Chapter 1 | General Principles |
Chapter 2 | Application for Drug Registration |
Chapter 3 | Pre-clinical Laboratory Study of Drugs |
Chapter 4 | Clinical Study of Drugs |
Chapter 5 | Application and Approval of New Drugs |
Chapter 6 | Application and Approval of Drugs Already with National Standards |
Chapter 7 | Application and Approval for Import Drugs |
Chapter 8 | Application and Approval for OTC Drugs |
Chapter 9 | Supplemental Application for Drug Registration |
Chapter 10 | Re-registration of Drugs |
Chapter 11 | Administration of Drug Inspection for Registration |
Chapter 12 | Administration of Drug Registration Standards, Standard Substance |
Chapter 13 | Drug Registration Prescribed Timeline |
Chapter 14 | Reconsideration |
Chapter 15 | Legal Liability |
Chapter 16 | Miscellaneous |
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Annex 1 | Registration Categories and Application Information Requirements of TCM and Natural Drugs |
Annex 2 | Registration Categories and Application Information Requirements of Chemical Drugs |
Annex 3 | Registration Categories and Application Information Items Requirements of Biological Products |
Annex 4 | Registration Items and Application Information Requirements of Supplemental Application of Drug Registration |
Annex 5 | Application Information Items of Drug Re-Registration |
Chapter 1: General Principles
Article 1: This Regulation is promulgated according to the Drug Administration Law of The People’s Republic of China (Drug Administration Law) and the Implementing Regulation of the Drug Administration Law of The People’s Republic of China (Implementing Regulation) to ensure the safety, efficacy and quality control of drugs and standardize drug registration.
Article 2: This Regulation shall apply to all drug research and clinical studies, application for clinical study, drug production or importation, as well as the related drug registration inspection and drug administration in The People’s Republic of China (PRC).
Article 3: Drug registration means the legal process by which a decision is made by SFDA, upon application of registration applicant, to either approve or not approve the conducting of a drug clinical trial, production or importation of a drug to be marketed, based on a systematic evaluation of the safety, efficacy and quality control of the drug.
Article 4: The State shall encourage research and development of new drugs and exercise fast track approval for innovative new drugs, those for difficult to treat and life threatening diseases, and drugs needed for emergency use.
Article 5: The State Food and Drug Administration (SFDA) is the competent national authority for drug registration, responsible for the review and approval of clinical studies, production and importation of drugs.
Provincial Drug Authorities (PDA) shall be authorized by SFDA to examine the completeness, standardization and authenticity of an application dossier, and organize inspection of the pilot manufactured drugs.
Article 6: A drug registration applicant (applicant) means an institution which makes application for and assumes corresponding liability for drug registration, and holds the drug approval certificate after approval has been obtained.
A local applicant shall be a legally registered institution in
The person handling the drug registration application shall have technical expertise, and be familiar with drug administration laws, regulations and technical requirements.
Chapter 2: Application for Drug Registration
Article 7: Drug registration application includes application for new drug, application for a drug already with national standards, and application for import drug as well supplemental application. A local applicant shall make application according to new drug or a drug already with national standards; a foreign applicant shall make application according to import drug.
Article 8: A new drug application means a registration application for a drug that has not been marketed in
Application for a drug already with national standards means application for production of a drug for which SFDA has already issued formal standards.
Application for import drug means application for a drug produced outside
Supplemental application means an application for the change, addition, or cancellation of any item or contents in the existing registration approval of a new drug, drug already with national standards, or import drug.
Article 9: Application for registration shall be made to PDA with submission of relevant documents and drug samples. However, application for import drug shall be made to SFDA.
Applicant should assume the liability for the truthfulness of all the application dossier..
Article 10: If two or more institutions jointly apply for new drug registration, the application shall be made to the PDA where the drug manufacturer is located. If all the applicants are manufacturers, the application shall be made to the PDA where the drug manufacturer of the preparation is located. If none of the applicants is a drug manufacturer, the application shall be made to the PDA where the drug sample is pilot manufactured.
Article 11: Regarding the drug or its formulation, manufacture processing, indication etc. the applicant shall submit documents explaining the
Article 12: If an infringement dispute occurs after completion of registration, the parties shall try to negotiate a resolution, or resolve the matter according to relevant laws, regulations, or rules through judicial organs or patent administration institutions.
Once there is a final rule from the Patent Administration or an enforcement judgment from People』 Court to determine the fact of infringement, Patent holder may apply at SFDA for cancellation of drug approval number of infringing party. SFDA shall based on the facts, cancel the certified drug approval of infringing party.
Article 13: For a drug that has obtained patent protection in
Article 14: For a period of 6 years from the date of the original applicant's approval, SFDA shall not approve a subsequent application that used, without the express consent of the original applicant, the undisclosed R&D data and other data generated by the original applicant for submission of application of manufacturing or marketing of a drug containing new chemical ingredients unless the submitted data is generated by the subsequent applicant itself.
Chapter 3: Pre-clinical Laboratory Study of Drugs
Article 15: The scope of pre-clinical laboratory study (pre-clinical study) of a drug for registration includes synthetic process, extraction methods, physical-chemical properties and purity, dosage form selection, screening of formulas, preparation process, inspection methods, specification, stability, pharmacology, toxicology and pharmacokinetic study. For TCM preparations, information such as the source and the processing of raw materials should also be included. For biological products, information such as specification, storage condition, genetic stability and immunology study of strain, cell strain as well as biological tissue should also be included.
Article 16: Pre-clinical study of a drug shall be conducted in accordance with relevant regulations; the drug safety evaluation shall be conducted in accordance with Good Laboratory Practice for Pre-Clinical Laboratory Studies (GLP).
Article 17: Institutions engaged in drug research and development shall have the necessary personnel, facility, equipment, instruments, conditions and management system needed corresponding to the research project. The animals, reagents and raw materials used for experiments shall comply with relevant national regulations and requirements. The authenticity of all data and materials shall be ensured.
Article 18: When an application is only made for registration of preparation, the raw materials of the investigative drug substance used for this preparation shall have a Drug Approval Number, Import Drug Certificate or Pharmaceutical Product Certificate, and the raw materials shall have been obtained from legal channels. Relevant certified documents should be provided if the drug substances registered by other party or still pending the approval process have been used. Any investigative drug substance which does not have a Drug Approval Number, Import Drug Certificate or Pharmaceutical Product Certificate shall go through SFDA approval process.
Article 19: If an applicant authorizes another institution to conduct the study of drugs, or any single experiment, inspection or pilot production and manufacture, the applicant shall sign a contract with the authorized party and maintain responsibility for the authenticity of study data.
Article 20: If an applicant uses the pre-clinical study documents from a foreign drug research institution as supporting materials for a drug registration application, an explanation for the items referencing the page numbers shall be provided by the institution and notarized certificate of the institution's legal overseas registration shall be attached. Only after the documents are authenticated by SFDA may they be included in the registration documents. SFDA may send people to conduct on-site inspections, if necessary.
Article 21: When there is a need to audit and inspect drug studies, SFDA and PDA may request the applicant or the drug research institute which conducted the experiments to repeat an experiment for any items by using the methods and data listed in the application dossier, and SFDA and PDA may send people to conduct on-site inspections of the experiment process. SFDA may also designate other drug control institutes or drug research institutions to repeat the experiments.
Article 22: The pre-clinical study of drugs shall be conducted in accordance with relevant technical guidelines issued by SFDA. If the applicant conducts the experiments according to other methods and techniques, the applicant shall provide information to evidence that the methods and techniques are scientific.
Chapter 4: Clinical Study of Drugs
Section 1: Basic Requirements
Article 23: Clinical study of drugs includes clinical trials and bioequivalence trials.
Only after approval from SFDA may a clinical trial study be conducted, and it shall be conducted in accordance with Good Clinical Practice (GCP).
Article 24: Clinical trials shall be conducted for the registration of a new drug.
Clinical trials are divided into Phase I, Phase II, Phase III and Phase IV. Clinical trials of Phase I, Phase II and Phase III are needed for a new drug application. In some cases only Phase II and Phase III clinical trials or, only Phase III clinical trials, are needed for a new drug application.
Phase I: Basic clinical pharmacology and human safety evaluation studies. To observe tolerance in human bodies and pharmacokinetics, providing a basis for a drug administration program.
Phase II: A preliminary exploration on the therapeutic efficacy. The purpose is to evaluate the safety and efficacy of a new drug on patients within the target indication of the drugs, and providing the basis to devise Phase III Clinical Trial and to determine a drug administration program. Phase II Clinical Trial may be conducted in many ways including randomized blind controlled clinical trial in accordance with the purpose of the study.
Phase III: The phase to confirm the therapeutic efficacy. The purpose is to further verify the safety and efficacy of a new drug for patients with targeted indication, to evaluate the benefit and risks relationship, and finally to provide sufficient data to support the registration approval of the drug. The trials usually are randomized, blind and controlled clinical trial with a large number of sample subjects.
Phase IV: A new drug post-marketing study, conducted by the applicant. The objective is to investigate the efficacy and adverse reactions under the conditions of wide use, and to evaluate the benefit and risk relationship when used by ordinary and special groups of patients and to improve dosage of the drug.
Article 25: Generally there is no need for clinical studies for the registration of a drug already with national standards. If clinical studies are needed, for a chemical drug only bioequivalence trials may be required. If the drug quality has to be controlled through the production processes and standards, clinical trials shall be conducted. For a supplemental application for a drug already marketed, clinical studies shall be conducted for an additional indication, or a significant change in the production process, or for any additional indication of TCM.
Bioequivalence Trials refers to the human trials of Bioequivalence study, where statistical difference of absorption degree and speed of active components, in term of parameter of pharmacokinetics, will be determined by comparison the same or different dosage form of the preparation at the same test conditions,
Article 26: The number of cases in the clinical study of a drug should be decided in accordance with the objective of the clinical trials and shall meet both the statistical requirements and the minimal cases required by this Regulation for a clinical study. For a drug used for the treatment of rare and special diseases or other special circumstances, any reduction in the number of cases in the clinical study or exemption must be approved by SFDA.
Article 27: For a vaccine and other special drugs prepared during the strains selection stage, if there is neither suitable animal experimental model nor a way to evaluate the efficacy of the drugs in laboratory study, application of clinical trials may made to SFDA, provided that safety of the subjects can be ensured.
Section 2: Requirements Before Implementation
Article 28: After approval of a clinical study, the applicant shall select qualified institutions to conduct the clinical study, negotiate and determine leading institution, principal investigator and participating institutions.
Article 29: The applicant shall sign a Clinical Trial Agreement with the leading and the participating institutes selected for the clinical study, and then provide the draft Informed Consent Form and Investigator’s Brochure, jointly improve the clinical trial protocol with reference to technical guidelines.
The applicant shall request the Ethics Committee of the institutions to review the clinical trial protocol.
Article 30: The applicant shall provide the institutions with the investigational drugs and comparator drugs (expect for Phase IV clinical trials) together with COA of drug samples, at no charge. The applicant shall bear the costs related to conducting the clinical study.
Article 31: The investigational drugs shall be produced in a workshop which meets GMP requirements and the production process shall be strictly in accordance with the requirements of GMP.
SFDA or the authorized PDA may conduct on-site audit, as necessary.
