Measures for The Administration of Drug Registration (for Tr

Measures for The Administration of Drug Registration
（for Trial Implementation）
Decree of the State Drug Administration No.35

The Measures for the Administration of Drug Registration （for trial implementation） were adopted at the executive meeting of the State Drug Administration on October 15, 2002 and are hereby promulgated. These Measures shall enter into force on December 1, 2002.

Director of the Administration: Zheng Xiaoyu
October 30, 2002

Measures for the Administration of Drug Registration
（for trial implementation）

Chapter I Principle Provisions

Article 1 In order to guarantee the safety, effectiveness and controllable quality of drugs, and to regulate the drug registration, these Measures are formulated in accordance with the Drug Administration Law of the People''s Republic of China （hereinafter referred to as Drug Administration Law）, and the Implementation Regulations of the Drug Administration Law of the People''s Republic of China （hereinafter referred to as Implementation Regulations）.

Article 2 These Measures shall apply to the drug development and clinic study, the application for drug clinic study, drug manufacturing or import, as well as the relevant drug registration, inspection, supervision and administration undertaken within the People''s Republic of China.

Article 3 Drug registration shall refer to the examination and approval process by conducting systematic evaluation of the safety, effectiveness and controllability of quality of the drugs to be marketed, and by making the decision on whether or not to approve the drug clinic study, drug manufacturing or import, the process shall include the examination and approval of the contents indicated in the certifications of approval for application for drug alteration and in the attachments thereof.

Article 4 The state encourages the study and development of new drugs, and employs accelerated examination and approval for new drugs developed and new drugs treating complicated and serious diseases.

Article 5 The State Drug Administration （hereinafter referred to as SDA） shall be in charge of the administration of drug registration throughout the country, and be responsible for the examination and approval of drug clinic study, drug manufacturing and import.

The drug administrations of the provinces, autonomous regions and municipalities directly under the Central Government shall, upon the entrustment by the SDA, examine the completeness, normalization and authenticity of the application materials for drug registration.

Article 6 An applicant for drug registration （hereinafter referred to as applicant） shall refer to an institution that files the application for drug registration, bears the corresponding legal liabilities, and holds the certifications of approval for drugs after the application is approved. A domestic applicant shall be an institution with legal person status that legally registered within China, and an overseas applicant shall be a legal overseas drug manufacturer. For an overseas applicant, its work office stationed in China or an agency within China commissioned by it shall make the drug registration for it.

The personnel handling the applications for drug registration shall be the corresponding professionals, and shall be familiar with the laws and regulations on and the technical requirements for the administration of drug registration.

Chapter II Application for Drug Registration

Article 7 Application for drug registration shall include the application for new drugs, application for drugs with existing state standards, application for imported drugs, and the supplementary application thereof. For a domestic applicant, the procedures for application for new drugs and application for drugs with existing state standards shall be followed, for an overseas applicant, the procedures for application for imported drugs shall be followed.

Article 8 Application for new drugs shall refer to the application for registration of drugs that haven''t been marketed within China. If the type of preparation or the route of administration of any drugs that have been marketed is changed, the said drugs shall be administered as new drugs.

Application for drugs with existing state standards shall refer to the application for registration of the drugs for which the SDA has promulgated official standards.

Application for imported drugs shall refer to the application for registration of the drugs that are manufactured overseas and marketed in China.

Supplementary application shall refer to the application for alteration, adding or cancellation of the approved matters or contents after the applications for new drugs, drugs with existing state standards or imported drugs have been approved. If an application for registration of the drugs during the examination and approval or an approved application for clinical study needs to be altered correspondingly, or if transferring the new drug technologies, repackaging the imported drugs, and formalizing the tentative drug standards, the procedures for supplementary application shall be followed.

Article 9 An applicant shall file the application for drug registration with the drug administration of the province, autonomous region or municipality directly under the Central Government where it is located, and shall submit the relevant materials and drug samples; in case of an application for registration of imported drugs, the applicant shall file the application with the SDA.

