Announcement of the State Food and Drug Administration and the State Health Commission on the Issuance of the Good Clinical Practice (No. 57 in 2020)

Published:

2021-11-26


Announcement of the State Food and Drug Administration and the State Health Commission on the Issuance of the Good Clinical Practice (No. 57 in 2020)

In order to deepen the reform of the drug evaluation and approval system, encourage innovation, and further promote the research and quality improvement of China's drug clinical trial specifications, the State Drug Administration, together with the National Health Commission, has organized the revision of the Quality Management Standards for Drug Clinical Trials, which is hereby issued and will be implemented as of July 1, 2020.
It is hereby announced.

 State Food and Drug Administration State Health Commission
April 23, 2020

Good Clinical Practice

 

Chapter I General Provisions

Article 1 In order to ensure the standardized clinical trial process, the scientific, authentic and reliable data and results, and protect the rights and security of the subjects, these specifications are formulated in accordance with the Drug Administration Law of the People's Republic of China, the Vaccine Administration Law of the People's Republic of China, and the Regulations for the Implementation of the Drug Administration Law of the People's Republic of China. This specification is applicable to drug clinical trials conducted for drug registration application. Relevant activities of drug clinical trials shall comply with this specification.
Article 2 The drug clinical trial quality management specification is the quality standard for the whole process of drug clinical trial, including scheme design, organization and implementation, supervision, inspection, record, analysis, summary and report.
Article 3 The clinical trial of drugs shall conform to the principles of the Helsinki Declaration of the World Medical Congress and relevant ethical requirements. The rights and security of the subjects are the primary factors to be considered, taking precedence over the benefits to science and society. Ethical review and informed consent are important measures to protect the rights and interests of subjects.
Article 4 Clinical trials of drugs should have sufficient scientific basis. The clinical trial should weigh the expected risks and benefits of the subject and society. Only when the expected benefits are greater than the risks can the clinical trial be implemented or continued.
Article 5 The test plan shall be clear, detailed and operable. The test plan can be implemented only after being approved by the Ethics Committee.
Article 6 During the clinical trial, researchers shall abide by the trial plan, and any medical judgment or clinical decision involved shall be made by the clinician. The researchers participating in the implementation of clinical trials shall have the corresponding education, training and experience to undertake the clinical trials.
Article 7 The paper or electronic data of all clinical trials shall be properly recorded, processed and saved, and can be accurately reported, interpreted and confirmed. The privacy of subjects and the confidentiality of their relevant information should be protected.
Article 8 The preparation of experimental drugs shall meet the relevant requirements for the quality control of the production of drugs for clinical trials. The use of the test drug shall conform to the test plan.
Article 9 The quality management system of clinical trials shall cover the whole process of clinical trials, with emphasis on the protection of subjects, the reliability of test results, and compliance with relevant laws and regulations.
Article 10 The implementation of clinical trials shall comply with the principle of avoiding conflicts of interest.

 

Chapter II Terms and Definitions

Article 11 The meanings of the following terms in this Code are:
(1) Clinical trial refers to a systematic trial aimed at finding or verifying the clinical medicine, pharmacology and other pharmacodynamic effects and adverse reactions of a test drug, or the absorption, distribution, metabolism and excretion of the test drug, with the human body (patient or healthy subject) as the object, so as to determine the efficacy and safety of the drug.
(2) Compliance of clinical trial refers to that all parties involved in the clinical trial comply with the requirements related to the clinical trial, this specification and relevant laws and regulations.
(3) Non clinical research refers to biomedical research not conducted on human body.
(4) The independent data monitoring committee (data and security monitoring committee, monitoring committee, data monitoring committee) refers to the independent data monitoring committee established by the sponsor, which regularly evaluates the progress, security data and important validity endpoints of the clinical trial, and advises the sponsor on whether to continue, adjust or stop the trial.
(5) The Ethics Committee refers to the committee composed of medical, pharmaceutical and other background personnel, whose responsibility is to ensure the protection of the rights and interests and safety of the subjects by independently reviewing, agreeing, tracking and reviewing the test plan and relevant documents, and obtaining and recording the methods and materials used for the informed consent of the subjects.
(6) Investigator refers to the person in charge of the trial site who carries out the clinical trial and is responsible for the quality of the clinical trial, the rights and interests of the subjects and the safety.
(7) The sponsor refers to the individual, organization or institution responsible for initiating, managing and providing funds for clinical trials.
(8) Contract research organization refers to the unit that executes certain duties and tasks of the sponsor or researcher in the clinical trial by signing the contract authorization.
(9) Subjects refer to those who participate in a clinical trial and serve as the recipients of drugs for trial, including patients and healthy subjects.
(10) Vulnerable subjects refer to those who are unable or have lost the ability to defend their own will and rights. Their willingness to participate in clinical trials may be expected to benefit from the trial or may be improperly affected by retaliation if they refuse to participate. They include students and subordinates of researchers, employees of sponsors, soldiers, prisoners, patients with incurable diseases, patients in critical conditions, people living in welfare homes, vagrants, minors and people without the ability to consent.
(11) Informed consent refers to the process in which subjects confirm their consent to voluntarily participate in clinical trials after being informed of all aspects that may affect their decision to participate in clinical trials. The process shall be documented by a written, signed and dated informed consent.
(12) An impartial witness refers to an individual who has nothing to do with the clinical trial and is not unfairly affected by the relevant personnel of the clinical trial. When the subject or his guardian is unable to read, he or she acts as an impartial witness, reading the informed consent and other written materials, and witnessing the informed consent.
(13) Monitoring refers to monitoring the progress of clinical trials and ensuring that clinical trials are implemented, recorded and reported in accordance with the requirements of the trial scheme, standard operating procedures and relevant laws and regulations.
(14) The audit plan refers to the document describing the audit strategy, methods, responsibilities and requirements.
(15) The audit report refers to the written report submitted by the supervisor to the sponsor after each on-site visit or other clinical trial related communication according to the sponsor's standard operating procedures.
(16) Audit refers to the systematic and independent inspection of clinical trial related activities and documents to assess and determine whether the implementation of clinical trial related activities, the recording, analysis and report of test data conform to the requirements of the test plan, standard operating procedures and relevant laws and regulations.
(17) The audit report refers to the written evaluation report on the audit results written by the auditor appointed by the sponsor.
(18) Inspection refers to the act of the drug regulatory department to review and inspect the relevant documents, facilities, records and other aspects of the clinical trial. The inspection can be conducted at the test site, the place where the sponsor or contract research organization is located, and other places that the drug regulatory department deems necessary.
(19) Direct reference refers to the direct inspection, analysis, verification or reproduction of important records and reports of clinical trials of drugs for evaluation. Any party directly consulting shall, in accordance with relevant laws and regulations, take reasonable measures to protect the privacy of the subject and avoid disclosing the ownership information of the sponsor and other confidential information.
(20) Test plan refers to the document describing the purpose, design, methodology, statistical considerations and organization and implementation of the clinical trial. The test plan should also generally include the background and theoretical basis of the clinical trial, which can also be given in other reference documents. The test protocol includes the protocol and its revision.
(21) Investigator's Manual refers to the compilation of clinical and non clinical research data of drugs for trial related to clinical trials.
(22) Case report form refers to the paper or electronic document designed according to the requirements of the trial scheme and reported to the sponsor to record the relevant information of the subject.
(23) Standard operating procedures refer to detailed written requirements formulated to ensure the consistency of a specific operation.
(24) Experimental drugs refer to experimental drugs and reference drugs used in clinical trials.
(25) Reference drugs refer to other research drugs, marketed drugs or placebos used for reference and control with the test drugs in clinical trials.
(26) Adverse events refer to all adverse medical events occurred after the subject received the drug for test, which can be manifested as symptoms and signs, diseases or abnormal laboratory tests, but may not necessarily have a causal relationship with the drug for test.
(27) Serious adverse events refer to adverse medical events such as death, life-threatening, permanent or serious disability or loss of function, the need for hospitalization or extension of hospitalization, as well as congenital abnormalities or birth defects, which occur after the subject receives the drug for trial use.
(28) The term "adverse drug reaction" refers to any adverse or unexpected reaction that may occur in the clinical trial and may be related to the drugs for trial use. The causal relationship between the investigational drug and the adverse event has at least one reasonable possibility, that is, the correlation cannot be excluded.
(29) Suspicious and unexpected serious adverse reactions refer to suspicious and unexpected serious adverse reactions whose nature and severity of clinical manifestations exceed the existing data and information such as the investigator's manual of the trial drug, the instructions of the marketed drug or the product characteristics abstract.
(30) The subject identification code refers to the unique code assigned to the subject in the clinical trial to identify its identity. When reporting the adverse events and other data related to the trial, the researcher used this code to replace the name of the subject to protect their privacy.
(31) Source documents refer to original records, documents and data generated in clinical trials, such as hospital medical records, medical images, laboratory records, memos, subject diaries or evaluation forms, drug delivery records, data automatically recorded by instruments, microfilm, photographic films, magnetic media, X-ray films, subject documents, and clinical trial related documents and records kept by pharmacies, laboratories and medical technology departments, Including certified copies, etc. The source document includes the source data, which can exist in paper or electronic forms.
(32) Source data refers to all information recorded in the original records or certified copies of clinical trials, including clinical findings, observation results and other relevant activity records required for reconstruction and evaluation of clinical trials.
(33) Necessary documents refer to the documents that can be used separately or collectively to evaluate the implementation process of clinical trials and the quality of trial data.
(34) A certified copy refers to a copy that has been verified and verified to be identical with the original in content and structure. The copy is either signed by the reviewer and dated, or directly generated by the verified system, and can exist in paper or electronic forms.
(35) Quality assurance refers to the planned systematic measures established in clinical trials to ensure that the implementation of clinical trials and the generation, recording and reporting of data comply with the trial scheme and relevant laws and regulations.
(36) Quality control refers to the technology and activities implemented in the clinical trial quality assurance system to verify whether all relevant activities of the clinical trial meet the quality requirements.
(37) The test site refers to the place where clinical trial related activities are carried out.

