Chapter 1 General Provisions

　　Article 1   In order to ensure the standardization of drug clinical trial conduct, the scien- tific integrity, authenticity and reliability of data and results, and the protection of rights, safety and well-being of human subjects, this regulation is developed in accordance with “Drug Administration Law of the People's Republic of China”, “Vaccine Administration Law of the People's Republic of China”, and “Regulations for the Implementation of the Drug Administration Law of the People's Republic of China”. This regulation is applicable to drug clinical trials supporting drug registration. The relevant activities of drug clinical trials should comply with this regulation.

　　Article 2 Good Clinical Practice sets the quality standards for the entire process of drug clinical trials, including protocol design, trial planning and conduct, monitoring, auditing, recording, analyses, summary and reporting.

　　Article 3  Drug clinical trials should comply with the principles of the Helsinki Decla- ration of the World Medical Association and relevant ethical requirements. The rights and safety of the subjects are the primary considerations and prevail over the interests of science and society. Ethical review and informed consent are important measures to protect the rights and well-being of the subjects.

　　Article 4 Drug clinical trials should  have  sufficient  scientific  basis.  Clinical  trials should weigh the foreseeable risks and anticipated benefits to the individual trial subjects and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.

　　Article 5 The trial protocol should be clear, detailed and operable. The trial protocol can be implemented only after obtaining the approval of the ethics committee (EC).

　　Article 6 The investigators should comply with the trial protocol during the clinical trial, and any medical judgment or medical decisions should be made by a physician. Investigators and staff participating in the conduct of clinical trials should have appropriate education, training, and experience to undertake the clinical trials.

　　Article 7 All paper or electronic data of clinical trials should be properly recorded, han- dled and stored in a way that allows its accurate reporting, interpretation and verification. The privacy of the subjects and the confidentiality of their related information should be protected.

　　Article 8   The investigational product should be manufactured and prepared in accord- ance with the requirements of applicable good manufacturing practice. The investigational product should be used in accordance with the trial protocol.

　　Article 9 The quality management system of clinical trials should encompass the entire process of clinical trials, with emphasis on subject protection, reliability of trial results, and compliance with relevant laws and regulations.

　　Article 10 The conduct of clinical trials should comply with the principle of conflict of interest avoidance.

　　Chapter 2 Terms and Definitions

　　Article 11 In this guideline, the following terms are defined as:

　　(1) Clinical trial: any investigation in human subjects (patients or healthy subjects) intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investi- gational product(s) with the object of ascertaining its safety and/or efficacy.

　　(2) Compliance (in relation to clinical trials): adherence to all the trial-related requirements, good clinical practice (GCP) requirements, and the relevant laws and regulations by all par- ties involved in the trial.

　　(3) Nonclinical Study: biomedical studies not performed on human subjects.

　　(4) Independent Data Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee, Data Monitoring Committee): an independent data monitoring com- mittee that may be established by the sponsor to assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial.

　　(5) Ethics Committee (EC): a board or a committee constituted of medical and pharmaceu- tical professionals and non-medical/pharmaceutical members, whose responsibility is to en- sure the protection of the rights, safety and well-being of human subjects involved in a trial, by, among other things, independently reviewing, approving, and following-up trial protocol and related documents, the methods and materials used to obtain and record the subject ’s informed consent, etc.

　　(6) Investigator: a person in charge of the conduct of the clinical trial at a trial site and who is responsible for the quality of the trial site and the rights and safety of trial subjects.

　　(7) Sponsor: an individual, institution, or organization that takes responsibility for the initi- ation, management, and/or financing of a clinical trial.

　　(8) Contract Research Organization (CRO): an organization contracted by the sponsor to perform one or more of trial-related duties and functions of the sponsor or the investigators.

　　(9) Subject: an individual who participates in a clinical trial as a recipient of the investiga- tional product, including patients and healthy subjects.

　　(10) Vulnerable Subjects: individuals who have insufficient or lost ability to maintain their will and rights, whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples are students and subordinates of the investigator, staff of the sponsor, members of the armed forces, persons kept in detention, patients with incurable diseases, patients in emer- gency situations, persons in nursing homes, homeless persons, minors, and those incapable of giving consent.

　　(11) Informed Consent: a process by which a subject voluntarily confirms his or her willing- ness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate. Informed consent is documented by means of a written, signed, and dated informed consent form.

　　(12) Impartial Witness: a person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends and witnesses the informed consent process if the subject or the subject’s legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject.

　　(13) Monitoring: the act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating pro- cedures (SOPs), and the applicable regulatory requirement(s).

　　(14) Monitoring Plan: a document that describes the strategy, methods, responsibilities, and requirements for monitoring the trial.

　　(15) Monitoring Report: a written report from the monitor to the sponsor after each site visit and/or other trial-related communication according to the sponsor’s standard operating pro- cedures (SOPs).

　　(16) Audit: a systematic and independent examination of trial-related activities and docu- ments to determine whether the evaluated trial-related activities were conducted, and the data were recorded, analyzed, and accurately reported according to the protocol, sponsor's stand- ard operating procedures (SOPs), and the applicable regulatory requirement(s).

　　(17) Audit Report: a written evaluation by the sponsor’s auditor of the results of the audit.

　　(18) Inspection: the act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the sponsor’s and/or contract research organization’s (CROs) facilities, or at other establishments deemed appropriate by the regulatory authority(ies).

　　(19) Direct Access: permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. Any party with direct access should take all reasonable precautions within the constraints of the applicable regulatory require- ment(s) to maintain the confidentiality of subjects’ identities and sponsor’s proprietary infor- mation and other confidential information.

　　(20) Protocol: a document that describes the objective(s), design, methodology, statistical considerations, and organization of a clinical trial. The protocol usually also gives the back- ground and rationale for the trial, but these could be provided in other protocol referenced documents. The term protocol refers to protocol and protocol amendments.

　　(21) Investigator’s Brochure (IB): a compilation of the clinical and nonclinical data on the investigational product(s) that is relevant to the study of the investigational product(s).

　　(22) Case Report Form (CRF): a printed or electronic document designed in accordance with the protocol requirements to record all of the protocol required information to be reported to the sponsor on each trial subject.

　　(23) Standard Operating Procedures (SOPs): detailed, written instructions to achieve uni- formity of the performance of a specific function.

　　(24) Investigational Product: an investigational medical product or reference product used in a clinical trial.

　　(25) Comparator (Product): an investigational or marketed product or placebo, used as a reference to an investigational product in a clinical trial.

　　(26) Adverse Event (AE): Any untoward medical occurrence in a trial subject administered with the investigational product, which can be any sign, symptom, disease, or abnormal la- boratory finding, and which does not necessarily have a causal relationship with the investi- gational product.

　　(27) Serious Adverse Event (SAE): any untoward medical occurrence in a trial subject ad- ministered with the investigational product that results in death, is life-threatening, results in persistent or significant disability/incapacity, requires inpatient hospitalization or prolonga- tion of existing hospitalization, or is a congenital anomaly/birth defect.

　　(28) Adverse Drug Reaction (ADR): any noxious or unintended reactions in the clinical trial that may be related to the investigational product. A causal relationship between an investi- gational product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out.

　　(29) Suspected Unexpected Serious Adverse Reaction: a serious adverse reaction, the nature or severity of which is beyond the currently available product information (e.g., IB for an investigational product or package insert/summary of product characteristics for a marketed product), and that is suspected and unexpected.

　　(30) Subject Identification Code: a unique identifier assigned to each trial subject in a clinical trial to protect the subject’s identity and used in lieu of the subject’s name when the investi- gator reports adverse events and/or other trial-related data.

　　(31) Source Document: original records, documents, and data generated during a clinical trial (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, microfilms, photographic negatives, magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments in- volved in the clinical trial), including certified copies, etc. Source documents contain source data, which can exist in a paper or electronic form.

　　(32) Source Data: all information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the recon- struction and evaluation of the trial.

　　(33) Essential Documents: documents that individually and collectively permit evaluation of the conduct of a clinical trial and the quality of the data produced.

　　(34) Certified Copy: a copy of the original record that has been verified to have the same content and structure, etc. This copy is signed and dated by a reviewer, or including data that describe the content and structure, as the original.

　　(35) Quality Assurance (QA): all those planned and systematic actions that are established in a clinical trial to ensure that the trial is performed, and the data are generated, documented (recorded), and reported in compliance with the protocol and relevant laws and regulations.

　　(36) Quality Control (QC): the operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activ- ities have been fulfilled.

　　(37) Trial Site: the location(s) where trial-related activities are actually conducted.

　　(38) Blinding/Masking: a procedure in which one or more parties to the trial are kept una- ware of the treatment assignment(s). Single-blinding usually refers to the subject(s) being unaware, and double- blinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s).