Article 32: The applicant may inspect the investigational drug itself in accordance with the drug's standards approved by SFDA, or authorize a drug control institute designated by Article 147 and Article 148 of this Regulation to conduct the quality test. The drug may not be used for Clinical Trails before it has passed the inspection. SFDA may designate a drug control institute to conduct a random inspection for the investigational drug.
Vaccine, blood products and other bio-products designated by SFDA as well as investigational drugs produced overseas must be inspected by a drug control institute designated by SFDA. The drug may not be used before it has passed the inspection. The applicant assumes all responsibility for the quality of the investigational drug.
Article 33: Before conducting the clinical study, the applicant shall file with SFDA information such as the clinical study protocol, name of the principle investigator of the leading institution, participating institutions and investigators, approval letter from ethics committee, and the sample of the Informed Consent Form, also providing a copy to the PDA where the institutions are located.
Section 3: Administration of a Clinical Study
Article 34: During the clinical study, the applicant shall designate inspectors to monitor the implementation of GCP.
Article 35: If an applicant discovers that an institution conducting clinical study is in violation of relevant regulations, or is not following the clinical study protocol, the applicant shall try to correct the situation. For serious violation, the applicant may request to suspend or stop the clinical study and shall submit a written report to SFDA and the relevant PDA.
Article 36: Upon the completion of each phase of the clinical study, the applicant shall submit a clinical study and statistical analysis report to SFDA and relevant PDA.
If the duration of clinical study exceeds 1 year, the applicant shall submit an annual clinical study progress report to SFDA and relevant PDA from the date of the approval of the study.
Article 37: A clinical study shall start within 2 years of approval. Otherwise the approval certificate shall automatically become null and void. A re-application shall be submitted to resume the study.
Article 38: The institutions and personnel participating in the clinical study shall be familiar with the characteristics, therapeutic activities, efficacy and safety of the investigational drugs and clearly understand their responsibility and liabilities, obtain Informed Consent Forms signed voluntarily by the subjects, keep accurate and true clinical study records.
Article 39: If an applicant violates GCP or requests to change the data and conclusions of clinical study, the participating institutions and personnel shall report the circumstances to PDA and SFDA.
Article 40: The institutions and investigators participating in the clinical study shall be responsible for taking all necessary measures to ensure the safety of the subjects.
During the clinical study the investigator shall carefully watch for the occurrence of adverse events, adopt appropriate measures, and keep a record.
The institutions shall report a serious adverse event to PDA and SFDA within 24 hours of occurrence, and immediately report to the Ethics Committee.
Article 41: SFDA and PDA shall conduct inspection or data audits for the approved clinical study.
Article 42: SFDA may request the applicant to amend the clinical study protocol, suspend or stop the clinical study in any of the following circumstances:
1)the Ethics Committee has failed to perform its duty; or;
2)the safety of the subjects cannot be effectively ensured;
3)serious adverse event was not timely reported;
4)the clinical study progress report was not timely submitted,
5)the completion of the clinical study is more than 2 years behind the original completion date and there are still no results which can be evaluated;
6)evidence that the investigative drug is not effective;
7)quality problems in the drug used for clinical trials;
8)fraud in the clinical study;
9)other circumstances violating GCP.
Article 43: The applicant or institutions shall implement the decision regarding amendment of the clinical study protocol, or suspension or cessation of the clinical study made by SFDA
Article 44: During the clinical study, in case a large range or unexpected adverse reaction or serious adverse event occurs, or there is evidence to prove that the investigational drug has significant quality problems, SFDA or PDA may adopt emergency mandatory administrative measures to suspend or stop the clinical study, and the applicant and institutions must immediately stop the study.
Article 45: The investigators shall be responsible for use of the investigational drug and ensure the investigational drug is only used by the subjects of the study and the dosage and usage of the drug are in accordance to the clinical study protocol. The investigators shall not give the drug to any person not participating in the clinical study. The investigational drug shall not be sold.
Article 46: A foreign applicant who wants to conduct an international multi–center clinical study shall apply at SFDA in accordance with the following provisions:
1)The drug used for an international multi–center clinical study shall be one already registered in a foreign country or in phase II or phase III clinical trials. An application for an international multi–center clinical study of new preventive vaccine from a foreign applicant still not registered outside
2)In approving an international multi–center clinical study in
3)During a study conducted in
4)Upon the completion of the study, the Applicant shall submit the complete clinical study report to SFDA.
5)Data generated from an international multi–center clinical trial used for drug registration in
Chapter 5: Application and Approval of New Drugs
Section 1: Basic Requirements
Article 47: The application dossier submitted for new drug registration shall be complete and standardized with authentic and reliable data. In citing literature and materials, the name of the work
Article 48: SFDA may use fast track approval process for the following new drug:
1)New active ingredients and its preparation extracted from TCM, natural drugs, or preparation made of material from plant, animal and minerals, which have not been marketed in
2)drug raw material and its preparations, and biological product that have not been marketed domestically or outside
3)new antiviral drug for AIDS and drug used for diagnosis and prevention of AIDS, cancer and orphan drug;
4)new drugs which treat diseases for which there is no effective therapy.
5)Drugs needed for emergency.
Article 49: After receipt of an application for a drug described in Article 48 of this Regulation, PDA shall examine and made recommendations as to whether the application meets the requirements for fast track approval. Upon receipt of PDA recommendations, SFDA shall then decide whether to use fast track approval for the drug application.
Article 50: When a new drug is jointly developed, the application shall be made by one of the parties, and other parties shall not apply. When a joint application needs to be made, the application shall be signed by all the parties. Except for a drug described in Article 48.1 and 48.2, after approval, the new drug shall only be manufactured by one party. Different strengths of one drug shall not be manufactured by different parties.
No one should attempt to make different applicant to apply for registration for the same technology of new drug, or make repeat application in any way. SFDA and PDA will organize the related inspection, if any needs. Once the foresaid fact is confirmed, the application will not be accepted, and the application will be returned if already accepted.
Article 51: During review process of new drug, even if the marketing approval of other domestic drug of the same active substance is approved overseas, the registration category and technical requirements of the drug shall remain unchanged in the review process in
During the review process of new drug, even when the marketing approval of other domestic drug of the same active substance is approved in
Section 2: Approval of Clinical Study for New Drugs
Article 52: Upon the completion of the pre-clinical study, the applicant shall complete the Application Form for Registration of New Drugs, and submit the authentic materials and sample drugs to PDA.
Article 53: PDA shall examine for form the application dossier, and if the requirement are met, the application will be accepted with issuing of acceptance notification of drug registration application. If the requirements are not met, the application will not be accepted with issuing of non-acceptance notification of drug registration application, with explanation of reasons.
PDA shall, within 5 days upon acceptance of the application, organize and conduct on-site inspection for production and research of the drug, take sample drugs of 1-3 batches, and notify the drug control institute for inspection. PDA shall, within the prescribed time limit, submit recommendations, inspection report and application dossier to SFDA, and notify the applicant.
Article 54: The drug control institute shall conduct drug inspections and drug standard inspection upon receiving notification, and submit the inspection reports to SFDA within the described time, notify the PDA which requested the inspection, and notify the applicant.
Article 55: Upon receipt of the application dossier, SFDA shall organizes the pharmaceutical, medicals and other technical people to conduct technical review of the new drug, and SFDA may request the applicant to provide supplemental information and drug sample. When SFDA consider the requirements are met, Approval for Drug Clinical Study will be issued. When SFDA does not consider the requirements are met, Notification of Approval Opinion will be issued with explanation.
Article 56: Upon receipt of verification recommendation, if the drug control institute concludes that the quality cannot be controlled by the drug standards, the applicant may withdraw the new drug application. If the applicant did not withdraw the new drug application, when SFDA proves the quality indeed cannot be controlled by the drug standards through a technical review, the application shall be returned.
Article 57: After inspection, if the drug sample does not meet the submitted drug standards, after verification, SFDA shall return the application of new drug.
Article 58: During SFDA's drug application review process, except for new information related to the innovative drug ingredients or drug safety, or the supplemental information required by SFDA, the applicant shall not submit supplemental technical material to SFDA. If new technical materials must be added, the applicant shall withdraw the application, and re-apply according to the original application procedures.
Article 59: For those withdrawn or returned application, after further studies, if the requirements of the Regulation are met and there is no new drug of the same kind enter into monitoring period, the original applicant may resubmit the application according to original application procedures.
Section 3: Approval of New Drug Production
Article 60: After completion of a clinical study, the applicant shall fill out the Drug Registration Form, and submit clinical study information, changes and supplemental information, with detailed explanation and justifications, to the PDA where the applicant is located. At the same time, the applicant shall submit raw material for the preparation of the standard substance to NICPBP.
Article 61: PDA shall examine for form the application dossier, and if the requirement are met, the application will be accepted with issuing of acceptance notification of drug registration application. If the requirements are not met, the application will not be accepted with issuing of non-acceptance notification of drug registration application, with explanation of reasons.
Article 62: PDA shall, within 5 days upon acceptance of the application, organize and conduct on-site inspection for production and research of the drug, take sample drugs of 3 consecutive batches, and notify the drug control institute for inspection. Upon completion, PDA shall, within the prescribed time limit, submit recommendations and , inspection report and application dossier to SFDA, and notify the applicant..
Article 63: The 3 consecutive batches of sample product used for new drug application shall be manufactured in a workshop with the GMP Certificate. For a newly established drug manufacturing enterprise or workshop or for the manufacture additional drug dosage forms, the production process of the sample product shall be in accordance with the requirements of GMP.
Article 64: The notified drug control institute shall inspect the sample product taken for registration inspection, and submit the drug inspection report within the prescribed time, send copies to the PDA which requested the inspection, and notify the applicant.
Article 65: Upon receipt of the application dossier, SFDA shall conduct a comprehensive review of the application dossier, and SFDA may request the applicant to provide supplemental information. SFDA will issue its decision through Drug Registration Approval Form. An application which meets requirements shall be issued a New Drug Certificate. If the applicant already has a Drug Manufacturing License and meets the necessary conditions for manufacture, the Drug Approval Number will also be issued at the same time. When SFDA does not consider the requirements are met, Notification of Approval Opinion will be issued with explanation.
Article 66: The insert sheet shall be approved by SFDA according to materials submitted by the applicant. SFDA shall simultaneously issue a registration standard and insert sheet in approving a new drug. The manufacturer shall be responsible for correctness and accuracy of the insert sheet, and monitor the efficacy and safety of the drug after launch, and apply to modify the insert sheet, if necessary.
Drug manufacture enterprise should be responsible for monitoring the post-marketing safety and efficacy of the drug, and if necessary, timely apply for revision of the insert sheet.
The insert sheet shall be printed according to relevant SFDA regulations.
Article 67: The 3 batches of new drug used for the new drug application, after passing the inspection by NICPBP and obtaining a Drug Approval Number, those manufactured in the workshop with Drug Manufacturing License and GMP Certificate may be sold within the expiration date.
Section 4: Administration of Monitoring Period of New Drugs
Article 68: In order to ensure public health, SFDA may implement a monitoring period for the approved new drugs to be produced so as to continue the safety monitoring of the new drug.
During the monitoring period, SFDA shall not approve production and/or importation of the drug by other enterprises.
