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On October 31, 2013, the State Food and Drug Administration issued the Guiding Principles for Quality Management of Vaccine Clinical Trials (Trial) with Food and Drug Administration Pharmacist Control [2013] No. 228. The Guiding Principles are divided into general rules, responsibilities, implementation conditions, test protocols, organizational implementation, ethical review, vaccine management for testing, biological sample management, contract management, data management and statistical analysis, quality management, and Chapter 12 of Article 53. Effective from the date of release.

Guidelines for quality management of vaccine clinical trials

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On October 31, 2013, the State Food and Drug Administration issued the Guiding Principles for Quality Management of Vaccine Clinical Trials (Trial) with Food and Drug Administration Pharmacist Control [2013] No. 228. The Guiding Principles are divided into general principles, job requirements, implementation conditions, test plans, organizational implementation, ethical review, and test use.

Notice of the State Food and Drug Administration on Printing and Distributing Guiding Principles for the Quality Management of Vaccine Clinical Trials (Trial)

Food and Drug Administration Pharmacy Tube [2013] No. 228

Food and Drug Administration of each province, autonomous region, and municipality directly under the Central Government, Food and Drug Administration of Xinjiang Production and Construction Corps, and Drug Administration of Ministry of Health:

In order to further strengthen the quality management of vaccine clinical trials, promote the improvement of the quality of clinical trials, and protect the rights and safety of subjects, in accordance with the "Quality Management Standards for Drug Clinical Trials" and in conjunction with the World Health Organization's requirements for quality management of vaccine clinical trials, National Food The General Administration of Drug Administration has formulated the "Guiding Principles for Quality Management of Vaccine Clinical Trials (Trial)", which is now being issued. All parties involved in the clinical trials of vaccines under the organization's jurisdiction are requested to study and follow the instructions.

Annex: 1.Guidelines for quality management of vaccine clinical trials (trial)

2.Guidelines for drafting guidelines for vaccine clinical trial quality management (for trial implementation)

State Food and Drug Administration

October 31, 2013

Guiding Principles for Quality Management of Vaccine Clinical Trials (Trial)

Chapter I General Provisions

The first is to strengthen the management of vaccine clinical trials and improve the quality of vaccine clinical trials. These guidelines are formulated in accordance with the Measures for the Administration of Drug Registration and the Good Manufacturing Practice (GCP).

Article 2 These guidelines are applicable to vaccine clinical trials approved by the national drug regulatory authority, and are intended to provide guidance for the organization, implementation, and quality management of vaccine clinical trials, to ensure that the vaccine clinical trial process is standardized, the results are scientific and reliable, and the subjects are protected Rights and security. Vaccine clinical trial sponsors, contract research organizations (CROs), clinical trial agencies / investigators, and ethics committees should follow these guidelines and accept the supervision and inspection of drug regulatory agencies.

Chapter II Duty Requirements

Article 3 The sponsor is responsible for the evaluation and selection of clinical trial institutions. According to the requirements of the implementation of clinical trials, a comprehensive on-site assessment of the responsible agency for vaccine clinical trials and all trial sites should be conducted, and an evaluation report should be written. Generally, disease prevention and control institutions at the provincial level or above should be selected as the clinical trial responsible institution, the main investigator should be selected, and with the assistance of the responsible institution, one or more city and county disease prevention and control institutions and / or medical institutions should be selected as the trial on site.

Article 4 The sponsor shall establish a quality management system for clinical trials of vaccines, and conduct full-process monitoring, inspection and risk control of the trials.

The sponsor may entrust the contract research organization to perform part of the work and tasks in the clinical trial. The sponsor is ultimately responsible for the quality of the clinical trial.

Article 5 The ethics committee responsible for reviewing vaccine clinical trials shall, in light of the particularity of vaccine clinical trials, optimize the composition of staff, standardize ethical review work, improve review quality, and protect the rights and safety of subjects.

Article 6 The responsible agency for vaccine clinical trials shall apply to the State Food and Drug Administration for the qualification certification of one-off vaccine clinical trials, organize approval to conduct clinical trials after approval, and conduct management and quality control of the trials.

