The Comprehensive Department of the National Drug Administration publicly solicits opinions on the "M4 Module 1 Administrative Documents and Drug Information (Draft for Soliciting Opinions)"

In order to do a good job in the preparation and revision of supporting documents for the "Drug Registration Management Measures", the National Drug Administration has organized the revision of the "M4 Module - Administrative Documents and Drug Information (Draft for Soliciting Opinions)". We are now soliciting opinions from the public. Please provide feedback on the relevant opinions or suggestions via email on May 30, 2020 xiaof@cde.org.cn Please indicate 'M4 Module 1 Administrative Documents and Drug Information Feedback' in the email title.

Attachment: M4 Module 1 Administrative Documents and Drug Information (Draft for Soliciting Opinions) and Revision Instructions

M4 Module 1 Administrative Documents and Drug Information

1.0 Explanation Letter (see attached: Explanation Letter)

Mainly summarizing and explaining the key information of this application.

1.1 Table of Contents

Submit the application materials catalog according to different modules.

1.2 Application Form

This mainly includes basic product information such as product name, dosage form, specifications, and application details.

1.3 Product Information Related Materials

1.3.1 Instructions

1.3.1.1 Study drug instructions and revision instructions (applicable to clinical trial applications)

1.3.1.2 Instructions and revision instructions for marketed drugs (applicable to applications for marketing and post marketing changes)

Overseas marketed drugs still need to provide the original instruction manual approved by the drug regulatory agency of the country or region where the drug is produced, as well as the actual sample of the instruction manual for use on the market in the country or region where the drug is produced, with a Chinese translation attached.

1.3.2 Packaging labels

1.3.2.1 Research drug packaging labels (applicable to clinical trial applications)

1.3.2.2 Packaging labels for marketed drugs (applicable to marketing and post marketing change applications)

Overseas marketed drugs still need to provide actual samples of the packaging labels used in the country or region where the drug is produced.

1.3.3 Product quality standards and production processes/manufacturing and verification regulations

Submit production process information sheets and quality standards for chemical drugs, and submit manufacturing and testing regulations and quality standards for biological products.

1.3.4 Clinical trial related data

1.3.4.1 Clinical trial plan and protocol

1.3.4.2 Sample of informed consent form

1.3.4.3 Researcher's Handbook

1.3.5 Application materials for approval of drug generic names (applicable to market registration applications)

1.3.6 Inspection related information (applicable to listing applications and supplementary applications involving inspection and inspection)

Including drug development information table, drug production information table, on-site master file list, drug registration clinical trial research information table, clinical trial information table, and inspection report.

1.3.7 Vaccine Biosafety and Environmental Impact Assessment (see attachment: Vaccine Biosafety and Environmental Impact Assessment)

1.3.8 Product related supporting documents

1.3.8.1 Certification documents for raw materials, pharmaceutical excipients, and drug packaging materials (if applicable)

Documents proving the legal source of raw materials, pharmaceutical excipients, and pharmaceutical packaging materials, including supply agreements, invoices, etc. And authorization letters for the use of raw materials, pharmaceutical excipients, and pharmaceutical packaging materials (applicable to the use of registered raw materials and packaging materials in the formulation).

1.3.8.2 Patent information and supporting documents

An explanation of the patent status and ownership status of the drugs applied for or the prescriptions, processes, and uses used, as well as a statement that they do not constitute infringement on others' patents.

1.3.8.3 Special drug development project approval documents (if applicable)

A copy of the approval document for the development of narcotic drugs and psychotropic substances is required.

1.3.8.4 Trademark information and supporting documents (if applicable)

1.3.8.5 Reference drug source certification documents (if applicable)

1.3.8.6 Certification documents related to drug clinical trials (applicable to marketing applications)

Drug Clinical Trial Approval Document/Clinical Trial Notification, Clinical Trial Drug Quality Standards and Clinical Trial Registration Number/Bioequivalence Trial Filing Registration Number (Internal Verification).

1.3.8.7 Supporting documents for commissioned research (if applicable)

If the applicant entrusts other institutions to conduct drug research or conduct individual experiments, tests, sample trial production, etc., a complete copy of the contract signed between the applicant and the entrusted party shall be provided. The second commissioned research should provide a complete commissioned research contract between the applicant and the intermediary institution, as well as between the intermediary institution and the commissioned research institution.

Non clinical research safety evaluation institutions should provide approval certificates that comply with the Good Clinical Practice for Drug Research (GLP), and clinical research institutions should provide record keeping certificates.

