Interpretation | What should I do if there is a change in a listed Chinese medicine?

On February 24, 2021, the National Medical Products Administration issued a notice on its official website "Announcement of the National Medical Products Administration on Issuing the "Changes in Listed Chinese Medicines and Requirements for Application Information" (2021 No.

The "Changes to Chinese Medicines on the Market and Requirements for Filing Documents" are based on the "Administrative Measures for Drug Registration" and "Administrative Measures for Post-Marketing Changes (Trial)", as well as the risks to drug safety, effectiveness and quality controllability And the degree of impact, the changes in the listed Chinese medicines are divided into approval changes, filing changes and reporting changes.

1.

Changes to the listed Chinese medicines are divided into three categories: approval changes, filing changes and reporting changes.

(1) Changes that require the approval of the State Drug Administration

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Others.

(2) Recorded matters by the national or provincial drug regulatory authority

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The following changes are moderate changes:

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1.
Change the drug packaging specifications;

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2.
Change the production process;

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3.
Change the excipients in the formulation;

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4.
Change of drug registration standards;

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5.
Change drug packaging materials and containers;

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6.
Change the validity period or storage conditions of the drug.

2.
According to the regulations of the State Drug Supervision and Administration Department, the modification of the instructions shall be supplemented and improved uniformly as required.

3.
Change the corresponding content of the label according to the content of the drug insert.

4.
Sub-packaging of medicines and their changes.

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Change the name of the drug marketing authorization holder, the name of the manufacturer, and the name of the production address (the drug marketing authorization holder has not changed).

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Others.

(3) Matters reported in the annual report

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The following changes are minor changes:

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1.
Change the drug packaging specifications;

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2.
Change the production process;

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3.
Change the excipients in the formulation;

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4.
Change drug packaging materials and containers.

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Others.

2.
Declared data items and requirements

(1) A copy of the drug registration certificate and its attachments

Including the previous approval documents obtained for the declared drug, it should be possible to clearly understand the complete historical evolution process and current status of the product.
Such as drug registration certificate, supplementary application approval notice (approval), drug standard formulation and revision, etc.
The attachments include the attachments of the above-mentioned approval documents, such as drug quality standards, production processes, instructions, labels and other attachments.

(2) Proof documents

1.
The "Drug Production License" and its change record page and business license of domestic holders and domestic manufacturing enterprises.

2.
If the foreign holder appoints an enterprise legal person in China to handle the relevant drug registration matters, it shall provide the entrusted documents, notarized documents and their Chinese translations, as well as a copy of the business license of the registration agency.
If the overseas drug registration agency changes, the overseas holder shall provide the document, notarized document and Chinese translation of the original entrusted agent registration relationship of the foreign holder.

3.
For drugs that are already on the market overseas, the certification documents that permit drug changes issued by the drug regulatory agency of the country or region where the drug is marketed overseas, as well as their notarized certification documents, and Chinese translations should be submitted.
For specific format requirements, please refer to the relevant acceptance review guidelines for Chinese medicines.
Except for changes in drug marketing license holders, drug specifications, manufacturing companies, and production sites, where the drug regulatory agencies of overseas listing countries or regions cannot issue relevant certification documents, they can make explanations in accordance with local laws and regulations.

(3) Check relevant information

Including drug development information sheet, drug production information sheet, on-site master file list, drug registration clinical trial research information sheet, clinical trial information sheet, quality standards, production technology, standard review opinions and sample inspection reports.

(4) The topic and basis

It is necessary to specify the purpose and basis of the drug change.

(5) A sample draft of the revised drug insert, with detailed revision instructions

Contains the explanation of the previous changes in the insert sheet since the approval of the national drug regulatory authority for marketing, and the current latest version of the insert sheet sample draft.

(6) The revised drug label sample draft with detailed revision instructions

(7) Pharmaceutical research materials

Carry out research in accordance with the relevant technical guidelines for changes in the pharmacy of listed traditional Chinese medicines published by the National Drug Administration, and provide part or all of the pharmacy research and test data and necessary original registration applications according to the specific requirements of the relevant technical guidelines for various changes.
data.

(8) Research materials on pharmacology and toxicology

Provide corresponding pharmacology and toxicology test data and/or literature data according to the category of the changed items.

(9) Clinical research materials

According to the category of clinical-related changes, the following clinical research data and/or literature data are provided.

