By Hazel Hart,2014-11-15 15:31
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    credible. Ethics Committee and informed consent form are 附录7 major measures to ensure the protection of the rights and Chinese benefits of human subjects. Good Clinical Practice ?9 Ethics Committee should be established within the medical institution where the clinical trial is conducted to Chapter 1 General Provisions ensure the protection of the rights and welfare of human ?1 The China GCP is formulated to ensure the subjects involved in a trial and to provide public reassurance. clinical trial process standardized, the results scientific and An Ethics Committee should consist of at least one law credible, and the rights, benefits and safety of trial subjects specialist, member from other institute, and non-medical protected. It is based on “Drug Administration Regulations person. At least five members of both genders should be in of People's Republic of China” and in accordance with the the Ethics Committee. The composition and operations of international recognized principles. Ethics Committee should be independent and not influenced ?2 The China GCP is a standard regarding the whole by those who are involved in the trials. process of clinical trials including protocol designing, ?10 Prior to a clinical trial, the protocol can not be organizing, conducting, monitoring, auditing, recording, implemented until it has been approved by the Ethics analyzing, and reporting. Committee. During the trial, any subsequent protocol ?3 The clinical trials of all drugs, in various phases, amendment must be approved by the Ethics Committee including human bioavailability or bioequivalance study before its implementation. All serious adverse events must be performed according to the China GCP Guidelines. (SAEs) occurred during the trial must be reported to the Ethics Committee. Chapter 2 Preparations and Prerequisites for a Clinical ?11 The decision from the review process should be Trial put to the vote, the ethics committee members involved in ?4 All research involving human subjects should be the trial should abstain from voting. The committee can conducted in accordance with the ethical principles, invite experts who are not committee members to attend the contained in “Declaration of Helsinki” (see appendix 1), meeting, but non-committee members are not expected to namely justice, respect for persons, beneficence (to vote. The Ethics Committee should have its own working maximize benefits and to minimize harms and wrongs) and procedures. All meetings and resolutions should be non-maleficent (to do no harm), as defined by the current documented and retained for a period of at least 5 years revision of “International Ethical Guidelines for Biomedical after the completion of the trial. Research Involving Human Subjects” issued by the Council ?12 In the light of protecting the rights and benefits of for International Organizations of Medical Sciences the trial subjects, Ethics Committee should review the (CIOMS). All individuals involved in the conduct of any protocol in the following aspects strictly. clinical trial must be fully informed of and comply with 1 The qualifications and experiences of the these principles, and adhere to Chinese laws and regulations investigator; whether the investigator is available to relating to the drug administration. participate in the clinical trial; whether the staff allocation ?5 To initiate a clinical trial, sufficient scientific and facilities are in conformity with the requirements of the rationale should be provided. Prior to planning of a clinical trial. trial in humans, the specific aims, the problems to be 2 Whether the protocol is appropriate, including the solvedanticipated efficacy and possible risks must be aim of the study, potential risks and benefits for the subjects considered thoroughly. Anticipated benefits should prevail and others, and the scientific efficiency of the study design. over possible risks. The chosen clinical trial solutions must 3 The methods for the subjects recruitment; whether conform to the scientific and ethical standard. the information given to the subjects, their relatives, ?6 Investigational product(s) should be prepared and guardians or legal representatives is complete and easy to

    understand; whether the means to obtain the informed provided by the sponsor. Before conducting clinical trials, consent form is appropriate. the sponsor is responsible for providing pre-clinical data of 4 Whether medical treatment and/or insurance are the investigational product, including composition of the available to the subjects in case of trial-related injury or formula, manufacturing process, and quality analysis reports. death. The pharmaceutical, pre-clinical, and existing clinical data 5 Whether revisions and/or amendments to the should meet the requirements for conducting respective protocol are acceptable. phases of the clinical trial. In addition, the information on 6 Regular reviews for the risk and its extent of the safety and efficacy collected in completed and ongoing trial subjects should be done during the clinical study. clinical trials elsewhere with the investigational product

    should be also provided to prove that the investigational ?13 After receiving the application, the Ethics product is appropriate for clinical trials, so as to indicate its Committee should arrange a meeting as early as possible to safety and possible clinical application. review, discuss and endorse its decisions in writing, with the ?7 The facilities and conditions of the study sites name list of the committee members present at the meeting,

    committee members' specialties and signatures. The involved in the clinical trial should comply with the decision of the ethics committee can be expressed in the requirements for conducting the trial safely and efficiently. following terms: Each investigator should have appropriate expertise, (1) approval/favorable opinion; qualifications and competence as well as training in the (2) approval/favorable opinion after necessary revision GCP to undertake a proposed study. Prior to the trial, the required; investigator(s) and the sponsor should reach an agreement (3) disapproval/negative opinion; on the protocol, the monitoring and auditing, standard (4) termination/suspension of approved trials. operating procedures (SOP), and the allocation of trial-

    related responsibilities. ?14 Investigators or their appointed representatives

     should provide trial subjects with detailed information Chapter 3 Protection of Trial Subjects' Rights and Benefits related to the clinical trial.

    ?8 The personal integrity and welfare of the trial 1 The subject should take part in the trial voluntarily

    and is at liberty to withdraw from the trial at any time subjects must be fully protected during the process of the

    clinical trial. The trial must also be ensured scientific and



    without being prejudiced, revenged and his/her medical and results from relevant clinical trials; the known potential treatment, rights and welfare impaired; risks and benefits to human subjects.

    2 The subject must be made aware that the personal 3. Sites of the clinical trial; name and address of the data and materials relating to the trial or regarding sponsor; names, qualifications, and addresses of participation of the trial should be kept confidential. investigators.