Article 10 If two or more entities apply for registration of new drugs as a joint applicant, they shall file the application with the drug administration of the province, autonomous region or municipality directly under the Central Government where the drug manufacturing enterprise is located; if the applicant entities are all drug manufacturing enterprises, they shall file the application with the drug administration of the province, autonomous region or municipality directly under the Central Government where the drug manufacturing enterprise that applies for the preparation is located; if none of the applicant entities are drug manufacturing enterprises, they shall file the application with the drug administration of the province, autonomous region or municipality directly under the Central Government where the sample is trial-produced.

Article 11 For the drugs applying for registration or the prescriptions or techniques used, the applicant shall provide the patent in China and explanations on its ownership, submit a guaranty of no infringement upon the patents of others, and promise to be responsible for the possible infringement consequences.

Article 12 Where any dispute arises after the application for drug registration is approved, the parties shall settle the dispute through consultation by themselves, or through judicial bodies or patent administrative bodies pursuant to the relevant laws and regulations.

Article 13 With respect to any drug to which a Chinese patent has been granted, other applicants may file an application for registration within 2 years before the expiration of the patent of that drug. The SDA shall make examination pursuant to these Measures, and, if the provisions are met, approve the manufacturing or import after the patent expires.

Article 14 According to Article 35 of the Implementation Regulations, with respect to the undisclosed experiment data or other data independently obtained and submitted by the manufacturer or seller that has acquired the license for manufacturing or selling drugs containing new chemical compounds, the SDA shall not approve any application for using such undisclosed data without the consent of the licensed applicant within 6 years from the day of approval for the license. But if other applicants submit the data independently obtained by themselves, the SDA may approve them.

When applying for drug registration, other applicants shall promise that all the experiment data are independently obtained by themselves and shall guarantee the authenticity of the data.

Article 15 With respect to the drugs processed in China upon the commission of overseas drug manufacturers, but not sold or used in China, the domestic drug manufacturing enterprise that processes the drug shall file the application with the drug administration of the province, autonomous region or municipality directly under the Central Government where it is located. The drug administration of the province, autonomous region or municipality directly under the Central Government shall approve the application if the provisions are met, but shall not issue the registered number of approval for the drug.

Chapter III Investigational Study of New Drugs before They Are Clinically Used

Article 16 Investigational study of new drugs conducted for application for drug registration shall include the synthetic techniques, extraction methods, physical and chemical properties, purity, choosing of form of this drug, selection of prescriptions, preparation techniques, inspection methods, quality indications and stability, pharmacology, toxicology, nuclein animal dynamics etc. As for Chinese medicine preparations, the sources and processing of the original medicine materials etc shall also be included; as for biologic products, the quality standard, preservation conditions, inheritance stability and immunological study of the initial materials such as microbial and toxic species, cell line or organism etc shall also be included.

Article 17 Relevant administration provisions shall be executed in the Investigational study of new drugs, and the Criterions for the Quality Control of Non-clinical Study of Drugs must be executed in the safety evaluation study.

Article 18 An institution engaging in drug study and development must have the personnel, site, equipment, instruments and management system accommodating to the experiment and study projects; the animals, reagents, and raw materials for experiment use shall meet the relevant provisions and requirements of the state, and the authenticity of all the experiment data and materials shall be guaranteed.

Article 19 For a separate application for the chemical raw material medicines used in the drug preparations and for the Chinese medicine materials and the crude slices of Chinese medicine subject to the administration by the registered number of approval, the registered number of approval for the drug, the Registration Certificate of Imported Drugs or the Registration Certificate of Pharmaceutical Products is required, the raw material medicines must be obtained through legal channels. Where the raw material medicines don''t have the registered number of approval, the Registration Certificate of Imported Drugs or the Registration Certificate of Pharmaceutical Products, the approval of the SDA is required.

