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Drugs
Review of the supplementary application for imported drugs (incl. from Hong Kong, Macao and Taiwan)
2013-12-06

I. Project name: Review of supplementary application of drugs


II. Content of licensing:
Review of supplementary application of imported drugs (incl. from Hong Kong, Macao and Taiwan), including supplementary application item2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17 and 18 as listed in Annex IV of the "Provisions for Drug Registration", namely:
Application item 2, Trade name of drugs
Application item 3, For enrichment of approved indications of TCM, chemicals and biological products in China
Application item 4, Change dosage or alter the scope of applicable population, but do not change the route of administration
Application item 5, Alteration of drug specifications
Application item 6, Change excipients that are required in pharmaceutical prescriptions
Application item 7, Changes in production processes that affect the quality of medicines
Application item 8, Modifying drug registration standards
Application item 9, Alternative or cancellation of toxic or endangered medicinal herbs that are listed in the national drug standard prescriptions
Application item 10, For imported drugs, domestically produced injections, ophthalmic preparations, aerosols, dry power inhalation, sprays that change the packaging materials or containers in direct contact with drugs; or using new packaging materials or containers in direct contact with drugs
Application item 11, Application for drug combination packaging
Application item 13, Revise or enrich the package inserts of TCM and natural medicine, such as the items of pharmacology and toxicology studies, clinical trials, pharmacokinetics etc.
Application item 14, Change the registered item of registration certificate for imported drugs, such as drug name, manufacturers name, registered address, drug validity, packaging specifications etc.
Application item 15, Changes of the origin of imported drugs
Application item 16, Changes in foreign packaging plants for imported drugs
Application item 17, Imported drugs repackaging in China
Application item 18, Others

III. Legal basis for formulation and implementation of licensing: "Drug Administration Law," "Regulations for Implementation of the Drug Administration Law,” “Provisions for Drug Registration”, and "Notice on the Renewal of imported drugs registration" (SFDA Department of drug registration [2009] No.18)

IV. Fees: No charge


V. Quantity restrictions: No quantity limit for the licensing


VI. List of application dossiers:
"Supplementary Application Form for Imported Drugs"
Data number (1) Copies of proof documents for drug approval and the annex:
Including all approval documents related to the application, such as drug registration approval document, supplementary application approval document, trade name approval documents, standards promulgation documents, drug standard revision approvals, drug approval number uniform renewal approvals, "Registration Certificate for Imported Drugs "," Registration Certificate for Pharmaceutical Product "and so on. The Annex includes the attachments of the above-mentioned approval documents, such as drug standards, package inserts, packaging labeling sample and other attachments.
Data number (2) Proof documents:
1. Where a foreign manufacturer’s representative office in China deals with the registration issues, copies of Registration Certificate of Resident Office of Foreign Enterprise shall be provided.
Where a foreign manufacturer authorizes a domestic enterprise or agency for the registration issues, copies of the authorization letters with notarized documents and the Chinese translation as well as the Business License of the domestic enterprise or agency shall be provided;
2. For different application items, relevant proof documents shall be separately provided according to the "Form of Items of Application Dossiers".
3. For imported drugs, the applicant shall submit the proof documents, notarized documents and Their Chinese translations issued by drug regulatory institutions of the manufacturing country or region to permit alterations of drugs. The format of these documents shall conform to the requirements of related proof documents in the application dossiers items for TCM, natural medicine, chemicals and biological products
If the drug regulatory authorities of the manufacturing country or region cannot provide relevant proof documents, explanations should be made according to the rules of the local laws and regulations, except for changes of drug specifications, the origin, the name and registered address of the pharmaceutical manufacturers.
Data number (3) Sample manuscript of revised package insert, along with a detailed description of revisions.
Data number (4) Sample manuscript of revised drug packaging labels, together with a detailed description of revisions.
Data number (5) Pharmaceutical research information:
According to the different requirements for registration items, some or all of the pharmaceutical research data and necessary dossiers of the original registration application shall be provided separately in accordance with the items provided in Annex 1 to 3.
Data number (6) Pharmacology and toxicology research data:
According to different requirements for registration items, some or all of the pharmacology and toxicology research data and necessary domestic and overseas research literature shall be provided separately in accordance with the items provided in Annex 1 to 3
Data number (7) Clinical trials data:
If clinical trials are needed, item-specific application dossiers shall be submitted separately before and after the clinical trials, it should be in accordance with the items provided in Annex 1 to 3. If clinical trials are not required, relevant clinical trial research data can be provided.