    However, the ethics committee, the drug regulatory 4. Design of the trial (control or open, parallel or authorities or the sponsor can have access to the subjects' crossover, double-blind or single-blind, randomization personal data and materials concerning the trial in methods and procedures, single or multiple centers, etc.). accordance with required procedures when needed; 5. Criteria for inclusion and exclusion of trial 3 The aim, process and duration of the trial, tests subjects and process of recruitment, methods of allocation and operation procedures, expected benefits, possible risks of subjects, withdrawal criteria.

    or inconveniences and the probability of allocation to 6. Number of trial subjects needed to achieve the different group of the trial should be explained to the trial objective based on statistical considerations. subjects in detail; 7. Route and frequency of administration, dosage 4 During the trial, the subject can have access to any and duration of treatment, concomitant medication for the information relating to him/her at any time. Enough time investigational product and comparator product being must be given to the subject for consideration of whether formulated in accordance with the results from he/she is willing to participate in the trial. When the subject pharmacodynamic and pharmacokinetic studies and dose-is incapable to give his/her informed consent, his/her legal response relationships.

    representative should be provided with the above 8. Items of clinical and laboratory examinations, information. The spoken and written language used for times of their measurements, and pharmacokinetic analysis, instruction of the informed consent must be easy to etc.

    understand by the subject and his/her legal representative. 9. Receipt registering, use recording, transferring, 5 If trial related damage occurs to the subject, dispensing and storage condition for the investigational he/she can be entitled to medical treatment and/or insurance product(s), including the placebo(s) and active control. compensation. 10. Clinical observation, follow-up procedures and

    measures to ensure patients' compliance with the protocol. ?15 The informed consent form is obtained after a 11. Criteria for suspension and termination of clinical sufficient and comprehensive explanation of the trial. trials, instructions on completing the clinical trial. 1 The informed consent form should be signed and 12. Defined criteria of efficacy assessment, including dated by the subject or subject's legally acceptable methods and timing for assessing, recording and analyzing representative, and by the investigator or appointed efficacy parameters. representative who conducted the process to obtain the 13. Procedures for the maintenance of subject informed consent form. identification code lists, treatment records, randomization 2 When both the subject and his/her legally list and case report form (CRF). acceptable representative are incapable to read, a witness 14. Recording requirements for adverse events and should be present during the entire process of obtaining the reporting methods for serious adverse events, measures for consent. After the subject or his/her legally acceptable management of complications, the way and time of the representative being provided with the detailed explanation follow-up visit. of the informed consent form and gives oral consent, the 15. Establishment and maintenance of trial witness is required to sign and date the consent form. randomization codes, and how and by whom it can be 3 If the subject is incapable to give personal consent broken in the event of an emergency. (e.g. children, those suffering from severe mental illness or 16. Description of methodology on the evaluation of disability), the inclusion of such patients in a trial may be results and rationale to withdraw patient from final report acceptable if the Ethics Committee is, in principle, in when necessary. agreement and if the investigator believes that the subject's 17. Regulations for data management and record participation is in his/her interest, for which the legal archiving. guardian of the subject is required to sign and date the 18. Quality control and quality assurance for clinical informed consent form. trials. 4 If none of the signed informed consent form from 19. Anticipated progress and completion date of the the subject, guardian and witness is obtained, such status clinical trial. and the reasons of failing to obtain the consent form must be 20. Medical care after completion of the clinical trials. documented in detail and signed by the investigator. 21. Statements regarding responsibilities for each 5 If any new important information related to the party and publication policy. investigational product arises, revision to the informed 22. List of references. consent form must be made and sent to the Ethics During clinical trials, if necessary, the protocol can be Committee for approval. It is necessary to regain the amended according to specific regulations. consent form from trial subjects. Chapter 5 Responsibilities of the Investigator Chapter 4 The Protocol ?18 The investigator responsible for the clinical trial ?16 Before the clinical trial is conducted, the protocol should meet the following requirements: should be worked out, agreed upon and signed by both 1. The investigator should be qualified as a medical investigator and sponsor. It can not be implemented until doctor working in a legally approved medical institution. reviewed and approved by Ethics Committee. 2. The investigator should have good knowledge and ?17 The contents of a trial protocol should include the experience of the field of medicine defined by the protocol. following topics: 3. The investigator should be experienced in 1. Title and rationale for the clinical trial. research methods of clinical trial, or be able to get (revive) 2. Purpose and objectives of the trial; background of scientific support from an experienced colleague. the trial, including name of the investigational product;

    findings with clinical significance from non-clinical studies



    4. The investigator should be aware of available ?31 The responsibilities of a sponsor include initiation, relevant data and literature and all information provided by application, organizing, funding and monitoring of a clinical the sponsor. trial. The sponsor is usually a pharmaceutical company, but 5. The investigator should have access to human and may also be an organization or institution. If the sponsor is other resources needed for the conduct of the trial. a foreign company or organization, it is required to have a 6. The investigator should be aware of GCP, and legal person as a registered representative in China to comply with relevant legal, regulatory and ethical perform duties defined by Chinese regulations. The sponsor requirements of the country. should submit application for a clinical trial to the State ?19 The investigator is required to have a thorough Drug Administration in the light of related law, regulations study and understanding of the protocol, sign the protocol and rules in China. The sponsor may transfer some together with the sponsor and carry out the trial in strict activities of a clinical trial to a contract research compliance with the protocol and the GCP guideline. The organization (CRO).