Chapter III Conditions of Implementation

Article 7 The responsible institutions for clinical trials of vaccines shall have the following conditions:

(1) Establish a sound vaccine clinical trial organization management system and quality management system. The clinical trial management department is responsible for the organization, management, and implementation of vaccine clinical trials. It is staffed with department heads, department secretaries, quality control personnel, and data archive managers. It has GCP and vaccine clinical trial technical training and is able to undertake the vaccine clinical trial Clinical research professionals in epidemiology and laboratory testing.

(2) It has management mechanisms and measures to prevent and deal with emergencies in clinical trials of vaccines, and has a team of experts for emergency treatment of severe adverse events (SAE) and technical capabilities for handling serious adverse events.

(3) It has complete cold chain equipment for vaccine delivery and storage, which can guarantee the safe storage and transportation of vaccines and samples for testing.

(4) Having the clinical trial site under its jurisdiction, having epidemiological background data and vaccine coverage information of vaccine-related diseases, and subject resources in its jurisdiction to meet the needs of vaccine clinical trials.

(5) Develop, revise and regularly review the management system and standard operating procedures (SOPs), conduct training and have training records to ensure that the relevant management systems and standard operating procedures are accurately implemented at each test site.

(6) Establish a complete education training and assessment system, formulate an annual training plan, conduct GCP and vaccine clinical trial technology training for researchers in the institution and the test site, and have a training record.

Article 8 The test site of a vaccine clinical trial shall have the following conditions:

(1) A city or county-level disease prevention and control institution or medical institution with a vaccination qualification approved by the health and family planning administrative department and an effective communication system and equipment.

(2) There is a relatively fixed and sufficient number of clinical trial researchers, and the researchers have been trained in GCP and vaccine clinical trial techniques.

(3) Having epidemiological background data of the vaccine-related diseases under study, determining the research area according to the research purpose, and ensuring that the number of subjects meets the requirements of clinical trials.

(4) Equipped with standard operating procedures for vaccine clinical trials, training and training records, standard operating procedures are easy to access.

(5) Establish a green channel for SAE medical treatment of vaccine clinical trials in cooperation with local medical institutions.

(VI) According to the different vaccination and visiting procedures of vaccine clinical trials, there are reception areas, informed consent rooms, physical examination and consultation screening rooms, biological specimen collection rooms, vaccination rooms, emergency rooms, medical observation rooms, vaccine storage Functional areas such as laboratories, archives rooms, sample processing and storage rooms, case screening laboratories, and temporary storage sites for medical wastes. First-aid green channels are established. Ambulances and related ambulances and first-aid items are available at the test site. Each functional area has clear indication signs.

Article 9 The clinical examination of the vaccine phase I clinical trial shall be carried out in the laboratory department of a general hospital above the second level. The clinical laboratory shall implement quality control on the clinical laboratory projects. Inspection instruments are regularly calibrated and maintained.

Chapter IV Test Plan

Article 10 The sponsor shall formulate the test plan before the clinical trial of the vaccine is carried out. The test plan shall be formulated in accordance with the relevant regulations and guiding principles, and explain the division of responsibilities between the sponsor, the responsible institution and the test site, and indicate the version number.

Article 11 The responsible agency for vaccine clinical trials accepts the commissioner's entrustment, undertakes the risk assessment of the clinical trial and the feasibility of the scheme, participates in the formulation of the trial scheme, and signs the confirmation.

Chapter V Organization and Implementation

Article 12 The responsible agency for vaccine clinical trials shall formulate a uniform standard operating procedure before the start of the trial and issue it to each trial site for strict implementation to ensure effective organization management and quality control of each trial site.

Article 13 The responsible agency for vaccine clinical trials shall divide the personnel before the trial begins, and designate the following personnel:

(1) Principal investigator: Responsible for the operation management and organization of the trial, formulate the on-site execution plan, quality management plan and standard operating procedures for the trial, organize the report and treatment of adverse events in the clinical trial, and write the summary report of the clinical trial.