VII. Requirements for application dossiers:
(I) General requirements for application dossiers:
1. The first page of the dossiers shall be a directory for application items, which shall be arranged in order as per Annex I of the “Provisions for Drug Registration” (SFDA Order No. 28). Each dossier shall indicate on its cover: the name of the drug and application item, document item number, and the name, phone number and address of contact person and the applicant.
2. All documents in the dossier shall be printed or copied in A4 size paper. The content shall be complete, standardized, clear, without alteration, and the data must be real and reliable.
3. The documents shall be put in portfolio envelope(s), on which the application classification, registration category, drug name, the envelope number of set X, the total number of envelopes in the set, original or copy, the contact person, phone number and the name of registration application agent shall be indicated.
4. Please submit two sets of complete application dossiers (including one set of originals, one set of copies), 3copies of the application form (1 original, two copies), which shall be enclosed separately into the portfolios
5. Please download the Drug Registration Application Form and the Application Form for Developing the Offer Program via www.cfda.gov.cn, the electronic version shall be sent to slzx@cfda.gov.cn mailbox along with the mail or delivery of application dossiers.
6. Chinese translations should be provided as required for foreign materials.
7. The historical approval documents and attachments of the product shall be provided according to the instructions of proof documents for drug approval as stated in Annex IV of the "Provisions for Drug Registration". For supplementary application prior to the completion of approval procedures for registration renewal, the applicant shall specify the relevant renewal application in the "Drug Supplementary Application Form", and provide a copy of the Notice on Acceptance of the Renewal Application
8. The applicant shall provide copies of the registration certificate of foreign enterprises’ resident representative office in China. If the application is performed by Chinese domestic enterprises or agencies entrusted by foreign pharmaceutical manufacturers, the applicant shall provide the entrustment documents, notarized documents and their Chinese translations.
9. The applicant shall submit the proof documents, notarized documents and their Chinese translations issued by drug regulatory authorities of the manufacturing country or region to permit alterations of drugs. The format of these documents shall conform to the requirements of related proof documents in the application dossiers items for TCM, natural medicine, chemicals and biological products. If the drug regulatory authorities of the manufacturing country or region cannot provide relevant proof documents, explanations shall be made according to the rules of the local laws and regulations, except for changes of drug specifications, the origin, the name and registered address of the pharmaceutical manufacturers.

(II) Specific requirements for application dossiers:
1 Drug’s Trade Name: trademark inquiry form shall be provided.


2 For enrichment of approved indications of TCM, chemicals and biological products in China, the corresponding pharmacology and toxicology studies and clinical trials should be conducted in accordance with the following:
(1) For enrichment of new TCM indications that needs to extend the treatment period or increase the dose, the applicant shall provide pharmacology and toxicology testing data or literature. After approval, clinical trials shall be conducted and follow the requirements for new TCM drugs;
(2) For enrichment of new TCM indications, if the medication period or dosage is unchanged, the applicant should provide the main pharmacodynamic testing data and literature, and shall conduct at least 100 pairs in clinical trials;
(3) For enrichment of functions or indications that are already used by domestic similar products, at least 60 pairs clinical trials shall be conducted, or as an alternative, the applicant shall conduct bioequivalence tests by taking similar products with the same indications as control group.


3 If the dosage, usage or scope of applicable population is changed, but the route of administration is unchanged, the applicant shall provide safety research data or literature in support of the change; if necessary, clinical trials should be conducted. For the major indications of TCM and natural medicine, the applicant should perform at least 100 pairs of clinical trials.


4 Alteration of drug specifications:
(1) The alteration of drug specifications shall meet the following requirements:
a. The applied specification shall, generally speaking, be consistent with that of the same marketed products. If not, it should follow the scientific, reasonable and necessary principles.
b. The applied specification shall be reasonably determined in accordance with the usage and drug dosage, generally it shall not be less than the minimum single dosage, or greater than the maximum single dosage.
c. If the usage, dosage and applicable population are changed, the applicant shall provide relevant information according to registration item 4, and conduct clinical trials if necessary.
(2) Provide clinical application reports or literature.
(3) Provide drug registration inspection reports for at least three batches of samples.


5 Change dosage, usage or alter the scope of applicable population, but do not change the route of administration.


6 Registration item 7, if the production process is changed and may affect drug quality, that change shall not lead to changes in the material basis of pharmaceutical substances. For changed TCM material basis, the applicant shall provide comparative test and research data on pharmacy,, pharmacology and toxicology, etc., and, based on the characteristics of drugs, conduct clinical trials for different purposes, the number of cases shall be generally not less than100 pairs.