(38) Blindness refers to the procedure that makes one or more parties do not know the treatment allocation of the subject in the clinical trial. Single blind generally means that the subject does not know, and double blind generally means that the subject, researcher, monitor and data analyst do not know the treatment allocation.
(39) Computerized system verification refers to the process of establishing and recording that the whole life cycle of a computerized system from design to decommissioning or conversion to other systems can meet specific requirements. The validation scheme shall be formulated based on the risk assessment considering the expected use of the system, the potential impact of the system on the protection of subjects and the reliability of clinical trial results.
(40) The audit trail refers to the record that can trace back to the event occurrence process.

 

Chapter III Ethics Committee

Article 12 The responsibility of the Ethics Committee is to protect the rights and security of subjects, and it shall pay special attention to vulnerable subjects.
(1) The documents that should be reviewed by the Ethics Committee include: the test plan and the revised version of the test plan; Informed consent and its update; Methods and information for recruiting subjects; Other written materials provided to the subject; Investigator's Handbook; Existing safety data; Documents containing compensation information of subjects; Documentary evidence of the investigator's qualifications; Other documents required by the Ethics Committee to perform its duties.
(2) The Ethics Committee shall review the scientific and ethical nature of the clinical trial.
(3) The Ethics Committee shall review the qualifications of researchers.
(4) In order to better judge whether the rights, security and basic medical care of the subjects can be ensured in the clinical trial, the Ethics Committee can require the provision of materials and information beyond the content of the informed consent form.
(5) When conducting a non therapeutic clinical trial (i.e. a trial that has no expected direct clinical benefits for the subject), if the informed consent of the subject is replaced by its guardian, the Ethics Committee should pay special attention to whether the corresponding ethical issues and laws and regulations have been fully considered in the trial plan.
(6) If the test protocol clearly states that the subject or his/her guardian cannot sign the informed consent form before the test in case of emergency, the Ethics Committee shall review whether the corresponding ethical issues and laws and regulations have been fully considered in the test protocol.
(7) The Ethics Committee shall examine whether there is any improper influence such as coercion or inducement on the subject to participate in the clinical trial. The Ethics Committee shall review that the informed consent form shall not contain the content that causes the subject or his guardian to abandon his or her legitimate rights and interests, nor the content that exempts the investigator, clinical trial institution, sponsor and its agency from their responsibilities.
(8) The Ethics Committee shall ensure that the informed consent form and other written materials provided to the subject explain the information about the compensation to the subject, including the compensation method, amount and plan.
(9) The Ethics Committee shall complete the review or filing process of clinical trial related data within a reasonable time limit and give clear written review opinions. The review comments shall include the name, document (including version number) and date of the clinical trial reviewed.
(10) The review opinions of the Ethics Committee include: Agreed; Agree after necessary modification; disagree; Terminate or suspend the agreed study. The examination opinions shall state the content of the request for modification or the reasons for negation.
(11) The Ethics Committee shall pay attention to and clearly require researchers to report in a timely manner: deviation or modification of the test plan to eliminate emergency hazards to subjects during the implementation of clinical trials; Changes that increase the risk of subjects or significantly affect the implementation of clinical trials; All suspicious and unexpected serious adverse reactions; New information that may adversely affect the safety of subjects or the implementation of clinical trials.
(12) The Ethics Committee has the right to suspend or terminate the clinical trial that is not implemented according to the relevant requirements, or the subject has unexpected serious damage.
(13) The Ethics Committee shall regularly follow up and review the ongoing clinical trials, and the frequency of review shall be determined according to the risk level of the subjects, but at least once a year.
(14) The Ethics Committee shall accept and properly handle the relevant claims of the subjects.
Article 13 The composition and operation of the Ethics Committee shall meet the following requirements:
(1) The composition and filing management of the Ethics Committee shall meet the requirements of the health authorities.
(2) All members of the Ethics Committee should receive training on ethical review and be able to review ethical and scientific issues related to clinical trials.
(3) The Ethics Committee shall perform its duties in accordance with its system and standard operating procedures. The review shall be recorded in writing, and the meeting time and discussion content shall be indicated.
(4) The voting members for the review opinions of the Ethics Committee meeting shall participate in the review and discussion of the meeting, including members of all categories, with different gender composition, and meet the required number of members. The review opinions of the meeting shall be written.
(5) The members who vote or put forward review opinions shall be independent of the clinical trial project under review.
(6) The Ethics Committee shall have detailed information about its members and ensure that its members are qualified for ethical review.
(7) The Ethics Committee shall require researchers to provide all kinds of materials required for ethical review and answer the questions raised by the Ethics Committee.
(8) The Ethics Committee may invite relevant experts other than the members to participate in the review as needed, but cannot participate in the voting.
Article 14 The Ethics Committee shall establish and implement the following written documents:
(1) Provisions on the composition, establishment and filing of the Ethics Committee.
(2) The schedule, notice and review procedure of the meeting of the Ethics Committee.
(3) Procedures for initial review and follow-up review by the Ethics Committee.
(4) For minor amendments to the test plan agreed by the Ethics Committee, the procedure of quick review and agreement shall be adopted.
(5) Procedures for timely notification of review comments to investigators.
(6) Review procedures for different opinions on ethical review opinions.
Article 15 The Ethics Committee shall keep all the records of the ethical review, including the written records of the ethical review, the information of the members, the documents submitted, the minutes of the meeting and the relevant transaction records. All records shall be kept for at least 5 years after the completion of the clinical trial. The researcher, sponsor or drug regulatory department may request the Ethics Committee to provide its standard operating procedures and the list of ethics review members.

 