    investigator should submit the protocol timely to the Ethics ?32 The sponsor recommends clinical trial institutions Committee for approval. and investigators, and confirms their qualifications and ?20 The investigator is required to understand the conditions to assure the completion of the clinical trial. nature, actions, efficacy and safety (including pre-clinical ?33 The sponsor is responsible for providing the data) of the investigational product(s). In addition, the Investigator's Brochure, which includes the investigator should be kept informed of any new chemical/pharmaceutical, toxicological, pharmacological, information about the product arising in the process of the and clinical data (including data from previous and ongoing clinical trial. trials) regarding the investigational product(s). ?21 The investigator is required to conduct the clinical ?34 After obtaining approvals from the State Drug trial in the institution with sound medical facilities, Administration and the Ethics Committee, the sponsor starts laboratory equipment and staff. The institution should have to implement the clinical trial in accordance with the all necessary facilities dealing with emergency to ensure protocol and the GCP. safety of trial subjects. The results of laboratory ?35 The sponsor should work together with the examinations should be correct and reliable. investigator to design the protocol, and specify trial related ?22 The investigator should obtain permission from responsibilities for each party, including data processing, the hospital or institution that he/she works for and ensure statistical analysis, preparation of trial report, the way of that he/she has sufficient time to conduct and complete the publication, etc. The agreed protocol and contract should be trial within the schedule defined in the protocol. The signed by both parties. investigator is required to illustrate relevant materials, ?36 The sponsor is responsible for providing the regulations and responsibilities to all of the staff involved in investigators with the easily distinguishable investigational the trial. It is the investigator's responsibility to ensure new drug(s), standards, controls, or placebo with proper sufficient number of subjects who meet the inclusion criteria code and specific labels, and ensuring the quality of the defined in the protocol to enter the trial. products. These products should be packaged appropriately ?23 The investigator should provide and explain the in accordance with the protocol (e.g., blinding, if applicable) detailed information about the trial approved by the Ethics and kept with batch/serial numbers. The sponsor should Committee to the subjects, and obtain informed consent establish management and recording systems for registering, forms from the subjects. maintaining and distribution of the products. ?24 The investigator is responsible for medical ?37 The sponsor should appoint monitors acceptable decision making in relation to the trial, to ensure adequate to the investigator for monitoring the carrying out of the medical treatment to be provided to the subject whenever clinical trial. any adverse event occurs. ?38 The sponsor is responsible for establishing the ?25 The investigator is obliged to take necessary quality control and quality assurance systems for clinical measures to ensure the safety of subjects, and such measures trials. If necessary, the sponsor can organize auditing for should be documented. In case of SAEs, the investigator the clinical trial to ensure the quality of the trial. must take appropriate measures to protect subjects, and ?39 The sponsor must discuss together with the report to the drug regulatory authorities, the sponsor and the investigator(s) as soon as serious adverse event occurs, take Ethics Committee immediately, and sign and date the report. necessary measures to safeguard trial subjects, and report to ?26 The investigator should ensure the case report drug regulatory authorities in time, and notify the other forms is filled with the data accurately, completely, investigators who involved in the same trial. legitimately, and timely. ?40 If the sponsor prematurely terminates or suspends ?27 To ensure the quality of the clinical trial, the a trial, the sponsor should inform the investigator(s), the investigator must accept monitoring or auditing by the Ethics Committee, and the State Drug Administration of the monitor(s) or auditor(s) sent by the sponsor, and accept decision as early as possible. The reason(s) for the auditing or inspection by the drug regulatory authorities. termination or suspension must be stated. ?28 The investigator should have an agreement with ?41 The sponsor should submit the final report(s), or the sponsor regarding trial related cost and specify the study termination report(s) with its reason(s) to the State details in the contract. Drug Administration. ?29 Upon completion of the trial, the investigator is ?42 The sponsor should provide insurance and required to submit the final report, signed and dated, to the treatment compensation to trial subjects in the event of trial sponsor. related injuries or death, and provide indemnity (legal and ?30 In the case of premature termination or suspension financial coverage) for the investigator, except for claims of the trial, the investigator must inform the subjects, the resulting from medical malpractice.

    sponsor, the Ethics Committee and the State Drug ?43 If the investigator is not adhere to the protocol, Administration. Reasons for the termination or suspension and not in compliance with the GCP, or applicable must be stated. regulatory requirement(s) during the trial, the sponsor should point out the problem(s) and request for correction(s). Chapter 6 Responsibilities of the Sponsor If the situation(s) is serious and/or persistent, the sponsor



    should report the situation(s) to the State Drug in the protocol. The case report form is considered to be the Administration and may terminate the investigator's original record and should not be changed. In making participation in the trial. corrections on the form, the original record must not be

     changed. Instead, only additional remarks can be added, Chapter 7 Responsibilities of the Monitor along with explanations. Then it should be signed and dated