　　(39) Validation of Computerized Systems: a process of establishing and documenting that the specified requirements of a computerized system can be consistently fulfilled from design until decommissioning of the system or transition to a new system. The approach to valida- tion should be based on a risk assessment that takes into consideration the intended use of the system and the potential of the system to affect human subject protection and reliability of trial results.

　　(40) Audit Trail: documentation that allows reconstruction of the course of events.

　　Chapter 3 Ethics Committee

　　Article 12 An Ethics Committee (EC) should safeguard the rights, safety, and well-being of all trial subjects. Special attention should be paid to vulnerable subjects.

　　(1) The EC should review the following documents: trial protocol(s)/amendment(s), written informed consent form(s) and consent form updates, subject recruitment procedures, other written information to be provided to subjects, IB, available safety information, information about payments and compensation available to subjects, the investigator’s documentation evidencing qualifications, and any other documents that the EC may need to fulfil its respon- sibilities.

　　(2) The EC should review the science and ethics of clinical trials.

　　(3) The EC should review the qualifications of the investigators.

　　(4) In order to better determine whether the rights, safety and basic medical care of subjects can be ensured in clinical trials. The EC may request additional data and information than the informed consent form.

　　(5) When a non-therapeutic trial (that is, a trial that do not have an expected direct clinical benefit for the subject) is to be carried out with the consent of the subject’s legally acceptable representative, the EC should determine that the proposed protocol adequately addresses rel- evant ethical concerns and meets applicable regulatory requirements for such trials.

　　(6) Where the protocol indicates that prior consent of the trial subject or the subject’s legally acceptable representative is not possible in emergency situations, the EC should determine that the proposed protocol adequately addresses relevant ethical concerns and meets applica- ble regulatory requirements for such.

　　(7) The EC should review whether there are undue influences such as coercion or temptation of the subjects to participate in clinical trials. The EC should determine that the informed consent form does not contain any language that causes the subject or the subject’s legally acceptable representative to waive any legal rights, or that releases the investigator, the insti- tution, the sponsor, or their agents from liability for negligence.

　　(8) The EC should ensure that information regarding payment to subjects, including the method, amount, and schedule of payment to trial subjects, is set forth in the written informed consent form and any other written information to be provided to subjects.

　　(9) The EC should review documents of a proposed clinical trial or complete filing process within a reasonable time and document its views in writing, clearly identifying the trial, the documents reviewed (and versions) and the dates.

　　(10) The review opinions of the EC are: approval/favorable opinion, modifications required prior to its approval/favorable opinion, disapproval/negative opinion, and termination/sus- pension of any prior approval/favorable opinion. The review opinion should state the content to be amended or the reasons for denial.

　　(11) The EC should pay attention to and specify that the investigators should promptly report: deviations from, or changes of, the protocol to eliminate immediate hazards to the trial sub- jects, changes increasing the risk to subjects and/or affecting significantly the conduct of the trial, all suspected unexpected serious adverse reactions, and new information that may ad- versely affect the safety of subjects or the conduct of clinical trials.

　　(12) The EC has the right to suspend or terminate clinical trials that have not been carried out in accordance with the relevant requirements, or where subjects have suffered unexpected serious hazard.

　　(13) The EC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least once per year.

　　(14) The EC should accept and properly handle claims of trial subjects.

　　Article 13 The composition and operations of the EC should meet the following require- ments:

　　(1) The composition and filing management of the members of the EC should meet the requirements of the competent health authorities.

　　(2) The members of the EC should receive appropriate training in ethics review and be able to review and evaluate the ethics and scientific issues related to clinical trials.

　　(3) The EC should perform its functions according to its regulations and standard operating procedures (SOPs), should maintain written records of its review activities and minutes of its meetings.

　　(4) Only members who participate in the EC review and discussion should vote their opinion. The voting members should be from different backgrounds, with different genders, and meet- ing the minimum number requirement. The review opinions should form a written document.

　　(5) The voting members or members raising review opinions should be independent of the clinical trial program being reviewed.

　　(6) The EC should maintain the detailed information of its members and ensure that its members are qualified for ethical review.

　　(7) The EC should request the investigator to provide all kinds of materials needed for ethics review and to provide response to the questions raised by the EC.

　　(8) The EC may invite relevant experts other than committee members to participate in the review as necessary, but these experts cannot participate in voting process.

　　Article 14 The EC should establish, document  in writing, and follow its  procedures,  which should include:

　　(1) Provisions on the composition, establishment and filing of the EC.

　　(2) The schedule, meeting notice and meeting review procedures of EC meetings.

　　(3) The procedures of the initial review and follow-up review of the EC.

　　(4) The minor amendments to the protocol approved by the EC, a procedure of rapid review and approval.

　　(5) The procedures to notify the investigator the reviewing opinions in a timely manner.

　　(6) The secondary review process when there is a different opinion on ethical review opin- ions.

　　Article 15 The EC should retain all the records pertaining the ethics review process, in- cluding the written documentation of the ethics review, the information of the committee members, the documents submitted, meeting minutes and the relevant correspondences, etc. All records should be retained for a period of at least 5 years after completion of the trial. The EC may be asked by investigators, sponsors or regulatory authorities to provide its stand- ard operating procedures (SOPs) and membership lists.

　　Chapter 4 Investigators

　　Article 16 The investigator/institution should meet the relevant qualifications and re- quirements, including:

　　(1) The investigator should have the medical qualification in the institution, should be qual- ified by education, training, and ability to conduct clinical trial, and should provide evidence of such qualifications through up-to-date curriculum vitae and/or other relevant documenta- tion requested by the sponsor, the EC, and/or the regulatory authority(ies).

　　(2) The investigator should be thoroughly familiar with the protocol, the IB, the investiga- tional product information.

　　(3) The investigator should be familiar with, and should comply with, this guideline and the applicable regulatory requirements for clinical trials.

　　(4) The investigator should maintain a delegation form which is signed by the investigator.

　　(5) The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the regulatory authority(ies).

　　(6) If the investigator/institution retains the services of any individual or party to perform trial-related duties and functions, the investigator/institution should ensure this individual or party is qualified to perform those trial-related duties and functions and should implement procedures to ensure the integrity of the trial-related duties and functions performed and any data generated. The investigator/institution should obtain approval from the sponsor for au- thorizing any external individual or party to perform trial-related duties and functions.

　　Article 17   The investigator and institution should have adequate resources to complete  the clinical trial:

　　(1) The investigator should be able to demonstrate a potential for recruiting the required number of suitable subjects in accordance with the protocol within the agreed recruitment period.

　　(2) The investigator should have sufficient time to properly conduct and complete the trial within the agreed trial period.

　　(3) The investigator should have an adequate number of qualified staffs and adequate facil- ities for the foreseen duration of the trial to conduct the trial properly and safely.

　　(4) The investigator should ensure that during the trial all persons assisting with the trial are adequately informed about the protocol, the investigational product(s), and their trial-related duties and functions, to ensure the integrity, completeness and accuracy of the data generated.

　　(5) The investigator supervises the conduct of the clinical trial by all staff members and takes measures to implement the quality management of clinical trials.

　　(6) The trial institution should establish an internal management department to undertake the management of clinical trials.

　　Article 18 The investigator should provide the subject with appropriate medical care:

　　(1) The investigator role should be undertaken by a clinician or authorized clinician and should be responsible for all trial-related medical decisions.

　　(2) During the trial and follow-up period, the investigator/institution should ensure that ad- equate medical care is provided to a subject for any adverse events, including informing sub- ject truthfully when there is a clinically significant laboratory values. The investigator/insti- tution should inform a subject when investigator realize medical care is needed for intercur- rent illness(es), and investigator should pay attention to the concomitant medication that may interfere with the results of the trial or the safety of the subject.

　　(3) It is recommended that the investigator inform the subject’s primary physician about the subject’s participation in the trial if the subject has a primary physician and if the subject agrees that the primary physician being informed.

　　(4) Subjects can withdraw from a trial for any reason. The investigator should make a rea- sonable effort to ascertain the reason(s), while fully respecting the subject’s rights.

　　Article 19 The communication between the investigator and the EC includes:

　　(1) Before the initiation of a trial, the investigator should obtain the written approval from the EC; no subject could be screened without prior written approval from the EC.

　　(2) Before and during the trial the investigator/institution should provide to the EC all doc- uments subject to review.

　　Article 20 The investigator should comply with the protocol.

　　(1) The investigator should conduct the trial in compliance with the protocol agreed to by the EC.

　　(2) The investigator should not implement any deviation from, or changes of, the protocol without agreement by the sponsor and prior review and documented approval/favorable opin- ion from the EC of an amendment, except where necessary to eliminate an immediate haz- ard(s) to trial subjects, or when the change(s) involves only logistical or administrative as- pects of the trial (e.g., change in monitor(s), change of telephone number(s)).