Chapter IV Researchers

Article 16 The qualifications and requirements that researchers and clinical trial institutions should possess include:
(1) Having the qualification to practice in a clinical trial institution; Have the professional knowledge, training experience and ability required by clinical trials; Be able to provide the latest work experience and relevant qualification documents according to the requirements of the sponsor, ethics committee and drug regulatory department.
(2) Be familiar with the test scheme, investigator's manual, and information related to the test drug provided by the sponsor.
(3) Be familiar with and comply with this specification and the laws and regulations related to clinical trials.
(4) Keep a copy of the authorization form signed by the researcher.
(5) Investigators and clinical trial institutions shall accept the supervision and inspection organized by the sponsor and the inspection of the drug regulatory department.
(6) When researchers and clinical trial institutions authorize individuals or units to undertake the duties and functions related to clinical trials, they should ensure that they have the corresponding qualifications, and should establish complete procedures to ensure that they perform the duties and functions related to clinical trials and generate reliable data. The investigator and the clinical trial institution shall obtain the consent of the sponsor to authorize the units other than the clinical trial institution to undertake the duties and functions related to the trial.
Article 17 Researchers and clinical trial institutions shall have the necessary conditions to complete clinical trials:
(1) The investigator has the ability to enroll a sufficient number of subjects according to the trial protocol within the period agreed in the clinical trial.
(2) The investigator has enough time to implement and complete the clinical trial within the agreed period of the clinical trial.
(3) During the clinical trial, researchers have the right to control the personnel participating in the clinical trial, have the right to use the medical facilities required by the clinical trial, and correctly and safely implement the clinical trial.
(4) During the clinical trial, the researcher shall ensure that all personnel participating in the clinical trial fully understand the trial plan and trial drugs, define their respective division of labor and responsibilities in the trial, and ensure the authenticity, integrity and accuracy of the clinical trial data.
(5) The investigator supervises all researchers to implement the trial protocol, and takes measures to implement the quality management of the clinical trial.
(6) A clinical trial institution shall set up corresponding internal management departments to undertake the management of clinical trials.
Article 18 The researcher shall give the subject suitable medical treatment:
(1) Investigators who are clinicians or authorized clinicians need to assume all medical decision-making responsibilities related to clinical trials.
(2) During the clinical trial and follow-up, when the subject has adverse events related to the trial, including laboratory abnormalities of clinical significance, the investigator and clinical trial institution shall ensure that the subject is properly treated and truthfully inform the subject of the relevant information. When the investigator is aware that the subject has concomitant diseases that need treatment, he/she should inform the subject and pay attention to the concomitant drugs that may interfere with the clinical trial results or the safety of the subject.
(3) With the consent of the subject, the researcher can inform the relevant clinician about the subject's participation in the trial.
(4) Subjects can withdraw from the clinical trial without reason. While respecting the individual rights of subjects, researchers should try to understand the reasons for their withdrawal.
Article 19 The communication between the researcher and the Ethics Committee includes:
(1) Before the implementation of the clinical trial, the researcher shall obtain the written consent of the Ethics Committee; Subjects cannot be screened without the written consent of the Ethics Committee.
(2) Before and during the clinical trial, the researcher shall provide all documents required for ethical review to the Ethics Committee.
Article 20 Researchers shall abide by the experimental scheme.
(1) The investigator shall carry out the clinical trial according to the trial scheme agreed by the Ethics Committee.
(2) Without the consent of the sponsor and the Ethics Committee, the researcher shall not modify or deviate from the trial plan, but not include changes that only involve clinical trial management in order to eliminate the emergency hazards to the subject in time or change the supervisor, telephone number, etc.
(3) The investigator or the designated investigator shall record and explain the deviation from the test protocol.
(4) In order to eliminate the emergency harm to the subject, if the researcher modifies or deviates from the test plan without the consent of the Ethics Committee, he/she should report to the Ethics Committee and the sponsor in a timely manner, explain the reasons, and report to the drug regulatory department when necessary.
(5) The investigator should take measures to avoid the use of concomitant drugs prohibited by the trial protocol.
Article 21 Investigators and clinical trial institutions shall be responsible for the administration of the drugs for trial provided by the sponsors.
(1) Researchers and clinical trial institutions shall assign qualified pharmacists or other personnel to manage the drugs for trial use.
(2) The management of the receipt, storage, distribution, recovery, return and disposal of unused drugs for trial use in clinical trial institutions shall comply with the corresponding regulations and keep records.
The records of the management of drugs for testing shall include date, quantity, batch number/serial number, validity period, allocation code, signature, etc. The investigator shall keep records of the quantity and dosage of drugs used by each subject. The quantity of drugs used and the remaining quantity shall be consistent with the quantity provided by the sponsor.
(3) The storage of drugs for testing shall meet the corresponding storage conditions.
(4) The researcher shall ensure that the drugs used in the test are used according to the test plan, and shall explain the correct use method of the drugs used in the test to the subjects.
(5) The researchers shall randomly select and retain samples of drugs for clinical trials of bioequivalence test. The clinical trial institution shall keep the samples for at least 2 years after the drug is marketed. The clinical trial institution may entrust a qualified independent third party to keep the retained samples, but may not return them to the sponsor or a third party related to its interests.
Article 22 Researchers shall observe the randomization procedure of clinical trials.
Blind test shall be performed according to the requirements of the test plan. In case of accidental blindness breaking or emergency blindness breaking due to serious adverse events, the researcher shall explain the reasons in writing to the sponsor.
Article 23 To implement informed consent, researchers should abide by the ethical principles of the Helsinki Declaration and meet the following requirements:
(1) The researcher should use the latest version of the informed consent form and other information provided to the subject with the consent of the Ethics Committee. If necessary, the subjects in the clinical trial shall sign the informed consent form again.
(2) When the researcher obtains new information that may affect the subject to continue to participate in the test, he/she shall timely inform the subject or his/her guardian and make corresponding records.
(3) Researchers shall not influence subjects to participate in or continue the clinical trial by force, inducement or other improper means.
(4) The investigator or designated investigator shall fully inform the subject of all relevant matters related to the clinical trial, including written information and consent of the Ethics Committee.
(5) The oral and written materials provided to the subject, such as the informed consent, shall be in easy to understand language and expression, so that the subject or his guardian or witness can easily understand.
(6) Before signing the informed consent form, the researcher or designated researcher shall give the subject or his guardian sufficient time and opportunity to understand the details of the clinical trial and answer in detail the questions related to the clinical trial raised by the subject or his guardian.
(7) The subject or his/her guardian and the researcher who performed the informed consent shall sign and date the informed consent form respectively. If the person who is not the subject signs in person, the relationship shall be indicated.
(8) If the subject or his guardian lacks reading ability, an impartial witness shall witness the whole informed consent process. The researcher shall explain in detail the content of the informed consent form and other written materials to the subject or his guardian or witness. If the subject or his guardian agrees to participate in the trial, he/she should sign the informed consent form as far as possible if he/she is able, and the witness should also sign and date the informed consent form to prove that the subject or his/her guardian has accurately explained the informed consent form and other written materials, understood the relevant contents, and agreed to participate in the clinical trial.