    by the investigator who make the changes. When making ?44 In the clinical trial, monitoring is to ensure the duplicate copies of the case report form, no changes should rights and welfare of the subjects protected, trial records and be made to the original record. All kinds of clinical data in the study report accurate and complete, and the trial laboratory data including the data within the normal conducted in accordance with the approved protocols, the reference range should be recorded on the CRF, and/or GCP, and related regulations. original records should be attached to the CRF. Values ?45 The monitor is the principal communication link outside a clinically accepted reference range or values that between the sponsor and the investigator. The number of differ importantly from previous values must be evaluated monitors depends on the complexity of the trial and the and commented upon by the investigator. Units of number of medical institutions involved in the trial. The measurement must always be stated. The investigator monitor should have adequate medical, pharmaceutical should confidentially keep the subject identification code and/or scientific qualifications and should be appropriately list and confirmation records. trained and fully aware of the GCP, relevant regulations, as ?48 The final report of the trial should be consistent well as the pre-clinical and clinical related information of with the protocol. It includes: the investigational product(s), the protocol and other related 1. Comparison of the basic conditions of the documents. different treatment groups, so as to ensure their ?46 The monitor is required to oversee the progress of comparability. the clinical trial according to the standard operating 2. Actual numbers of the randomized subjects procedures (SOP), to ensure the protocols are implemented entering into each treatment group; analysis of the reasons accordingly. The following actions should be taken: of exclusion for the cases excluded during the trial. 1. Prior to the trial, the monitor should make sure 3. Expressing the efficacy and safety of each that the trial sites are in appropriate situation, including staff treatment group with writing explanation, figures, tables, allocation and training, sound and complete test and test parameters and P values. laboratory facilities, satisfactory working conditions, 4. Calculating differences and confidence limits sufficient number of subjects by estimation, and that the among the treatment groups and testing on statistically participating staff well understand the requirements of the significant differences of the results from treatment groups. protocol. 5. Consideration of existing differences among the 2. The monitor should visit trial sites and centers and their impacts, when assessing the efficacy in investigators in the early, mid, and late stage of the trial, to multi-center trials. confirm that informed consent have been obtained prior to 6. Assessing and discussing reports of serious each subject's participation in the trial, to know the subject adverse events. recruitment rate and the status of the trial progression. The 7. Comprehensive analysis and conclusions for monitor should assure that all data are correctly and information described as above. completely recorded and reported, and submit a written ?49 All the data and documents from the clinical trial monitor report to the sponsor after each site visit. Reports should be kept (see Appendix 3) and handled according to should clearly describe the date and time of the monitoring regulatory requirements. The investigator should retain the visit, name of the monitor, significant findings and data and documents at least 5 years after completion of the corrections for the errors or omissions. clinical trial. The sponsor should retain the data and 3. The monitor is responsible for ensuring that all documents at least 5 years after the approval of marketing. case report forms (CRFs) are correctly filled in accordance with the source documents, that all errors/omissions are Chapter 9 Statistical Analysis And Data Processing corrected or noted, signed and dated by the investigators, ?50 During the process of conveying and analyzing that changes of dosage or treatment, concomitant

    medications, intermittent illness, lost follow-up and miss of the statistic results of clinical trials, ones should adopt examinations, etc. are confirmed and recorded, and all standardized statistical analysis methods. The methods withdrawal and lost follow-up of enrolled subjects are should apply to every phase of the clinical trial. Each verified, reported and explained on the CRFs. procedure must involve personnel familiar with bio-4. The monitor should ensure that all adverse events statistics. The methods of statistical analysis to be used are documented and serious adverse events are reported and must be specified in the protocol, and any other subsequent documented within the specified period. changes to the protocol should be described and justified in 5. The monitor should verify that the supply, storage, the final report of the trial. If the interim analysis is dispensing, and retrieve of investigational product(s) are required, its reason and procedures must be clearly conducted and properly recorded in accordance with explained. The results of analysis should be presented in relevant regulations. such a manner as to facilitate interpretation of their clinical 6. The monitor should assist the investigators in significance. When estimating the treatment effect, carrying out any necessary notification/application, and consideration should be given to confidence limits and should report the data and results of the trial to the sponsor. results from the significant testing. An account must be

     made of omission, unused or unnecessary data during Chapter 8 Recording and Reporting statistical analysis. The clinical trial statistical report should

    be consistent with the clinical final report. ?47 The case report form (CRF) is a form to record the

    ?51 The aim of data management is to ensure the data clinical data from a trial subject during the clinical trial. All

    data concerned with each subject in the trial are recorded in collected from the subject are rapidly, completely and the pre-designed case report form according to the trial accurately entered into the report. All steps involved in data requirements. The investigator should ensure that any management should be documented in order to allow the observation or finding is recorded correctly and completely assessment of data quality and study performance. in the CRF and signed by the responsible person designated Appropriate standard operational procedures should be used



    to ensure the confidentiality of the database. Satisfying documents of the clinical trials in the medical institutions procedures for maintenance and support of the computer and laboratories should be available for inspection by the database should be available. Before the trial, an drug regulatory authorities.

    appropriate clinical report form that can be read and entered

    with data by computer should be designed, as well as Chapter 12 Multi-Center Trials

    corresponding computer programs. ?62 Multi-center trial is defined as a trial conducted ?52 The distribution of subjects during the clinical simultaneously by several investigators at different locations trial must comply with the randomization method defined in and sites following the same protocol. The trial is required the trial design. The blinded code for each subject should to begin and end simultaneously at all sites. The principal be maintained by the sponsor or the investigators. In the investigator should be the overall person responsible for the case of a blinded trial, the protocol must state the conditions multi-center trials, and he/she should also coordinate under which the code is allowed to be broken and by whom. investigators at different centers participating in the clinical The blinded code of individual subject may be broken to trial.