　　(3) The investigator, or person designated by the investigator, should document and explain any deviation from the approved protocol.

　　(4) The investigator may implement a deviation from, or a change in, the protocol to elimi- nate an immediate hazard(s) to trial subjects without prior approval/favorable opinion from the EC. As soon as possible, the implemented deviation or change and the reasons for it should be submitted to the EC and the sponsor, and where necessary, the regulatory author- ity(ies).

　　(5) The investigator should take measures to avoid the use of concomitant medications pro- hibited by the protocol.

　　Article 21 The investigator/institution is responsible for the accountability of the inves- tigational product(s) provided by the sponsor.

　　(1) The investigator/institution should assign some or all of the investigator’s/institution’s duties for investigational product(s) accountability at the trial site(s) to an appropriate phar- macist or another appropriate individual.

　　(2) The acceptance, storage, distribution, recovery, return of the investigational product(s) and the disposal of unused investigational product(s) in the institution should comply with the relevant regulations and be documented.

　　The records of investigational product(s) accountability should include dates, quantities, batch/serial numbers, expiration dates, and the unique code numbers assigned to the investi- gational product(s) and signatures. The investigator should maintain records of the amount and doses of the investigational product(s) received by each subject. The quantity of investi- gational product(s) used and used should be consistent with the quantity provided by the sponsor.

　　(3) The storage of investigational products should meet the relevant storage conditions.

　　(4) The investigator should ensure that the investigational product(s) are used only in ac- cordance with the approved protocol, and should explain the correct use of the investiga- tional product(s) to each subject.

　　(5) The investigator should reserve sample in a randomized manner for bioequivalence clin- ical trial of investigational product(s). The institution should maintain the reserve sample for at least 2 years after the marketing of the product. The institution may delegate the responsi- bility of maintaining the reserve sample to a qualified independent third party, but should not return it to the sponsor or a third party with conflict of interests.

　　Article 22 The investigator should follow the trial’s randomization procedures.

　　A blinded trial should be broken only in accordance with the protocol. In the event of acci- dental unblinding or emergency unblinding due to serious adverse events, the investigator should promptly document and explain to the sponsor.

　　Article 23  In obtaining and documenting informed consent, the investigator should com- ply with the ethical principles that have their origin in the Declaration of Helsinki, and should adhere to the following requirements:

　　(1) The investigator should use the latest version of the informed consent form approved by the EC and other information provided to the subjects to obtain informed consent. If neces- sary, re-consent should be obtained from the subject during the course of a trial.

　　(2) The investigator should inform the subject or the subject’s legally acceptable representa- tive in a timely manner if new information becomes available that may be relevant to the subject’s willingness to continue participation in the trial and document accordingly.

　　(3) Neither the investigator, nor the trial staff, should resort to unduly methods such as co- ercion or temptation to influence the willingness to participate or continue participation in the trial.

　　(4) The investigator, or a person designated by the investigator, should fully inform the sub- ject of all pertinent aspects of the trial including the written information and the approval/ favorable opinion by the EC.

　　(5) The language and expressions used in the oral and written information about the trial, including the written informed consent form, should be as non-technical as practical and should be understandable to the subject or the subject's legally acceptable representative and the impartial witness, where applicable.

　　(6) Before informed consent may be obtained, the investigator, or a person designated by the investigator, should provide the subject or the subject’s legally acceptable representative ample time and opportunity to inquire about details of the trial. All questions about the trial should be answered to the satisfaction of the subject or the subject’s legally acceptable rep- resentative.

　　(7) Prior to a subject’s participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject’s legally acceptable representa- tive, and by the person who conducted the informed consent discussion. If a person other than the subject signs the informed consent form, the relationship to the subject should be indicated.

　　(8) If a subject is unable to read or if a legally acceptable representative is unable to read, an impartial witness should be present during the entire informed consent discussion. The in- vestigator should explain in detail the informed consent from and other written materials to the subject, his or her legally acceptable representative and the impartial witness. If the sub- ject or the subject’s legally acceptable representative has orally consented to the subject’s participation in the trial and, if capable of doing so, has signed and personally dated the informed consent form, the witness should sign and personally date the consent form. By signing the consent form, the witness attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject’s legally acceptable representative, and that informed consent was freely given by the subject or the subject’s legally acceptable representative.

　　(9) Prior to participation in the trial, the subject or the subject's legally acceptable representa- tive should receive a copy of the signed and dated written informed consent form and any other written information provided to the subjects, including a copy of the signed and dated consent form updates and a copy of any amendments to the written information provided to subjects.

　　(10) If the subject is incapable of civil conduct, the written informed consent should be obtained from his or her legally acceptable representative; if the subject is a person with limited capacity for civil conduct, the written informed consent should be obtained from the subject and his or her legally acceptable representative. When the subject’s legally acceptable representative provides informed consent on behalf of the subject, the subject should be in- formed about the trial to the extent compatible with the subject’s understanding and, if capa- ble, the subject should sign and personally date the written informed consent.

　　(11) In emergency situations, when prior consent of the subject is not possible, the consent of the subject’s legally acceptable representative, if present, should be requested. When prior consent of the subject is not possible, and the subject’s legally acceptable representative is not available, enrollment of the subject should require measures described in the protocol and/or elsewhere, with documented approval/favorable opinion by the EC. The subject or the subject’s legally acceptable representative should be informed about the trial as soon as pos- sible and consent to continue and other consent as appropriate should be requested.

　　(12) A non-therapeutic trial should be conducted in subjects who personally give consent and who sign and date the written informed consent form.

　　Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable rep- resentative provided the following conditions are fulfilled: the objectives of the trial cannot be met by means of a trial in subjects who can give informed consent personally; the fore- seeable risks to the subjects are low; the negative impact on the subject’s well-being is min- imized and low and the trial is not prohibited by relevant law and regulations; and the ap- proval/favorable opinion of the EC is expressly sought on the inclusion of such subjects. Such trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended. Subjects in these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly dis- tressed. Necessary treatment should also be provided to ensure the safety of the subjects.

　　(13) The specific time when the subject’s informed consent is obtained and the person con- ducting the informed consent discussion should be documented in the subject’s medical rec- ord.

　　(14) When the subject is a child, the informed consent should be obtained from and the informed consent form signed by his or her legal guardians. When a child is able to make a decision to agree to participate in a clinical trial, the informed consent should also be obtained from him- or herself. If the child does not agree to participate in the clinical trial or decides to withdraw from the clinical trial, even if his or her guardians have agreed to his or her participation or is willing to continue his or her participation in a trial, the child’s decision shall prevail. Unless in a therapeutic clinical trial for a serious or life-threatening disease, the investigator and his or her guardians believe that the child’s life will be jeopardized if he or she does not participate in the trial, at this time, the consent from his or her guardians allows the child to continue to participate in the study. During the course of clinical trials, if the child meet the conditions for signing informed consent, he or she need to personally sign the informed consent before proceeding.

　　Article 24 The written informed consent form and any other written information to be provided to subjects should include explanations of the following:

　　(1) Overview of the trial.

　　(2) The purpose of the trial.

　　(3) The trial treatment(s) and the probability for random assignment to each treatment.

　　(4) The trial procedures to be followed, including all invasive procedures.

　　(5) The subject’s responsibilities.

　　(6) Those aspects of the trial that are experimental.

　　(7) The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus, or nursing infant.

　　(8) The reasonably expected benefits. When there is no intended clinical benefit to the sub- ject, the subject should be made aware of this.

　　(9) The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks.

　　(10) The compensation and/or treatment available to the subject in the event of trial- related injury.

　　(11) The anticipated prorated payment, if any, to the subject for participating in the trial.

　　(12) The anticipated expenses, if any, to the subject for participating in the trial.

　　(13) That the subject’s participation in the trial is voluntary and that the subject may refuse to participate or withdraw from the trial, at any time, without penalty or retaliation, or loss of medical treatment or benefits to which the subject is otherwise entitled.

　　(14) That the monitor(s), the auditor(s), the EC, and the regulatory authority(ies) will be granted direct access to the subject’s original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent per- mitted by the applicable laws and regulations.

　　(15) That records identifying the subject will be kept confidential and will not be made publicly available. If the results of the trial are published, the subject’s identity will remain confidential.

　　(16) That the subject or the subject’s legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the subject’s will- ingness to continue participation in the trial.

　　(17) The investigator and the EC to contact for further information regarding the trial and the rights of trial subjects, and whom to contact in the event of trial-related injury and their contact information.

　　(18) The foreseeable circumstances and/or reasons under which the subject’s participation in the trial may be terminated.