Article 16 The qualifications and requirements that researchers and clinical trial institutions should possess include:
(1) Having the qualification to practice in a clinical trial institution; Have the professional knowledge, training experience and ability required by clinical trials; Be able to provide the latest work experience and relevant qualification documents according to the requirements of the sponsor, ethics committee and drug regulatory department.
(2) Be familiar with the test scheme, investigator's manual, and information related to the test drug provided by the sponsor.
(3) Be familiar with and comply with this specification and the laws and regulations related to clinical trials.
(4) Keep a copy of the authorization form signed by the researcher.
(5) Investigators and clinical trial institutions shall accept the supervision and inspection organized by the sponsor and the inspection of the drug regulatory department.
(6) When researchers and clinical trial institutions authorize individuals or units to undertake the duties and functions related to clinical trials, they should ensure that they have the corresponding qualifications, and should establish complete procedures to ensure that they perform the duties and functions related to clinical trials and generate reliable data. The investigator and the clinical trial institution shall obtain the consent of the sponsor to authorize the units other than the clinical trial institution to undertake the duties and functions related to the trial.
Article 17 Researchers and clinical trial institutions shall have the necessary conditions to complete clinical trials:
(1) The investigator has the ability to enroll a sufficient number of subjects according to the trial protocol within the period agreed in the clinical trial.
(2) The investigator has enough time to implement and complete the clinical trial within the agreed period of the clinical trial.
(3) During the clinical trial, researchers have the right to control the personnel participating in the clinical trial, have the right to use the medical facilities required by the clinical trial, and correctly and safely implement the clinical trial.
(4) During the clinical trial, the researcher shall ensure that all personnel participating in the clinical trial fully understand the trial plan and trial drugs, define their respective division of labor and responsibilities in the trial, and ensure the authenticity, integrity and accuracy of the clinical trial data.
(5) The investigator supervises all researchers to implement the trial protocol, and takes measures to implement the quality management of the clinical trial.
(6) A clinical trial institution shall set up corresponding internal management departments to undertake the management of clinical trials.
Article 18 The researcher shall give the subject suitable medical treatment:
(1) Investigators who are clinicians or authorized clinicians need to assume all medical decision-making responsibilities related to clinical trials.
(2) During the clinical trial and follow-up, when the subject has adverse events related to the trial, including laboratory abnormalities of clinical significance, the investigator and clinical trial institution shall ensure that the subject is properly treated and truthfully inform the subject of the relevant information. When the investigator is aware that the subject has concomitant diseases that need treatment, he/she should inform the subject and pay attention to the concomitant drugs that may interfere with the clinical trial results or the safety of the subject.
(3) With the consent of the subject, the researcher can inform the relevant clinician about the subject's participation in the trial.
(4) Subjects can withdraw from the clinical trial without reason. While respecting the individual rights of subjects, researchers should try to understand the reasons for their withdrawal.
Article 19 The communication between the researcher and the Ethics Committee includes:
(1) Before the implementation of the clinical trial, the researcher shall obtain the written consent of the Ethics Committee; Subjects cannot be screened without the written consent of the Ethics Committee.
(2) Before and during the clinical trial, the researcher shall provide all documents required for ethical review to the Ethics Committee.
Article 20 Researchers shall abide by the experimental scheme.
(1) The investigator shall carry out the clinical trial according to the trial scheme agreed by the Ethics Committee.
(2) Without the consent of the sponsor and the Ethics Committee, the researcher shall not modify or deviate from the trial plan, but not include changes that only involve clinical trial management in order to eliminate the emergency hazards to the subject in time or change the supervisor, telephone number, etc.
(3) The investigator or the designated investigator shall record and explain the deviation from the test protocol.
(4) In order to eliminate the emergency harm to the subject, if the researcher modifies or deviates from the test plan without the consent of the Ethics Committee, he/she should report to the Ethics Committee and the sponsor in a timely manner, explain the reasons, and report to the drug regulatory department when necessary.
(5) The investigator should take measures to avoid the use of concomitant drugs prohibited by the trial protocol.
Article 21 Investigators and clinical trial institutions shall be responsible for the administration of the drugs for trial provided by the sponsors.
(1) Researchers and clinical trial institutions shall assign qualified pharmacists or other personnel to manage the drugs for trial use.
(2) The management of the receipt, storage, distribution, recovery, return and disposal of unused drugs for trial use in clinical trial institutions shall comply with the corresponding regulations and keep records.
The records of the management of drugs for testing shall include date, quantity, batch number/serial number, validity period, allocation code, signature, etc. The investigator shall keep records of the quantity and dosage of drugs used by each subject. The quantity of drugs used and the remaining quantity shall be consistent with the quantity provided by the sponsor.
(3) The storage of drugs for testing shall meet the corresponding storage conditions.
(4) The researcher shall ensure that the drugs used in the test are used according to the test plan, and shall explain the correct use method of the drugs used in the test to the subjects.
(5) The researchers shall randomly select and retain samples of drugs for clinical trials of bioequivalence test. The clinical trial institution shall keep the samples for at least 2 years after the drug is marketed. The clinical trial institution may entrust a qualified independent third party to keep the retained samples, but may not return them to the sponsor or a third party related to its interests.
Article 22 Researchers shall observe the randomization procedure of clinical trials.
Blind test shall be performed according to the requirements of the test plan. In case of accidental blindness breaking or emergency blindness breaking due to serious adverse events, the researcher shall explain the reasons in writing to the sponsor.
Article 23 To implement informed consent, researchers should abide by the ethical principles of the Helsinki Declaration and meet the following requirements:
(1) The researcher should use the latest version of the informed consent form and other information provided to the subject with the consent of the Ethics Committee. If necessary, the subjects in the clinical trial shall sign the informed consent form again.
(2) When the researcher obtains new information that may affect the subject to continue to participate in the test, he/she shall timely inform the subject or his/her guardian and make corresponding records.
(3) Researchers shall not influence subjects to participate in or continue the clinical trial by force, inducement or other improper means.
(4) The investigator or designated investigator shall fully inform the subject of all relevant matters related to the clinical trial, including written information and consent of the Ethics Committee.
(5) The oral and written materials provided to the subject, such as the informed consent, shall be in easy to understand language and expression, so that the subject or his guardian or witness can easily understand.
(6) Before signing the informed consent form, the researcher or designated researcher shall give the subject or his guardian sufficient time and opportunity to understand the details of the clinical trial and answer in detail the questions related to the clinical trial raised by the subject or his guardian.
(7) The subject or his/her guardian and the researcher who performed the informed consent shall sign and date the informed consent form respectively. If the person who is not the subject signs in person, the relationship shall be indicated.
(8) If the subject or his guardian lacks reading ability, an impartial witness shall witness the whole informed consent process. The researcher shall explain in detail the content of the informed consent form and other written materials to the subject or his guardian or witness. If the subject or his guardian agrees to participate in the trial, he/she should sign the informed consent form as far as possible if he/she is able, and the witness should also sign and date the informed consent form to prove that the subject or his/her guardian has accurately explained the informed consent form and other written materials, understood the relevant contents, and agreed to participate in the clinical trial.

 

