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Drugs
Approval for clinical trials of imported (incl. from Hong Kong, Macao and Taiwan) chemicals
2013-12-06

I. Project name: Imported Drug Registration


II. Content of licensing: Approval for clinical trials of imported (including Hong Kong, Macao and Taiwan) chemicals, which are classified in accordance with Annex II of the “Provisions for Drug Registration”, namely:
Registration Category 1, drugs not marketed at home and abroad.
Registration Category 3, drugs that have been marketed overseas but not yet in the domestic market.


III. Legal basis: "Drug Administration Law," "Regulations for Implementation of the Drug Administration Law,” and “Provisions for Drug Registration”


IV. Charges:
Review and approval fee for imported drugs: RMB45,300yuan
Charging basis: "Notice of the State Planning Commission and the Ministry of Finance on the Adjustment of Fees for Drug Review, Approval and Tests" [J.J.G. (1995) No.340]


V. Quantity restrictions: No quantity limit for this licensing


VI. List of application dossiers:
"Application Form for the Registration of Imported Drugs”
(I) Summary data
a) Name of drug;
b) Approval documents;
c) Objective and rationale for the study;
d) Summary and evaluation of study results;
e) A draft of insert sheet, notes to the draft and the latest literatures;
f) Draft of the designed package and label.


(II) Pharmaceutical research data
g) Overview of pharmaceutical research data.
h) API production process research data and literature; drug formulations and processes research data and literature.
i) Testing data and literature for confirmation of chemical structure or components.
j) Testing data and literature data for quality research.
k) Drug standards and the drafting instructions, and standard substance or reference substance.
l) Sample inspection report.
m) Sources of pharmaceutical APIs and excipients, quality standards, and inspection reports.
n) Testing data and literature for drug stability studies.
o) Rationale for selection and specifications of immediate packaging material and container.


(III) Pharmacology and toxicology research data
p) Review of pharmacology and toxicology research data.
q) Main pharmacodynamic testing data and literature.
r) General pharmacology testing data and literature.
s) Acute toxicity testing data and literature.
t) Long-term toxicity testing data and literature.
u) Allergic (topical, systemic and light sensitive toxicity), hemolytic and local (blood vessels, skin, mucous membranes, muscle, etc.) irritation and other special safety related testing data and literature.
v) Testing data and literature for interactions of the efficacy, toxicity and pharmacokinetics of multiple ingredients in compound preparation.
w) Carcinogenicity testing data and literature.
x) Reproductive toxicity testing data and literature.
y) Carcinogenicity testing data and literature.
z) Dependence testing data and literature.
aa) Non-clinical pharmacokinetic studies and literature.


(IV) Clinical trials data
bb) Summary of related clinical trial data at home and abroad.
cc) Clinical trial protocols and study protocol.
dd) Clinical investigator's brochures.
ee) A draft of Informed Consent, Ethics Committee’s approval letters.
ff) Clinical trial reports.
Specific requirements for the above application dossiers are detailed in Annex II of the “Provisions for Drug Registration”.


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. Two sets of complete application dossiers (at least one set is in the original) and one set of review documents in hard copy shall be submitted for registration application. Four application forms (1 in the original and 3 in hard copy) shall be separately put into each set of dossier (the original application form and a hard copy shall be put in the set of the dossier in the original).
5. "Import Drug Registration Application Form": the drug registration application form submission program could be downloaded from CFDA website (www.cfda.gov.cn); the application form shall be filled in as required, printed and saved, and shall be signed by the overseas applicant, and signed & sealed by its domestic agent.
6. When mailing or submitting the application dossiers, the electronic version of the application form shall be sent to the following e-mail address dedicated for drug registration: slzx@cfda.gov.cn.
7. The data checking code on the electronic and paper application form should be identical.
8. Foreign language materials shall be translated into Chinese.

(II) Specific requirements for application dossiers:
a) The "Application Form for the Registration of Imported Drug" should be filled in an accurate and standardized manner in line with the requirements of explanatory notes.
(1) Drug Registration Category: Fill in as per the corresponding article of Annex II of the “Provisions for Drug Registration” (SFDA Order No. 28). The application dossiers shall be submitted in accordance with the requirements for "Items of application dossiers" for chemicals. As for the application for drugs not approved for marketing at home and abroad, dossiers in accordance with the requirements of Registration Category 1 shall be submitted while for the application for other products, provisions on Registration Category 3 shall be followed. ICH-required CTD information can also be submitted, but the "Summary data" section should be submitted in accordance with the requirements for "Items of application dossiers" for chemicals. Drugs in Registration Category I should at least have entered Phase II clinical trials in a foreign country.
(2) Additional application: other applications can be raised at the same time, such as exemption from clinical trials, non-prescription drugs, etc.
(3) Specifications: where the drug for registration has multiple specifications, an acceptance number shall be designated for each specification in a separate application form.
(4) Packaging specifications: multiple packaging specifications shall be filled in one application form. Multiple package volumes and sizes of non-injectable formulations like agents, oral solutions, granules, ointments, eye drops, and pastes with the same drug formulations shall be subject to uniform management according to different packaging sizes, and filled in one application form.
(5) The applicant: on the application form, organization 1 and organization 2 refer to information of overseas licensed providers and production plant, these two items cannot be left blank. Except for the applicants in Hong Kong, Macao and Taiwan regions, the business name, address, etc. should be filled in English; Organization 3 refers to the information for overseas packaging plants, which should be completed in accordance with the actual situation. Except for the applicants in Hong Kong, Macao and Taiwan regions, the business name, address, etc. should be filled in English; the relevant information of domestic agencies should be filled in Chinese.
(6) The information on the application form should be consistent with the proof documents as provided.