　　(19) The expected duration of the subject’s participation in the trial.

　　(20) The approximate number of subjects involved in the trial.

　　Article 25 The recording and reporting of the trial should meet the following require- ments:

　　(1) The investigator should supervise the data collection at the trial site, and the performance of each site staff in performing his or her responsibilities.

　　(2) The investigator should ensure that all clinical trial data are derived from source docu- ments and trial records, and should be accurate, complete, readable, and timely. The source data should be attributable,legible, contemporaneous, original, accurate, complete, con- sistent, and durable. Changes to source data should be traceable, should not obscure the orig- inal entry, and should be explained. For clinical trials conducted in patients, the relevant medical records should be included in the outpatient or inpatient medical record system. When the institution's information system is capable to establish clinical trial electronic med- ical records, the investigator should prioritize the use of electronic system. The corresponding electronic system should have proper access management and audit trails, which can be used to track the person who created or modified the record, so that the collected source data can be traced back to the source document.

　　(3) The investigator should complete the case report forms (CRFs) in accordance with the instructions provided by the sponsor to ensure the accuracy, completeness, legibility, and timeliness of the data in various CRFs and other reports. Data reported on the CRF, that are derived from source documents, should be consistent with the source documents or the dis- crepancies should be explained. Any change to a CRF should not obscure the original entry, with audit trail, explained if necessary, and signed and dated by the person who made the change.

　　Sponsors should have written procedures to assure that changes or corrections in CRFs made by sponsor's designated representatives are necessary, are documented, and are endorsed by the investigator. The investigator should retain records of the changes and corrections.

　　(4) The investigator and institution should maintain the trial documents as specified in Es- sential Documents and as required by the applicable regulatory requirement(s).

　　(5) The clinical trial information and subject information should be handled properly to avoid illegal or unauthorized access, disclosure, dissemination, modification, damage, and loss. The recording, processing and preservation of clinical trial data should ensure the confiden- tiality of records and subject information.

　　(6) The storage time, cost and post-expiry disposal of essential documents should be speci- fied in the agreement between the sponsor and the investigator/institution.

　　(7) Upon request of the monitor, auditor, EC, or regulatory authority, the investigator and institution should make available for direct access all requested trial-related records.

　　Article 26 The safety reporting from the investigator should meet the following require- ments:

　　All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g., IB) identifies as not needing immediate reporting. The immediate reports should be followed promptly by detailed, written reports. The SAE and follow-up reports should identify subjects by unique code numbers assigned to the trial subjects rather than by the subjects' names, personal identification numbers, and/or addresses. Adverse events and/or laboratory abnormalities identified in the protocol as criti- cal to safety evaluations should be reported to the sponsor according to the reporting require- ments and within the time periods specified in the protocol.

　　For reported deaths, the investigator should supply the sponsor and the EC with any addi- tional requested information (e.g., autopsy reports and terminal medical reports).

　　After receiving the relevant safety information of the clinical trial provided by the sponsor, the investigator should sign and read it in a timely manner. The investigator should consider whether adjustments to the subject's treatment is needed, communicate with the subject as soon as necessary. The investigator should also report to the EC any suspected unexpected serious adverse reactions provided by the sponsor.

　　Article 27 If the trial is prematurely terminated or suspended, the investigator should promptly inform the trial subjects, and should assure appropriate therapy and follow-up for the subjects. In addition:

　　(1) If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should promptly inform the institution, the sponsor and the EC, and should provide a detailed written explanation of the termination or suspension.

　　(2) If the sponsor terminates or suspends a trial, the investigator should promptly inform the institution and the EC, and provide a detailed written explanation of the termination or sus- pension.

　　(3) If the EC terminates or suspends its approval/favorable opinion of a trial, the investigator should inform the institution and the sponsor, and provide a detailed written explanation of the termination or suspension.

　　Article 28 The investigator should provide the trial progress reports.

　　(1) The investigator should submit written summaries of the trial status to the EC annually, or more frequently, if requested by the EC.

　　(2) The investigator should promptly provide written reports to the sponsor, the EC and, the institution on any changes significantly affecting the conduct of the trial, and/or increasing the risk to subjects.

　　(3) Upon completion of the trial, the investigator, should inform the institution; the investi- gator should provide the EC with a summary of the trial's outcome, and the sponsor with any trial-related reports required by the regulatory authority(ies).

　　Chapter 5 Sponsor

　　Article 29 The sponsor should take the protection of the rights and safety of the subjects and the authenticity and reliability of clinical trial results as the basic considerations for clin- ical trials.

　　Article 30 The sponsor should implement a system to manage quality throughout  all  stages of the trial process.

　　The sponsor’s quality management system for clinical trials should encompass the entire process of the clinical trial, including the design, implementation, recording, evaluation, re- porting, and filing of clinical trials. Quality management includes the design of efficient clin- ical trial protocols, methods and procedures for data collection, as well as the collection of information that is essential to decision making.

　　The methods used to assure and control the quality of the trial should be proportionate to the risks inherent in the trial and the importance of the information collected. The sponsor should ensure that all aspects of the trial are operationally feasible and should avoid unnecessary complexity in the procedures and data collection. Protocols, case report forms, and other operational documents should be clear, concise, and consistent.

　　The sponsor should perform management responsibilities. A research and management team for clinical trials can be established to guide and supervise the conduct of the trial if necessary. Work within the research and management team should be communicated in a timely manner. During the inspection by the regulatory authority(ies), the research and management team should send personnel to participate.

　　Article 31 The sponsor carries out quality management using a risk-based approach.

　　(1) During protocol development, the sponsor should identify those processes and data that are critical to ensure human subject protection and the reliability of trial results.

　　(2) The sponsor should identify risks to critical trial processes and data. Risks should be considered at both the system level (e.g., facilities and equipment, standard operating proce- dures, computerized systems, personnel, and suppliers) and clinical trial level (e.g., investi- gational product(s), trial design, data collection and recording, and informed consent process).

　　(3) The sponsor should evaluate the identified risks, against existing risk controls by consid- ering: the likelihood of errors occurring; the impact of such errors on human subject protec- tion and reliability of trial results; and the extent to which such errors would be detectable.

　　(4) The sponsor should decide which risks to reduce and/or which risks to accept. Risk re- duction activities may be incorporated in protocol design and implementation, monitoring plans, agreements between parties defining roles and responsibilities, systematic safeguards to ensure adherence to standard operating procedures, and training in processes and proce- dures.

　　Predefined quality tolerance limits should be established, taking into consideration the med- ical and statistical characteristics of the variables as well as the statistical design of the trial, to identify systematic issues that can impact subject safety or reliability of trial results. De- tection of deviations from the predefined quality tolerance limits should trigger an evaluation to determine if action is needed.

　　(5) The sponsor should document quality management activities during the trial. The sponsor should communicate quality management activities to those who are involved in or affected by such activities, to facilitate risk review and continual improvement during clinical trial execution.

　　(6) The sponsor should periodically review risk control measures to ascertain whether the implemented quality management activities remain effective and relevant, taking into ac- count emerging knowledge and experience obtained during the trial.

　　(7) The sponsor should describe the quality management approach implemented in the trial and summarize important deviations from the predefined quality tolerance limits and reme- dial actions taken in the clinical study report.

　　Article 32 The sponsor’s quality assurance and quality control activities should meet the following requirements:

　　(1) The sponsor is responsible for developing, implementing and maintaining quality assur- ance and quality control systems with standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, documented (recorded), and reported in compli- ance with the protocol, this guideline, and the applicable laws and regulations.

　　(2) All stages of clinical trials and laboratory testing must be carried out in strict accordance with quality management standard operating procedures. Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.

　　(3) The sponsor should sign a contract with all relevant parties participating in a clinical trial, such as the investigator/institution, to clarify the responsibilities of all parties.

　　(4) The contract signed between the sponsor and the relevant parties should indicate that the monitor(s), the auditor(s), and the regulatory authority(ies) will be granted direct access to the subject’s original source data, source documents and reports at the trial site.

　　Article 33 The contract research organization (CRO) contracted by the sponsor should  meet the following requirements:

　　(1) A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor who should ensure oversight of any trial-related duties and functions carried out by CRO. The CRO should implement quality assurance and quality control.

　　(2) Any trial-related duty and function that is transferred to and assumed by a CRO from a sponsor should be specified in a contract. The contract should specify the following: the spe- cific duty and function that is transferred and relevant corresponding standard operating

　　procedures; that the sponsor has the right to confirm the adherence to the standard operating procedures for the duties and functions transferred; the requirements for CRO in written; the requirements for the reports submitted to the sponsor by the CRO; matters related to the damage compensation to the subjects; other matters related to the duties and functions trans- ferred. If the CRO subcontracts part or all of its duties and functions to a third party, a written approval from the sponsor should be obtained.