    obtain the information on related treatment in the case of an ?63 Since the multi-center trial is more complex in emergency. However, explanations must be given in the organization and execution than single-center trial, the case report form. following items should be taken into consideration in planning and implementing the trial: Chapter 10 Management of Investigational Products 1. The protocol and its attachments should be ?53 The investigational product(s) should not be sold discussed and finalized by the principal investigators from on the market. each center and agreed upon by the sponsor. The protocol

    can be executed only after it is approved by the Ethics ?54 The recording of the drug usage should include Committee. the information on the amount, load and transport, delivery, 2. At the beginning and the mid-term of the clinical acceptance, distribution of the trial drugs, retrieving and trial, investigator meetings should be held. destroying the surplus drugs. 3. Clinical trial is carried out in each center at the ?55 The investigator is responsible for the use of the same period. investigational products. The investigator should ensure 4. The sample size in each center must comply with that the investigational product(s) are used only for subjects statistical requirements. entered in the trial, the dosage and administration are in 5. The same measures for the management of accordance with the protocol, and surplus investigational investigational products in the different centers, including products should be returned to the sponsor. The above dispensing and storage, should be ensured. described procedures are documented by designated 6. The investigators involved in the trial should be personnel. The investigator should not transfer the trained according to the same protocol. investigational products to anyone who is not a trial subject. 7. Standardized methods for evaluation should be ?56 The sponsor is responsible for properly packaging established. The laboratory and clinical evaluation methods and labeling all the investigational products. The label used in the trial should have unified quality control. If should state that the product is for clinical research purposes available, a central laboratory should conduct the tests. only. In double-blinded trials, all study products, including 8. Data management and analysis should be investigational products, control products and placebo, centralized. Data transfer and query procedures should be should be indistinguishable in appearance, smell, package, established. label and other characteristics. 9. It should be ensured the investigators at every ?57 Monitors are responsible for monitoring the whole center adhere to the protocol. The investigators' process of supply, use, storage of the investigational product participation in the trial should be stopped when they and handling of the surplus drugs. violate the protocol. 10. The monitor's function should be reinforced. Chapter 11 Quality Assurance 11. The final report should be drafted upon ?58 Both the sponsor and the investigators should completion of the clinical trial. follow standard operating procedures to ensure the ?64 It is necessary for the multi-center trial to have a implementation of quality control and quality assurance management system based on the number of the participants, systems in the clinical trial. final requirements of the trial, and the extent of knowledge ?59 All observation results and findings in the trial on the trial drugs. A coordinating committee responsible for should be verified to ensure the credibility of data and to the implementation of the clinical trial should be established assure that the conclusions presented are derived correctly within the management system, and keeps communication from the original data. Quality control must be applied to with the State Drug Administration. each stage of data processing to ensure that all data are reliable and have been processed correctly. Chapter 13 Supplementary Articles/ ?60 The drug regulatory authorities and the sponsor Additional Rules can entrust auditors to carry out systematic auditing for the ?65 The right to amend and interpret the GCP belongs clinical trial to determine whether the trial implementation to the State Drug Administration. is in accordance with the protocol, and whether the reported ?66 The GCP is implemented upon the issue. data conform to those recorded by all the participating institutions, that means, whether the data filled in case report forms or recorded data conform to the data in the case Appendix 1: files or other original records. The auditing should be DECLARATION OF HELSINKI carried out by personnel not directly involved in the clinical trial. RECOMMENDATIONS GUIDING PHYSICIANS IN ?61 Drug regulatory authorities should carry out BIOCHEMICAL RESEARCH INVOLVING HUMAN inspection on the respective responsibilities of the SUBJECTS investigator and the sponsor and the implementation status Adopted by the 18th World Medical Assembly, Helsinki, of the trial. All the data (including case files) and Finland, June 1964, and amended by the 29th World



    Medical Assembly, Tokyo, Japan, October 1975. the objective is in proportion to the inherent risk to the Afterwards it was further revised in 1983, 1989, and 1996, subject.

    during the thirty-fifth, forty-first, and forty-eighth meetings 5. Every biomedical research project involving of the World Medical Assemblies. human subjects should be preceded by careful assessment of INTRODUCTION predictable risks in comparison with foreseeable benefits to It is the mission of the physician to safeguard the health of the subject or to others. Concern for the interests of the the people. His or her knowledge and conscience are subject must always prevail over the interests of science and dedicated to the fulfillment of this mission. society.

    The Declaration of Geneva of the World Medical 6. The right of the research subject to safeguard his Association binds the doctor with the words “The health of or her integrity must always be respected. Every precaution my patient will be my first consideration” and the should be taken to respect the privacy of the subject and to International Code of Medical Ethics declares that “A minimize the impact of the study on the subject's physical physician shall act only in the patient's interest when and mental integrity and on the personality of the subject. providing medical care which might have the effect of 7. Physicians should abstain from engaging in weakening the physical and mental condition of the research projects involving human subjects unless they are patient.” satisfied that the hazards involved are believed to be The purpose of biomedical research involving human predictable. Physicians should cease any investigation if the subjects must be to improve diagnostic, therapeutic and hazards are found to outweigh the potential benefits. prophylactic procedures and the understanding of the 8. In publication of the results of his or her research, aetiology and pathogenesis of disease. the physician is obliged to preserve the accuracy of the In current medical practice most diagnostic, therapeutic or results. Reports of experimentation not in accordance with prophylactic procedures involve hazards. This applies the principles laid down in this Declaration should not be especially to biomedical research. accepted for publication.

    Medical progress is based on research which ultimately 9. In any research on human beings, each potential must rest in part on experimentation involving human subject must be adequately informed of the aims, methods, subjects. anticipated benefits and potential hazards of the study and In the field of biomedical research a fundamental distinction the discomfort it may entail. He or she should be informed must be recognized between medical research in which the that he or she is at liberty to abstain from participation in the aim is essentially diagnostic or therapeutic for a patient, and study and that he or she is free to withdraw his or her medical research, the essential object of which is purely consent to participation at any time. The physician should scientific and without implying direct diagnostic or then obtain the subject's freely-given informed consent, therapeutic value to the person subjected to the research. preferably in writing.