Article 20 Where an applicant entrusts any other institution to conduct drug study, separate experiment, testing, trial manufacturing or production of samples etc, it shall sign a contract with the trustee. The applicant shall be responsible for the authenticity of the drug study data in the application materials.

Article 21 If the application materials for drug registration include any drug experiment and study materials submitted by any overseas drug study institution, there must be attached explanations produced by that overseas drug study institution on the projects and page numbers of the materials provided, and the certifications which can prove that the institution has been legally registered and notarized overseas, and the attached materials may be used as the application materials only after they have been acknowledged by the SDA. The SDA shall send personnel to make on-spot examinations according to the needs.

Article 22 When inspecting drug study according to the needs, the SDA and the drug administrations of a province, autonomous region or municipality directly under the Central Government may request the applicant or the drug study institution undertaking the experiment to conduct respeated experiment according to the projects, methods and data specified in the application materials, and shall send personnel to examine the experiment on the spot; or an institute for drug control or other drug study institution may be entrusted to make the repeated experiment.

Article 23 Investigational study of new drugs shall be conducted by referring to the relevant technical guiding principles promulgated by the SDA. Where the applicant adopts other evaluation methods and techniques in the experiment, it shall submit the materials that can prove the scientificity of such methods and techniques.

Chapter IV Clinical Study of Drugs

Section I Basic Requirements

Article 24 Clinical study of drugs includes clinical trial and bioequivalence trial.

Clinical study of drugs must be approved by the SDA before it is carried out, and must follow the Criterions for the Quality Control of Clinical Trial of Drugs.

Article 25 For the application for registration of new drugs, clinical trial or bioequivalence trial shall be conducted.

Generally, it is not necessary to conduct clinical study for the application for registration of drugs with existing state standards. If clinical study is needed, as for the chemical drugs, the applicant may conduct only the bioequivalence trial; as for Chinese traditional patent medicines and biological products the quality of which needs to be controlled by techniques and standards, the clinical trial shall be conducted.

In supplementary application, it is needed to conduct clinical study if new indications are added for any drug already on the market or if the manufacturing techniques of the drug are altered significantly.

Article 26 Clinical trial is divided into phases I, II, III, and IV. For the application for registration of new drugs, Clinical trial of phases I, II, and III shall be conducted, under certain circumstances, the applicant may only conduct clinical trial of phases II and III or only phase III.

Phase I clinical trial: preliminary trial on clinical pharmacology and human body safety evaluation, which observes the degree of tolerance of human body against the new drug and the drug dynamics, and provides basis for working out the administration scheme.

Phase II clinical trial: preliminary evaluation of the treating effect, the purpose of which is to preliminarily evaluate the treating effect and safety of the drug on the target patient with the applicable disease, and also to provide basis for the determination of study design and dosage administration scheme for phase III clinical trial. Various forms may be employed for the study design of this phase in accordance with the specific study purpose, including randomized controlled clinical trial.

Phase III clinical trial: confirmation phase of the treating effect, the purpose of which is to further verify the treating effect and safety of the drug on the target patient with the applicable disease, to evaluate the relationship between interest and risk, and to eventually provide adequate basis for the application for drug registration for gaining approval. Generally, the trial shall be a randomized controlled trial with sufficient samples.

Phase IV clinical experiment: application study conducted by the applicant independently after the new drug comes into the market, the purpose of which is to examine the curative effect of the drug and the adverse reactions when it is widely used; to evaluate the relationship between interest and risk when the drug is used in ordinary or special groups; and to improve the dosage administration etc.

Article 27 The number of cases experimented in drug clinical study shall be in accordance with the study purpose and meet the relevant statistics requirements and the minimum clinical study case number specified in these Measures. As for rare diseases, special diseases or other circumstances where it is needed to reduce clinical study cases or to exempt the clinical trial, examination and approval by the SDA is required.

Article 28 With respect to bacterins or other special drugs prepared at the phase of seed selection of bacterial or toxic species, if there are no suitable animal models and the laboratories can not evaluate the curative effect thereof, the applicant may apply for clinical study with the SDA on the premise that the safety of the experimented person is secured.