7 Modifying drug registration standards.


8. Alternative or cancellation of toxic or endangered medicinal herbs in national standard prescription of drugs refers only to the applicant’s voluntary application for doing so, excluding such cases conducted uniformly according to national provisions.
(1) Application of using approved TCM herbs as substitutes of corresponding Chinese crude drugs in TCM set prescriptions of preparations The applicants should provide the latest preparation process, drug standards, stability tests and other pharmaceutical research data, which may exempt them from providing pharmacological, toxicological and clinical trial data.
(2) If applications were made to use herbal medicines recorded in legal standards as an alternative, if the replaced herbal medicine plays a secondary role in the prescription, the applicant should provide the latest preparation process, drug standards, stability studies and other pharmaceutical research data, and, when necessary, the pharmacology, toxicology and clinical trial data. If the alternative medicinal herbs are toxic, the applicant should furthermore provide information on drug safety, including toxicological comparative testing data and, when necessary, pharmacodynamic testing data, and conduct clinical trials. If the replaced herbal medicine is in a primary position in the prescription, the applicant shall, aside from providing the above pharmaceutical research data, conduct comparative tests in efficacy and toxicology, and clinical bioequivalence studies for relevant preparations.
(3) For application of removing toxic herbs, the applicant should provide the latest processing technology, drug standards, stability studies and other pharmaceutical research data, pharmacological testing data, and perform clinical trials.
(4) Requirements for pharmacy, pharmacology, toxicology studies and clinical trials are as follows:
Pharmacy: ① the production process: the production process after substitution or cancellation of medicinal herbs shall be consistent with the original one. ② Drug Standards: property identification and contents determination should be established for alternative medicine. If specificity identification and contents determination cannot be established, further research data should be provided. ③ Stability test: Alternative medicine may affect the stability of drugs, therefore stability tests should be performed
Pharmacology, toxicology: after substitution, a comparative study shall be carried out for alternative medicine and original medicine with respect to main pharmacodynamics and acute toxicity for major illnesses. After removing the toxic herbs, studies shall be performed to compare the main pharmacodynamics for major illnesses before and after the change
Clinical trials: should be directed to the primary, indications and perform 100 pairs of randomized controlled trials to evaluate the equivalence of the two.


9. For imported drugs, domestically produced injections, ophthalmic preparations, aerosols, dry power inhalation, sprays that change the packaging materials or containers in direct contact with drugs; or using new packaging materials or containers in direct contact with drugs: the applicant may provide only the sample inspection reports for three consecutive batches, testing data of drug stability studies, the basis for selection and quality standards for packaging materials and containers in direct contact with drugs


10. Refers to the revision or addition of test items of pharmacology, toxicology and clinical trials in the package inserts of TCM and natural drugs, excluding the addition or revision of indications, usage, dosage and other items.


11. For changes in the registration items of registration certificate for imported drugs: the applicant should submit proof documents issued by drug regulatory authorities of the manufacturing country or region to permit alterations of drugs, notarized documents and their Chinese translations.


12. For changes of the origin of imported drugs: the applicant should submit proof documents issued by drug regulatory authorities of the manufacturing country or region to permit alterations of drugs, notarized documents and their Chinese translations.


13. Changes in foreign packaging plants for imported drugs:
(1) Shall submit the proof documents, notarized documents and their Chinese translations issued by drug regulatory authorities of the manufacturing country or region to permit alterations of drugs.
(2) Provide proof documents issued by drug regulatory authorities of the manufacturing country or region to prove GMP compliance of the drug packaging plant
(3) Need only to provide sub-packaging process, drug stability testing data, the basis for selection and quality standards of packaging materials and containers in direct contact with drugs, and sample inspection report for three consecutive batches.


14. Imported drugs repackaging in China:
(1) Provide repackaging contract of imported drugs (including authorization of using the trademark of imported drugs).
(2) Need only to provide sub-packaging process, the basis for selection and quality standards of packaging materials and containers in direct contact with drugs.
(3) Shall be submitted together with the registration application for Bulk packaging specifications for imported drugs Share data. Application forms shall be filled in separately.
(4) The application for sub-packaging shall be accepted by the provincial Food and Drug Administration.
(5) Application for corresponding changes of the sub-packaged drugs shall be accepted by the provincial Food and Drug Administration.