Article 69: Different monitoring period will be set for different new drugs based on the existing safety information and research from inside and outside
Article 70: During the monitoring period of a new drug, drug manufacture enterprise shall regularly inspect the production process, quality, stability, efficacy and adverse reaction, and annually report to PDA.
When a serious quality problem, or serious or unexpected adverse reactions is discovered by relevant institutions of drug manufacture, distribution, use or inspection, or administration, it shall be reported to PDA immediately.
Article 71: PDA shall organize an investigation of a drug with serious quality problems, serious and / or unexpected adverse reactions, and report to SFDA.
Article 72: PDA shall order an enterprise that fails to fulfill its responsibilities within the drug-monitoring period to take corrective action.
Article 73: If a new drug with a monitoring period has not begun production within 2 years from the approval date, SFDA may approve the production application for the new drug of another applicant and continue to monitor.
Article 74: As a new drug enters monitoring period, for an application whose clinical study has already been approved by SFDA, the application shall continue in the regular review process. SFDA may approve the production or importation of an application meeting requirements; monitor the new drug within the monitoring period of the previously approved new drug.
Article 75: As a new drug enters the monitoring period, for an application which has been accepted but whose clinical study has not been approved by SFDA, the application shall be returned. Upon the completion of monitoring period, another applicant may apply as for a drug already with national standards.
Article 76: For an import drug that has already received marketing approval, for an application whose clinical study has already been approved, the application may continue in the regular review process. SFDA may approve the production of a drug whose application meets the requirements. The applicant may withdraw the application and apply as for a drug already with national standards.For an application which has been accepted but whose clinical study has not been approved, the application shall be returned and application shall be made as for a drug already with national standard
Section 5: New Drug Technology Transfer
Article 77: New drug technology transfer means the process by which the owner of a New Drug Certificate transfers its new drug processing technology to a drug manufacturing enterprise that will apply for the drug production.
Article 78: The transferor usually is a party holding a New Drug Certificate. In the event that a Drug Approval Number has been obtained, the application for cancellation of the Drug Approval Number should also be made at the time of the application for new drug technology transfer.
Article 79: The new drug technology shall be transferred in whole at one time to a pharmaceutical production enterprise. If the transferee for special reasons is unable to produce the drugs, the holder of New Drug Certificate may re-transfer the technology by evidencing a written waiver to produce the drugs from the original transferee. SFDA shall cancel the Drug Approval Number from the original transferee in accordance with requirements.
A transferee may not re-transfer the technology to any other party.
Article 80: The transferee shall have obtained a Drug Manufacturing License, GMP Certificate and the new drug shall be consistent with the production scope described in Drug Manufacturing License and GMP Certificate of the transferee.
In the newly established drug manufacture enterprise, newly established drug manufacture workshop of any enterprise and / or for a newly added dosage form, if the GMP Certificate has not been obtained for the corresponding scope, GMP Certificate should be obtained within the time limit setout in Article 6 of Implementing Regulation. The drug with an approval number cannot be marketed before the certificate is obtained.
Article 81: In transferring the new drug technology, the transferor shall sign a Technology Transfer Contract with the transferee and transfer all technology and materials to the transferee without reservation, and guide the transferee in trial manufacture of 3 continuous batches of qualified products.
Article 82: For a new drug technology jointly developed by more than one party, any transfer should be made by all the signatories of the New Drug Certificate, who will sign a Technology Transfer Contract.
Article 83: An application for a new drug technical transfer shall be jointly submitted by the owner of the New Drug Certificate and the transferee at PDA where the transferee is located. The applicant shall complete the Drug Supplemental Application Form, submit relevant materials and the Technology Transfer Contract shall be attached.
Article 84: Upon acceptance of the application for a new drug technology transfer, PDA shall inspect the trial production site, equipment, production of sample products and inspection records of the transferee, take sample product and notify the drug control institute for drug inspection.
Article 85: The drug control institute responsible for drug inspection shall complete inspection within the prescribed time, issue an inspection report and submit it to PDA.
Article 86: PDA shall examine the inspection report it has received and the relevant information provided by the drug control institute, make recommendations and report to SFDA, and notify the applicant about the recommendations.
Article 87: SFDA shall conduct a comprehensive review of the supplemental application of new drug technology transfer, and issue an Approval for Clinical Study of Drugs, if a clinical study is needed.
Upon the completion of the clinical study, the applicant shall submit clinical study information to SFDA.
Article 88: SFDA shall issue its decision on whether to approve the production through Drug Supplemental Application Approval Form. If the requirements are met, Drug Approval Number will be issued. If the Drug Approval Number has already been issued to the transferor, it shall be canceled. When SFDA does not consider the requirements are met, Notification of Approval Opinion will be issued with explanation.
Article 89: No new drug technology transfer is allowed for the drug within its monitoring period. After the monitoring period, applicant may make application of drug already with National Standards.
Chapter 6: Application and Approval of Drugs Already withNational Standards
Article 90: To apply as for a drug already with national standards, the applicant shall hold Drug Manufacturing License, and GMP Certificate. The drug for which application is made shall be consistent with the production scope described in Drugs Manufacturing License and GMP Certificate of the enterprises.
Article 91: A newly established drug manufacturing enterprise or workshop or the production of additional drug dosage forms without GMP Certificate shall obtain GMP Certificate within the time prescribed in Article 6 of Implementing Regulation. The drug with an approval number cannot be marketed before the certificate is obtained.
Article 92: After completion of pilot production according to relevant technical requirements, the applicant shall complete the Application Form for Drug Registration and submit relevant technical materials and sample products to PDA.
Article 93: PDA shall examine for form the application dossier, and if the requirement are met, the application will be accepted with issuing of acceptance notification of drug registration application. If the requirements are not met, the application will not be accepted with issuing of non-acceptance notification of drug registration application, with explanation of reasons.
PDA shall, within 5 days upon acceptance of the application, organize and conduct on-site inspection for production and research of the drug, take sample drugs of 3 consecutive batches, and notify the drug control institute for inspection. Upon completion, PDA shall, within the prescribed time limit, submit recommendations and , inspection report and application dossier to SFDA, and notify the applicant.
Article 94: The notified drug control institute shall inspect the 3 batches of the sample products taken for registration inspection, and submit the drug inspection report within the prescribed time, send copies to PDA requesting the inspection and notify the applicant.
Article 95: SFDA shall conduct review of the application dossier submitted by PDA, and SFDA may request the applicant to provide supplemental information. If a clinical study is needed, SFDA shall issue an Approval for Clinical Study of Drugs.
After completion of the clinical studies, the applicant shall submit the clinical study information to SFDA.
Article 96: SFDA shall issue its decision of whether to approve the production of the drug through the Drug Registration Approval decision form. If the requirements are met, a Drug Approval Number will be issued. When SFDA does not consider the requirements are met, Notification of Approval Opinion will be issued with explanation.
Article 97: No application will be accepted by SFDA or PDA for registration of drug with temporary national standards.
Article 98: SFDA may suspend the acceptance and approval of the application of a drug already with National Standards when there is a need to further evaluate the efficacy and safety of the drug.
Article 99: The 3 batches of new drug used for the application of a Drug Approval Number manufactured in the workshop with Drug Manufacturing License and GMP Certificate, after passing the inspection by the drug control institute designated by SFDA and obtaining a Drug Approval Number, may be sold within the expiration date of the drugs.
Chapter 7: Application and Approval for Import Drugs
Section 1: Registration of Import Drugs
Article 100: An import drug, for which application is made, shall have obtained marketing approval in its country/region of manufacture. An import drug without such a marketing approval may still be approved after SFDA confirms the safety and efficacy of the kind of drug, and there is a clinical need for the drug.
The drug for which import application is made shall meet the GMP standard in the foreign country / region as well as the requirements of GMP in
Article 101: For an import drug application, the applicant shall complete Application Form for Drug Registration and submit the relevant application dossier and sample product and relevant certified documents. The application shall be made with SFDA.
Article 102: SFDA shall examine for form the application dossier, if the requirements are met, the application shall be accepted, and an acceptance notification shall be issued. SFDA shall notify NICPBP for drug registration inspection. When SFDA does not consider the requirements are met, Notification of Non- Acceptance will be issued with explanation. SFDA may organize the on-site inspection about the research status and manufacturing condition, if necessary.
Article 103: Upon completion of the drug inspection, NICPBP shall submit the verified drug standards, the drug inspection report and inspection recommendations to SFDA.
Article 104: SFDA shall conduct a comprehensive review of the application dossier submitted and if necessary SFDA may request the applicant to provide supplemental information. SFDA shall issue its decision of whether clinical study is approved through Approval of Clinical Study of Drugs Form. When SFDA does not consider the requirements are met, Notification of Approval Opinion will be issued with explanation
Article 105: Upon approval of the clinical study, the applicant shall conduct the clinical study in accordance with the provision under Chapter 4 of this Regulation.
Upon the completion of clinical study, the applicant shall, in accordance with relevant requirements, submit to SFDA the clinical study report, sample products, relevant changes and supplemental information, with detailed explanation and justifications, and the relevant certified documents.
Article 106: SFDA shall organize and conduct a comprehensive review of the submitted clinical study information and if necessary SFDA may request the applicant to provide supplemental information. If the requirements are met, issue an Import Drug Certificate. Regulation for import drug will apply for applicants from
Article 107: For an import drug preparations application, documents to evidence the legal channels of immediate packaging materials or containers of the drug, documents to evidence the legal channels of drug raw material and supplemental material must be provided. For raw material and supplemental material of drug that has not been approved by SFDA, the information of relevant production processes, quality specification, and inspection methods should be submitted.
Article 108: SFDA shall simultaneously issue a registration standard and insert sheet in approving an import drug.
Section 2: Approval of Repackaging of Import Drugs
Article 109: Repackaging of import drugs means taking from offshore finished drug preparation in large packaging and putting them into smaller packaging, or taking drugs in smaller packaging and placing them into final (outside) packaging with an insert sheet, labeling, etc. in China.
Article 110: The application for repackaging of import drug shall comply with following requirements:
1)an Import Drug Certificate or Pharmaceutical Product Certificate has already been obtained for the import drugs;
2)the drug should not yet be manufactured in
3)the drug of one pharmaceutical company shall only be repackaged by one pharmaceutical production enterprise, generally for a period not exceeding the valid period of Import Drug Certificate or Pharmaceutical Product Certificate.
4)The onshore pharmaceutical production enterprise shall have a Drug Manufacturing License. If the tablet with no packing or capsule is to be repacked in
5)Any application for repacking of import drug should be made one year prior to expiration of Import Drug Certificate or Pharmaceutical Product Certificate.
Article 111: The offshore pharmaceutical company shall sign a Repackaging Contract for Import Drugs with an onshore pharmaceutical production enterprise, complete the Drug Supplemental Application Form.
Article 112: An application for repackaging a drug shall be submitted by the onshore pharmaceutical production enterprise to the PDA where the party is located, and the Drug Supplemental Application Form signed by the offshore pharmaceutical company should be submitted with the relevant information and sample products. PDA shall examine for form the application dossier, and if the requirements are met, the application will be accepted with issuing of acceptance notification of drug registration application. If the requirements are not met, the application will not be accepted with issuing of non-acceptance notification of drug registration application, with explanation of reasons.
PDA should make recommendation after completion of the review process and submit the application dossier and recommendation to SFDA for approval, and notify the applicant.