    Special caution must be exercised in the conduct of research 10. When obtaining informed consent for the research which may affect the environment, and the welfare of project the physician should be particularly cautious if the animals used for research must be respected. subject is in a dependent relationship to him or her or may Because it is essential that the results of laboratory consent under duress. In that case the informed consent experiments be applied to human beings to further scientific should be obtained by a physician who is not engaged in the knowledge and to help suffering humanity, the World investigation and who is completely independent of this Medical Association has prepared the following official relationship.

    recommendations as a guide to every doctor in biomedical 11. In case of legal incompetence, informed consent research involving human subjects. They should be kept should be obtained from the legal guardian in accordance under review in the future. It must be stressed that the with national legislation. Where physical or mental standards as drafted are only a guide to physicians all over incapacity makes it impossible to obtain informed consent, the world. Physicians are not relieved from criminal, civil or when the subject is a minor, permission from the and ethical responsibilities under the laws of their own responsible relative replaces that of the subject in countries. accordance with national legislation.

    I. BASIC PRINCIPLES Whenever the minor child is in fact able to give a 1. Biomedical research involving human subjects consent, the minor's consent must be obtained in addition to must conform to generally accepted scientific principles and the consent of the minor's legal guardian. should be based on adequately performed laboratory and 12. The research protocol should always contain a animal experimentation and on a thorough knowledge of the statement of the ethical considerations involved and should scientific literature. indicate that the principles enunciated in the present 2. The design and performance of each experimental Declaration are complied with.

    procedure involving human subjects should be clearly II. MEDICAL RESEARCH COMBINED WITH

    formulated in an experimental protocol which should be PROFESSIONAL CARE (Clinical Research)

    transmitted for consideration, comment and guidance to a 1. In the treatment of the sick person, the physician specially appointed committee independent of the must be free to use a new diagnostic and therapeutic investigator and the sponsor provided that this independent measure, if in his or her judgment it offers hope of saving committee is in conformity with the laws and regulations of life, re-establishing health or alleviating suffering. the country in which the research experiment is performed. 2. The potential benefits, hazards and discomfort of 3. Biomedical research involving human subjects a new method should be weighed against the advantages of should be conducted only by scientifically qualified persons the best current diagnostic and therapeutic methods. and under the supervision of a clinically competent medical 3. In any medical study, every patient - including person. The responsibility for the human subject must those of a control group, if any - should be assured of the always rest with the medically qualified person and never best proven diagnostic and therapeutic method. rest on the subject of the research, even though the subject 4. The refusal of the patient to participate in a study has given his or her consent. must never interfere with the physician-patient relationship. 4. Biomedical research involving human subjects 5. If the physician considers it essential not to obtain cannot legitimately be carried out unless the importance of informed consent, the specific reasons for this proposal



    should be stated in the experimental protocol for protected, and to evaluate if the trial protocol and its transmission to the independent committee (I, 2). attachment meet ethics standard, thereby providing public 6. The physician can combine medical research with reassurance. Ethics Committees should be constituted and professional care, the objective being the acquisition of new operated so that their tasks can be executed free from bias medical knowledge, only to the extent that medical research and from any influence of those who are organizing and is justified by its potential diagnostic or therapeutic value conducting the trial.

    for the patient. 7. Investigator

    III. NON-THERAPEUTIC BIOMEDICAL A person who is responsible for the conduct of clinical trials, RESEARCH INVOLVING HUMAN SUBJECTS ( Non-the quality of clinical trials, and the safety and right/benefit Clinical Biomedical Research) of trial subjects. The investigator should receive qualified 1. In the purely scientific application of medical approval from qualification reviews, and they should have research carried out on a human being, it is the duty of the professional skills, qualification and capabilities for clinical physician to remain the protector of the life and health of trial. A principal investigator is a responsible leader of the that person on whom biomedical research is being carried trial as well as serving as the coordinator among different out. centers participating in a multi-center trial. 2. The subjects should be volunteers - either healthy 8. Coordinating Investigator

    persons or patients for whom the experimental design is not An investigator who is assigned the responsibility for the related to the patient's illness. coordination of investigators at different centers 3. The investigator or the investigating team should participating in a multi-center trial.

    discontinue the research if in his/her or their judgment it 9. Sponsor

    may, if continued, be harmful to the individual. A company, an institution, or an organization which takes 4. In the research on man, the interest of science and responsibility for the initiation, management, financing, and society should never take precedence over considerations monitoring of a clinical trial.

    related to the well-being of the subject. 10. Monitor

     A person with relevant knowledge appointed by the sponsor

     and responsible to the sponsor, for the monitoring and Appendix 2 reporting of progress of the trial and for verification of data. Definition of Terms 11. Audit

     A systematic examination by personnel not directly 1. Clinical Trial involved in the trial to determine whether the trial Any systematic study on pharmaceutical products in human implementation, data recorded and analysis are in subjects (patients or non- patient volunteers) in order to accordance with the protocol, the GCP, and the applicable discover or verify the effect and any adverse reaction of the regulatory requirement(s).

    investigational products, and/or absorption, distribution, 12. Inspection

    metabolism and excretion of the products, with the object of An officially conducted examination by the drug ascertaining their efficacy and safety. administrative management departments of documents, 2. Protocol facilities, records, and any other aspects related to the The main document of a clinical trial which states the clinical trial at the site of the investigation, of the sponsor's, background, rationale and objectives of the trial and or of contract research organization's.