If the change requires clinical trial data to provide supporting basis, the clinical trial should be applied first, and the plan and plan for the clinical trial should be provided.

Those who intend to apply for exemption of clinical trials at the same time need to provide evidence-based clinical research data of high quality and good quality (if any, a complete clinical research summary report is required), and relevant domestic and foreign literature supporting the application items.
Other supporting evidence and related supporting documents.

(10) Summary of relevant information on product safety

Product safety related information includes post-marketing safety research and related literature data, adverse reaction data fed back by the National Adverse Reaction Monitoring Center, adverse reaction data spontaneously collected by enterprises, relevant clinical studies, clinical applications, literature reports, etc.
, as well as domestic and foreign Details of the adverse reactions of this product collected from various channels.

A summary of product safety-related data refers to a summary of the above-mentioned safety-related data based on the content of the change to provide supporting evidence for the change.

Three, four changes that require approval

(1) Change the scope of applicable people

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What is the scope of the applicable population for the change?

Changing the scope of the applicable population refers to the addition, limitation or deletion of the scope of the applicable population under the condition that the original function and indication scope is basically unchanged, and the route of administration and dosage form remain the same.

2.
Change the application materials and requirements for the scope of the applicable population

The application should generally provide all the application materials except the pharmaceutical research materials in the application materials 1-10.
If pharmaceutical problems or changes are involved at the same time, the research should be carried out in accordance with the relevant technical guidelines and the corresponding pharmaceutical research materials should be provided.

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The basis and basis for changing the scope of the applicable population

It should focus on the disease characteristics, treatment status and clinical needs of the same function and the same function in different applicable populations before and after the proposed change, as well as the possible safety and effectiveness support of traditional Chinese medicine theory, existing drug safety and effectiveness evidence for the applicable population after the change Happening.
Where the scope of the applicable population is limited or deleted, the rationality of the limitation or deletion of the scope of the applicable population shall be explained.

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Clinical research data

If the scope of the applicable population is changed, clinical trials should be carried out.
Clinical trials generally follow the requirements of new drugs; according to the increase in the scope of the applicable population and the degree of support of the existing drug effectiveness and safety evidence, at least a confirmatory clinical trial of sufficient exposure for the scope of the new applicable population and meeting the requirements of the safety evaluation should be carried out test.
When applying for a clinical trial, according to the changes in the scope of the applicable population, pharmacology and toxicology research data supporting the change should be provided, such as toxicological test data and/or literature data supporting the scope of the new applicable population; the scope of the proposed new applicable population should be provided Clinical trial plans and programs and related information.

(2) Change of usage and dosage

1.
What is the change of usage and dosage?

Changing the usage and dosage refers to changing the dosage, medication plan (change usage, course of treatment), etc.
, under the premise that the function and indication, the scope of the applicable population and the route of administration remain unchanged.

2.
Change the application materials and requirements for usage and dosage

The application should generally provide all the application materials except the pharmaceutical research materials in the application materials 1-10.
If pharmaceutical problems or changes are involved at the same time, the research should be carried out in accordance with the relevant technical guidelines and the corresponding pharmaceutical research materials should be provided.

2.
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Change the usage and dosage and the basis for the topic

The reasons and rationality of changing the usage and dosage should be emphasized.

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Clinical research data

If the change of usage and dosage involves an increase in dosage or an extension of the treatment course, when applying for a clinical trial, toxicology test data and/or literature data supporting the change should be provided, and the clinical trial shall be based on the requirements of the new drug; A confirmatory clinical trial before and after the change should be carried out to demonstrate the rationality of the dose change.
If the change of usage and dosage is not supported by clinical experience data, a dose exploratory study should be carried out.

For other changes in usage and dosage (such as changing the solvent, dripping speed, medication time, medication interval, clear dosing schedule, etc.
), relevant clinical trials should be conducted and/or literature information should be provided to explain the rationality of the changes.

(3) Substituting or subtracting toxic or endangered flavors in prescriptions from national drug standards or drug registration standards

1.
What is the substitution or subtraction of toxic or endangered medicinal flavours in prescriptions from national drug standards or drug registration standards?

Substituting or subtracting the toxic drug flavor or the drug flavor in the endangered state in the national drug standard or drug registration standard prescription only refers to the situation where the applicant requests to replace or subtract the drug flavor on its own.

2.
Change the application materials and requirements for usage and dosage

The application should generally provide all the information of the application materials 1-10.