(2) Project Coordinator: assist the main researcher to effectively manage the trial implementation and ensure the quality of the trial implementation; be responsible for communicating with the sponsor, contract research organization, and the responsible researcher at the test site, and report the communication results to the main researcher in a timely manner; Participate in the formulation of the test plan, the design of the informed consent form and the field application form; participate in the training arrangements for the researcher's training; organize field test work, guide the reporting and treatment of adverse events, and consult the main researcher if necessary.

(3) Clinical trial quality controller: assist the project coordinator to jointly carry out on-site quality control work and manage different process links, including compliance with the test plan and GCP, the informed consent of the subject, vaccine management, and specimen collection , Verification of adverse events and data modification specifications; Responsible for coordinating various work, guidance of field operation technology and interpretation of test plans, and assist in handling emergencies.

Article 14 The division of labor at the test site must be confirmed by the main investigator to ensure that all researchers participating in the project have the appropriate qualifications, have been trained and authorized, clarify their respective tasks, and master and implement relevant standard operating procedures. .

(1) Researcher responsible for the test site: responsible for coordinating and organizing various work at a test site, grasping the progress of the work, and formulating a field work plan; responsible for the coordinated handling of emergency events at the test site, ensuring that records are timely, complete, accurate, and clear to ensure The deviation from the plan and the measures taken are recorded in detail.

(2) On-site researcher: refers to the doctors and nurses involved in clinical trials, responsible for the registration of subjects, informed consent, physical examination, interrogation, collection of biological samples, vaccination, observation and so on.

(3) Vaccine materials manager: responsible for vaccine, material management, distribution, collection, recovery, and cold chain maintenance of vaccines.

(IV) Adverse event investigator: responsible for follow-up visits or telephone follow-up of subjects at specified time points after each vaccination. The follow-up content includes whether adverse events occurred after vaccination, whether body temperature was measured on time, and the follow-up results were recorded in a timely manner. Assist in the investigation and handling of adverse events.

(5) Biological sample manager: responsible for the processing, storage, registration and recording of biological samples.

(6) Data manager: responsible for the management, storage and transfer of test site data.

Article 15 Before the start of a clinical trial, the sponsor and the main investigator divide the responsibilities of all personnel participating in the clinical trial, conduct pre-startup training on the trial protocol and standard operating procedures, and keep training records.

Article 16 Researchers shall fully inform the clinical trials, the benefits, risks, compensations, and personal rights of the clinical trials before the subjects participate in the clinical trials, and jointly sign with the subjects approved by the ethics committee. Informed consent.

In principle, the legal guardian is required to give informed consent to the juvenile subject in principle. If the legal guardian is not present, he can authorize it in writing. When a minor subject can make a decision to participate in a study, his or her consent should also be obtained.

If the subject and his legal guardian are not literate, the informed consent process should be attended by a witness. After the subject or his legal guardian agrees, the witness reads the informed consent and is consistent with the oral informed process. Handprints, witnesses sign the informed consent form.

Article 17 The sponsor is the responsible body for monitoring, evaluating, and SAE reporting of vaccine clinical trial safety information. Full-time personnel should be designated to manage clinical trial safety information monitoring and SAE reports. Standard operating procedures for clinical trial safety information monitoring and SAE reporting should be developed with the investigator and all relevant personnel should be trained. The latest status of the safety information of the entire clinical trial should be kept up to date, and all clinical trial institutions / investigators and regulatory authorities should be notified in a timely manner.

The sponsor should set up data and safety monitoring committees according to the needs of vaccine clinical trials. The Data and Safety Monitoring Committee finds any information that directly affects the safety of the subject and reports it to the sponsor in a timely manner.

Article 18 The monitoring and reporting of adverse events in vaccine clinical trials shall be completed jointly by the subjects, adverse event investigators, and researchers at different observation points in stages.