Article 113: Upon receipt of the application dossier, SFDA shall review the submission. When SFDA consider the requirements are met, Approval for Drug Supplemental Application and Drug Approval Number will be issued. When SFDA does not consider the requirements are met, Notification of Approval Opinion will be issued with explanation.
Article 114: The registration standards for the import drug shall be applied to the repackaged drug.
Article 115: The package, label and insert sheet of a repackaged drug shall be consistent with that of the import drug to be repacked, and shall include the approval number for drug to be repacked and name of the drug repackaging manufacturer.
Article 116: The import inspection of finished drug preparations in large packaging should be conducted in accordance with SFDA regulations. The same standards shall be applied to both the inspection of the repackaged drug and import drug.
Article 117: The offshore pharmaceutical company shall be responsible for the quality of the repackaged drugs. If a quality problem arisen, SFDA may cancel the approval number of the drug repackaging, and if necessary, cancel the Import Drug Certificate or Pharmaceutical Product Certificate of the drug in accordance with Article 42 of Drug Administration Law.
Chapter 8: Application and Approval for OTC Drugs
Article118: An OTC drug means a drug designated by SFDA, for which consumers may purchase and use by own judgment without a prescription from a practicing physician or a practicing assistant physician.
Article 119: In the following circumstances, an applicant may apply for OTC drug registration, in making drug application:
1)the production and / or importation of OTC drugs already with national standards;
2)change in dosage form, but without change in indications, dosage, route of administration of an OTC drug as designated by SFDA;
3)new combination preparations developed from active OTC ingredients designated by SFDA.
Article 120: For a drug meeting the requirement of Article 119.1), applicant should check the OTC items in the 「supplemental application item」 of the Drug Registration Form. SFDA shall designate the drug as OTC in approving its registration. In the event of failure to check the OTC items in the Drug Registration Form, after SFDA approved the drug registration, applicant should proceed the registration according to the Regulation of Categorized Administration of Prescription Drug and OTC Drugs (temporary) and the provision of OTC registration.
Article 121: For a drug meeting the requirement of Article 119.2) or 3), applicant should check the OTC items in the 「supplemental application item」 of the Drug Registration Form. When SFDA consider the drug meet the OTC drug requirement, SFDA shall designate the drug as OTC in approving its registration. When SFDA does not consider the drug meet the OTC drug requirement, SFDA shall approve the drug as prescription drug. .
Article 123: Generally, for a drug meeting the requirement of Article 119.1) or 2), a clinical study is not needed. However, bioequivalence trials may be needed for solid oral dosage forms of drug. A clinical trial setout in this Regulation is needed for TCM preparation.
Article 124: For a drug meeting the requirement of Article 119.3), basis of formula should be explained, and if necessary, a clinical study is needed.
Article 125: OTC regulation should apply for OTC registration, drug insert sheet and packing as well as label. Prescription regulation should apply for other application information.
Article 126: Import drug application and approval process should apply for application of import OTC drug, where technical requirement of import OTC drug should e the same of the domestic one.
Article 127: SFDA shall approve the re-registration application of import OTC drug based on the procedure of import drug re-registration application and approval process and OTC administration regulation. Applicant need not to complete OTC registration at PDA when applying the re-registration application of import OTC drug
Article 128: If an OTC drug has been approved by SFDA for marketing, but if during its use if discovered if is not suitable for use as OTC drug, SFDA can change the drug to prescription status.
Chapter 9: Supplemental Application for Drug Registration
Article 129: An applicant should submit a supplemental application for changes in the items in the drug approval certificate and its attached drug standards, insert sheet, content on the label, as well as a change in production process that might affect drug quality.
Article 130: The applicant shall complete the Supplemental Application Form, submit to PDA where the applicant is located with relevant documents and explanations. PDA shall examine for form the application dossier, and if the requirements are met, the application will be accepted with issuing of acceptance notification of drug registration application. If the requirements are not met, the application will not be accepted with issuing of non-acceptance notification of drug registration application, with explanation of reasons..
Article 131: For a supplemental application related to import drugs, the applicant shall apply to SFDA with relevant information and document, and the approval document of incorporating the change from the competent authorities of the foreign country or region where the drug is manufactured. SFDA shall examine for form the application dossier, and if the requirements are met, the application will be accepted with issuing of acceptance notification of drug registration application. If the requirements are not met, the application will not be accepted with issuing of non-acceptance notification of drug registration application, with explanation of reasons.
Article 132: For a supplemental application of change of enterprise name, amendment of drug packing and label as requirement by regulation, and amendment of insert sheet required by SFDA, the application should be accepted and approved by PDA. When PDA consider all the requirements are met, Approval of Drug Supplemental Application will be issued and file the approval at SFDA for record. If the requirements are not met, Notification of Approval Opinion will be issued with explanation.
Article 133: For a supplemental application for changes such as change of drug standards, change of supplemental materials, or addition of new indications or functions of TCM, , the application should be accepted by PDA, who shall submit review recommendations to SFDA for approval, and then notify the applicant.
Article 134 Any supplemental application related to an import drug shall be approved by SFDA. For some of supplemental application of import drug, such as amendment of insert sheet according to the National Standard or requirement of SFDA, supplementing and perfecting of safety related content of insert sheet, change of design of packing or label of import drug or drug appearance, change of registration agent, the application needs to be filed for record, and the applicant shall implement the supplemental application if SFDA has not commented within 30 days of its receipt by SFDA.
Article 135 For a supplemental application for a drug approval number by a New Drug Certificate holder, or for a change of drug manufacturing location and / or production process, PDA shall organize on-site inspection of the pilot production, take sample product for inspection, and notify the designated drug control institute to conduct inspection of the sample product.
For a supplemental application for change of drug standards, if necessary, drug control institute shall conduct a quality inspection of the standards.
Article 136 SFDA shall examine the supplemental application of a drug, and SFDA may request the applicant to provide supplemental information. When SFDA consider the requirements are met, Drug Supplementary Application Approval Form will be issued. When SFDA does not consider the requirements are met, Notification of Approval Opinion will be issued with explanation.
When the drug approval certificate needs to be renewed, the old drug approval certificate shall be canceled. When additional drug approval certificate needs to be issued, the old certificate shall continue to be effective.
Article 137 The expiration date of the Drug Supplementary Application Approval Form shall be same with the original certificate, upon expiration, re-application needs to be made for all certificates together.
Chapter 10: Re-registration of Drugs
Article 138: The re-registration of drug means the approval process for continuing the production and/or importation of the drug upon expiration of the current approval certificate of the drug.
Article 139: The validity period of the Drug Approval Number, the Import Drug Certificate and Pharmaceutical Product Certificate issued by SFDA is 5 years. 6 months prior to the expiration, application for re-registration shall be made.
Article 140: An applicant holding the Drug Approval Number shall apply for re-registration of the drug with PDA, complete the Application Form for Drug Re-registration according to relevant requirements and submit relevant application material.
The application for re-registration of an import drug shall be submitted to SFDA.
Article 141: PDA shall examine the application dossier, and if the requirement are met, the application will be accepted with issuing of acceptance notification of drug registration application. If the requirements are not met, the application will not be accepted with issuing of non-acceptance notification of drug registration application, with explanation of reasons..
Article 142: PDA shall issue review recommendation for the re-registration within 3 months, and submit to SFDA for examiniation.
Upon receipt of the recommendation, if there is no notification from SFDA not to approve the re- registration, PAD should approve the re-registration.
Article 143: SFDA shall complete review of the application for re-registration of the import drug within 6 months of receipt, and approve the re-registration of an application that meets the requirements.
Article 144: An application for re-registration shall not be accepted in any of the following situations:
1)failure in applying for re-registration of the drug within the prescribed time;
2)failure in meeting the relevant requirements of SFDA upon approval for marketing;
3)failure in completing Phase IV clinical trials according to relevant requirements;
4)failure in monitoring drug adverse reactions according to relevant requirements;
5)the kind of drug whose registration should be canceled based on the re-evaluation of SFDA,
6)the kind of drug that should be withdrawn according to the requirements of Drug Administration Law;
7)a drug which does not meet production requirements in the Drug Administration Law;
8)failure to fulfill the responsibility during the monitoring period; or,
9)other situations in which relevant requirements have not been met.
Article 145: In the event that relevant requirements of re-registration are not met, SFDA shall issue the notification of rejection of the drug for re-registration with explanations, and in addition to the certified drug approval document need to be canceled by regulation, the Drug Approval Number, Import Drug Certificate or Pharmaceutical Product Certificate of the drug shall be canceled before the valid period expire.
Chapter 11: Administration of Drug Inspection for Registration
Article 146: Drug reverse registration inspection must be conducted for application for registration. The inspection includes inspection of sample products and inspection of drug quality standards.
Inspection of sample products means a drug control institute conducts drug inspection according to the quality standards submitted by the applicant.
Inspection of drug quality standards means laboratory inspection by a drug control institute to verify the feasibility and scientific ness of inspection methods described in the quality standards of the drug and whether or not the assumed parameters can control the drug quality.
Article 147: Drug inspections for registration usually shall be conducted by the provincial drug control institute, inspections for import drug registration shall be conducted by NICPBP.
Article 148: Drug inspection shall be conducted by NICPBP or the designated drug control institute for the following:
1)a drug belonging to categories of Article 48.1 and 48.2 of this Regulation;
2)biological product;
3)other drugs designated by SFDA.
Article 149: The drug control institute shall give priority to a drug belonging to categories in Article 49 for inspection and verification.
Article 150: A drug control institute engaged in drug inspection for registration shall be staffed and equipped according to requirements of the Good Laboratory Practice of Drug Control Institutes and National Measurement Certification, and meet the needs of the quality assurance system and technical requirements of the drug registration inspection.
Article 151: The applicant shall provide the drug control institute with information needed for drug registration inspection, submit sample product or co-operate in taking sample products used for inspection, and provide the standard drug substance used for inspection. The amount of sample products supplied shall be three times the amount of the drug needed for inspection. For a biological product, the record of preparation and inspection for the corresponding batches shall also be provided.
Article 152: During the application for production of drugs already with national standards, the drug control institute shall conduct drug inspection according to national standards. A comprehensive analysis should be made to analyze the change in quality parameters caused by the changes in production process. If necessary, the institute shall request the applicant to establish necessary quality parameters to ensure the control of drugs quality.
Article 153: During the inspection of drug standards, in addition to inspection of the sample products, the drug control institute shall also issue an inspection recommendation regarding the drug standards of the drug, items to be inspected and inspection methods, based on the research data of the drug, the drug standards of similar products domestic and in the foreign countries as well as national requirements.
Before the issuance of inspection recommendations, the drug control institute should notify the applicant if necessary. If the applicant disagrees with the recommendations, it should file an objection with the drug control institute within 10 days. If the drug control institute disagrees with the applicant's objection (explanation), it shall submit the recommendation together with the applicant's explanation to SFDA with copies to the applicant and PDA which requested the drug registration inspection.
Article 154: In re-making a drug's standards, the applicant shall not authorize the drug control institute which issued the recommendations to conduct the research work. Similarly, such Institute shall not accept such authorization.