VIII. Application process diagram:
Items call for Technical review:

Items not call for Technical review:

IX. Licensing procedures:
(I) Acceptance:
After the application is filed to the Administrative Acceptance Service Center, and the application dossier submitted is in accordance with the list in VI of this Notice, the format examination shall be conducted by the work staff of the Center. Where the application item is not subject to administrative approval according to law, a decision of non-acceptance shall be notified to the applicant immediately. Where the application item is not within the functions of the administrative authority, a decision of non-acceptance shall be made immediately, and the applicant shall be informed to launch the application to relevant administrative authority. Where in the application dossier, there are errors that can be corrected on the spot, the applicant shall be allowed to make the corrections on the spot. Where the application dossier is incomplete or does not meet the statutory format, the applicant shall be informed of all the supplements and amendments to be made once and for all on the spot or within five days. If the applicant is not informed within the above-mentioned period, the application shall be deemed as accepted from date of receipt of application dossiers. Where the application dossier is within the functions of the administrative authority, the application dossiers are complete and comply with the statutory format, or where the applicant has submitted all supplements and amendments in accordance with the requirements of the administrative authority, the application for administrative approval shall be accepted.


(II) Drug registration inspection (if required):
After the Administrative Acceptance Service Center accepting the application, CFDA shall inform NIFDC to conduct registration inspection, determine issues related to the approval or review, which shall be completed within 30 days from the date of acceptance.
NIFDC has a time limit of 85 days to test samples and review the standards, and a time limit of 115 days for inspection of special drugs and vaccine products, the time frame for NIFDC inspection is in parallel with that for CFDA examination and technical review, and the specific time frame is allocated as follows:
After receiving information and samples, NIFDC shall arrange drug control institutions to conduct registration test within five days. The competent drug control institutions shall complete the registration inspection within 60 days from the receipt of dossiers, samples and related standard substances and submit the report to NIFDC; the sample tests and re-review of drug standards for special drugs and vaccine products can be completed in 90 days. After receiving the registration test reports and imported drug registration standards, which have been reviewed, the technical review shall be carried out by experts within 20 days; if necessary, re-review shall be conducted as per the review comments.


(III) Technical review (if necessary):
Along with drug registration, CFDA Administrative Acceptance Service Center shall transfer the application dossiers to CFDA Center for Drug Evaluation for overall technical review. CDE shall, in accordance with relevant principles, complete the technical review within 40 days. For application dossiers that need to be enriched, a notice for supplementary information shall be issued to the applicant, who shall supplement the information within four months, thereafter CDE shall complete the review of the supplementary information in no more than 13 days.


(IV) Decision of administrative examination & approval:
After receiving CDE’s completed technical review data, CFDA shall make licensing decisions within 20 days. If a decision cannot be made within 20 days, and extension of 10 days can be granted with competent leader’s consent.


(V) Delivery:
Within 10 days from the date of decision making of administrative examination & approval, CFDA Administrative Acceptance Service Center shall deliver the decision to the applicants.


(VI) Review:
For disagreements of CFDA decision, the applicant can, prior to administrative reconsideration or administrative litigation, explain the reasons and apply for re-review to CFDA within 60 days from the date of receipt of the decision. The contents of the re-review shall be limited to only the original application items and the original application dossiers.
After receiving the application for re-review, CFDA shall make a decision within 50 days and notify the applicant. If the original decision is maintained, CFDA shall no longer accept repeated application for re-review.
If the re-review requires technical re-review, CFDA should organize relevant professional and technical personnel to perform the re-review within the original application time limits.

X. Commitment of time frame:
(I) Supplementary application that needs for technical review:
The administrative licensing decision shall be made within 60 days from the date of acceptance. (Note: CFDA shall complete the examination & approval within 20 days after completion of the technical review; if CFDA failed to do so, an extension of 10 days can be granted with competent leaders’ consent). The above time frames do not encompass the time required for the applicants to supplement information and the re-review of supplementary information.


(II) Supplementary application that do not need technical review:
The administrative licensing decision shall be made within 20 days from the date of acceptance. (Note: CFDA shall complete the examination & approval within 20 days after completion of the technical review; if CFDA failed to do so, an extension of 10 days can be granted with competent leaders’ consent). The above time frames do not encompass the time required for the applicants to supplement information and the re-review of supplementary information.

XI. License validity and renewal:
The validity of the approval certificate for supplementary application is the same with that of the original certificate, the two certificates shall apply for renewal jointly upon expiry.

XII. Annual inspection or annual review of the license: None


XIII. Authority of Implementation:
Implemented by: CFDA
Accepted at: CFDA Administrative Acceptance Service Center

XIV. Institutions for inquiries and complaints:
For Inquiries: CFDA
For Complaints: CFDA Bureau of Investigation and Enforcement, Department of Legal Affairs
Note: The time frame of this GUIDANCE counts on working days, excluding legal holidays

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