The responsible agency should establish a sensitive monitoring system that combines active and passive reporting of adverse events. For clinical trials of vaccines with disease as the clinical endpoint, a case detection and confirmation system should be established. A clinical medical expert with business expertise should form an endpoint event evaluation committee to evaluate the endpoint events found in the trial.

Article 19 The responsible organization shall establish an emergency plan for SAE treatment in clinical trials. If a serious adverse event occurs in a subject, the researcher shall immediately take appropriate measures and record it on the subject. Researchers should report to the sponsor, ethics committee, and provincial regulatory authority in a timely manner (within 24 hours) when they learn of SAE, and submit follow-up reports.

The clinical trial institution / investigator should promptly report the sponsor's latest safety information report on the clinical trial to the ethics committee.

The ethics committee receives safety information reports such as SAE reports, grasps the occurrence and treatment of SAE in the entire clinical trial in a timely manner, and conducts follow-up review of SAE processing and reporting during clinical trials.

Article 20 After receiving information about vaccine safety from any source, the sponsor should analyze and evaluate, including the severity, relevance to the test vaccine, and whether it is an expected event.

For suspicious and unexpected severe adverse reactions (SUSAR) that are fatal or life-threatening, sponsors should report to the Drug Evaluation Center of the General Administration as soon as possible after the first knowledge, but not more than 7 natural days, and report the relevant follow-up within the next 8 days information;

For non-lethal or life-threatening suspicious and unexpected serious adverse reactions, or other information about potential serious safety risks, the sponsor should report to the Drug Evaluation Center of the General Administration as soon as possible after the first information, but it should not exceed 15 natural days.

Sponsors must not arbitrarily change the investigator's judgment on the relevance of serious adverse events to vaccines. If the opinions of the sponsor and the researcher are inconsistent, the opinions of the sponsor and the researcher should be specified in the report and reported in accordance with higher management requirements.

Under special circumstances, researchers and sponsors should provide SAE-related information and safety reports in a timely manner in accordance with the requirements of regulatory authorities and ethics committees.

Article 21 The sponsor shall regularly (at least once a year) summarize the adverse events that occurred in the trial and the SAE and other safety information of similar test vaccines at home and abroad, conduct safety analysis and risk assessment of clinical trials, and submit it to the General Administration of Drug Review. The assessment center, the local provincial regulatory authority, and all institutions / main investigators participating in the clinical trial submit periodic safety reports.

Periodic safety reports are mainly annual reports, or are submitted regularly as required by regulatory authorities and ethics committees. The report includes at least the safety and risk analysis of the subjects in the clinical trials of the same test vaccine, all emerging safety information during the reporting period, a summary list of all SAEs, and a summary table of all suspicious and unexpected severe adverse reactions.

Article 22 According to the clinical trial safety information and risk assessment, if the safety of the subject is found to be threatened, any of the sponsor, the clinical trial institution / researcher, and the ethics committee may suspend or terminate the clinical trial, explain the reasons, and inform Other relevant parties and report to the regulatory authorities.

Article 23 The responsible researcher at each test site shall ensure that the test plan is strictly implemented. If there is a deviation or violation of the test plan, relevant records shall be recorded and reported to the ethics committee.

Chapter VI Ethical Review

Article 24 The responsible institution shall submit an ethics review application to the ethics committee in accordance with the regulations and requirements of the ethics committee, and explain the test at the ethics review meeting.

Article 25 During the trial, the revision of the protocol shall be approved by the ethics committee. The main investigator changes, SAE, deviations and violations of the trial protocol during the trial shall be reported to the ethics committee in a timely manner. For special subject groups (such as children), placebo control should be used with due ethical considerations.

The main investigator should communicate with the ethics committee in a timely manner, submit safety-related information, and submit research progress reports (at least once a year) and conclusion reports in accordance with the requirements of the ethics committee. If the clinical trial is terminated early, a termination report should be submitted.

Article 26 The ethics committee shall conduct ethical review on the particularity of clinical trials of vaccines in accordance with the requirements of relevant regulations and guidelines.