　　(3) Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor.

　　(4) All references to a sponsor in this guidance also apply to a CRO to the extent that a CRO has assumed the trial-related duties and functions of a sponsor.

　　Article 34 The sponsor should designate appropriately qualified medical personnel who will be readily available to advise on trial-related medical questions or problems.

　　Article 35 The sponsor should utilize qualified individuals (e.g., biostatisticians, clinical pharmacologists, and physicians) as appropriate, throughout all stages of the trial process, from designing the protocol and CRFs and planning the analyses to analyzing and preparing interim and final clinical trial reports.

　　Article 36 The sponsor should meet the following requirements in trial management, data handling, and record keeping:

　　(1) The sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports.

　　(2) The sponsor may consider establishing an independent data monitoring committee (IDMC) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop an ongoing trial. The IDMC should have written operating procedures and maintain written records of all its meetings.

　　(3) The electronic data management system used by the sponsor should pass a system relia- bility verification and conforms to the sponsor's established technical performance to ensure the completeness, accuracy and reliability of the data, and that the system is always in a valid and verified state throughout the trial.

　　(4) The electronic data management system should have complete standard operating pro- cedures (SOPs) for use. The SOPs should cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security testing, change control, data backup, recovery,

　　contingency planning, and decommissioning. The responsibilities of the sponsor, investiga- tor, and institution with respect to the use of these computerized systems should be specified in the SOPs. The users should be provided with training in their use of these computerized systems.

　　(5) The method of data modification in the computerized system should be predefined. The systems should be designed to permit data changes in such a way that the data changes are documented and that there is no deletion of entered data (i.e., maintain an audit trail, data trail, edit trail). The integration, content and structure of electronic data should be clearly defined to ensure the integrity of electronic data. Ensuring the integrity of the electronic data is particularly important when making changes to the computerized systems, such as software upgrades or migration of data.

　　If data are transformed during processing, ensure that the transformed data is consistent with the original time, and the visibility of the data transformation process.

　　(6) Maintain a security system that prevents unauthorized access to the data; maintain a list of the individuals who are authorized to make data changes; maintain adequate backup of the data; safeguard the blinding for blinded trials (e.g., maintain the blinding during data entry and processing).

　　(7) The sponsor should use an unambiguous subject identification code that allows identifi- cation of all the data reported for each subject. After a blinded trial is unblinded, the sponsor should promptly inform the investigator in writing of the use of the investigational product(s) by the subjects.

　　(8) The sponsor should retain all of the sponsor-specific essential documents pertaining to the trial. Other data obtained by some relevant parties participating in clinical trials should also be retained as sponsor-specific data in the essential documents.

　　(9) If the sponsor suspends or discontinues prematurely an ongoing trial, the sponsor should notify all the trial investigators/institutions and all the regulatory authorities.

　　(10) Any transfer of ownership of the data should be compliant with the applicable laws and regulations.

　　(11) The sponsor should inform the investigator(s)/institution(s) in writing of the need for record retention and should notify the investigator(s)/institution(s) in writing when the trial- related records are no longer needed.

　　Article 37 The investigators chosen by the sponsor should meet the following require- ments:

　　(1) The sponsor is responsible for selecting the investigator(s)/institution(s). Each investiga- tor should be qualified by training and experience in clinical trials and should have adequate resources to properly conduct the trial for which the investigator is selected. For clinical trials conducted in multiple trials sites, the sponsor should be responsible for selecting leading site.

　　(2) Sample testing laboratories involved in medical judgment should comply with relevant regulations and possess corresponding qualifications. The management, testing, shipment and storage of specimens collected in clinical trials should be conducted in a manner to ensure quality. Biological sample tests that are not related to the protocol approved by the EC (such as genes, etc.) are forbidden. After the completion of a trial if the remaining specimens con- tinue to be stored or may be used in the future, a signed informed consent should obtained from the subject, with the storage time and data confidentiality issues and under what circumstances the data and samples can be shared with other investigators specified in the form.

　　(3) The sponsor should provide the investigator(s)/institution(s) with the protocol and an up- to-date IB, and should provide sufficient time for the investigator/institution to review the protocol and the information provided.

　　Article 38 Prior to initiating a trial, the sponsor should define all trial-related duties and functions in the agreements signed with involved parties.

　　Article 39 The sponsor should take appropriate measures to ensure that the subjects and investigators can be compensated or indemnified.

　　(1) The sponsor should provide the investigator/institution legal and economic insurance or guarantees related to the trial that are proportionate to the nature and degree of risk of trial, except for claims that arise from malpractice and/or negligence from the investigator/institu- tion.

　　(2) The sponsor should bear the cost of diagnosis and treatment of the damage or death of the subject related to the trial, as well as the corresponding compensations. The sponsor and the investigator should promptly pay the compensation or indemnification given to the sub- jects.

　　(3) The method and mechanism through which the sponsor compensates the subjects should comply with applicable laws and regulations.

　　(4) The sponsor should provide the investigational product(s) to the subjects free of charge, and undertake the testing fees related with the trial.

　　Article 40 The agreements signed between the sponsor and the investigator(s)/institu- tion(s) should specify the responsibilities, rights and interests of the involved parties, and the possible conflicts of interest that the parties should avoid. The funding as defined in the agreements should be reasonable and in line with market conditions. The sponsor and the investigator(s)/institution(s) should sign and confirm on the agreement.

　　The content of the agreement should include: compliance with this guideline and applicable laws and regulations governing clinical trials during the conduct of the trial; implementation of the protocol agreed by the sponsor and the investigator and approved by the EC; compli- ance with data recording and reporting procedures; permission to monitoring, audits, and inspections; the maintenance and duration of essential trial-related documents; agreement regarding publications and intellectual property rights, etc.

　　Article 41  Before initiating the clinical trial(s), the sponsor should submit relevant clini- cal trial documents to the appropriate authority(ies) and obtain the permission or complete the filing to conduct the trial. The submitted documents should indicate the version number and date.

　　Article 42 The sponsor should obtain from the investigator/institution: the name and ad- dress of the investigator's/institution's EC; the list of EC members participating in the pro- gram review; a statement obtained from the EC that it is organized and operates according to this guideline and the applicable laws and regulations; and the documents and other relevant materials reviewed and approved by the EC.

　　Article 43  When designing the protocol, the sponsor should ensure that sufficient safety and efficacy data are available to support human exposure by the route, at the dosages, for the duration. The sponsor should update the IB as significant new information becomes avail- able.

　　Article 44 The manufacturing, packaging, labeling, and coding of investigational prod- uct(s) should meet the following requirements:

　　(1) The investigational product(s) should be manufactured in accordance with good manu- facturing practice (GMP). The packaging label of the investigational product(s) should indi- cate that it is only intended to be used in clinical trials, as well the information regarding the trial and the investigational product(s). The investigational product(s) should be coded and labelled in a manner that protects the blinding, if applicable.

　　(2) The sponsor should determine, for the investigational product(s), acceptable storage tem- peratures, shipment conditions (e.g., protection from light), storage times, reconstitution flu- ids and procedures, and devices for product infusion, if any. The sponsor should inform all involved parties (e.g., monitors, investigators, pharmacists, storage managers) of correct use of the investigational product(s).

　　(3) The investigational product(s) should be packaged to prevent contamination and unac- ceptable deterioration during transport and storage.

　　(4) In blinded trials, the coding system for the investigational product(s) should include an emergency blinding mechanism that permits rapid identification of the product(s) in case of a medical emergency, but does not permit undetectable breaks of the blinding.

　　Article 45 The supplying and handling of investigational product(s) should meet the fol- lowing requirements:

　　(1) The sponsor is responsible for supplying the investigator(s)/institution(s) with the inves- tigational product(s).

　　(2) The sponsor should not supply an investigator/institution with the investigational prod- uct(s) until the sponsor obtains all required documentation (e.g., approval/favorable opinion from EC and regulatory authority(ies)).

　　(3) The sponsor should ensure that written procedures include instructions that the investi- gator/institution should follow for the handling and storage of investigational product(s) for the trial and documentation thereof. The sponsor develops the investigational product supply and management procedures, including the receipt, storage, dispensing, use and return of investigational product(s). Investigational product(s) retrieved from the subject and unused by the investigator should be returned to the sponsor, or be destroyed at the institution upon authorization by the sponsor.

　　(4) The sponsor should: ensure timely delivery of investigational product(s) to the investi- gator(s)/institution(s) so that no dosing delay would occur; maintain records that document shipment, receipt, disposition, return, and destruction of the investigational product(s); main- tain a system for retrieving investigational products and documenting this retrieval (e.g., for deficient product recall, reclaim after trial completion, expired product reclaim); maintain a system for the disposition of unused investigational product(s). The management process of all investigational product(s) should be documented in writing and accurately accounted for.