Chapter V Applicants

Article 29 The sponsor shall take the protection of the rights and security of the subjects and the authenticity and reliability of the clinical trial results as the basic consideration of the clinical trial.
Article 30 The sponsor shall establish a quality management system for clinical trials.
The quality management system of the clinical trial of the sponsor shall cover the whole process of the clinical trial, including the design, implementation, recording, evaluation, result report and filing of the clinical trial. Quality management includes effective trial scheme design, data collection methods and processes, and information collection necessary for making decisions in clinical trials.
The methods for quality assurance and quality control of clinical trials should be consistent with the inherent risks of clinical trials and the importance of the information collected. The sponsor should ensure the operability of each link of the clinical trial, and avoid the complexity of the trial process and data collection. The test protocol, case report form and other relevant documents should be clear, concise and consistent.
The sponsors shall perform their management duties. According to the needs of clinical trials, a research and management team of clinical trials can be established to guide and supervise the implementation of clinical trials. Work within the research and management team should be communicated in a timely manner. The research and management team shall send personnel to participate in the inspection by the drug regulatory department.
Article 31 The sponsor shall conduct quality management based on risk.
(1) The key links and data for protecting the rights and security of subjects and ensuring the reliability of clinical trial results shall be clearly defined when the trial plan is formulated.
(2) Risks affecting key links and data of clinical trials should be identified. This risk should be considered from two levels: system level, such as facilities and equipment, standard operating procedures, computerized systems, personnel and suppliers; Clinical trial level, such as trial drug, trial design, data collection and recording, and informed consent process.
(3) The risk assessment shall consider the possibility of error under the existing risk control; The impact of the error on the protection of the rights and security of the subject and the reliability of the data; The extent to which the error is detected.
(4) Risks that can be reduced or accepted shall be identified. The control measures to reduce risks should be reflected in the design and implementation of the test plan, the audit plan, the contract with clear responsibilities of all parties, the compliance of standard operating procedures, and various trainings.
When setting the tolerance of quality risk in advance, the medical and statistical characteristics and statistical design of variables should be considered to identify systemic problems that affect the safety and reliability of the subject. When the tolerance of quality risk is exceeded, the need for further measures should be evaluated.
(5) During clinical trials, quality management should be recorded and communicated with relevant parties in a timely manner to promote risk assessment and continuous quality improvement.
(6) The sponsor shall regularly evaluate the risk control measures in combination with the new knowledge and experience during the clinical trial to ensure the effectiveness and applicability of the current quality management.
(7) The sponsor shall describe the quality management method adopted in the clinical trial report, and outline the events and remedial measures that seriously deviate from the tolerance of quality risk.
Article 32 The quality assurance and quality control of the applicants shall meet the following requirements:
(1) The sponsor is responsible for formulating, implementing and timely updating the standard operating procedures related to the quality assurance and quality control system of the clinical trial, and ensuring that the implementation of the clinical trial, data generation, recording and reporting comply with the requirements of the trial scheme, this specification and relevant laws and regulations.
(2) The whole process of clinical trial and laboratory testing shall be carried out in strict accordance with the standard operating procedures for quality management. Each stage of data processing has quality control to ensure that all data are reliable and the data processing process is correct.
(3) The sponsor shall sign a contract with all relevant units participating in the clinical trial, such as researchers and clinical trial institutions, to clarify the responsibilities of each party.
(4) The contract signed between the sponsor and each relevant unit shall indicate that the sponsor's supervision and inspection, and the inspection of the drug regulatory department can directly go to the test site to consult the source data, source documents and reports.
Article 33 A contract research organization commissioned by a sponsor shall meet the following requirements:
(1) The sponsor may entrust part or all of the work and tasks of the clinical trial to the contract research organization, but the sponsor is still the final responsible person for the quality and reliability of the clinical trial data, and shall supervise the work undertaken by the contract research organization. The contract research organization shall implement quality assurance and quality control.
(2) A contract shall be signed for the work entrusted to the contract research organization by the sponsor. The contract shall specify the following contents: the specific work entrusted and the corresponding standard operating procedures; The sponsor has the right to confirm the implementation of the SOP for the entrusted work; Written requirements for the entrusted party; The report requirements that the entrusted party needs to submit to the sponsor; Matters related to the subject's compensation measures; Other matters related to the entrusted work. The contract research organization shall obtain the written approval of the sponsor if there is any task subcontracting.
(3) The sponsor is still responsible for the work and tasks not explicitly entrusted to the contract research organization.
(4) The requirements for the sponsor in this specification are applicable to contract research organizations that undertake the relevant work and tasks of the sponsor.
Article 34 The sponsor shall designate competent medical experts to timely consult the relevant medical issues of the clinical trial.
Article 35 The applicant shall select qualified biostatisticians, clinical pharmacologists and clinicians to participate in the trial, including designing the trial scheme and case report forms, formulating statistical analysis plans, analyzing data, and writing interim and final trial summary reports.
Article 36 The sponsor shall meet the following requirements in test management, data processing and record keeping:
(1) The sponsor shall select qualified personnel to supervise the implementation of the clinical trial, data processing, data verification, statistical analysis and the writing of the trial summary report.
(2) The sponsor can establish an independent data monitoring committee to regularly evaluate the progress of clinical trials, including safety data and important validity endpoint data. The independent data monitoring committee can recommend whether the sponsor can continue to implement, modify or stop the ongoing clinical trial. The independent data monitoring committee shall have a written workflow and keep all relevant meeting minutes.
(3) The electronic data management system used by the sponsor shall pass the reliable system verification and conform to the pre-set technical performance, so as to ensure the integrity, accuracy and reliability of the test data, and ensure that the system is always in the valid state of verification throughout the test process.
(4) The electronic data management system shall have complete standard operating procedures for use, covering the setting, installation and use of electronic data management; The SOP shall describe the verification, function test, data acquisition and processing, system maintenance, system security test, change control, data backup, recovery, system emergency plan and software retirement of the system; The SOP shall specify the responsibilities of the sponsor, researcher and clinical trial institution when using the computerized system. All personnel using computerized systems should be trained.
(5) The method of data modification of computerized system shall be specified in advance. The modification process shall be fully recorded, and the original data (such as electronic data inspection track, data track and editing track) shall be retained; The integration, content and structure of electronic data shall be clearly defined to ensure the integrity of electronic data; When the computerized system changes, such as software upgrading or data transfer, it is more important to ensure the integrity of electronic data.
If data conversion occurs during data processing, ensure that the converted data is consistent with the original data and the visibility of the data conversion process.
(6) Ensure the security of the electronic data management system, and unauthorized personnel cannot access it; Save the list of persons authorized to modify data; Electronic data shall be backed up in a timely manner; Blind clinical trials should always be kept in a blind state, including data entry and processing.
(7) The sponsor shall use the subject identification code to identify all clinical trial data of each subject. After the blind method test is uncovered, the sponsor shall promptly inform the investigator in writing of the drug used for the test by the subject.
(8) The sponsor shall keep the clinical trial data related to the sponsor, and other data obtained by some relevant units participating in the clinical trial shall also be kept in the necessary documents of the clinical trial as the specific data of the sponsor.
(9) The sponsor shall notify all relevant researchers, clinical trial institutions and drug regulatory departments to suspend or terminate the clinical trial in progress.
(10) The transfer of ownership of test data shall comply with the requirements of relevant laws and regulations.
(11) The sponsor shall inform the investigator and clinical trial institution in writing of the requirements for the preservation of test records; When relevant test records are no longer needed, the sponsor shall also inform the investigator and clinical trial institution in writing.
Article 37 The applicant shall meet the following requirements when selecting researchers:
(1) The sponsor is responsible for selecting researchers and clinical trial institutions. All researchers should be trained in clinical trials, have experience in clinical trials, and have sufficient medical resources to complete clinical trials. For clinical trials involving multiple clinical trial institutions, the sponsor shall be responsible for selecting the team leader if necessary.
(2) The sample testing laboratory involving medical judgment shall comply with relevant regulations and have corresponding qualifications. The management, testing, transportation and storage of samples collected in clinical trials shall ensure the quality. It is prohibited to carry out biological sample testing (such as gene, etc.) unrelated to the test scheme agreed by the Ethics Committee. After the completion of the clinical trial, if the remaining samples are to be kept or may be used in the future, the subject should sign an informed consent form, and explain the time of storage and the confidentiality of the data, and under what circumstances the data and samples can be shared with other researchers.
(3) The sponsor shall provide the investigator and clinical trial institution with the trial scheme and the latest investigator manual, and shall provide sufficient time for the investigator and clinical trial institution to review the trial scheme and relevant data.
Article 38 Before all parties to a clinical trial participate in the clinical trial, the sponsor shall clearly define their responsibilities and indicate them in the signed contract.
Article 39 The applicants shall take appropriate measures to ensure that they can compensate or compensate the subjects and researchers.
(1) The sponsor shall provide legal and economic insurance or guarantee related to the clinical trial to researchers and clinical trial institutions, which shall be compatible with the nature and degree of risk of the clinical trial. However, it does not include the damage caused by the negligence of researchers and clinical trial institutions.
(2) The sponsor shall bear the diagnosis and treatment expenses of the injury or death related to the clinical trial of the subject, as well as the corresponding compensation. The sponsor and researcher shall timely honor the compensation or compensation given to the subject.
(3) The ways and means of compensation provided by the sponsor to the subjects shall comply with relevant laws and regulations.
(4) The sponsor shall provide the test drug to the subject free of charge and pay the medical testing fees related to the clinical trial.
Article 40 The contract signed between the sponsor and the researcher and the clinical trial institution shall specify the responsibilities, rights and interests of all parties to the trial, as well as the possible conflicts of interest that all parties should avoid. The contract test funds shall be reasonable and conform to market rules. The sponsor, researcher and clinical trial institution shall sign on the contract for confirmation.
The contents of the contract shall include: the implementation of the clinical trial shall comply with this specification and relevant clinical trial laws and regulations; Implement the test plan agreed by the ethics committee and negotiated by the sponsor and researcher; Comply with data recording and reporting procedures; Agree to audit, check and inspect; Retention and duration of necessary documents related to clinical trials; Agreement on publishing articles, intellectual property rights, etc.
Article 41 Before the start of a clinical trial, the sponsor shall submit the relevant clinical trial materials to the drug regulatory department, and obtain the approval of the clinical trial or complete the filing. The submitted documents shall indicate the version number and version date.
Article 42 The sponsor shall obtain the name and address of the Ethics Committee, the list of members of the Ethics Committee participating in the project review, the review statement in compliance with this Code and relevant laws and regulations, as well as the documents and other relevant materials approved by the Ethics Committee from the researchers and clinical trial institutions.
Article 43 When drawing up a clinical trial plan, the sponsor shall have sufficient safety and effectiveness data to support its route of administration, dosage and duration of drug use. When important new information is obtained, the sponsor shall timely update the researcher's manual.
Article 44 The preparation, packaging, labeling and coding of drugs for experimental use shall meet the following requirements:

(1) The preparation of the trial drug shall meet the relevant requirements for the production quality management of drugs for clinical trials; The package and label of drugs for trial use shall indicate that they are only used for clinical trials, information on clinical trials and information on drugs for clinical trials; The blind state can be maintained in the blind test.
(2) The sponsor shall clearly specify the storage temperature, transportation conditions (whether it is necessary to avoid light), storage time limit, preparation method and process of drug solution, and requirements for drug infusion devices, etc. of drugs for test. The use method of the test drug shall be informed to all relevant personnel of the test, including supervisors, researchers, pharmacists, drug custodians, etc.
(3) The packaging of drugs for testing shall ensure that the drugs will not be contaminated or deteriorated during transportation and storage.
(4) In blind trial, the coding system of drugs for trial shall include emergency unblinding procedures, so as to quickly identify which drugs for trial can be used in an emergency medical state without destroying the blindness of clinical trials.
Article 45 The supply and management of drugs for experimental use shall meet the following requirements:
(1) The sponsor is responsible for providing experimental drugs to researchers and clinical trial institutions.
(2) Before the clinical trial is approved by the Ethics Committee and approved or filed by the drug regulatory department, the sponsor shall not provide drugs for the trial to researchers and clinical trial institutions.
(3) The sponsor shall provide the investigator and clinical trial institution with a written description of the drug for trial, which shall specify the use, storage and relevant records of the drug for trial. The sponsor shall formulate the supply and management procedures of test drugs, including the receipt, storage, distribution, use and recovery of test drugs. The drugs recovered from the subjects and not used by the researchers shall be returned to the sponsor or destroyed by the clinical trial institution with the authorization of the sponsor.
(4) The sponsor shall ensure that the drugs for trial use are delivered to the researchers and clinical trial institutions in a timely manner and that the subjects use them in a timely manner; Keep the records of transportation, receipt, distribution, recovery and destruction of drugs for testing; Establish a management system for the recovery of test drugs to ensure the recall of defective products, the recovery after the test and the recovery after expiration; Establish a destruction system for unused test drugs. The management process of all test drugs shall be recorded in writing, and the whole process shall be counted accurately.
(5) The sponsor shall take measures to ensure the stability of the drugs used in the experiment during the experiment. The retention period of the retention samples of the drugs for trial use shall, within the storage period of the drugs for trial use, be kept until the end of the clinical trial data analysis or the time limit required by relevant laws and regulations. If the two are inconsistent, the longer time limit shall prevail.
Article 46 The sponsor shall specify the right of access to the test records.
(1) The sponsor shall specify in the trial plan or contract that the investigator and the clinical trial institution allow supervisors, inspectors, reviewers of the ethics committee and inspectors of the drug regulatory department to directly consult the source data and source documents related to the clinical trial.
(2) The sponsor shall confirm that each subject agrees in writing to the supervisor, the inspector, the reviewer of the ethics committee and the inspector of the drug regulatory department to directly consult the original medical records related to the clinical trial.
Article 47 The sponsor shall be responsible for the safety evaluation of the drugs used in the trial during the drug trial. The sponsor shall timely notify the researcher, clinical trial institution and drug regulatory department of the problems found in the clinical trial that may affect the safety of the subject, may affect the implementation of the clinical trial, and may change the consent of the ethics committee.
Article 48 The sponsor shall report adverse drug reactions according to the requirements and time limit.
(1) The sponsor shall immediately analyze and evaluate the safety related information from any source, including the severity, relevance to the test drug and whether it is an expected event. The sponsor shall quickly report the suspicious and unexpected serious adverse reactions to all the researchers participating in the clinical trial, clinical trial institutions and ethics committees; The sponsor shall report the suspicious and unexpected serious adverse reactions to the drug regulatory department and the competent health department.
(2) The safety update report provided by the sponsor during the drug research and development period shall include the evaluation of the risks and benefits of the clinical trial, and the relevant information shall be reported to all researchers participating in the clinical trial, clinical trial institutions and ethics committees.
Article 49 The supervision of clinical trials shall meet the following requirements:
(1) The purpose of the audit is to ensure the rights and interests of the subjects in the clinical trial, to ensure the accuracy and completeness of the data in the trial records and reports, and to ensure that the trial complies with the agreed protocol, this specification and relevant regulations.
(2) The supervisors appointed by the sponsor shall have received corresponding training, have the knowledge required for clinical trial supervision such as medicine and pharmacy, and be able to effectively perform the supervision duties.
(3) The sponsor shall establish a systematic, prioritized and risk assessment based method to supervise the clinical trial. The scope and nature of the audit can be flexible, allowing different audit methods to improve the efficiency and effectiveness of the audit. The sponsor shall write the reasons for choosing the audit strategy in the audit plan.
(4) The sponsor shall formulate a supervision plan. The monitoring plan should particularly emphasize the protection of the rights and interests of the subjects, ensure the authenticity of the data, and ensure that various risks in the clinical trial are dealt with. The audit plan shall describe the audit strategy, audit responsibilities for all parties to the test, audit methods, and reasons for applying different audit methods. The audit plan should emphasize the audit of key data and processes. The audit plan shall comply with relevant laws and regulations.
(5) The sponsor shall formulate the standard operating procedures for supervision, and the supervisors shall implement the standard operating procedures in the supervision work.
(6) The sponsor shall carry out clinical trial supervision. The scope and nature of the supervision depends on the purpose, design, complexity, blinding method, sample size and clinical trial endpoint of the clinical trial.
(7) On site supervision and centralized supervision shall be carried out based on the risk of clinical trial. On site monitoring is conducted at the clinical trial site, usually before, during and after the clinical trial. The centralized supervision is a timely remote evaluation of the ongoing clinical trials, as well as a remote evaluation of the data collected by different clinical trial institutions. The centralized monitoring process is helpful to improve the monitoring effect of clinical trials and is a supplement to on-site monitoring.
The application of statistical analysis in centralized monitoring can determine the trend of data, including the data range and consistency within different clinical trial institutions and between clinical trial institutions, and can analyze the characteristics and quality of data, which is conducive to the selection of monitoring sites and procedures.
(8) Under special circumstances, the sponsor can combine the monitoring with other experimental work, such as researcher training and meetings. During the audit, statistical sampling survey can be used to check the data.
Article 50 The duties of supervisors include:
(1) The supervisor shall be familiar with the relevant knowledge of the drugs used in the test, the contents of the test protocol, the informed consent form and other written materials provided to the subjects, and the standard operating procedures for clinical trials, this specification and other relevant regulations.
(2) The supervisor shall earnestly perform his/her supervision duties according to the requirements of the sponsor to ensure that the clinical trial is correctly implemented and recorded according to the trial plan.
(3) The supervisor is the main contact between the sponsor and the researcher. Before the clinical trial, it should be confirmed that the researchers have sufficient qualifications and resources to complete the trial. The clinical trial institution has the appropriate conditions to complete the trial, including staffing and training. The laboratory is fully equipped and operates well, and has various inspection conditions related to the trial.
(4) The supervisor shall verify that the drugs for trial use are within the validity period, the storage conditions are acceptable, and the supply is sufficient during the clinical trial; The test drug is only provided to the appropriate subjects according to the dose specified in the test plan; Subjects received instructions on the correct use, handling, storage and return of test drugs; The clinical trial institution has proper control and records on the receipt, use and return of drugs for trial; The disposal of unused experimental drugs by the clinical trial institution complies with relevant laws and regulations and the requirements of the sponsor.
(5) The supervisor verifies the investigator's implementation of the trial protocol during the clinical trial implementation; Confirm that all subjects or their guardians have signed the informed consent form before the test; Ensure that the researchers receive the latest version of the investigator's manual, all test related documents, and test necessities, and implement in accordance with the requirements of relevant laws and regulations; To ensure that researchers have a full understanding of clinical trials.
(6) The supervisor shall verify that the researcher performs the duties specified in the test protocol and contract, and whether these duties are delegated to unauthorized personnel; Confirm that the selected subjects are qualified and report the enrollment rate and clinical trial progress; Confirm that data records and reports are correct and complete, and test records and documents are updated and kept in good condition in real time; Verify that all medical reports, records and documents provided by the investigator are traceable, clear, synchronous, original, accurate and complete, and marked with date and test number.
(7) The supervisor checked the accuracy and completeness of the case report form and compared it with the source document. The supervisor should pay attention to checking that the data specified in the test protocol are accurately recorded in the case report form and consistent with the source document; Confirm that the dose change, treatment change, adverse event, concomitant medication, complication, lost interview, inspection omission, etc. of the subject are recorded in the case report form; Confirm that the follow-up, test and inspection that the investigators failed to do, and whether the errors and omissions were corrected are recorded in the case report form; Verify that the withdrawal and loss of interview of the selected subjects have been recorded and explained in the case report form.
(8) The supervisor shall notify the researcher of any error, omission or unclear handwriting in the case report form; The supervisor shall ensure that the corrections, additions or deletions made are made by the researcher or authorized person, and are signed and dated by the modifier, and explain the reasons for the modification when necessary.
(9) The supervisor confirmed that the adverse event was reported within the specified time limit according to the requirements of relevant laws and regulations, test scheme, ethics committee and the sponsor.
(10) The supervisor confirms whether the researcher has saved the necessary documents according to this specification.
(11) The supervisor shall timely communicate with the researcher about the deviation from the test scheme, standard operating procedures and relevant laws and regulations, and take appropriate measures to prevent recurrence.
Article 51 After each inspection, the inspectors shall promptly report in writing to the applicant; The report shall include the date and place of the audit, the name of the supervisor, the name of the researcher and other personnel contacted by the supervisor, etc; The report shall include the summary of the audit work, the problems found in the clinical trial and the statement of facts, the deviations and defects from the test plan, and the audit conclusion; The report shall state the corrective measures taken or proposed to be taken for the problems found in the audit, and the suggestions for the implementation of the test plan to ensure that the test complies with the test plan; The report should provide sufficient details to review compliance with the audit plan. The centralized audit report can be submitted separately from the on-site audit report. The sponsor shall review and follow up the problems in the audit report and form a document for preservation.
Article 52 The examination of clinical trials shall meet the following requirements:
(1) In order to evaluate the implementation of the clinical trial and compliance with laws and regulations, the sponsor can carry out audit in addition to the routine audit.
(2) The sponsor shall select a person who is independent of the clinical trial as the auditor, not a supervisor concurrently. The inspectors shall be trained and have inspection experience and be able to effectively perform their inspection duties.
(3) The sponsor shall formulate the audit procedures for clinical trials and trial quality management system to ensure the implementation of the audit procedures in clinical trials. The procedure shall formulate the purpose, method, frequency and format of the audit report. The problems observed and found by the inspectors during the inspection shall be recorded in writing.
(4) The sponsor shall formulate the audit plan and procedures based on the content of the materials submitted to the drug regulatory department, the number of subjects in the clinical trial, the type and complexity of the clinical trial, the risk level affecting the subjects and other known related issues.
(5) The drug regulatory department may require the sponsor to provide an inspection report according to work needs.
(6) When necessary, the applicant shall provide an inspection certificate.
Article 53 The applicant shall ensure the compliance of the clinical trial.