    describes its design, methodology and organization, 13. Case Report Form (CRF)

    including statistical considerations, and the conditions under A document designed to record data on each trial subject which it is to be performed and completed. The protocol during the course of the trial, as defined by the protocol. should be dated and signed/stamped by the principle 14. Final Report

    investigator/institution involved and the sponsor. A comprehensive description of the trial after its completion 3. Investigator's Brochure including a description of experiment methods and materials, A collection of the clinical and non-clinical data consisting a presentation and evaluation of the results, statistical of all the relevant information on the investigational analysis and a critical, ethics, statistical and clinical product(s) known prior to the onset of a clinical trial in appraisal.

    human subjects. 15. Pharmaceutical Product

    4. Informed Consent Any substance that has a prophylactic, therapeutic or A process by which a subject voluntarily confirms his or her diagnostic purposes, or is intended to modify physiological willingness to participate in a particular trial, after having functions, and with indication, instruction, and dose been informed of all aspects of the trial. Informed consent specified.

    is confirmed by means of a written, signed and dated 16. Investigational Product

    informed consent form. Any pharmaceutical product or placebo being tested or used 5. Informed Consent Form as control in a clinical trial.

    A document which prove that a subject voluntarily confirms 17. Adverse Drug Reaction

    his or her willingness to participate in a particular trial. A noxious and unintended response to a pharmaceutical Investigators need to provide subjects information regarding product occurring at doses normally used. The adverse drug the nature of the trial, objectives of the trial, potential reaction implies a causal relationship between the medical benefits and risks, alternative treatment that may be product and the adverse event. In the clinical experience available, and of the subject's right and responsibilities in with a new pharmaceutical product or its new usage, accordance with “Declaration of Helsinki”. Informed particularly as the therapeutic dose(s) may not be consent is then obtained after subjects fully understand all established, all noxious and unintended responses to a the information. pharmaceutical product having a causal relationship with 6. Ethics Committee the treatment should be considered as adverse drug reactions. An independent body constituted of medical and legal 18. Adverse Event

    professionals and non-medical members, whose Any untoward medical occurrence in a patient or clinical responsibility is to verify that the safety, health and human investigation subject administered a pharmaceutical product right of the subjects participating in a particular trial are


    CHINA GOOD CLINICAL PRACTICE and that does not necessarily have a causal relationship with blinding usually refers to the subject(s) being unaware, and

    this treatment. double-blinding usually refers to the subject(s), 19. Serious Adverse Event investigator(s), monitor(s), and data analyst(s) being

    An event that is associated with inpatient hospitalization or unaware of the treatment assignment(s). prolongation of hospitalization, disability/incapacity, 22. Quality Control

    affecting working ability, or is life threatening or results in The operational techniques and procedures to ensure that the

    death, and/or congenital anomaly/birth defect. requirements for quality of the trial-related activities have

    20. Standard Operating Procedure (SOP) been fulfilled.

    Detailed, written standards and instructions to achieve 23. Contract Research Organization, CRO effective implementation and completion of a specific A scientific organization (commercial or academic) to

    function in a clinical trial. which a sponsor may transfer some of its tasks and 21. Blinding/Masking obligations. Any such transfer should be defined in writing.

    A procedure in which one or more parties to the trial are

    kept unaware of the treatment assignment(s). Single-

Appendix 3

    Documents for the Conduct Of A Clinical Trial and the Filing Systems

I. Before the clinical phase of the trial commences

     Clinical Filing Documents Located in Files of

     Investigator Sponsor

    1 Investigator's Brochure X X

    2 Signed protocol and amendments X (original) X

    3 Sample case report form (CRF) X X

    4 Informed Consent Form X (original) X

    5 Financial specifications of the trial X X

    6 Signed agreement among involved parties, (investigator, sponsor, CRO) X X

    7 Approval of Ethics Committee X (original) X

    8 Composition of Ethics Committee X (original) X

    9 Application for clinical trial X (original)

    10 Pre-clinical laboratory data X (original)

    11 Approval of SDA X X (original)

    12 Investigators' Curriculum Vitae and other relevant documents X X (original)

    13 Normal ranges for trial-related laboratory test X X

    14 Quality control verifications for medical/laboratory operations X (original) X

    15 label(s) of investigational product X (original)

    16 Shipment records for investigational product(s) and trial-related materials X X

    17 Certificate(s) of analysis of investigational product(s) X (original)

    18 Broken procedures for blinded code in blinded trials X (original)

    19 Master randomization list X (original)

    20 Trial monitoring report X (original)

II. During the clinical conduct of the trial

     Clinical Filing Documents Located in Files of

     Investigator Sponsor

    21 Any revision of Investigator's Brochure X X

    22 Any revision of other documents (protocol, CRF, Informed Consent Form, other X X

    written notification)

    23 Curriculum Vitae for new investigator(s) X X(original)

    24 Updates to normal ranges for medical/laboratory test and operations X X

    25 Documentation of investigational product(s) and trial-related materials shipment X X

    26 Certificate(s) of analysis for new approved batches of investigational products X(original)

    27 Monitoring visit reports X(original)

    28 Signed Informed Consent Forms X(original)

    29 Source documents X(original)

    30 Signed, dated, and completed Case Report Forms X(original) X(transcript)

    31 SAE report provided by investigator to sponsor X(original) X

    32 Unexpected SAE report provided by sponsor to SDA and Ethics Committee(s) X X(original)

    33 Interim or annual reports X X

    34 Subject identification code list X(original)

    35 Subject screening and enrollment logs X X

    36 Investigational products accountability at the site X X

    37 Investigators' Signature list sample X X

III. After completion or termination of the trial

     Clinical Filing Documents Located in Files of

     Investigator Sponsor



     Clinical Filing Documents Located in Files of 38 Verification of investigational product destruction X X 39 Completed subject identification code list X X 40 Audit certificate X(original) 41 Close-out monitoring report X(original) 42 Treatment allocation and blinded code broken verification documentation X(original) 43 Report of the trial completion (to Ethics Committee, SDA) X(original) 44 Final report X X(original)