　　(5) The sponsor should take steps to ensure that the investigational product(s) are stable over the period of use. To the extent stability permits, samples of the investigational product(s) should be retained either until the analyses of the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the longer retention period.

　　Article 46 The sponsor should clarify the access of the trial records.

　　(1) The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) provide direct access to source data/documents for trial- related monitoring, audits, ethic committee review, and regulatory inspection.

　　(2) The sponsor should verify that each subject has consented, in writing, to direct access to his/her original medical records for trial-related monitoring, audit, EC review, and regulatory inspection.

　　Article 47 The sponsor is responsible for the ongoing safety evaluation of the investiga- tional product(s) during a trial. The sponsor should promptly notify all concerned investiga- tor(s)/institution(s) and the regulatory authority(ies) of findings that could affect adversely the safety of subjects, impact the conduct of the trial, or alter the approval/favorable opinion of the ethic committee to continue the trial.

　　Article 48 The sponsor should report adverse drug reactions in accordance with the rele- vant requirements and time limit.

　　(1) After receiving the safety-related information from any source, the sponsor should per- form an immediate analysis and evaluation, including the seriousness, the relatedness to the investigational product(s), and the expectedness. The sponsor should expedite the reporting to all investigator(s), institutions(s) and the EC(s) participated in the clinical trial of all sus- pected unexpected serious adverse reactions. The sponsor should report all suspected unex- pected serious adverse reactions to drug administration authority(ies) and health author- ity(ies) .

　　(2) The safety update report during the drug development provided by the sponsor should include an assessment of the risks and benefits of the clinical trial, and relevant information should be notified to all concerned investigator(s)/institutions(s), and to the EC(s).

　　Article 49 The monitoring of a clinical trial should meet the following requirements:

　　(1) The purposes of trial monitoring are to verify that: the rights and well-being of human subjects are protected; the trial records and reported trial data are accurate and complete; and the conduct of the trial is in compliance with the currently approved protocol, with this guide- line, and with the applicable regulatory requirement(s).

　　(2) The monitors appointed by the sponsor should be appropriately trained, and should have medical and pharmaceutical knowledge required for the monitoring of a trial, and should be able to effectively perform the duties of monitoring.

　　(3) The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The flexibility in the extent and nature of monitoring described in this section is intended to permit varied approaches that improve the effectiveness and efficiency of mon- itoring. The sponsor should document the rationale for the chosen monitoring strategy in the monitoring plan.

　　(4) The sponsor develops an audit plan. The audit plan should specifically emphasize the protection of the rights and interests of the subjects, ensure the authenticity of the data, and ensure that all risks in clinical trials are properly addressed. The plan should describe the monitoring strategy, the monitoring responsibilities of all the parties involved, the various monitoring methods to be used, and the rationale for their use. The plan should also empha- size the monitoring of critical data and processes. The monitoring plan should comply with the applicable laws and regulations.

　　(5) The sponsor should have in place standard operating procedures for monitoring, and the monitors should follow standard operating procedures in the monitoring work.

　　(6) The sponsor should determine the appropriate extent and nature of monitoring. The de- termination of the extent and nature of monitoring should be based on considerations such as the objective, design, complexity, blinding, sample size, and endpoints of the trial.

　　(7) On-site monitoring and centralized monitoring should be conducted based on a combi- nation of risks in clinical trials. On-site monitoring is performed at the sites at which the clinical trial is being conducted, and should generally be conducted before, during, and after the trial. Centralized monitoring is a remote evaluation of an ongoing trial, performed in a timely manner, and of accumulating data pooled from different trial site. Centralized moni- toring processes provide additional monitoring capabilities that can complement on-site mon- itoring.

　　Centralized monitoring utilizes statistical analysis to determine the trend of data, including the range and consistency of data within and across sites, and can analyze the characteristics and quality of data, which helps to select trial sites to be monitored and the monitoring pro- cedures.

　　(8) In exceptional circumstances the sponsor may combine the monitoring with procedures such as investigators' training and meetings. During monitoring statistically controlled sam- pling may be an acceptable method for selecting the data to be verified.

　　Article 50 The monitor's responsibilities include:

　　(1) The monitors should be familiar with the relevant information of the investigational product(s), the protocol, the informed consent form and other written materials provided to the subject, as well as the standard operating procedures (SOPs) governing clinical trials and this guideline and other applicable regulations.

　　(2) The monitor(s) should perform the monitoring duties in accordance with the sponsor's requirements and ensure that the trial is conducted and documented properly in accordance with the protocol.

　　(3) The monitors act as the main line of communication between the sponsor and the inves- tigator. The monitors should verify that the investigator has adequate qualifications and re- sources and these remain adequate throughout the trial period, that the institution has the appropriate conditions to complete the trial, including staffing and training, laboratories and equipment, and various testing capabilities related to the trial.

　　(4) The monitors should verify that the investigational product(s) have not expired, and that storage times and conditions are acceptable, and that supplies are sufficient throughout the trial; that the investigational product(s) are supplied only to subjects who are eligible to re- ceive it and at the protocol specified dose(s); that subjects are provided with necessary in- struction on properly using, handling, storing, and returning the investigational product(s); that the receipt, use, and return of the investigational product(s) at the trial sites are controlled and documented adequately; that the disposition of unused investigational product(s) at the trial sites complies with applicable regulatory requirement(s) and is in accordance with the sponsor.

　　(5) The monitors should verify the implementation of the protocol by the investigator during a trial; verify that written informed consent was obtained from the subject or the subject’s legally acceptable representative before each subject's participation in the trial; ensure that the investigator receives the current IB, all documents, and all trial supplies needed to con- duct the trial properly and to comply with the applicable regulatory requirement(s); and en- sure that the investigator and the investigator's trial staff are adequately informed about the trial.

　　(6) The monitors should verify that the investigator and the investigator's trial staff are per- forming the specified trial functions, in accordance with the protocol and any other written agreement between the sponsor and the investigator/institution, and have not delegated these functions to unauthorized individuals; ensure that the investigator is enrolling only eligible subjects and report the enrolment rate and the trial progress; verify that source documents and other trial records are accurate, complete, kept up-to-date, and maintained; verify that the investigator provides all the required medical reports, records, and documents, and that these documents are traceable, legible, contemporaneous, original, accurate, complete, dated, and identify the trial.

　　(7) The monitors should check the accuracy and completeness of the CRF entries, source documents and other trial-related records against each other. The monitor should verify that: the data required by the protocol are reported accurately on the CRFs and are consistent with the source documents; that any dose and/or therapy modifications, adverse events, concomi- tant medications, intercurrent illnesses, loss of follow-up, missing tests are well documented for each of the trial subjects in the CRFs; that visits that the Investigator fail to make, tests that are not conducted, examinations that are not performed, and whether any corrections are made to the errors and omissions are clearly reported as such on the CRFs; that all withdraw- als and dropouts of enrolled subjects from the trial are reported and explained on the CRFs.

　　(8) The monitors should inform the investigator of any CRF entry error, omission, or illegi- bility. The monitor should ensure that appropriate corrections, additions, or deletions are made, dated, explained (if necessary), and initialed by the investigator or by a member of the investigator's trial staff who is authorized to initial CRF changes for the investigator.

　　(9) The monitors should determine whether all adverse events (AEs) are appropriately re- ported within the time periods required by applicable laws and regulations, the protocol, the ethic committee, and the sponsor.

　　(10) The monitors should determine whether the investigator is maintaining the essential documents in accordance with this guideline.

　　(11) The monitors should communicate deviations from the protocol, SOPs, and the appli- cable regulatory requirements to the investigator in a timely manner and take appropriate action designed to prevent recurrence of the detected deviations.

　　Article 51 The monitor should submit a written report to the sponsor after each monitor- ing visit. Reports should include the date, site, name of the monitor, and name of the inves- tigator or other individual(s) contacted. Reports should include a summary of what the mon- itor reviewed and the monitor's statements concerning the significant findings/facts, devia- tions from and deficiencies of the protocol, and conclusions of the monitoring. Reports should detail actions taken or to be taken and/or actions recommended to secure compliance to the protocol. Results of monitoring activities should be documented in sufficient detail to allow verification of compliance with the monitoring plan. Centralized monitoring reports can be submitted independently from on-site monitoring reports. The sponsor should review and follow up the problems noted in the monitoring reports, and document accordingly in a file.

　　Article 52       The audit of a clinical trial should meet the following requirements:

　　(1) In order to evaluate the implementation of clinical trials and compliance with applicable laws and regulations, the sponsor may conduct audits in addition to routine monitoring.