(1) If it is found that the researchers, clinical trial institutions, and the sponsor's personnel do not comply with the trial scheme, standard operating procedures, this Code, and relevant laws and regulations in the clinical trial, the sponsor shall immediately take measures to correct them, so as to ensure the good compliance of the clinical trial.
(2) If important compliance problems are found that may have a significant impact on the safety and rights of the subjects, or on the reliability of the clinical trial data, the sponsor shall promptly conduct a root cause analysis and take appropriate corrective and preventive measures. If the violation of the test protocol or this specification is serious, the sponsor can investigate the responsibility of the relevant personnel and report to the drug regulatory department.
(3) If it is found that the researcher or clinical trial institution has serious or dissuaded non-compliance, the sponsor shall terminate the researcher or clinical trial institution from continuing to participate in the clinical trial and report to the drug regulatory department in writing in a timely manner. At the same time, the sponsor and researcher shall take corresponding emergency safety measures to protect the safety and rights of the subjects.
Article 54 If the applicant terminates or suspends the clinical trial ahead of time, he shall immediately inform the researcher, the clinical trial institution and the drug regulatory department, and explain the reasons.
Article 55 When the clinical trial is completed or terminated in advance, the sponsor shall submit the clinical trial report to the drug regulatory department in accordance with the requirements of relevant laws and regulations. The clinical trial summary report shall comprehensively, completely and accurately reflect the clinical trial results. The safety and effectiveness data of the clinical trial summary report shall be consistent with the clinical trial source data.
Article 56 The applicant shall meet the following requirements when conducting a multicenter trial:
(1) The sponsor shall ensure that all centers participating in the clinical trial can comply with the trial protocol.
(2) The sponsor shall provide the same test scheme to each center. All centers follow the same unified evaluation criteria for clinical and laboratory data and the instructions for filling in the case report form according to the protocol.
(3) Each center shall use the same case report form to record the trial data obtained in the clinical trial. If the sponsor needs the investigator to increase the collection of test data, this content should be indicated in the test plan, and the sponsor should provide the investigator with an additional case report form.
(4) Before the start of the clinical trial, there should be written documents specifying the responsibilities of the researchers in each center participating in the clinical trial.
(5) The sponsor should ensure communication among researchers in each center.

 

Chapter VI Test Scheme

Article 57 The test plan usually includes basic information, research background data, test purpose, test design, implementation methods (methods, contents, steps), etc.
Article 58 The basic information in the test plan generally includes:
(1) Test plan title, number, version number and date.
(2) Name and address of the sponsor.
(3) Name, title and unit of the person authorized by the sponsor to sign and modify the test plan.
(4) Name, title, address and telephone number of the medical expert of the sponsor.
(5) The name, title and position of the investigator, and the address and telephone number of the clinical trial institution.
(6) Name and address of units and relevant departments participating in the clinical trial.
Article 59 The research background information in the test plan usually includes:
(1) Name and introduction of test drug.
(2) Discovery of investigational drugs in non clinical studies and clinical studies that are related to clinical trials and have potential clinical significance.
(3) Known and potential risks and benefits to the subject population.
(4) Description of the administration route, dosage, administration method and treatment schedule of the test drug, and reasons.
(5) It is emphasized that clinical trials should be carried out in accordance with the trial plan, this specification and relevant laws and regulations.
(6) Target population of the clinical trial.
(7) Research background information, references and data sources related to clinical trials.
Article 60 The purpose of the clinical trial shall be described in detail in the trial plan.
Article 61 The scientificity of a clinical trial and the reliability of the trial data mainly depend on the trial design, which usually includes:
(1) Identify the primary and secondary endpoints of the clinical trial.
(2) The reason for selecting the control group and the description of the trial design (such as double blind, placebo control, parallel group design), and the study design, process and different stages are represented in the form of flow charts.
(3) Measures taken to reduce or control bias, including methods and processes of randomization and blinding. The use of single blind or open trial requires explanation of reasons and measures to control bias.
(4) Treatment method, dosage and administration plan of the trial drug; The dosage form, package and label of the test drug.
(5) The expected duration and specific arrangement of the subject's participation in the clinical trial, including follow-up, etc.
(6) "Test suspension standard" and "test termination standard" for subjects, some clinical trials and all clinical trials.
(7) Management process of test drugs.
(8) Procedures for blind bottom preservation and unblinding.
(9) Specify which test data can be directly recorded in the case report form as source data.
Article 62 The test plan usually includes the items of clinical and laboratory examination.
Article 63 The selection and withdrawal of subjects usually include:
(1) Inclusion criteria of subjects.
(2) Exclusion criteria for subjects.
(3) Criteria and procedures for subjects to withdraw from the clinical trial.
Article 64 The treatment of the subject usually includes:
(1) Name, dosage, administration scheme, administration route, treatment time and follow-up period of all test drugs used by the subject in each clinical trial group.
(2) Combination drugs (including first-aid drugs) or treatments allowed before and during clinical trials, and drugs or treatments prohibited from use.
(3) Methods to evaluate the compliance of subjects.
Article 65 Formulate a clear visit and follow-up plan, including the clinical trial period, clinical trial end point, adverse event evaluation, follow-up and medical treatment after the trial.
Article 66 Effectiveness evaluation usually includes:
(1) Describe the effectiveness indicators of the clinical trial in detail.
(2) Describe the evaluation, record, analysis method and time point of effectiveness indicators in detail.
Article 67 Safety evaluation usually includes:
(1) Describe the safety indicators of the clinical trial in detail.
(2) Describe the evaluation, record, analysis method and time point of safety indicators in detail.
(3) Procedures for recording and reporting adverse events and concomitant diseases.
(4) Follow up methods and duration of adverse events.
Article 68 Statistics generally include:
(1) Determine the sample size of the subject, and explain the reason according to the previous experiment or literature data.
(2) The significance level, if any, shall be considered.
(3) Explain the statistical assumptions of the main evaluation indicators, including the original assumptions and alternative assumptions, and briefly describe the specific statistical methods and statistical analysis software to be used. If interim analysis is required, reasons, analysis time and operation procedures shall be stated.
(4) Handling of missing data, unused data and illogical data.
(5) Clarify the modification procedures that deviate from the original statistical analysis plan.
(6) The data set of subjects used for statistical analysis shall be clearly defined, including all randomized subjects, all subjects who have taken the trial drug, all eligible subjects and those who can be used for the evaluation of clinical trial results.
Article 69 The trial plan shall include the implementation of quality control and quality assurance for clinical trials.
Article 70 The test plan usually includes consideration of ethical issues related to the test.
Article 71 The test plan usually describes the process of test data collection and management, the system used for data management and collection, the steps and tasks of data management, and the quality assurance measures for data management.
Article 72 If there is no provision in the contract or agreement, the trial plan usually includes direct access to source documents, data processing and record keeping, finance and insurance related to clinical trials.