    CHINA GOOD CLINICAL PRACTICE 利益的考虑。伦理委员会与知情同意书是保障受试者权《药物临床试验质量管理规范》 益的主要措施。 ;局令第3号, 国家食品药品监督管理局令 第九条 为确保临床试验中受试者的权益:须成立独立3 的伦理委员会:并向国家食品药品监督管理局备案。伦 《药物临床试验质量管理规范》于200364理委员会应有从事医药相关专业人员、非医药专业人日经国家食品药品监督管理局局务会审议通过:现予发员、法律专家及来自其他单位的人员:至少五人组成:布。本规范自200391日起施行。 并有不同性别的委员。伦理委员会的组成和工作不应受 任何参与试验者的影响。 局长~郑筱萸 二??三年八月六日 第十条 试验方案需经伦理委员会审议同意并签署批准 意见后方可实施。在试验进行期间:试验方案的任何修药物临床试验质量管理规范 改均应经伦理委员会批准?试验中发生严重不良事件: 应及时向伦理委员会报告。 第一章 总则 第十一条 伦理委员会对临床试验方案的审查意见应在第一条 为保证药物临床试验过程规范:结果科学可讨论后以投票方式作出决定:参与该临床试验的委员应靠:保护受试者的权益并保障其安全:根据《中华人民当回避。因工作需要可邀请非委员的专家出席会议:但共和国药品管理法》、《中华人民共和国药品管理法实不投票。伦理委员会应建立工作程序:所有会议及其决施条例》:参照国际公认原则:制定本规范。 议均应有书面记录:记录保存至临床试验结束后五年。 第二条 药物临床试验质量管理规范是临床试验全过程第十二条 伦理委员会应从保障受试者权益的角度严格的标准规定:包括方案设计、组织实施、监查、稽查、按下列各项审议试验方案~ 记录、分析总结和报告。 ;一,研究者的资格、经验、是否有充分的时间参 加临床试验:人员配备及设备条件等是否符合试验要第三条 凡进行各期临床试验、人体生物利用度或生物求? 等效性试验:均须按本规范执行。 ;二,试验方案是否充分考虑了伦理原则:包括研 究目的、受试者及其他人员可能遭受的风险和受益及试第四条 所有以人为对象的研究必须符合《世界医学大验设计的科学性? 会赫尔辛基宣言》;附录1,:即公正、尊重人格、力 ;三,受试者入选的方法:向受试者;或其家属、求使受试者最大程度受益和尽可能避免伤害。 监护人、法定代理人,提供有关本试验的信息资料是否 完整易懂:获取知情同意书的方法是否适当? 第二章 临床试验前的准备与必要条件 ;四,受试者因参加临床试验而受到损害甚至发生 死亡时:给予的治疗和/或保险措施? 第五条 进行药物临床试验必须有充分的科学依据。在 ;五,对试验方案提出的修正意见是否可接受? 进行人体试验前:必须周密考虑该试验的目的及要解决 ;六,定期审查临床试验进行中受试者的风险程的问题:应权衡对受试者和公众健康预期的受益及风度。 险:预期的受益应超过可能出现的损害。选择临床试验 方法必须符合科学和伦理要求。 第十三条 伦理委员会接到申请后应及时召开会议:审 阅讨论:签发书面意见:并附出席会议的委员名单、专第六条 临床试验用药品由申办者准备和提供。进行临业情况及本人签名。伦理委员会的意见可以是~ 床试验前:申办者必须提供试验药物的临床前研究资 ;一,同意? 料:包括处方组成、制造工艺和质量检验结果。所提供 ;二,作必要的修正后同意? 的临床前资料必须符合进行相应各期临床试验的要求: ;三,不同意? 同时还应提供试验药物已完成和其它地区正在进行与临 ;四,终止或暂停已批准的试验。 床试验有关的有效性和安全性资料。临床试验药物的制 备:应当符合《药品生产质量管理规范》。 第十四条 研究者或其指定的代表必须向受试者说明有 关临床试验的详细情况~ 第七条 药物临床试验机构的设施与条件应满足安全有 ;一,受试者参加试验应是自愿的:而且有权在试效地进行临床试验的需要。所有研究者都应具备承担该验的任何阶段随时退出试验而不会遭到歧视或报复:其项临床试验的专业特长、资格和能力:并经过培训。临医疗待遇与权益不会受到影响? 床试验开始前:研究者和申办者应就试验方案、试验的 ;二,必须使受试者了解:参加试验及在试验中的监查、稽查和标准操作规程以及试验中的职责分工等达个人资料均属保密。必要时:药品监督管理部门、伦理成书面协议。 委员会或申办者:按规定可以查阅参加试验的受试者资 料? 第三章 受试者的权益保障 ;三,试验目的、试验的过程与期限、检查操作、 受试者预期可能的受益和风险:告知受试者可能被分配第八条 在药物临床试验的过程中:必须对受试者的个到试验的不同组别? 人权益给予充分的保障:并确保试验的科学性和可靠 ;四,必须给受试者充分的时间以便考虑是否愿意性。受试者的权益、安全和健康必须高于对科学和社会参加试验:对无能力表达同意的受试者:应向其法定代



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