1.3.8.8 Supporting documents related to pharmaceutical and mechanical combination products (if applicable)

If it belongs to a drug or a combination of pharmaceutical and mechanical products mainly composed of drugs, a notice of attribute definition results for the combination of pharmaceutical and mechanical products (internal verification) should be submitted.

1.3.8.9 Certification documents for allowing drugs to be marketed and sold (applicable to drugs already marketed overseas)

A certificate issued by an overseas drug regulatory agency that allows the drug to be marketed and sold, a notarized certification document, and a Chinese translation.

1.3.8.10 Supporting documents for drug changes allowed (applicable to drugs already listed overseas)

Proof documents, notarized certification documents, and Chinese translations issued by overseas drug regulatory agencies allowing drug changes.

1.3.9 Other product information related materials (if applicable)

1.4 Application status (if applicable)

1.4.1 Previous approval status

Provide a description of the previous application status and approval/non approval documents related to the variety (internal verification)

1.4.2 Application for adjustment of clinical trial protocol, suspension or termination of clinical trials

1.4.3 Application for resumption of clinical trials after suspension

1.4.4 Re application for clinical trial after termination

1.4.5 Application for withdrawal of unapproved drug clinical trial applications, marketing registration permit applications, supplementary applications, or re registration applications

1.4.6 Changes during the review period of application for listing registration only include changes to the applicant's name, change of registered address, and other changes that do not involve technical review content

1.4.7 Application for Cancellation of Drug Registration Certificate

1.5 Accelerate the application for listing and registration procedures (if applicable)

1.5.1 Accelerate the application for listing and registration procedures

Including breakthrough treatment drug procedures, conditional approval procedures, priority review approval procedures, and special approval procedures

1.5.2 Accelerate the application for termination of listing registration procedures

1.5.3 Application for other accelerated registration procedures

1.6 Communication and exchange meetings (if applicable)

1.6.1 Meeting Application

1.6.2 Background information of the meeting

1.6.3 Meeting related letters, meeting minutes, and responses

1.7 Clinical trial process management information (if applicable)

1.7.1 Increase indications during clinical trials

1.7.2 Changes in clinical trial protocols, non clinical or pharmaceutical changes, or new discoveries that may increase the safety risks of subjects

1.7.3 Requesting the sponsor to adjust the clinical trial protocol, suspend or terminate the drug clinical trial

1.8 Risk Management (if applicable)

1.8.1 Safety update report during research and development

1.8.1.1 Safety update report during research and development

1.8.1.2 Accumulated Summary of Serious Adverse Reactions (SAR)

1.8.1.3 List of subjects who died within the reporting period within China

1.8.1.4 List of subjects who withdrew from clinical trials due to any adverse events within the reporting period

1.8.1.5 Summary Table of Changes/Updates during the Reporting Period

1.8.1.6 Summary of overall research plan for the next reporting period

1.8.2 Other potential serious safety risk information

1.8.3 Risk Management Plan (RMP)

Including drug vigilance activity plans and risk minimization measures.

1.9 Post market research (if applicable)

Including Phase IV and studies with specific research objectives.

1.10 Changes after listing (if applicable)

1.10.1 Approval type changes

1.10.2 Filing type changes

If the information stated in the drug registration certificate that does not involve technical evaluation is changed, the overseas holder shall submit a certificate issued by the drug regulatory agency of their country or region allowing the change; Domestic holders shall submit copies of the relevant regulatory authorities' approval documents for renaming, such as the "Business License", "Drug Production License", and the change record page.

The application for drug packaging requires submission of a packaging contract (including authorization to use imported drug trademarks), a drug production license from the packaging production enterprise, packaging technology, selection criteria and quality standards for packaging materials and containers that come into direct contact with drugs.

1.10.3 Report type changes

1.11 Supporting documents of the applicant/production enterprise

1.11.1 Qualification certification documents for domestic drug production applicants/production enterprises

The applicant/production enterprise organization's legal registration certificate (business license, etc.). When applying for a drug marketing license, the applicant and the production enterprise should have obtained the corresponding "Drug Production License" and the change record page (internal verification).

Applicants for clinical trials should provide a description of the preparation of their clinical trial drugs under conditions that comply with drug production quality management standards.

1.11.2 Qualification certification documents for overseas drug production applicants/production enterprises

Proof documents, notarized certification documents, and Chinese translations of the compliance of the production and packaging factories with drug production quality management standards.