Section II Requirements Before the Study

Article 29 After a drug clinical study has been approved, the applicant shall select, from the institutions qualified for drug clinical trial, an institution to undertake the drug clinical trial, decide on, through consultation, the entity responsible for the clinical study, the major researchers and the entities participating in the clinical study.

Article 30 The applicant shall sign a clinical study contract with the selected entity responsible for and the entities participating in the clinical study, supply the draft of letter of consent with knowledge of the experimented person and the manuals for the researchers conducting the clinical trial, perfect the clinical study scheme by referring to the relevant technical guiding principles, and request the ethic committee of the clinical trial institution to examine the scientificity of the clinical study and the ethic issues involved.

Article 31 The applicant shall provide the selected clinical study entities with free medicines for use in clinical study and drugs for comparison use （except for phase IV clinical trial）, enclose the sample inspection report; and bear the expenses needed for the clinical study.

Article 32 Drugs for use in clinical study shall be prepared in workshops meeting the conditions provided for in the Criterions for the Quality Control of Drug Manufacturing. The preparing process shall strictly follow the Criterions for the Quality Control of Drug Manufacturing.

The SDA or the entrusted drug administration of the province, autonomous region or municipality directly under the Central Government may make on-spot examinations according to the needs.

Article 33 An applicant may inspect the drugs for use in clinical study by itself according to the drug standards determined by the SDA, either may it entrust the National Institute for the Control of Pharmaceutical and Biological Products or an institute for drug control designated by the SDA to make the inspection, the drugs can be used in clinical study only after they have passed the inspection. The SDA may designate an institute for drug control to make selective inspection over the drugs for use in the clinical study.

Vaccine products and blood products, and other biological products as well as overseas-manufactured drugs for use in clinical study provided for by the SDA, must be inspected by the institutes for drug control designated by the SDA, and can be used in clinical study only after they have passed the inspection. The applicant shall bear all the responsibilities for the quality of the drugs for clinical study use.

Article 34 An applicant shall, before carrying out the clinical study of drugs, submit the clinical study scheme and the names of the principal researchers of the entity responsible for the clinical study, the list of the participating entities and the researchers thereof, the letter of approval of the ethics committee, the sample of the letter of consent with knowledge to the SDA for record, and shall submit them to the drug administrations of the provinces, autonomous regions or municipalities directly under the Central Government where the clinical study entities are located.

Section III Administration of Clinical Study

Article 35 In the clinical study of drugs, the applicant shall appoint personnel with certain professional knowledge to supervise the implementation of the Criterions for the Quality Control of Clinical Trial of Drugs.

Article 36 If an applicant finds out that any clinical researcher violates the relevant provisions or fails to carry out the clinical study scheme, it shall urge the researcher to correct; if the circumstances are serious, it may demand suspension or termination of the clinical study, and shall report to the SDA and the drug administration of the relevant province, autonomous region or municipality directly under the Central Government.

Article 37 After finishing each phase of clinical trial, the applicant shall submit the clinical study and statistics analysis report to the SDA and to the drug administration of the relevant province, autonomous region or municipality directly under the Central Government.

If the period of clinical study exceeds 1 year, the applicant shall submit a report on the clinical study process to the SDA and the drug administration of the relevant province, autonomous region or municipality directly under the Central Government.

Article 38 The clinical study of drugs shall be carried out within 2 years from the day of approval. If it hasn''t been carried out within that period, the original certifications of approval shall be invalidated automatically; a new application shall be filed if it is still needed to carry out the clinical study.

Article 39 The entities and personnel participating in the clinical study shall be familiar with the properties, functions, curative effect and safety of the drugs for clinical trial use; understand the responsibilities and obligations of clinical researchers; obtain the letter of consent with knowledge voluntarily signed by the experimented person; and make the clinical study records timely, accurately and truthfully.