(1) Ethics committee members (pharmaceutical related professionals, non-medical professionals, legal experts, and personnel independent of research / experimental units) in each category of the ethics committee shall have alternate members. ; Balance the number of internal and external members of the test institution; The ethics review meeting should involve members of various categories and experts in the corresponding field. In principle, there should be no less than 2 members outside the institution for every 5 members attending the meeting.

(2) The ethics committee shall record and report to the General Administration in accordance with the requirements of the "Guiding Principles for Ethical Review of Drug Clinical Trials." For the first time to apply for a one-time qualification for a disease prevention and control institution, the filing materials of the ethics committee should be attached to the application materials. For disease prevention and control institutions that have approved vaccine clinical trials, their ethics committee should report the annual ethical review to the General Administration and promptly Report changes to the information filed by the Ethics Committee.

(3) The ethics committee should strengthen information disclosure. The review opinion of the ethics committee shall be accompanied by a list of members attending the ethics review meeting, their professional status and their signatures. The ethics committee shall disclose the contact information and member list, professional background, affiliated units of the committee to the society through its official website, and disclose the ethics committee charter and working procedures. The website address of the information disclosure shall be submitted to the General Administration for the record.

Chapter VII Management of Test Vaccines

Article 27 The sponsor shall provide the researcher with a researcher's manual for the researcher, and provide the researcher with a test vaccine and a control vaccine (including placebo) that are easy to identify and have the correct coding, and an inspection report issued by the China Food and Drug Testing Institute. And marked for clinical trial use only. The production of test vaccines should meet the requirements of the "Good Manufacturing Practice for Drugs". The sponsor should establish a management system and a record system for vaccines for trials. There should be clear documented requirements for cold chain management requirements for vaccines used for testing, and vaccine disposal for cold chain interruptions.

Editing is done by an independent third party commissioned by the sponsor. The emergency blind bottom should be sealed by the blind formula, and should be handed over to the researcher with the packaged blind vaccine. The emergency envelope should be stored at the test site and managed by designated personnel to ensure that it can be opened in time when needed. There is a procedure for illiteracy, emergency illiteracy needs to report to the responsible agency and sponsor, and keep relevant records.

Article 28 The responsible agency for vaccine clinical trials shall guide each test site to formulate a management system for test vaccines. The management of the receipt, storage, preparation, recovery, return / destruction of test vaccines shall comply with relevant laws and regulations.

Article 29 The entire process of vaccine management must meet the requirements of the cold chain, and there must be vaccine transportation and storage conditions that meet the requirements of the plan.

Article 30 The responsible agency and trial site for vaccine clinical trials shall designate personnel who have received GCP and related training to be responsible for the management of vaccines for trials.

Article 31 The vaccines for testing shall be stored in separate zones and according to the project; the special counters shall be locked and managed, and the storage conditions shall meet the storage conditions for the vaccines for testing.

Article 32 The collection, distribution and use of vaccines shall have detailed records. To meet the randomization requirements of the plan, blinded trials shall be maintained in blind management.

Article 33 The vaccination process should be traceable, including the subject's distribution time, the assignee, and the vaccine information such as serial number and batch number, etc., and retain all vaccine packages (at least the outer packaging of the active vaccine) until the inspector confirm.

Article 34 The vaccine administrator shall collect the remaining vaccines in a timely manner, carry out regular inventory and keep inventory records. If the vaccine use and remaining quantity do not match the total, the reasons shall be explained.

Article 35 Abandoned, expired, and remaining vaccines shall be returned to the sponsor or destroyed according to the test plan, and relevant records shall be made and signed by the vaccine administrator and sponsor representatives.

Chapter VIII Biological Sample Management

Article 36 The management of biological samples shall comply with the requirements of the test protocol and standard operating procedures. Collection and processing shall be performed within the prescribed time window. Special persons shall be responsible for storage and transportation to ensure that their integrity and activity are not affected. recording. Biological samples should be set up for backup. The samples sent for inspection and backup should not be transferred at the same time. The backup samples should be properly stored until the clinical trial report is completed.