Applicants for clinical trials should provide a description of the preparation of their clinical trial drugs under conditions that comply with drug production quality management standards.

1.11.3 Certification documents of registered agency

If an overseas applicant designates an enterprise legal person within China to handle relevant drug registration matters, they shall provide a power of attorney, notarized documents and their Chinese translations, as well as a copy of the business license of the registered agency.

1.12 Certification documents for small and micro enterprises (if applicable)

1.13 Declaration of Authenticity of Application Materials

The applicant should declare that they are responsible for the authenticity of the materials submitted and ensure the authenticity and validity of the application materials. At the same time, the legal representative needs to sign and stamp.

Two or more applicants are responsible for the authenticity of the entire set of application materials.

The listing permit holder is responsible for the authenticity of the entire set of application materials. For drugs produced overseas that apply for registration, the authenticity statement must be notarized and certified.

Declaration of Authenticity of Application Materials (Template)

State Drug Administration:

My unit applies for ______, Registration Classification______ Class, submit the following application materials:

one

two

three

Our unit guarantees the authenticity and validity of the information submitted above, and is responsible for the authenticity of the substantive content of the application materials. If there are any inaccuracies, we are willing to bear corresponding legal responsibilities and bear all consequences arising therefrom.

Hereby declare!

Signature (seal) of the legal representative of the unit

Date:

Explanation: 1. The applicant should select the applicable documents to submit during the entire drug lifecycle application process, and each document can be an overview. Please refer to the corresponding modules and documents for specific research materials. 2. If the certification documents issued by the overseas drug regulatory agency or region for drugs produced overseas (including proof of drug marketing permission, GMP proof documents, and proof of drug change permission documents, etc.) comply with the original unified format recommended by the World Health Organization, they may not be notarized by the notary public in the host country or certified by the Chinese embassy or consulate in the host country.

Attachment: Explanation Letter

XX application for XX products declared by XX company

1. Brief Description

Including but not limited to: product name, (proposed) indication, usage and dosage, dosage form, specifications.

2. Background information

Briefly explain the progress of the product's domestic and international marketing, registration classification and basis, application matters, and relevant supporting research.

Accelerate the application for listing registration procedures (including breakthrough treatment drug procedures, conditional approval procedures, priority review approval procedures, and special approval procedures) and their basis (if applicable).

Additional application items, such as exemption from clinical, over-the-counter, or pediatric medication (if applicable).

3. Other important relevant information that requires special explanation

Attachment: Vaccine Biosafety and Environmental Impact Assessment

For vaccines that do not contain live microorganisms or do not significantly change the concentration and distribution of corresponding microorganisms and their metabolites and degradation products in nature, such as inactivated vaccines, polysaccharide vaccines, and attenuated live vaccines prepared by traditional methods, only the product ingredients need to be explained, and a statement that the product has no environmental impact risk and does not require preventive measures is provided.

For vaccines that may have certain growth and reproduction abilities in the human body and environment, such as carrier vaccines, genetically modified live attenuated vaccines, etc., biosafety and environmental impact assessments should be conducted to analyze the impact of such products on human health and the environment (including animals and plants) during use, storage, disposal, and after detoxification by the recipient, Conduct environmental risk assessment and provide prevention and control measures throughout the entire lifecycle of vaccine launch.

The clinical trial application should provide the following research data: (1) The key modification methods, host range, transmission routes, pathogenicity, and types of added substances of the pathogenic microorganisms contained in the product, and analyze their genetic stability and potential impact on the environment. (2) The degree of distinguishability and identification methods between vaccine strains/strains and wild strains. (3) Evaluate the sensitivity or drug resistance of products and their metabolites, degradation products to physicochemical factors, and establish effective control measures for accidents. (4) Conduct in vivo detoxification studies on animals, including products and their metabolism, detoxification time and quantity of degradation products, survival ability after detoxification and release into the environment, evaluation of susceptible species, and risk of recombination or regression.

During the listing application stage, the following research materials need to be provided: (1) the time and quantity of detoxification after human vaccination, as well as the analysis and evaluation of the pathogenic effects on humans and animals after detoxification; Analyze the genetic stability, selection advantages, exposure and species susceptibility (especially the impact on endangered species) of products, metabolites, and degradation products, and whether there are natural barriers to control their transmission. (2) Conduct a comprehensive analysis of environmental impact risks based on research data during clinical trials, and propose environmental risk prevention and control measures.

