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 China and be competent to independently assume legal liability. A foreign applicant shall be a legally established pharmaceutical company outside of China. In making application for an import drug registration, the foreign applicant shall use its office in China, or authorize an agent in China to handle the application.

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 China. A drug that has been marketed in China for which an application is made for a change in dosage form, or route of administration, add new indication shall be treated as a new drug application

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 China to be marketed in China.

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 China patent status and ownership rights. If other party holds patent in China, the applicant shall submit a letter of guarantee stating that the drug will not infringe on the patent rights of others and that the applicant assumes liability for any possible infringement.

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 China, another applicant may apply for registration within two years prior to the patent expiration. SFDA shall review the application according to this Regulation and, after expiration of the patent, approve production or import for an application that meets requirements.

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 China shall not be accepted.

2)In approving an international multi–center clinical study in China, SFDA may first request the applicant to firstly conduct the Phase I clinical trials in China, if needed.

3)During a study conducted in China, the Applicant shall, in accordance with the relevant regulations, report to SFDA any serious adverse events or unexpected adverse events which occur in any countries.

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 China, shall be in accordance with the relevant provision of this Regulation, and the applicant shall submit the complete research information of the study.

 

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 and journal as well as volume, issue and page number shall be provided. For unpublished literature and materials, an authorization letter from the owner must be provided. For any foreign language materials a Chinese translation should be provided in accordance with relevant requirements.

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 China and;

2)drug raw material and its preparations, and biological product that have not been marketed domestically or outside China;

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 China.

During the review process of new drug, even when the marketing approval of other domestic drug of the same active substance is approved in China, the registration category and technical requirements of the same kind of drug shall remain unchanged in the review process in China.

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 China. The drug-monitoring period shall start from the date of approval for production, and shall not exceed 5 years.

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.