evaluation Department concludes that it is necessary to submit additional technical data, it is suggested that the Applicant should actively withdraw the application and explain the reasons.)

　　……

　　[Explanation Requirements]

　　Please give a written reply via the Window of Applicants prior to DD/MM/YYYY (within five (5) business days of the issuance of this Notice). The Center will not accept any additional information.

　　Please give a detailed and clear reply to each content needing explanation. During the inquiry period, the counting of the review period shall not be suspended. If no reply is given within the prescribed period, the corresponding inquiry will be closed automatically.

　　Professional Department

　　DD/MM/YYYY

　　Statements (Template)

　　1. The additional information submitted is complete and sufficient, and contains no content beyond the scope of the notice of information Supplement.

　　2. The additional information submitted is fully consistent with the table of contents, and the translation thereof is accurate.

　　3. The photocopies submitted are fully consistent with the originals.

　　4. The electronic documents submitted are fully consistent with the paper ones.

　　5. The supporting documents submitted are in compliance with local laws and regulations.

　　6. The Applicant warrants that it will timely upload the relevant electronic information on the website of the Center for Drug Evaluation of National Medical Products Administration as required.

　　7. If any false information is submitted, the Applicant is willing to bear all legal liability arising therefrom.

　　Person-in-charge / Head of Registration Agency (signature)   Applicant / Responsible representative  of Registration Agency (official seal)

　　DD/MM/YYYY