Article 37 The identification of biological samples shall be easy to identify, unique and traceable. A special person should be set up at the sampling site to check the quality of the specimen.

Article 38 Biological samples shall be managed by a special person, and sample storage files and temperature and humidity records shall be established. The disposal of the remaining samples must be confirmed by the sponsor and a record kept.

Article 39 Testing of biological samples for vaccine clinical trials shall be performed by a laboratory with relevant qualifications entrusted by the sponsor. The construction and management of biological sample analysis laboratories for vaccine clinical trials shall be in accordance with the "Guidelines for the Management of Biological Clinical Samples for Drug Clinical Trials (Trial) ) "(Guo Food and Drug Administration Note [2013] No. 482).

Chapter IX Contract Management

Article 40 Before the start of a clinical trial, the sponsor and the responsible agency, the responsible agency, and the trial site sign a clinical trial contract, respectively, to clarify the supervision, audit, division of responsibilities, and clinical trial costs of the clinical trial.

Article 41 If a sponsor entrusts certain tasks and tasks in a clinical trial to a third party such as a contract research organization for execution, it shall clearly specify the responsibilities of the sponsor and the commissioned party in the contract.

Article 42 Researchers participating in clinical trials of vaccines shall proactively declare and disclose any conflicts of interest related to clinical trial projects.

Article 43 If a research assistant is required during the trial, it shall not be sent by the sponsor.

Chapter 10 Data Management and Statistical Analysis

Article 44 The original documents of a clinical trial refer to the documents originally recorded during the trial, such as: original record form, informed consent, test vaccine use and management records, laboratory records, and subject diary cards.

Article 45 The original records shall meet the requirements of "timely, accurate, complete, standardized and true", and the data shall be traceable to the source. The original records should be completed at the same time as the visit. The information in the case report form is consistent with the original data.

Article 46 If electronic records are adopted, corresponding rules and regulations and standard operating procedures shall be established to ensure the reliability of the electronic record formation process, and traces shall be left in the record modification.

Article 47 The sponsor may entrust an independent third party to carry out statistical analysis of clinical trials, but the clinical trial agency shall not conduct statistical analysis of trial results.

Article 48 The sponsor, the responsible agency and each test site shall reach an agreement on the archiving of test data. After the test, the responsible organization and the test site shall archive the test data as soon as possible, and the responsible organization shall confirm the archive of the test data.

Chapter XI Quality Management

Article 49 The sponsor's quality management of vaccine clinical trials shall run through the entire research process. Fully evaluate and predict the efficacy and safety of the vaccine before the trial, and assess the type, distribution and incidence of adverse reactions. In the course of the trial, supervision and inspection were organized to strengthen the monitoring and reporting of adverse events to ensure the safety of the subjects. Fully analyze the risks and problems in the implementation of the test, and formulate countermeasures in advance according to the impact degree and possibility assessment.

Article 50 The sponsor shall appoint a sufficient number of inspectors to conduct a full-scale inspection of the clinical trial. The inspector should have educational background and work experience in medicine, pharmacy or related fields. The number of auditors designated by the sponsor for clinical trials of vaccines should be determined based on the frequency of monitoring the trials and the complexity of the design of the trial protocol. The inspector shall conduct a clinical trial audit and submit an audit report in accordance with the requirements of the audit plan.

The test site shall cooperate with the monitoring and / or audit of the clinical trial project and keep relevant records. For the problems found in the supervision, inspection and audit, formulate improvement plans and adopt corresponding management measures to improve the quality of the tests.

Article 51: Responsible agencies shall guide each test site, formulate a quality management plan, perform quality control on the work of each link of the test site, track problems found during inspection until they are resolved, and keep relevant records.

Chapter XII Supplementary Provisions

Article 52 The interpretation of these guidelines is the responsibility of the State Food and Drug Administration.

Article 53 These Guidelines shall be implemented as of the date of promulgation.