b) While there is a same product in observation period, the product as filed shall not apply for import registration.


c) Requirements for proof documents:
i. Proof documents issued by relevant drug regulatory authority of the manufacturing country or region for marketing authorization and GMP-compliance, as well as their notarization documents, proof documents and Chinese translations thereof.
The proof documents for drugs in Registration Category I can be submitted together with the clinical trial reports after the trials are completed in China; however, when applying for clinical trials, the applicant must provide proof documents issued by drug regulatory authorities of the manufacturing country or region to approve GMP compliance of the manufacturers.
① The above proof documents shall comply with the WHO recommended uniform format. Files in other formats must be notarized by public notary organizations of the country of origin and certified by Chinese embassies and consulates in the country.
② For preparations produced in one place and packaged in another, the applicant must provide proof documents issued by drug regulatory authorities of the manufacturing country or region to permit drug marketing and prove GMP compliance of the manufacturers.
③ For drugs not yet approved for marketing in the manufacturing country or region, the applicant can provide proof documents issued by drug regulatory authorities of the country or region of the certificate holders' headquarters to permit drug marketing and prove GMP compliance of the manufacturers. Proof documents issued by drug regulatory authorities of countries or regions other than those of the certificate holders’ headquarters to permit drug marketing and prove the GMP compliance of manufacturers must be certified by CFDA.
④ For APIs, the applicant can provide proof documents issued by drug regulatory authorities of the manufacturing country or region to permit the marketing of drugs and to prove the GMP compliance of the manufacturers. The applicant can also provide certificate of European Pharmacopoeia (CEP) and attachments, or API drug master files (DMF), as well as proof documents approving the marketing of preparations made with such APIs overseas and documents proving GMP compliance of the manufacturers
⑤ As for the international multi-center clinical trials, introductions of the preparations of clinical trial drugs under conditions in compliance with GMP standards shall be provided for the application.
⑥ For APIs or formulations that are managed as foods in the manufacturing country or region, the applicant shall provide the proof documents issued by the drug regulatory authorities of the manufacturing country or region to prove GMP compliance of the manufacturers, or proof documents issued by related institutions to prove compliance with ISO9000 Quality Management system, and certificates issued by relevant regulatory agencies in the country or region to authorize the marketing of drugs.
⑦ The originals shall be provided. While hard copies are submitted, the original copy of notarization document(s) issued by the public notary office of the country of origin, and the original copy of the certificate(s) issued by the Chinese Embassy in the country shall be filed at the same time..
⑧ Government proof documents, notarial documents and certificates shall not be unpacked without permission.
⑨ The key information of the documents should be consistent with the corresponding information filled in the application form, such as the exporting country, importing country, drug name, product name (especially foreign trade name), specification, status of whether or not approved for marketing or already marketed in the exporting country, certificate holder, and manufacturers etc.
⑩ All proof documents as provided must be within the validity period.
(2) 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
(3) Introductions of the patent status and ownership situation of the drug for application or its prescriptions and production processes, as well as statements of non-infringement to other patents.

VIII. Application process diagram:

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:
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 CDE 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:
Along with drug registration, Administrative Acceptance Service Center shall transfer the application dossiers to CFDA Center for Drug Evaluation for overall technical review.
CDE of CFDA shall complete the technical review within 90 days in accordance with the technical review principles (80 days for products approved of special approval process).After the completion of the technical review, the Notice for supplementary material should be issued to applicants failed to meet the technical review requirements of the CDE, who shall supplement the dossiers within four months, and CDE shall complete the review of the supplementary dossiers in no more than 30 days (20 days for products approved of special approval process).


(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:
The administrative licensing decision shall be made within 110 days from the date of acceptance (100 days for products allowed to enter into the special approval procedures) (Note: CFDA shall make the decision 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.)
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:
Drug clinical trials should be implemented in three years after being approved. The original approval documents shall be automatically annulled for overdue implementation; under such cases, if the clinical trial still needs to be conducted, it should be subject to re-application.

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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