　　(2) The sponsor should appoint individuals, who are independent of the clinical trials, to conduct audits. The auditing role cannot be undertaken by a monitor. The auditors are qual- ified by training and experience to conduct audits properly and are able to effectively perform their audit duties.

　　(3) The sponsor should develop audit procedures for clinical trials and trial quality manage- ment systems to ensure the implementation of audit procedures in clinical trials. The proce- dures should specify what to audit, how to audit, the frequency of audits, and the form and content of audit reports. The observations and findings of the auditor(s) should be docu- mented in writing.

　　(4) The sponsor's audit plan and procedures for a trial audit should be guided by the docu- ments submitted to regulatory authorities, the number of subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any identified problem(s).

　　(5) The sponsor may be requested to provide the audit report by the regulatory authority(ies) as needed.

　　(6) The sponsor should provide an audit certificate when necessary. Article 53 The sponsor should ensure the compliance of clinical trials.

　　(1) If noncompliance with the protocol, SOPs, this guideline, and/or applicable laws and regulations by an investigator/institution, or by member(s) of the sponsor's staff is discovered, the sponsor should implement appropriate corrective actions immediately to ensure good compliance of the trial.

　　(2) If noncompliance that significantly affects or has the potential to significantly affect human subject protection or reliability of trial results is discovered, the sponsor should per- form a root cause analysis in a timely manner and implement appropriate corrective and pre- ventive actions. If significant noncompliance with the protocol or this guideline is discovered, the sponsor may hold the relevant personnel accountable and notify promptly the regulatory authority(ies).

　　(3) If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator's/institu- tion's participation in the trial and notify promptly the regulatory authority(ies) in writing. At the same time, the sponsor and the investigator should take appropriate emergency safety measures to protect the safety and rights of the subjects.

　　Article 54 If a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension.

　　Article 55 Whether the trial is completed or prematurely terminated, the sponsor should ensure that the clinical trial reports are prepared and provided to the regulatory agency(ies) as required by the applicable regulatory requirement(s). The clinical trial report should be a

　　comprehensive, complete, and accurate representation of the trial results, and the safety and efficacy data within the report should be consistent with the source data.

　　Article 56 For multicenter trials, the sponsor should meet the following requirement:

　　(1) The sponsor should ensure that all trials sites conduct the clinical trial in accordance with the protocol.

　　(2) The sponsor should provide each site with identical protocols. Each site should comply with a uniform set of standards for the assessment of clinical and laboratory findings, and on completing the CRFs.

　　(3) Each site should use identical CRFs to capture trial data emerging from the trial. If the investigators are requested to collect additional data, this should be reflected in the protocol, and the investigators should be provided with additional CRFs.

　　(4) Before the initiation of the trial, there should be written documents that clearly specify the responsibilities of the investigators of each site participating in the trial.

　　(5) The sponsor should facilitate the communication between investigators.

　　Chapter 6 Clinical Trial Protocol

　　Article 57 The protocol usually includes basic information, research background infor- mation, trial objectives, trial design, implementation mode (method, content, steps) etc.

　　Article 58 The basic information in the protocol generally includes:

　　(1) Protocol title, protocol identifying number, version and date.

　　(2) Name and address of the sponsor.

　　(3) Name, title and affiliation of the person(s) authorized to sign the protocol and the protocol amendment(s) for the sponsor.

　　(4) Name, title, address, and telephone number(s) of the sponsor's medical expert for the trial.

　　(5) Name, title and role of the investigator(s), as well the address and telephone number(s) of the institution(s).

　　(6) Names and addresses of the concerning parties and units participating in the trial. Article 59 Background information in a protocol usually includes:

　　(1) Name and description of the investigational product(s).

　　(2) A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial.

　　(3) Summary of the known and potential risks and benefits, to human subjects.

　　(4) Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s) of the investigational product(s).

　　(5) A statement that the trial will be conducted in compliance with the protocol, this guide- line, and the applicable laws and regulations.

　　(6) Description of the targeted population to be studied.

　　(7) Research background information, references and data sources that are relevant to the trial.

　　Article 60 The protocol should provide a detailed description of the objectives and the purpose of the trial.

　　Article 61 The scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design. A description of the trial design should include:

　　(1) A specific statement of the primary endpoints and the secondary endpoints to be meas- ured during the trial.

　　(2) The rationale for the choice of the control group and a description of the type/design of trial to be conducted (e.g., double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures, and stages.

　　(3) A description of the measures taken to minimize/avoid bias, including randomization and blinding. The use of a single-blinded or open-label trial should be justified and measures to control bias should be provided.

　　(4) A description of the trial treatment(s) and the dosage and dosage regimen of the investi- gational product(s). Also include a description of the dosage form, packaging, and labelling of the investigational product(s).

　　(5) The expected duration of subject participation, and a description of scheduled activities, including follow-up, if any.

　　(6) A description of the "stopping rules" or "discontinuation criteria" for individual subjects, parts of trial, and entire trial.

　　(7) Accountability procedures for the investigational product(s).

　　(8) Maintenance of trial treatment randomization codes and procedures for breaking codes.

　　(9) The identification of any data to be recorded directly on the CRFs and to be considered to be source data.

　　Article 62 The protocol usually includes a description of clinical examinations and la- boratory tests to be conducted.

　　Article 63 Selection and withdrawal of subjects usually include:

　　(1) Subject inclusion criteria.

　　(2) Subject exclusion criteria.

　　(3) Subject withdrawal criteria and procedures. Article 64 Treatment of subjects usually includes:

　　(1) The treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration, and the treatment pe- riod(s), including the follow-up period(s) for subjects for each treatment group of the trial.

　　(2) Concomitant (s)/treatment(s) (including rescue medication) permitted and not permitted before and/or during the trial.

　　(3) Methods for assessing subject compliance.

　　Article 65 The protocol should specify a clear visit and follow-up schedule, including during the clinical trial, endpoints collected, adverse events evaluation, and follow-up and medical treatment after the trial.

　　Article 66 Assessment of efficacy usually includes:

　　(1) A detailed description of the efficacy parameters.

　　(2) A detailed description of methods and timing for assessing, recording, and analyzing efficacy parameters.

　　Article 67 Assessment of safety usually includes:

　　(1) A detailed description of the safety parameters

　　(2) A detailed description of methods and timing for assessing, recording, and analyzing safety parameters.

　　(3) Procedures for recording and reporting adverse event and intercurrent illnesses.

　　(4) The type and duration of the follow-up of subjects after adverse events. Article 68 Statistics usually include:

　　(1) The determination of sample size, including reasons for choice of sample size based on the previous trials or literature data.

　　(2) The level of significance to be used, and the considerations of adjustments (if any).

　　(3) A description of the statistical hypothesis of the primary endpoint, including null hypoth- esis and alternative hypothesis, and a brief description of the specific statistical methods and statistical analysis software to be used. If an interim analysis is to be conducted, the reasons, time point, and operating procedures should be explained.

　　(4) Procedure for accounting for missing, unused, and spurious data.

　　(5) Procedures for reporting any clear deviation(s) from the original statistical plan.

　　(6) A clear definition of the subject datasets to be used in statistical analysis, including all randomized subjects, all subjects who have received the investigational product(s), all eligi- ble subjects, and all evaluable subjects.

　　Article 69 The protocol should include a description of the quality control and quality assurance to be implemented.

　　Article 70     The protocol usually includes a description of ethical considerations relating to the trial.

　　Article 71 The protocol usually includes a description of the collection and management process of trial data, 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 not addressed in the contract or agreement, the protocol usually includes a description of direct access to source documents, data handling and record-keeping, and fi- nancing and insurance.

　　Chapter 7 Investigator’s Brochure

　　Article 73    The Investigator's Brochure (IB) provided by the sponsor is a compilation of the pharmaceutical, nonclinical and clinical data on the investigational product(s). It contains information and data of the chemistry, pharmaceutics, toxicology, pharmacology, and clini- cal properties of the investigational product(s). Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration, primary and secondary efficacy measures, and safety observation and monitoring procedures.

　　Article 74 If the investigational product is marketed and its pharmacology is widely un- derstood, a simplified IB can be provided. A package leaflet may by an alternative to part of the IB, provided that it includes clinical trial related, important, current, comprehensive, and detailed information of the investigational product(s).

　　Article 75 The sponsor should develop a written procedure for the revision of the IB. The IB should be reviewed at least annually during the clinical trial. Depending on the stage of development, the sponsor should update the IB with the new information about the safety and efficacy of the product obtained during the trial. However, relevant new information should be communicated to the investigators, and where necessary to the EC and regulatory authorities before it is included in a revised IB. The sponsor is responsible for ensuring that an up-to-date IB is made available to the investigator(s), and the investigators are responsible for providing the up-to-date IB to the responsible EC.