Chapter 12: Administration of Drug Registration Standards
Section 1: Basic Requirements
Article 155: 「National drug standards」 means the technical requirements for quality parameters, inspection methods and production processes of drugs established by the State to ensure the drug quality, including Pharmacopoeia of People’s Republic of China, drug registration standards and other drug standards issued by SFDA.
「Drug registration standards」 means the standards approved by SFDA for the specific drug of the applicant. The pharmaceutical production enterprise shall comply with the drug registration standards for the drug.
Article 156: The determination of items and inspection methods for drug registration standards shall meet the requirements of the technical guidance principles, relevant principles and rules for compiling national drug standards issued by SFDA.
Article 157: An applicant shall, conditioned on the stability of the quality of raw materials and production process, select representative sample products for the study of standards.
Section 2: Transfer of Temporary Drug Standards to
Formal Standards
Article 158: After approval of a new drug fo
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Article 158: After approval of a new drug for production, the quality standards of the new drug will be temporary standards for a trial period of 2 years. If after the approval of other drugs, the stability of production processes and quality standards needs further review, the quality standards may be approved as temporary standards.
Article 159: For the drug produced with temporary drug standards, three months prior to the expiration of temporary standards, the enterprise shall apply to transfer the temporary standards to formal standards at the PDA where the enterprise is located, by filling out the Drug Supplemental Application Form and with the submission of quality inspection information during the trial period of the drug standards and recommendations for modification of the temporary standards.
After approval of supplemental application of change of drug standards, if the drug standard is still temporary, the enterprise should apply to transfer the temporary standards to formal standards three months prior to the expiration of original temporary standards,
Article 160: PDA shall complete the review of the application for the transfer of temporary standards to formal standards within 10 days of receipt of the application, and submit the recommendations and relevant documents to SFDA.
Article 161: SFDA shall organize the State Pharmacopoeia Commission to examine the temporary standards of a drug.
The State Pharmacopoeia Commission shall, based on the use of the drugs during the period of the temporary standards, quality standards of the relevant products domestic and overseas and relevant national requirements, issue recommendations as to whether inspection of the temporary quality standards is needed. If an inspection is needed, the relevant drug control institute should be organized for inspection and inspection of the temporary standards, and other inspection work.
Article 162: If more than one pharmaceutical production enterprise manufactures the same drug, drug inspection and inspection of quality standards for transfer of temporary quality standards to formal standards should be conducted by NICPBP or drug control institute designated by SFDA.
Article 163: If more than one applicant has applied to transfer temporary standards of the same drug into formal standards, the proposed standards may not be lower than already approved drug standards. The subsequent applicant may include additional inspection items depending on the characteristics of its drug production process.
Article 164: When there is a need for supplemental test or supplemental inforation, upon receipt of the notification of stardard inspection or verification, applicant shall, within 50 days of notification for quality standard inspection, complete and update relevant supplemental experiment or information and submit to the PDA.
Article 165: SFDA shall comprehensively examine the information submitted by State Pharmacopoeia Commission, and when SFDA consider the requirements are met, Publication for National Drug Standard will be issued. When SFDA does not consider the requirements are met, Notification of Approval Opinion will be issued with explanation. At the same time, SFDA will cancel the temporary standards and the drug approval number approved according to the temporary standards. .
Article 166: For the same kind of drug with different trial period expiration dates, the drug with temporary standards which will first expire shall begin the process of transferring to formal standards. For the drug with temporary standards which will subsequently expire, the State Pharmacopoeia Commission shall notify the applicant to make early application to PDA to transfer to formal standards.
Article 167: If an applicant fails to apply to transfer to formal standards before the expiration of the temporary standards according to relevant regulations, SFDA shall cancel the temporary standards and the corresponding drug approval number for drug production.
During the application process to transfer of the temporary standards into formal standards, the pharmaceutical production enterprise shall continue to manufacture the drug in accordance with the requirements of the temporary standards.
Section 3: Establishment and Administration of Drug
Standard Substance
Article 168: Drug standard substance means a substance with specific values, used in physical, chemical inspection and biological methods inspection needed for the drug quality standards, and used to calibrate equipments, to evaluate the measuring methods or to assay the inspection drugs including standards, control products, raw material control products, and reference products.
Article 169: NICPBP shall be responsible for standardization and administration of national drug standard substances.
NICPBP may organize the relevant provincial drug control institute, research institutions or pharmaceutical production enterprise for cooperation in standardization and administration.
Article 170: During the application process for production of a new drug, the applicant shall provide NICPBP with raw materials needed for preparation and standardization of the standard substances, with the relevant research information of the standard substances.
Article 171: NICPBP shall be responsible for the comprehensive technical review of the standard substance regarding the selection of raw materials, production methods, standardization methods, standardization results, accuracy of assay values, tracing of origin of various values, stability and conditions for repackaging and packaging, to reach a conclusion as to whether they can be used as national standard substances.
Chapter 13: Drug Registration Prescribed Timeline
Article 172: SFDA and PDA shall publicly publish in the official website and registering office the condition, procedure, duration and list of all the document of application dossier needed for drug registration, as well as template of application forms.
Article 173: SFDA and PDA shall issue notification in writing of acceptance and non-acceptance of the drug registration application, which will be chopped, dated and server as future evidence.
Article 174: The prescribed timeline for drug registration means the maximum allowed time for the relevant review, inspection, and providing of supplemental information related to drug registration. If any work is finished within the timeline of drug registration, the dossier should be forwarded into the next step timely.
Article 175: Upon receipt of an application, PDA shall, within 5 days , notify the applicant in one notification all of supplemental information and incomplete information required by the examination, and in the event of failure to notify, the application will be deemed to consider as accepted.
Application should be accepted within 5 days for an application with complete information meeting the examination for form, or after applicant complete all the required supplemental information.
Article 176: Upon acceptance of the application, PDA shall begin within 5 days, and complete within 30 days the on-site inspection, taking of sample products, notification of the drug control institute for inspection of sample product and submission of the recommendation and inspection report together with information submitted by the applicant to SFDA, and at the same time, notify the applicant of the inspection recommendations.
Article 177: A drug control institute shall, within 30 days of receipt of the notification and sample products, complete the inspection and issue the inspection report.
The inspection for special drugs and vaccine products shall be completed within 60 days.
Article 178: If inspection of sample products and verification of drug standards are needed, drug control institutes shall complete such work within 60 days.
An inspection for special drugs and vaccine products shall be completed within 90 days.
Article 179: For registration of import drug, DA shall examine for form the application dossier, and if the requirements are met, the application will be accepted. SFDA shall begin the relevant work within 5 days, and complete examination of application information within 30 days, and notify NICPBP to conduct the inspection. SFDA shall, if necessary, organize on-site inspection of the research and production condition, and take sample products. .
When SFDA does not consider the requirements are met, SFDA shall within 5 days notify the applicant with explanation. Failure to notify the application should be deem as acceptance of application.
Article 180: NICPBP shall, within 5 days upon receipt of the information and the sample product, arrange for a drug control institute to conduct the inspection.
Article 181: The drug control institute responsible for inspection of import drug shall complete the inspection and submit to NICPBP within 60 days of receipt of the information, the sample products and the related standard substances.
Article 182: NICPBP shall organize the experts to conduct a technical review within 20 days of receipt of the inspected import drug standards, and conduct a re-inspection of specific items based on the review recommendation, if necessary.
Article 183: SFDA shall administer the technical review during the drug registration in accordance with the following prescribed timeline.
1)complete in 120 days for a new clinical study, complete in 100 days if a drug meets the requirements under Article 48 of this Regulation;
2)complete in 120 days for production of new drug, complete in 100 days if a drug meets the requirements under Article 48 of this Regulation; and,
3)complete in 80 days for application registration of a drug already with national standards.
4)Complete in 40 days for supplemental application if a technical review is needed.
This Article shall also apply to the technical review of import drugs.
Article 184: During the technical review, SFDA shall issue one notification regarding submission of all needed supplementary materials.
Except for application meeting the requirement of Article 48 of this Regulation, the applicant shall at one time submit all the required supplemental materials within 4 months. If the applicant fails to submit within the prescribed time SFDA shall return the application.
Article 185: If an applicant objects to providing the materials described in the notification for supplementary materials by SFDA, the applicant shall object within the prescribed time. If there is still disagreement, the applicant may submit a written report to SFDA, explaining its reasons and providing technical materials and the scientific basis to support its reasons. SFDA shall issue its decision after review.
Article 186: When an application is returned or withdrawn by the applicant, if the applicant need to re-apply, after the applicant supplements and completes relevant experiments and gathering of information, the application may be re-submitted following the original procedure.
If an application meets the provision of this regulation and there is no other drug of the same kind enter into monitoring period, SFDA or PDA should accept the application.
Article 187: Upon receipt of the supplemental information, SFDA shall complete the technical review within one third of original prescribed time, for a drug meets the requirements under Article 48, SFDA shall complete the technical review within one fourth of original prescribed time.
Article 188: SFDA shall complete the approval process within 20 days upon the completion of technical reviewFor a supplemental drug application that needs SFDA approval, SFDA shall complete the approval process within 20 days.
When approval cannot be completed with 20 days, an extension of 10 can be granted by approval from the management, and further extension exceeding 10 days will need approvals from State Council.
Article 189: The State Pharmacopoeia Commission shall complete the review of the transfer of temporary drug standards to formal standards within 60 days.
The responsible drug control institute shall complete the inspection for drug and quality standards within 60 days, and deliver the inspection recommendations and inspection report to the State Pharmacopoeia Commission. For special drugs and vaccine products, the inspection for drug and quality standards shall be completed within no more than 90 days and for same kind of drug manufactured by more than one manufacturer, shall be completed with 80 days.
Article 190: During the examination of drug registration application, SFDA or PDA should public pubis the approval procedure and approval result. For those matter of significant interest, the applicant and related party may submit written opinion as statement or for defending.
Article 191: When making decision of the drug registration application from lawful authority, SFDA and PDA shall issue notification in writing of registration acceptance or approval and registration non-acceptance or non- approval, with explanation of reminder that applicant is lawfully entitled to applying for re-consideration, administrative re-consideration or filing administrative lawsuit.
Article 192: SFDA and PDA shall notify applicant of the entitlement to applying for hearing. During drug registration, food and drug administration consider approval as an issue of significant public interest, the issues should be publicly announced and hearing should be held.
Article 193: Once a decision of drug registration approval is made, SFDA should, within 10 das, announce and deliver the decision.
Article 194: SFDA should periodically publicly publish over its official website a list of drug formulary of the drug already approved by SFDA to provides access for public retrieval.
Article 195: In special situations, if there is a need to extend the time limit for drug registration inspection or technical review, the extension should be submitted to SFDA for approval.
Article 196: If one of the provisions of Article 70 of Administrative Permitting Laws of People’s Republic of China (Administrative Permitting Laws) occurs, SFDA should proceed with the cancellation of relevant drug approval document.
Chapter 14: Reconsideration
Article 197: When an applicant object to the decision of non approval, before applying for administrative re-consideration, and filing an administrative lawsuit, the applicant may apply for reconsideration with SFDA within 10 days upon receipt of rejection decision for drug registration by filling out Drug Supplemental Application Form together with an explanation and its reasons.
The scope of reconsideration shall only be for original application items.
Article 198: SFDA shall complete the review and issue its decision and notify the applicant within 50 days upon receipt of the application for reconsideration. If SFDA maintains its original rejection decision, no further review will be given to the application.