Article 40 If an applicant violates the Criterions for the Quality Control of Clinical Trial of Drugs or requests to change the data or conclusion of the trial, the entities and personnel participating in the clinical study shall report to the drug administration of the relevant province, autonomous region or municipality directly under the Central Government and the SDA.

Article 41 The entities undertaking the clinical study and the clinical researchers are obliged to take necessary measures to guarantee the safety of the experimented person.

Clinical researchers shall pay close attention to the occurrence of any adverse reaction case involving the drugs for clinical study use, take proper treating measures for the experimented person without delay, and write the case into the records.

If any serious adverse reaction case occurs in the course of a clinical study, the researchers shall, within 24 hours, report to the drug administration of the relevant province, autonomous region or municipality directly under the Central Government and the SDA, and shall make a timely report to the ethics committee.

Article 42 For the clinical studies that have been approved, the SDA and the drug administrations of the relevant provinces, autonomous regions and municipalities directly under the Central Government shall conduct regular or specific on-spot examinations or data checks.

Article 43 If any of the following cases occurs in the course of a clinical study, the SDA may request the applicant to modify the clinical study scheme, or to suspend or terminate the clinical study:

（1） The ethics committee fails to perform its duties;

（2） Safety of the experimented person can''t be effectively guaranteed;

（3） A serious adverse reaction case hasn''t been reported within the prescribed time limit;

（4） Report on the clinical study progress is not submitted in timely and truthfully;

（5） Approved clinical study fails to acquire evaluable results within 2 years after the scheduled end of the study;

（6） There is, already, evidence proving that the drugs for clinical trial use are ineffective;

（7） Drugs for clinical trial use encounter quality problems;

（8） Frauds are committed in the clinical study;

（9） Other cases of violation of the Criterions for the Quality Control of Clinical Trial of Drugs.

Article 44 Where the SDA makes the decision of modifying the clinical study scheme, ordering suspension or termination of the clinical study, the applicant or the entity conducting the clinical study shall execute such decision. If they have any objections, they may present their opinions within 10 days and explain the reasons in written form.

Article 45 If large-scope and unanticipated adverse reactions or serious adverse reaction cases occur in a clinical study, or there has been evidence that can prove the drugs for clinical trial use have serious quality problems, the SDA or the drug administration of the relevant province, autonomous region or municipality directly under the Central Government may take urgent measures and order suspension or termination of the clinical study, the applicant and the clinical study entity must stop the clinical study immediately.

Article 46 The use of drugs for clinical trial use shall be taken care of by the clinical researchers. The researches must guarantee that all the drugs for study use are only used on the experimented persons, and the method of use and dosage shall conform to the study scheme. The researchers may not pass the drugs for study use to any person not participating in the clinical study. Drugs for clinical study use may not be marketed.

Article 47 If an overseas applicant wishes to conduct an international multi-center clinical study of drugs, it shall file an application with the SDA pursuant to these Measures and meet the requirements of the following provisions:

（1） The drugs for clinical study use shall be drugs that have been registered overseas or have entered Phase II clinical trial; the SDA will not accept any application filed by an overseas applicant for international multi-center clinical study of new preventive vaccine drugs not yet registered overseas;

（2） The SDA may, when granting approval for the conduction of international multi-center clinical study of drugs, request the applicant to carry out Phase I clinical trial in China according to the needs;

（3） In the conduction of international multi-center clinical study of drugs in China, if serious adverse reactions and unanticipated adverse reactions relating to such drugs are found in any country, the applicant shall report to the SDA timely pursuant to the relevant provisions;

（4） After a clinical study is ended, the applicant shall submit the complete clinical study report to the SDA;

（5） Where the data obtained in an international multi-center clinical study of drugs are used in the application for drug registration in China, the provisions relating to clinical study provided for in the Drug Administration Law, the Implementation Regulations, and these Measures must be met, and the applicant must submit all the study materials of the international multi-center clinical study