　　Article 76 The title page of the IB should provide the sponsor's name, the identity of each investigational product, version, release date, and a reference to the version number and date of the edition it supersedes.

　　Article 77 The IB should include:

　　(1) Table of Contents: confidentiality statement, signature page, table of contents, summary, introduction, physical, chemical, pharmacological properties and structural formula(e) of the investigational product(s), nonclinical studies (nonclinical pharmacology, pharmacokinetics in animals, and toxicology), effects in humans (pharmacokinetics in humans, safety and ef- ficacy, and marketing experience), summary of data and guidance for the investigator, pre- cautions, and references (published literature and reports which should be listed at the end of each chapter).

　　(2) Summary: a brief summary highlighting the significant physical, chemical, pharmaceu- tical, pharmacological, toxicological, pharmacokinetic, and clinical information available that is relevant to the stage of clinical development of the investigational product(s).

　　(3) Introduction: a brief introductory statement containing the chemical name(s), or approved generic and trade name(s) of the investigational product(s), all active ingredients, the inves- tigational product(s) pharmacological class and its expected position within this class (e.g., advantages), the rationale for performing research with the investigational product(s), and the anticipated prophylactic, diagnostic, or therapeutic indication(s). Finally, the introductory statement should provide the general approach to be followed in evaluating the investiga- tional product(s).

　　(4) The IB should specify the chemical structural formula(e) of the investigational product(s), and provide a brief description of the physical, chemical, and pharmaceutical properties.

　　Instructions for the storage and handling of the dosage form(s) should also be given. To per- mit appropriate safety measures to be taken in the course of the trial, a description of the formulation(s) to be used, including excipients should be provided and justified if clinically relevant.

　　(5) Any structural similarities to other known compounds should be mentioned.

　　(6) Introduction of nonclinical studies: a brief description of the results of all relevant non- clinical pharmacology, toxicology, pharmacokinetic studies. This summary should address the methodology used, the results, and a discussion of the relevance of the findings to the investigated therapeutic and the possible unfavorable and unintended effects in humans.

　　(7) The IB should provide the information from nonclinical studies: species tested, number and sex of animals in each group, unit dose, dose interval, route of administration, duration of administration, information of systemic distribution, and duration of post-exposure follow- up. The results of the studies should include the nature and frequency of the pharmacological and toxic effects of the investigational product(s), severity or intensity of the pharmacologi- cal and toxic effects, time to onset of effects, reversibility of effects, duration of effects, and dose response. The IB should discuss the most important findings from the nonclinical stud- ies, including the dose response of observed effects, the relevance to humans, and any aspects to be studied in humans. If applicable, the effective and nontoxic dose findings in the same animal species should be compared (i.e., the therapeutic index should be discussed). The relevance of this information to the proposed human dosing should be addressed. Whenever possible, comparisons should be made in terms of blood/organ levels.

　　(8) Introduction of nonclinical pharmacologic studies: a summary of the pharmacological aspects of the investigational product and, where appropriate, its significant metabolites stud- ied in animals. Such a summary should incorporate studies that assess potential therapeutic activity (e.g., efficacy models, receptor binding, and specificity) as well as those that assess safety (e.g., special studies to assess pharmacological actions other than the intended thera- peutic effect(s)).

　　(9) Introduction of pharmacokinetic studies in animals: a summary of the pharmacokinetics and biological transformation and disposition of the investigational product in all species studied. The discussion of the findings should address the absorption and the local and sys- temic bioavailability of the investigational product and its metabolites, and their relationship to the pharmacological and toxicological findings in animal species.

　　(10) Introduction of toxicological studies: a summary of the toxicological effects found in relevant studies conducted in different animal species, including single dose, repeated dose,carcinogenicity, special studies (e.g., irritancy and sensitization), reproductive toxicity, gen- otoxicity (mutagenicity), etc.

　　(11) Effects in humans: a thorough discussion of the known effects of the investigational product(s) in humans, including information on pharmacokinetics, pharmacodynamics, dose response, safety, efficacy, and other pharmacological activities. Where possible, a summary of each completed clinical trial should be provided. Information should also be provided re- garding results of any use of the investigational product(s) other than from in clinical trials, such as from experience during marketing.

　　(12) A summary of information on the pharmacokinetics of the investigational product(s) in humans should be presented, including pharmacokinetics (including absorption and metabo- lism, plasma protein binding, distribution, and elimination), bioavailability of the investiga- tional product (absolute and/or relative bioavailability) using a reference dosage form, pop- ulation subgroups (e.g., gender, age, and impaired organ function), interactions (e.g., drug- drug interactions and effects of food), and other pharmacokinetic data (e.g., results of popu- lation studies performed within clinical trial(s)).

　　(13) Safety and efficacy of the investigational product(s): a summary and discussion of in- formation about the investigational product's (including metabolites, where appropriate) safety, pharmacodynamics, efficacy, and dose response that were obtained from preceding trials in humans. In cases where a number of clinical trials have been completed, the use of summaries of safety and efficacy across multiple trials by indications in subgroups may pro- vide a clear presentation of the data. Tabular summaries of adverse drug reactions for all the clinical trials (including those for all the studied indications) would be useful. Important dif- ferences in adverse drug reaction types/incidences across indications or subgroups should be discussed.

　　(14) Marketing experience: countries/regions where the investigational product has been marketed or approved. Any significant information arising from the marketed use should be summarized (e.g., formulations, dosages, routes of administration, and adverse product reac- tions). The IB should also identify all the countries/regions where the investigational product did not receive approval/registration for marketing or was withdrawn from marketing/regis- tration.

　　(15) Summary of data and guidance for the investigator: an overall discussion of the non- clinical and clinical data, summarizing the information from various sources on different aspects of the investigational product(s), wherever possible, to help the investigators antici- pate adverse drug reactions or other problems in clinical trials.

　　(16) The IB is to provide the investigator with a clear understanding of the possible risks and adverse reactions, and of the specific tests, observations, and precautions that may be needed for a clinical trial. This understanding should be based on the available physical, chemical, pharmaceutical, pharmacological, toxicological, and clinical information on the investiga- tional product(s) in the IB. Guidance should also be provided to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reactions that are based on previous human experience and on the pharmacology of the investigational product.

　　(17) The IB for traditional Chinese medicines and minority medicines should be developed with reference to the above requirements. It should also indicate the theoretical basis of the formulation, screening information, compatibility, function, indications, existing clinical ex- periences in humans, origin and place of origin of medicinal materials, etc. For compound Chinese medicine preparations derived from ancient classic prescriptions, their source should be indicated in the IB. Relevant medicinal materials and prescriptions should also be pro- vided.

　　Chapter 8 Management of Essential Documents

　　Article 78 Essential Documents are those documents that individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These docu- ments serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of this guideline and with all applicable laws and regulations governing clinical trials.

　　Essential documents are an important part of the sponsor’s audits and inspection of clinical trials from the regulatory authority(ies), and serve as the basis for confirming the validity of the conduct of clinical trials and the integrity of the data collected.

　　Article 79  The sponsor and the investigator/ institution should confirm that there are  places and conditions for storing the essential documents for clinical trials. The conditions of the facilities for storing documents should be such as to prevent direct light exposure, waterproofing, and fire prevention, which is conducive to the long-term preservation of doc- uments. Standard operating procedures for document management should be developed. The retained documents should be easily identified, searched, retrieved and returned. The medium used to preserve clinical trial data should ensure that the source data or its certified copy is kept complete and readable during the retention period, and regularly tested or checked the ability to recover data, so as not to be intentionally or unintentionally changed or lost.

　　If some documents generated during the conduct of a trial are not listed in the catalog of essential documents for the trial, the sponsor and the investigator/institution may also file them in their essential documents depository, based on the importance and relevance of the specific documents to the trial.

　　Article 80 For clinical trials used to support drug registration, essential documents should be kept for at least 5 years after the drug is approved for marketing; for clinical trials not used to support drug registration, essential documents should be kept for at least 5 years after the termination of the clinical trial.

　　Article 81 The sponsor should ensure that the investigator has control of and continuous access to the CRF data reported to the sponsor. The sponsor should not have exclusive control of those data.

　　The sponsor should ensure that the investigator can retain the data of the case report form that has been submitted to the sponsor. Copies used as source documents should meet the requirements for certified copies.

　　Article 82 Trial master files for essential documents should be established at the begin- ning of the trial, both at the investigator/institution's site and at the sponsor's office. At the end of the trial, the monitor should review and confirm the existence essential documents of the investigator/institution and sponsor, and these documents should be properly kept in their respective trial master files.

　　Chapter 9 Supplementary Provisions

　　Article 83 This guideline is effective as of 1 Jul 2020.