Article 199: When there is a need for technical review during the reconsideration, SFDA shall organize the technical experts to complete the review within the original prescribed time.
Chapter 15: Legal Liability
Article 200: If one of the provisions of Article 69 of Administrative Permitting Laws occurs, SFDA should proceed with the cancellation of relevant drug approval document, based on the request of the related party or from its lawful authority.
Article 201: If an applicant is found to have provided fraudulent drug registration information and / or sample product of the drugs during the application of clinical study, SFDA shall not approve the application, and warn the applicant. No more new application for clinical trail from the same applicant will be accepted for one year. If the application has already been approved, the approval certificate shall be canceled, and a fine of RMB 10,000 - 30,000 shall be imposed. An application for the drug which is signed by this individual or institution shall not be accepted for 3 years.
A database of fraudulent conduct by applicants shall be maintained, and may be published.
Article 202: If an applicant is found to have provided fraudulent drug registration information and / or sample product of the drugs during the application of drug production or importation, SFDA shall not approve the application, and warn the applicant. No more new application for clinical trail from the same applicant will be accepted for one year. If the application of production and / or importation of the drugs has already been approved, the approval certificate shall be canceled, and a fine of RMB 10,000 - 30,000 shall be imposed, an application for the drug which is signed by this individual or institution not be accepted for 5 years.
A database of fraudulent conduct by applicants shall be maintained, and may be published.
Article 203: During the drug registration, if SFDA and /or PDA and its staff are found to violate the provisions of this regulation with one of the following occurrences, provisions of Article 72, Article 73, Article 74, and Article 72 of Administrative Permitting Laws shall apply:
1)Did not want to accept a drug regulation that met the lawful requirement.
2)Did not want to publicly publish the information items of drug registration.
3)Failure to fulfill obligation to notify applicant during the process of acceptance and approval.
4)Failure to notify the applicant in one notification of all the supplemental information that must be supplemented, when information submitted by applicant is incomplete or not meeting the statutory form.
5)Failure to explain the reasons not to accept or not to approval.
6)Approval of an application not meeting the requirement of this regulation, or approval made beyond its authority.
7)Decision to not approve an application meeting the requirement of this regulation, or failure to approve within the time limit set out in this regulation.
8)Collect fee with no consultation, or collect fee without reference to the statutory regulation.
9)Ask for or accept valuables or other interest from any party.
Article 204: Upon the cancellation of Drug Manufacturing License of a drug manufacturer, the Drug Approval Number held by the manufacturer shall subsequently become null and void, and shall be cancelled by SFDA, and the cancellation should be public announced.
Article 205: In the event that GLP or GCP requirements were not complied with during the drug registration, sanctions shall be imposed according to Article 79 of the Drug Administration Law.
Article 206: If a drug control institute issues a fraudulent inspection report during performance of its legal duty for drug inspection during the drug registration process, sanctions shall be imposed according to Article 87 of the Drug Administration Law.
Article 207: If provision of Article 21 calls for an experiment to be repeated, but an applicant refuses to repeat the experiment according to relevant requirements, the applicant shall be warned, and ordered to correct the situation. If the applicant refuses to make corrections, the application entitlement shall be canceled.
Chapter 16: Miscellaneous
Article 208: Format of Drug Approval Number should read Guoyaozhun H(Z, S, J)+ 4 digit of year + 4 digit of serial number, where H denote chemical drug, Z denote TCM, S denote biological products and J denote import drug.
Format of Import Drug License should read H(Z, S)+ 4 digit of year + 4 digit of serial number, and Format of Drug Product License should read H(Z, S)C+ 4 digit of year + 4 digit of serial number, where H denote chemical drug, Z denote TCM, and S denote biological products. For the registration certificate number of repacking of large package from ex-China, B will added as the prefix of the original certificate number.
Format of New Drug Certificate should read Guoyaozheng H(Z, S)+ 4 digit of year + 4 digit of serial number, where H denote chemical drug, Z denote TCM, and S denote biological products.
Article 209: In addition to this Regulation, the application for narcotics, psychotropic, medical-use toxic drugs and radioactive drugs shall also be administered according to other relevant national regulations.
Article 210: SFDA shall promulgate separate regulation for the registration of TCM material, TCM herb and import TCM material that regulated with approval number.
SFDA shall promulgate separate regulation for the registration of in vitro diagnosis reagent that regulated with drug regulation.
Article 211: This Regulation is effective date of publication. Drug Registration Regulation (temporary) promulgated by SDA (SDA order 35) on October 30, 2002 shall be abolished accordingly.
Annex 2:
Registration Categories and Application Information Requirements of Chemical Drugs
I Registration Categories
1) New chemical entity never marketed in any country.
i. Drug substance and its preparations made by synthesis or semi-synthesis.
ii. Chemical monomer (including drug substance and preparation) extracted from natural sources or by fermentation.
iii. Optical isomer (including drug substance and preparation) obtained by chiral separation or synthesis.
iv. Drug with fewer components derived from marketed multi-component drug.
v. New combination products.
vi. A preparation already marketed in
2) Drug preparation with changed administration route and not marketed in any country
3) Drug marketed ex-China, including:
i. Drug substance and its preparations, and / or with changed dose form, but no change of administration route.
ii. Combination preparations, and / or with changed dose form, but no change of administration route.
iii. Preparations with changed administration route and marketed ex-China.
iv. A preparation already marketed in
4) Drug substance and its preparation with changed acid or alkaline radicals (or metallic elements), but without any pharmacological change, and the original drug entity already approved in
5) Drug preparation with changed dose form, but no change of administration route, and the original preparation already approved in
6) Drug substance or preparation following national standard.
II Application Dossier Items
A Summary
1) Name of the drugs.
2) Certified Documents.
3) Objectives and basis for R & D.
4) Summary of main study work.
5) Draft of packaging insert, note to the draft, and latest literature.
6) Design of packaging and labeling.
B Pharmaceutical data
7) Summary of Pharmaceutical Study,
8) Research information and relevant literature of the production process of the drug substance, research information and relevant literature of formula and process of the preparations.
9) Study information and relevant literature for the chemical structure and components determination.
10) Study information and literature for quality specification.
11) Draft of quality specification and notes, and providing reference standard.
12) Test report of drug sample.
13) The source, test report and quality specification of drug substance and excipient.
14) Stability study and relevant literature.
15) Selection basis and quality specification of immediate packing material and container.
C Pharmacology and toxicology study information.
16) Summary of pharmacology and toxicology study.
17) Primary pharmacodynamics study and literature.
18) General Pharmacology study and literature.
19) Acute/single dose toxicity study and literature.
20) Repeated dose toxicity study and literature.
21) Special safety study and literature of hypersensitive (topical, systemic and photo-toxicity), hemolytic and topical irritative (blood vessel, skin, mucous membrane, and muscle) reaction related to topical and systemic use of the drugs.
22) Study and relevant literature on Pharmacodynamics, toxicity and pharmacokinetics change caused by the interactions amongst multiple components in the combination products.
23) Study and literature of mutagenicity test.
24) Study and literature of reproductive toxicity.
25) Study and literature of carcinogenicity test.
26) Study and literature of drug dependence.
27) Study and literature of pre-clinical pharmacokinetics.
D Clinical Study Information
28) Summary of global clinical study information.
29) Clinical study protocol.
30) Investigator’s Brochure.
31) Draft of Informed Consent Form, approval of the Ethics Committee.
32) Clinical study report.
III Notes to Application Information Items
1) Information Item 1, Name of the drugs, includes International Nonproprietary Name (INN), Chemical Name, English Name, and Chinese Phonetics. Chemical structure, Molecular Weight, Molecular Formula shall be noted. The Nomenclature of the drug should be explained for any new name.
2) Information Item 2, Certified Documents, includes,
i. Certified Documents of lawful registration of the Applicant, copies of Drug Manufacturing License, GMP Certificate. For the application of production of new drugs, copies of GMP Certificate for the workshop where the sample product of the drugs was manufactured should be provided.
ii. Certified Documents stating patent status and ownership of this entity and formula, production process of the drug, and letter of guarantee stating that no infringement upon the patent rights of others.
iii. Copies of official approvals of the research proposal of narcotics, psychotropic, medical-use toxic drugs and radioactive drugs.
iv. For the application of production of new drugs, copy of Approval of Clinical Study of New Drugs and the quality standard of investigational drugs should be provided for the market authorization approval.
v. For the application of production of preparation, certified documents to evidence the legal channels of drug substance should be provided, including copies of certified approval document of drug substance, drug standards, test report, business licenses of manufacturers of drug substance, Drug Manufacturing License, GMP Certificate, sales invoice, and supply contract.
vi. Copies of the Drug Packing Material and Container Certificate or Import Drug Packing Material and Container Certificate for the immediate packing material and container.
3) Information Item 3, objectives and basis of the application, includes R&D, marketing status, and the related literature of the drugs, as well as the summary of the use and production of the drugs, domestically and overseas,
4) Information Item 4, summary and evaluation of main research results, includes the summary of main research results by the Applicant, and a comprehensive analysis of safety, efficacy, and quality controllability of the drugs of the application.
5) Information Item 5, draft of insert sheet, notes to the draft and latest literature, includes the sample of draft of packaging insert sheet drafted in accordance with the relevant regulations, notes on how each items of the insert sheet were drafted, latest relevant literature.
6) Information Item 7, Summary of Pharmaceutical Study, refers to the summary of experiment and global literature of Pharmaceutical Study of the drug in the application (synthesis process, selection of dosage form, screening of formula, determination of structure, quality study and determination of quality standards, and stability study).
7) Information Item 8, research information of the production process of the drug substance, includes technology process and chemical reaction equation, initial raw material and organic menstruum, reaction conditions (temperature, pressure, duration, catalyst) and operation procedure, refining method and main physical-chemical constants. The raw material input, and output yield, as well as possible impurities or other by-products produced or mixed during the production process should be explained.
8) Information Item 10, experiments information and literature for quality research, includes physical-chemical properties, purity inspection, dissolution, assay, and methodology validation, as well as the data and results collected at various stages.
9) Information Item 11, draft of drug quality specification and notes, and reference standard shall be provided: Quality specification shall comply with the format of the current version of Chinese Pharmacopoeia, and the terminology and units of measure of Chinese Pharmacopoeia should be used. Reagents, reagent solution, buffer solution, titrant and others used and their concentration should follow the current version of Chinese Pharmacopoeia. In the event of a different one was used, detailed explanations should be provided. Reference standard shall be provided with separate information attached to explain the source, physical-chemical constants, purity, content, and measurement method and data of the drugs.
Notes to the draft of drug standards shall include the selection of items to be controlled, selection of method, inspection and purity and limitation range, as well as the basis to decide each item.
10) Information Item 12, the test report of the sample products, means the self-test report of the sample products of the drugs in the application. Self-test report for at least one batch of sample product should be provided before the clinical study. Self-test reports of the consecutive 3 batches of sample products should be provided for the market authorization approval after completion of the clinical study.
11) Information item 14, experiments information and literature of the stability study of the drugs, includes stability test conducted together with the use of the immediate packing material and container.
12) Information item 16, Summary of pharmacology and toxicology study, refers to the summary of experiment and global literature of pharmacology and toxicology study of the drug in the application (including pharmacodynamics, mechanism of action, general pharmacology and toxicology, and pharmacokinetics).