 

Chapter VII Investigator's Manual

Article 73 The Investigator's Manual provided by the sponsor is a compilation of pharmaceutical, non clinical and clinical data of the trial drug, which includes chemical, pharmaceutical, toxicological, pharmacological and clinical data and data of the trial drug. The purpose of the Investigator's Manual is to help researchers and other personnel involved in the trial better understand and comply with the trial protocol, and help researchers understand many key basic elements of the trial protocol, including the dosage, number of times of administration, interval time of administration, and prescription of the clinical trial, as well as the observation and monitoring of primary and secondary efficacy indicators and safety.
Article 74 When clinical trials are carried out for drugs already on the market and researchers have fully understood their pharmacology and other relevant knowledge, researchers' manuals can be simplified. Some contents of the investigator's manual can be replaced by drug instructions and other forms, and only the latest, comprehensive and detailed information related to clinical trials, important, and experimental drugs need to be provided to the investigator.
Article 75 The sponsor shall formulate a written procedure for revising the researcher's manual. Review the investigator's manual at least once a year during the clinical trial. According to the research and development steps of the clinical trial and the new information about the safety and effectiveness of the relevant drugs obtained during the clinical trial, the sponsor should inform the investigator before updating the investigator's manual, and communicate with the Ethics Committee and the drug regulatory department when necessary. The sponsor is responsible for updating the researcher's manual and delivering it to the researcher in time, and the researcher is responsible for submitting the updated manual to the Ethics Committee.
Article 76 The title page of the investigator's manual shall indicate the name of the sponsor, the number or name of the trial drug, the version number, the date of release, the replacement version number, and the replacement date.
Article 77 The researcher's manual shall include:
(1) Catalog entries: confidentiality description, signature page, catalog, abstract, foreword, physical, chemical, pharmaceutical properties and structural formula of the test drug, non clinical research (non clinical pharmacology, pharmacokinetics in animals, toxicology), human internal effects (pharmacokinetics in human body, safety and effectiveness, marketing and use), data summary and researcher's guide, precautions References (published literature and reports, listed at the end of each chapter).
(2) Abstract: It focuses on the important information of physics, chemistry, pharmacology, pharmacology, toxicology, pharmacokinetics and clinical aspects in the research and development of experimental drugs.
(3) Preface: Briefly describe the chemical name or approved general name and approved trade name of the test drug; All active ingredients of the test drug, pharmacological classification, and its expected position in similar drugs (such as advantages); The basis for setting up the clinical trial of the investigational drug; The proposed investigational drug is used for disease prevention, diagnosis and treatment. The routine methods for evaluating the investigational drug should be described in the foreword.
(4) The chemical formula and structural formula of the test drug shall be clearly stated in the investigator's manual, and its physicochemical and pharmaceutical properties shall be briefly described. Explain the storage method and use method of the test drug. When the preparation information of the test drug may affect the clinical trial, the ingredients of the excipients and the reasons for the formula shall be stated to ensure that necessary safety measures are taken in the clinical trial.
(5) If the structure of the test drug is similar to that of other known drugs, it shall be explained.
(6) Introduction to non clinical studies: briefly describe the relevant results of the pharmacological, toxicological and pharmacokinetic research findings of the non clinical studies of the test drug. Explain the methodology and research results of these non clinical studies, and discuss the implications of these findings for human clinical treatment, the possible adverse effects on human body and the correlation of unexpected effects on human body.
(7) The investigator's manual shall provide information in non clinical studies: species of test animals, number and sex of animals in each group, dosage unit, dosage interval, route of administration, duration of administration, systematic distribution data, and follow-up period after exposure. The research results shall include the characteristics and frequency of pharmacological effects and toxic effects of the test drug; Severity or intensity of pharmacological and toxic effects; Effective time; Reversibility of efficacy; Duration of drug action and dose response. The most important findings in non clinical studies should be discussed, such as dose effect response, possible correlation with human body, and various aspects of possible human research. If the results of effective dose and non-toxic dose of animals of the same genus can be compared, the results can be used to discuss the treatment index, and explain the correlation between the research results and the proposed human dose. The comparative study shall be based on the blood or organ tissue level as much as possible.
(8) Introduction to non clinical pharmacological research: it shall include the summary of the pharmacology of the test drug, and if possible, it shall also include the important metabolism research of the test drug in animals. The abstract should include studies to evaluate the potential therapeutic activity of the investigational drug (such as efficacy model, receptor binding and specificity), as well as studies to evaluate the safety of the investigational drug (such as special studies to evaluate pharmacological effects that are different from the evaluation of therapeutic effects).
(9) Introduction to animal pharmacokinetics: it shall include the summary of pharmacokinetics, biotransformation and distribution of the test drug in the studied species of animals. The discussion on the discovery should explain the absorption, local and systematic bioavailability and metabolism of the test drug, as well as their relationship with the animal species, pharmacology and toxicology findings.
(10) Toxicology introduction: The summary of toxicological effects found in relevant studies of different animal species should include single dose administration, repeated administration, carcinogenicity, special toxicological studies (such as irritation and sensitization), reproductive toxicity, genetic toxicity (mutagenicity), etc.
(11) Human internal effects: the known effects of the test drug on human body should be fully discussed, including information in pharmacokinetics, pharmacodynamics, dose response, safety, effectiveness and other pharmacological fields. Summaries of all completed clinical trials of investigational drugs should be provided as far as possible. The use of trial drugs other than clinical trials, such as experience during marketing, should also be provided.
(12) Summary of pharmacokinetics information of the test drug in human body, including pharmacokinetics (absorption and metabolism, plasma protein binding, distribution and elimination); The bioavailability (absolute and relative bioavailability) of a reference dosage form of the test drug; Population subgroups (such as gender, age and organ function impairment); Interaction (such as drug drug interaction and food interaction); Other pharmacokinetic data (such as results of population studies completed during clinical trials).
(13) Safety and effectiveness of the test drug: the summary and discussion of the safety, pharmacodynamics, effectiveness and dose response information of the test drug (including metabolites) obtained from previous human trials shall be provided. If multiple clinical trials have been completed, the safety and effectiveness data of multiple studies and subgroups should be summarized. Adverse drug reactions (including all indications studied) of all clinical trials can be clearly summarized in the form of tables. Important differences in the type and incidence of adverse drug reactions between indications or subgroups should be discussed.
(14) Marketing use: the main countries and regions where the trial drug has been marketed or approved shall be stated. Important information obtained from marketing use (such as prescription, dosage, route of administration and adverse drug reactions) should be summarized. The major countries and regions that have not obtained approval for or withdrawn from the market of the trial drugs shall be stated.
(15) Data summary and researcher's guide: comprehensive analysis and discussion of non clinical and clinical data shall be carried out, and information about different aspects of the trial drug from various sources shall be summarized to help researchers predict adverse drug reactions or other problems in clinical trials.
(16) The investigator's manual should enable researchers to clearly understand the possible risks and adverse reactions of the clinical trial, as well as the special examinations, observation items and preventive measures that may be required; This understanding is based on the physical, chemical, pharmaceutical, pharmacological, toxicological and clinical data of the investigational drug obtained from the investigator's manual. Based on the previous human application experience and the pharmacology of the test drug, the researchers should also be provided with guidance on the identification and treatment of possible overdose and adverse drug reactions.
(17) The content of the manual for researchers of traditional Chinese medicine and ethnic medicine is formulated with reference to the above requirements. It shall also indicate the theoretical basis, screening information, compatibility, functions, indications, existing experience in drug use, the origin and origin of the medicinal materials, etc; Chinese herbal compound preparations derived from ancient classical famous prescriptions, indicating their origins; Relevant medical materials and prescriptions.

 

Chapter VIII Management of Necessary Documents

Article 78 The necessary documents for clinical trials refer to the documents for evaluating the implementation of clinical trials and the quality of data, which are used to prove that researchers, sponsors and supervisors have complied with the requirements of this Code and relevant laws and regulations on clinical trials of drugs in the course of clinical trials.
The necessary documents are the important content of the sponsor's inspection and the drug regulatory department's inspection of the clinical trial, and serve as the basis for confirming the authenticity of the clinical trial implementation and the integrity of the data collected.
Article 79 The applicants, researchers and clinical trial institutions shall confirm that they have the places and conditions for keeping the necessary documents for clinical trials. The equipment for saving documents shall be protected from direct light, waterproof, fireproof, etc., which is conducive to long-term preservation of documents. Standard operating procedures for document management shall be formulated. The saved documents shall be easy to identify, search, access and return. The media used to store clinical trial data shall ensure that the source data or its certified copy is kept complete and readable during the retention period, and regularly test or check the ability to restore reading, so as to avoid intentional or unintentional change or loss.
If some documents generated during the implementation of the clinical trial are not listed in the management directory of the necessary documents for the clinical trial, the sponsor, researcher and clinical trial institution can also include them in their respective necessary document archives according to the necessity and relevance.
Article 80 The necessary documents for clinical trials used to apply for drug registration shall be kept for at least five years after the trial drug is approved for marketing; For clinical trials that are not used to apply for drug registration, the necessary documents shall be kept for at least 5 years after the termination of the clinical trial.
Article 81 The sponsor shall ensure that the researchers can always consult and input and correct the data in the case report form reported to the sponsor during the trial. The data shall not be controlled by the sponsor only.
The sponsor shall ensure that the investigator can retain the case report form data submitted to the sponsor. Copies used as source documents shall meet the requirements for certified copies.
Article 82 At the beginning of a clinical trial, both the researcher, the clinical trial institution and the sponsor shall establish archives for the management of necessary documents. At the end of the clinical trial, the supervisor shall review and confirm the necessary documents of the investigator, clinical trial institution and sponsor, which shall be properly kept in their respective clinical trial archives.

 

Chapter IX Supplementary Provisions

Article 83 This Code shall come into force as of July 1, 2020.

 

 

 

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