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1.
Substitution or subtraction of the national drug standard or drug registration standard prescription toxic drug flavor or endangered drug flavor and the basis

Evidence data on the safety and effectiveness of the original preparation function; the necessity and feasibility of substituting or subtracting the toxic drug flavor or the endangered drug flavor in the prescription; the person who replaces or subtracts the endangered drug flavor in the prescription should provide Evaluation report of traditional Chinese medicine resources and relevant supporting documents, etc.
; those who substitute or subtract the toxic medicinal flavour of the prescription shall provide all safety information and research data such as the adverse reaction of the original preparation, and analyze the possible relationship with the toxic medicinal flavour; the function of the alternative medicinal flavour Indications, basis for selection, etc.

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Pharmacology and toxicology research data and clinical research data

Corresponding pharmacological and toxicological research data and clinical trial data should be provided based on the toxic or endangered flavors and alternative flavors.
If toxic or endangered medicinal flavours are substituted, pharmacodynamic and toxicological comparative test data and literature data are required; if toxic medicinal flavours or endangered medicinal tastes are subtracted, pharmacodynamic comparative test data shall be provided; clinical aspects should Conduct a comparative study.
If alternative medicinal flavors are not included in the national drug standards, drug registration standards, and medicinal material standards of provinces, autonomous regions, and municipalities directly under the Central Government, relevant research should be conducted according to the requirements of new medicinal materials.

(4) Change the safety and other contents in the drug insert

Change the safety and other content in the drug insert, including revision of warnings, [adverse reactions], [taboos], [precautions], [pharmacology and toxicology], medication information for special populations, [drug interactions] and other items.

Such as revision of warnings, [adverse reactions], [taboos], [precautions], [pharmacology and toxicology], information on medications for special populations, [drug interactions] and other safety related items, application materials 4-10 should be provided The information related to the changes should at least include the title and basis (application material 4), the instructions and label samples for the application for change, the original approved instructions and labels, the revision instructions, and the comparison table before and after the revision (application data 5-6 ), and a summary of relevant product safety data (application data 10).
Marketing authorization holders need to focus on evaluating the potential impact of the change on the safety, effectiveness, and clinical use of the drug, and evaluate and analyze all adverse drug reactions, and reflect targeted measures in the instructions related to the project.

If the item of [Pharmacology and Toxicology] is revised, it should be revised according to the relevant requirements of the instruction manual, and corresponding supporting information should be provided.

to sum up

In the event of a change, the drug marketing authorization holder of a listed Chinese medicine shall determine whether the change is an approval type change, a record type change, or a record type change in accordance with the requirements of approval type change, record type change and report type change.
If it is an approval type change, the holder of the drug marketing authorization must declare and be approved by the national drug regulatory authority.
If it is a record-keeping change, the holder of the drug marketing authorization shall declare it and file it with the national or provincial drug regulatory authority.
Among them, domestically produced drugs are reported to the provincial drug regulatory authority where the holder is located, and overseas-produced drugs are reported to the Drug Evaluation Center of the State Drug Administration for record.
If it is a report type change, the drug marketing authorization holder can report it in the annual report.

If the change of the drug marketing authorization holder of a listed Chinese medicine is an approval type change or a filing type change, the drug marketing authorization holder shall apply in accordance with the "Application Document Items and Requirements".
The application materials include (1) a copy of the drug registration certificate and its attachments; (2) supporting documents; (3) checking related information; (4) setting up the title and basis; the purpose and basis of the drug change need to be explained in detail; ( 5) A sample of the revised drug insert sheet with detailed revision instructions; (6) A sample of the revised drug label with detailed revision instructions; (7) Pharmaceutical research data; (8) Pharmacological and toxicological research data; (9) Clinical research Data; (10) Summary of related data on product safety.
If there are items that are not applicable, the drug marketing holder should indicate that they are not applicable and explain the reasons.

When a drug marketing authorization holder declares a change, if it declares multiple changes at the same time, the research and declaration shall generally be carried out according to the highest technical requirements, and all the requirements of the application must be met at the same time.
For example, if the scope of applicable population or usage and dosage is changed while adding functions and indications, it is necessary to apply for registration as an improved new drug; if the scope of application is increased while increasing the dosage or course of treatment, non-clinical safety trials and tests should generally be carried out in accordance with the requirements of new drugs.
Clinical Trials.
The declaration materials for different declaration items must be complete.