13) Information item 27, summary of pre-clinical pharmacokinetics, refer to the summary of experiment and literature of pre-clinical pharmacokinetics (animal) of the drug in application (absorption, metabolite, distribution, execration)
14) Information item 28, Summary of global clinical study information, refers to summary of global literature, abstract and latest updating regarding the clinical trial of the drug in the application.
15) Information item 29, Clinical study protocol: Clinical study protocol should cover details to deal with the critical items including proposed indication, usage and dosage, which should be supported with submission of study information. Clinical study protocol should be scientific, complete and there should be a comprehensive summary of pre-clinical and clinical information related to the key analysis of the potential risks and benefit of proposed trials.
16) Information item 29, Investigator’s Brochure, refers to summary of existing pre-clinical and clinical information of the drug in the application, for the purpose to provide Investigator and other participators with information to aid them in understanding the characteristic of the drug and Clinical study protocol. Investigator’s Brochure should be concise and objective.
IV Table of Application Information Item and Notes
Table of Application Information Item
Information category | information item | Registration category and information item requirement | ||||||
1 | 2 | 3 | 4 | 5 | 6 | |||
Summary information | 1 | + | + | + | + | + | + | |
2 | + | + | + | + | + | + | ||
3 | + | + | + | + | + | + | ||
4 | + | + | + | + | + | + | ||
5 | + | + | + | + | + | + | ||
6 | + | + | + | + | + | + | ||
Pharmaceutical Information | 7 | + | + | + | + | + | + | |
8 | + | *5 | + | + | *5 | *5 | ||
9 | + | + | + | + | + | + | ||
10 | + | + | + | + | + | + | ||
11 | + | + | + | + | + | + | ||
12 | + | + | + | + | + | + | ||
13 | + | + | + | + | + | + | ||
14 | + | + | + | + | + | + | ||
15 | + | + | + | + | + | + | ||
Pharmacology and toxicology study information | 16 | + | + | + | + | + | + | |
17 | + | *16 | ± | *18 | － | － | ||
18 | + | *16 | ± | *18 | － | － | ||
19 | + | *16 | ± | *18 | － | － | ||
20 | + | *16 | ± | *18 | － | － | ||
21 | *19 | *19 | *19 | *19 | *19 | *19 | ||
22 | *13 | － | － | － | － | － | ||
23 | + | ± | ± | ± | － | － | ||
24 | + | ± | ± | ± | － | － | ||
25 | *8 | － | *8 | *8 | － | － | ||
26 | *9 | － | － | － | － | － | ||
27 | + | *20 | *20 | + | *20 | － | ||
Clinical Study information | 28 | + | + | + | + | + | + | |
29 | + | + | + | + | + | △ | ||
30 | + | + | + | + | + | △ | ||
31 | + | + | + | + | + | △ | ||
32 | + | + | + | + | + | △ | ||
Notes:
1. + Denote the information must be submitted,
Denote2. literature can be used instead of test information,
Denote the3. information may be exempted,
Denote the information shall be submitted4. 8 refer to note 8.according to the requirement,
5. △ denote that the provisions 4 of 「V , Requirement For Clinical Study」 shall apply.
6. literature refers to literature and / or summary of literature of all Pharmacology and toxicology study information of the drug in the application (including pharmacodynamic, mechanism of action, general pharmacology and toxicology and pharmacokinetics)
B Notes
1) Drugs under Registration Categories 1-5 refer to as new drugs. Drugs under Registration Category 6 refer to as the drugs already following National Standards. New indications referred in Registration Categories 1.6 and 3.4 mean the cases where preparation already marked in
2) Information Items 1-30 (except Information Item 6) shall be submitted for the application for new drugs as required under the Table of Application Information Items. Re-compiled summary Information Items 1-6, Information Item 12 and 14, clinical Information Items 28-32 and other changes and supplemental information shall be submitted and numbered with the numbers of Information Items upon the completion of the clinical study.
For the drugs under Registration Category 1, upon the completion of the clinical study, all the required information of Information Items 1-30 should be re-edited according to the result of trails conducted during clinical study, and then be re-submitted.
When the registration of drug substance and registration of preparation of the chemical drug under Registration Category 3 and 4 are applied at the same time, the registration of drug substance should comply with the requirement for production.
3) Information Items 1-16 and 28-30 shall be submitted for the application for a drug already with National Standard as required under the Table of Application Information Items. If the clinical study was required, upon completion of the clinical study, Information Items 28-32 and other changes and supplemental information shall be submitted and numbered with the numbers of Information Items.
4) During the registration of the drug already with National Standards, there should be a comprehensive quality study of the process and formula of the drug, and quality comparison with the already marketed drugs according to the national standards. When it is not possible to conduct the quality comparison with the already marketed drugs according to the national standards, a quality study should be conducted according to the requirement for registration of new drug, and if necessary, quality provisions in the national standard can be appended and /or revised.
5) During the application only for preparations, the lawful Certified Documents to evidence the lawful sourcing of the drug substances shall be provided in 2 duplicates, which should be respectively categorized into information item 2 (certified document) and information item 13 (The source, test report and quality specification of drug substance and excipient). For the applicant using domestic drug substance, the documents that should be provided include copies of certified approval document of drug substance, drug standards, test report, business licenses of manufacturers of drug substance, Drug Manufacturing Certificate, and GMP Certificate, supply contract signed with manufacturers of drug substance, purchasing receipts. When the import drug substances were used, copies of supply contract signed with manufacturers of drug substance or its legal domestic agent, Import Drug Certificate, or Pharmaceutical Product Certificate, test report from Drug Control Institute of the local Customs, and drug standards shall be provided. During drug registration, use in investigative preparation with the drug substances without Import Drug Certificate, or Pharmaceutical Product Certificate must be approved by SFDA.
6) For the registration of the drugs transformed among injections, powder for injection and intravenous infusion, the application shall be applied by the qualified enterprise with the production scope of the corresponding dosage form.
7) The reproductive toxicity research information corresponding to the drug used for the people at child-bearing age should be submitted based on the natures of the indications and characteristic of the new drug
8) For any of the drugs with expected treatment period longer than 6 months inclusive, or used for treatment of chronic and recurrent disease, or intermittent use for a regular period of time, experiment information or literature on Carcinogenicity should be provided, and information of carcinogenicity test or literature should be submitted for the following new drugs, based on the indication and characteristic of action:
i. New drugs with chemical structure relating to the known carcinogen or the metabolite of the new drugs are similar to the known carcinogen.
ii. During long-term toxicity experiment, cytotoxic effects were shown or extraordinary activation on the growth of cells in certain visceral organs and tissues were caused.
iii. Drug with a positive test result during mutagenicity test.
9) For new drugs acting on central nervous system, such as analgesics, depressants, stimulants, and drugs with chemical structure related to those compounds liable to cause drug dependence, experiment information of drug dependence should be submitted.
10) For the new drug under Registration Category 1, toxicokinetics study should usually be conducted during the repeated doses toxicity study.
11) Under the Registration Category 1, the optical isomer obtained from a known drug through chiral separation or synthetic method and its preparation, the research information and relevant literature compared between racemate and mono-isomer in areas on pharmacodynamics, pharmacokinetics and toxicology (normally acute toxicity) should be provided to indicate the justification of the R&D. When the safety range of racemate is narrow, and the available information indicates that the unexpected toxicology (irrelevant to pharmacology) is considerably high, the toxicology test of mono isomer with repeated doses (normally lasting for 3 months) or other toxicology tests (such as reproductive toxicology) shall be provided based on the comprehensive information such as clinical course of treatment, dosage, and indications of the drugs, as well as the people using the drugs.
12) For drugs under Registration Category 1 with fewer components derived from already marketed multi-component drugs, if the component did not include the substance explained in note 8 herein, then Information Items 23-25 may be exempted.
13) For the new combination products under Registration Category 1, Information Item 22 should be submitted.
14) For the new combination products under Registration Category 1, information of toxicity test of repeated dosage compared with single dosage should be provided, and if the - toxicity test of repeated dosage indicated no increase in toxicity, and no change in the target tissue, Information Item 27 should be exempted.
15) For the new combination products under Registration Category 1, if there is no significant change in animal pharmacokinetic study results, then Item 23-25 should be exempted.
16) For the new drugs under Registration Category 2, the route of administration during the pharmacology and toxicology study should be the same with that to be used in clinical study. Generally, the pharmacokinetic test or the related toxicology study information (such as topical and repeated dose toxicity) compared with the original route of administration should be provided.
17) For the drugs under Registration Category 3, the preparations with change in route of administration and already marketed overseas, emphasis should be focused more on the drug absorption or topical toxicity influenced by the excipient, and if necessary, the pharmacokinetic test or other toxicology study should be provided.
18) For the new drugs under Registration Category 4, pharmacokinetic, main pharmacodynamic, normal pharmacology and acute toxicity test information compared with the already marketed drugs should be provided to reflect the difference before and after the changes, and if necessary, the research information on repeated doses toxicity and other relevant pharmacology and toxicology study should be provided. If the preparation is made by changing the acidic or alkaline radicals (or metallic elements) of the salt of a marketed drug, it has been already marketed overseas, then the application information requirement under Registration Category 3 shall be provided.
19) For the drugs for topical use, in addition to the information required under the relevant Registration Category and Information Items, the information under Information Item 21 should also be submitted; topical absorption test should be conducted, if necessary.
20) When there is an obvious safety concerns in the immediate, sustained and controlled released preparations (narrow safety range, significant increase in dosage), animal pharmacokinetic study information compared with the marketed immediate, sustained and controlled released preparations regular preparations should also be provided at single dose.
V Requirement for Clinical Study
1) For the new drugs under Registration Category 1 and 2, clinical trials should be conducted.
i. Cases of patients for clinical trials should meet the statistical requirement and the minimal cases required.
ii. The minimal cases required (trial group) of clinical trials are as following, 20-30 for Phase I, 100 for Phase II, 300 for Phase III, 2000 for Phase IV,
iii. Phase I clinical trial of the contraceptives should be conducted following this Regulation. In Phase II clinical trial, a randomized controlled clinical study should be conducted on at least 100 pairs of subjects for at least 6 menstruation cycles. In Phase III trial, an open trial on at least 1000 cases for 12 menstruation cycles should be accomplished. In Phase IV trial, variable factors of such kind of drugs should be carefully considered to finish the trial with adequate numbers of cases.
2) For the new drugs under the Registration Categories 3 and 4, human pharmacokinetic study and randomized controlled clinical trials on at least 100 pairs of subjects should be conducted. In the event of more than one indication, cases for each main indication shall not be less than 60 pairs. Human pharmacokinetics study and an open trial on at least 500 cases for 12 menstruation cycles should be accomplished for contraceptives.
Human pharmacokinetics study may be exempted for the following 2 cases:
preparation of topical use with only topical treatment effect.
oral preparation that not be absorbed.