After listing, it is necessary to continue conducting research in accordance with the post listing biosafety monitoring and risk assessment plan, including organizing the monitoring of bacteria/strains (such as differences in circulating strains or strains, and the phenomenon of strain or strain substitution); Continue to study the possibility of post vaccination detoxification on human and animal diseases, as well as its impact on non target organisms and the ecological environment.

M4 Module 1 Administrative Documents and Drug Information

(Draft for Soliciting Opinions) Revision Explanation

In order to apply the relevant requirements of the new Drug Administration Law, Vaccine Administration Law, and Drug Registration Administration Law (hereinafter referred to as the "Measures"), our bureau has revised the administrative documents and drug information (hereinafter referred to as M4 Module 1) in the "Notice on the Release of Module 1 Document and CTD Chinese Version of M4: General Technical Document for Human Drug Registration Application (CTD)" (No. 17 of 2019). The revised content includes the submission method for the approval of generic names, inspection of relevant information, vaccine biosafety, supporting documents for the review and approval of raw and auxiliary packaging, supporting documents for overseas production of drugs, registration application process status, acceleration of market registration procedures, clinical trial process management, risk management, post market changes, and supporting documents for the applicant/production enterprise. The specific revised terms are as follows:

1、 Added terms

According to Article 37 of the Measures, "Applicants shall submit an application for universal name approval at the same time as applying for drug marketing license." "1.3.5 Application Materials for Drug Universal Name Approval" has been added.

According to Article 97 of the Measures, "The Drug Evaluation Center shall notify the Drug Verification Center to initiate verification within 40 days after the acceptance of drug registration." In order to efficiently initiate inspections based on risks, "1.3.6 Inspection related information" has been added.

According to Article 11 of the Vaccine Management Law, "A sound biosafety management system should be established during the development, production, and testing of vaccines, strictly controlling biosafety risks, and strengthening the safety management of pathogenic microorganisms such as bacterial and viral strains." "1.3.7 Vaccine biosafety and environmental impact assessment" has been added.

4. According to the requirements for the registration process in Chapter 3 of the Measures, "Drug Listing Registration", "1.4.2 Application for Adjustment of Clinical Trial Plan, Suspension or Termination of Clinical Trial", "1.4.3 Application for Resumption of Clinical Trial after Suspension", "1.4.4 Re application for Clinical Trial after Termination", and "1.4.6 Change during the Review Period of Application for Listing Registration" have been added under "1.4 Application Status".

5. According to Article 30 of the Measures, "Applicants may be required to adjust the drug clinical trial plan, suspend or terminate the drug clinical trial in any of the following circumstances", and "1.7.3 Applicants are required to adjust the clinical trial plan, suspend or terminate the drug clinical trial" has been added.

2、 Adjusted terms

1. Considering the requirement of M4 CTD submission for all subsequent chemicals, the scope of application for chemicals in the "Product Quality Standards and Production Processes/Manufacturing and Inspection Regulations" has been adjusted from "New Chemical Entities" to "All Chemicals".

2. According to Chapter 4 of the "Measures", the relevant content of "Drug Accelerated Market Registration Procedure" has been adjusted from "1.5 Accelerated Review and Approval Channel Application" to "1.5 Drug Accelerated Market Registration Procedure", and specific procedures for accelerating market registration have been added.

3. The "1.8 Risk Management" has been adjusted in accordance with the relevant content of the "Requirements and Management Regulations for Safety Update Reports during Research and Development Period".

4. Change the relevant content in "1.11 Applicant/Production Enterprise Certification Documents" to "For those who apply for clinical trials, they should provide a description of the preparation of their clinical trial drugs under conditions that comply with drug production quality management standards".

3、 Deleted terms

1. In accordance with the Announcement of the State Food and Drug Administration on Cancelling 68 Certification Matters (No. 102 of 2019), the requirements for submitting GCP and GLP qualification certificates, defining the attributes of pharmaceutical and mechanical combination products, registration certificates and approvals within the validity period, registration status certificates, and drug production licenses issued by the State Food and Drug Administration have been removed, and replaced with internal verification.

2. Removed the relevant instructions for self use or exclusive supply of raw materials, medicinal excipients, and drug packaging materials in 1.3.8.1

3. The Drug Administration Law cancels the requirements for administrative licensing of Good Manufacturing Practice (GMP) certification and removes the requirement for GMP certification documents in section 1.11.1.1.