3) The clinical study for the new drug under Registration Category 5 should be conducted in accordance with the following principles,
i. Bioequivalence trials should be conducted for oral solid preparations on normally 18-24 cases.
ii. When a bioequivalence trial is difficult to be conducted for oral solid preparations or other non- oral solid preparations, clinical trails should be conducted, and cases for the clinical trials should be at least 100 pairs.
iii. For the preparations of sustained and controlled released preparations, controlled human pharmacokinetic study and clinical trials related to therapeutics should be conducted on single dose and repeated doses of the drugs, and the cases for clinical trials should be at least 100 pairs.
iv. For registration of drug transformed among injections, powder for injection and intravenous infusion, if the route of administration, dosage, and usage are identical with the original dosage form, the clinical study can be exempted.
4) For the oral solid preparations under the Registration Category 6, bioequivalence tests should be conducted on normally 18-24 cases.
If the quality of drug needs to be controlled by process and standards, clinical tests should be conducted on normally 100 cases.
5) During the new drug registration of chemical drug, when at the same time the registration of injection, powder injection and intravenous infusion that made of this chemical drug is also applied, if the preparations are from the same applicant, clinical trial is only needed for one of the preparation. For other preparation, as long as requirement of exemption of clinical trail are met, clinical trail may be exempted. If the preparations are from different applicants, clinical trail should be conduction respectively.
6) Application for reduction or exemption of clinical trial should be made during the application of drug registration with detail of reasons and information for reduction or exemption of clinical trials. If a clinical trial is already approved, with exception of the case where reduction or exemption of clinical trial is allowed by this Regulation, reduction or exemption of clinical trial generally should not be allowed. If there is indeed difficulty to complete the clinical trial, application should be made with detail of the basis and plan for reduction or exemption of clinical trial, where the rational should be justified in term of clinical statistic, status of group of patients in the clinical trials.
7) The comparative drug used for the controlled clinical trails shall be already marketed in
i. Drug from the original manufacturer
ii. The same drug of definite clinical test data
iii. Drug of the same active substance and route of administration but different dosage form
iv. Other drug of similar mechanism of action effect and the same indication.
VI Requirement on Import Chemical Drug
A Requirement of Application Information Items
1) Application Information should be submitted in accordance with the requirement under Table of the Application Information Items of Chemical Drugs. For the application of the new chemical entity not yet marketed in any country, Application Information should be submitted in accordance with the Registration Category 1. For other drugs, Application Information should be submitted in accordance with the Registration Category 3. Drug under Registration Category 1 refers to those that are at least in the stage of Phase II Clinical Trials ex-China.
2) Information Item 5, include draft of packaging insert sheet, notes to the draft and the updated literature, the original PI from the manufacturing country, the actual commercial sample of PI used in the manufacturing country and the Chinese translation. The original commercial packaging and labeling should also be provided for Registration Category 6.
3) All the clinical study information used for the market authorization approval in the original manufacturing countries shall be submitted for Information Item 28.
4) All the application information shall be in Chinese with the original text attached, information in other language (ex-English) may be attached as reference. The Chinese translation shall be consistent with the original language.
5) The Chinese translation of quality specification must comply with the format of the National Drug Standards of China.
B Requirement and notes to the Information Item 2, Certified Documents
1) Information Item 2, Certified Documents, includes,
i) Certified Documents, notarized document for the free sale certificate (FSC) issued from the competent authorities of the local country or region where the manufacturer is located, and the GMP Certificate of the manufacturer, and the Chinese translation.
Application for the drugs under Registration Category 1, the above Certified Documents can be submitted together with the clinical study report upon the completion of the clinical study in
ii) When the registration of a foreign drug manufacturer is conducted by manufacturer’s office in
When a foreign drug manufacturer authorizes domestic agent to conduct the registration, copies of the authorization document, notarized document and the Chinese translation, as well as the Business License of the domestic agent shall be provided.
iii) Documents and explanations to evidence the patent status and ownership of the drugs of the application, the formula of the drugs, the production technology and process of the drugs, as well as letters of guarantee stating that the new drug will not infringe upon the patent rights of others.
2) Notes,
i) Certified Documents, notarized document for the FSC and GMP Certificate of the manufacturer should comply with the recommended format by World Health Organization (WHO). The document in other format must be legalized by the Chinese embassy in the original country.
ii) When the manufacturing site and packaging site separated, the Certified GMP Certificates of manufacturing and packaging site issued by the corresponding countries should be provided.
iii) In the event that the products not yet approved in the manufacturing country or region, the Certified Documents from the country where the products being marketed and GMP Certificates from this country could be provided. The Certified Documents from the country where the products being marketed and GMP Certificates from this country should be recognized by SFDA.
iv) For the drug substance, the Certified Documents for the approval of the marketing for the drug substance or its preparation issued by the competent authorities of the original manufacturing country, and the GMP Certificate of the manufacturer should be provided. Drug Master File (DMF) or Certificate of Suitability to the Monographs of the European Pharmacopoeia of the drug substance may also be accepted.
v) To apply for an international multi–center clinical study, certified document of GMP Certificate of the drug manufacturer issued by local drug administration where the manufacturer is located must be provided.
vi) For drug substance or preparation, whenever applicable, certified document of GMP Certificate of the drug manufacturer issued by local food and drug administration where the manufacturer is located, ISO9000 quality assurance certificate issued by the competent organization, and / or free sale certificate (FSC) issued from the competent authorities of the local country or region where the manufacturer is located should be provided
C Requirement for the clinical study conducted in
1) During application of drug never marketed in any country, clinical trials should be conducted according to CT study requirement of Registration Category 1.
2) During application of drug that marketed ex-China but not in
3) During application of drug with same route of administration but different dosage form of that of the drug marketed in
4) During application of drug already with National Standards, if information item 28 of the application meet the requirement, clinical trials should be conducted according to CT study requirement of Registration Category 6. If information item 28 of the application did not meet the requirement, clinical trials should be conducted according to CT study requirement of Registration Category 3. No clinical trial is needed for application of drug substance already with National Standards.
5) For the application only for the importation of the drug substance without available National Drug Standards in
VII Application Information and Requirement for Radioactive Drugs
A Requirement of Information Items
1) For the application of radioactive drugs, the application information shall be prepared for nuclide, drug substance, packing case and preparations respectively, and be in accordance with the corresponding Category of chemical drugs, and the Requirement of Application Information Items. Information Items 22 and 26 may be exempted.
2) For the application of diagnosis radioactive drugs, Information Items 23, 24 and 25 may be exempted.
3) For the application of radioactive chemicals and packing case, Information Item 17 and 18 may be exempted. Information required under preparation should also be provided for the application of packing case.
B Notes to the Information Items
1) Information Item 8 shall be submitted in accordance with the following,
i) Radioactive chemicals: the selection of the production method of the nuclide, irradiation condition, nuclear reaction equation, chemical processing technology after target material eradiated (with the chemical reaction equation and production process attached), detailed operation procedure, possible nuclear impurity introduced, refining (purifying) method, and the specification, standards and analysis of the other chemical reagent (in particular target material), relevant literature and information at domestic and overseas should be provided.
ii) Packing case: the experiment basis for the determining of packing case, the preparation process, route, reaction condition, operation steps and quality standards of all components of the packing case shall be provided. If any components was made by the manufacturer, then the basis of determining of the detailed synthesis route, synthesis process flow, reaction equation, chemical equation, reaction condition, operation procedure, material input, output ratio, and possible impurity introduced and mixed, quality control of the intermediate products at each steps, refining (purifying) method of finished product, quality standard of the raw material, literature and information at domestic and overseas shall be provided.
iii) Preparation: basis to choose the formula of the preparation, preparation process, reaction condition, operation procedure, refining or purifying method, quality standards and analysis and test data of raw material, and literature and information at domestic and overseas shall be provided.
2) Information Item 9 shall be submitted in accordance with the following,
i) Radioactive chemicals: global literature and experiment data (illustrating spectrum and a comprehensive interpretation) used to determine the structure should be provided. If the radioactive nuclide of the radioactive drug is not yet listed in the Chinese Pharmacopoeia, then the decay illustrating chart of the nuclide, experiment data (or spectrum) to determine the nuclear characteristic, as well as experiment information and literature compared with the nuclear characteristic of the nuclide widely recognized at domestic and overseas should be provided.
ii) Packing case: The detailed component and usage of the packing case should be provided, with explanation of the function of each and every components of the packing case. If any components was made by the manufacturer, then global literature and the detailed experiment data (illustrating spectrum and a comprehensive interpretation) used to determine the structure should be provided.
iii) Preparation: Experiment data to determine the chemical structure should be provided. If there is a difficulty to provide, the reason should be explained and reasonable logic can be used to conclude the possible chemical structure or quote the relevant literature that can be used as basis.
3) Information Item 10 shall be submitted in accordance with the following,
i) Radioactive chemicals: research items for the physical-chemical constants, items of the purity testing, the screening of the method to measure the content, and the basis to determine the method should be provided with details of the measuring method, and measuring data.
ii) Packing case: the analyzing and measuring method, principle and data of the characteristic, determination, clarity, and PH value of the solutions should be provided. Determining of the content measuring method, the experiment data, testing method for bacteria, intracellular toxicity, and the research information to decide the limitation should be provided.
iii) Preparation: determining method and experiment data of the physical-chemical properties, characteristic, determining and principle, PH value, radioactive nuclear purity (including main nuclear impurity), radioactive chemical purity, radioactivity, chemical purity of the drug should be provided. For the injection, methods used for testing for bacteria, intracellular toxicity, data, basis to determine the limitation of intracellular toxicity should be provided.
4) Information Item 17 shall be submitted in accordance with the following,
i) For the diagnosis radioactive drug, information about the testing and measuring method, testing conditions and result explanation of image of the target organ and whole body planar image should be provided. The image picture or its copies of the development at all phase of test, as well as the function measuring result should be provided.
ii) For the therapeutically radioactive drug, experiment information of animal experimental model within the main indications should be provided, , detailed global literature of pharmacodynamic study of the drug or other similar drug should also be provided.
5) Information Item 19 shall be submitted in accordance with the following,
Acute toxicity test should be conducted on mouse for the drug substance of radioactive drug under Registration Categories 1 and 3packing case and preparations should be tested with abnormal toxicity test. If there is only a limited quantity produced from refining and synthesis of the drug substance and there is only a trivial clinical usage, then the abnormal toxicity test may also be adopted.
6) Information Item 20 shall be submitted in accordance with the following,
i) For the radioactive drug under Registration Category 1, experiment information and literature of long-term toxicity test and medical internal irradiation absorption dose (MIRD) on rat and dog should be provided.
ii) For the radioactive diagnosis and therapeutic radioactive drug under Registration Category 1, internal irradiation absorption dose after the full decay of the radioactive nuclide of the drug, estimation of absorption dose of the human target organ and non-target organ, or the literature of the drug or similar drug at domestic and overseas should be provided.
C Requirement of Clinical Study
The clinical study of the radioactive drug should be conducted in accordance with the corresponding Category of the chemical drugs. In some special case, cases of clinical trials may be adjusted to an appropriate level subject to the statistical requirement.
D Definition
Radioactive chemicals, packing case and preparation referred in this provision have the following definition:
Radioactive chemicals: means the material of Radioactive Nuclide, which will be directly used for the preparation of radioactive drug preparation.
Packing case: a collective name for unidentified ligand, reducing agent, oxidant, separator,, which will be used as auxiliary of the radioactive chemicals for the purpose of quick preparation before any application.
Preparation: refers to the radioactive drug made of Radioactive Nuclide and other substance.