Attachments: 1. Standard Operating Procedures (SOPs) for vaccine clinical trials

2. Functional partition requirements for vaccine clinical trials

3. Major work of vaccine clinical trial sponsors

Functional division requirements for vaccine clinical trials

1. Reception area: There is appropriate space for registration and verification of subject information.

2. Informed Consent Room: There is a relatively private space. The researcher in charge of informed consent informs the subject or his legal guardian about the clinical trial and signs the informed consent before the subject is enrolled.

3. Physical Examination and Interview Screening Room (District): There is a proper space for conducting physical examination and medical history inquiry. Physical examination equipment and equipment, such as stethoscopes, sphygmomanometers, thermometers, height and weight scales, should be equipped according to research needs. Instruments and equipment must be calibrated, and SOP is easy to access.

4. Biological specimen collection room: there is a proper space, equipped with equipment and facilities according to the type of biological specimens to be collected, and the specimens should be collected strictly in accordance with the requirements of the scheme.

V. Vaccination room: The vaccination room should meet the hygienic requirements of the vaccination room, and vaccination should be carried out strictly by qualified personnel according to the immunization regulations.

6. Emergency room: There is an independent emergency room on the same floor as the vaccination room and medical observation room, and not far away. The emergency room is equipped with a flow chart of green channels for medical treatment, indicating the contact phone number. First-aid doctors should have qualifications, be trained in cardiopulmonary resuscitation and other skills, and are currently engaged in first-aid work. They should be familiar with emergency treatment methods for common adverse reactions to vaccination, especially emergency treatment for rapid-type hypersensitivity reactions, and be proficient in the green channel process of medical treatment. If the clinical trial involves a child subject, a pediatric emergency doctor should be available.

The emergency vehicle is equipped with a dedicated person to manage, and is equipped with portable oxygen bags, vital signs monitors (ECG, blood pressure and pulse), simple ventilator, pediatric resuscitation capsules and epinephrine and other commonly used first-aid drugs. Regular inspections, timely replacement and replacement of first-aid drugs and various article. Check the oxygen inhalation device and accessories regularly.

Medical Observation Room: There is a large space, good sanitation and ventilation conditions, room temperature is maintained properly, and an emergency bed is provided. Subjects should observe in the observation room for at least 30 minutes before leaving. If adverse events occur, they should be dealt with in a timely manner. .

8. Vaccine storage room: equipped with perfect cold chain equipment for vaccine delivery and storage. Inactivated and live attenuated vaccines, biological sample storage and temperature monitoring equipment, cold storage bags with various temperature requirements. Different vaccines are stored in separate cabinets and clearly labeled. Control access personnel. There are written records of temperature and humidity, and emergency plans for power outages in cold chain management.

Nine, archive room: There is a data room or data cabinet to meet the requirements of anti-theft, confidentiality, fire prevention, moisture resistance, insect resistance, dust prevention, rodent prevention and long-term storage. The clinical trial data is managed by a person, and it is stored by project. The directory and account are clear and easy to consult. Control the entry and exit personnel, and formulate the management rules for the borrowing of data files.

X. Sample processing and storage room: It has equipment and facilities for processing, storing, and transporting samples as required by the plan.

11.Temporary storage place for medical waste: temporary storage facilities and equipment equipped with medical waste shall be classified and stored according to the type of medical waste, clearly marked, and placed in special packagings that prevent leakage and penetration of sharps, respectively. The sealed container shall be handed over to the medical waste centralized disposal unit in time.

Twelve, green corridors and ambulances: At least one general hospital with a good medical level, closest to the subject's enrollment site and with smooth traffic is selected as the supporting institution for responding to vaccination emergencies. Open a green channel for emergency treatment with a partner hospital, establish a green channel emergency procedure, and clarify the responsible person and contact phone number for each link. An ambulance is required at the vaccination site. The ambulance is parked at a fixed location and equipped with a mobile oxygen delivery device. The driver and designated medical staff are trained, familiar with the routes and procedures for transfer to higher medical institutions, and stand by at the test site at any time.

XIII. Case screening laboratory: Set up a laboratory for case screening as required, equipped with appropriate equipment.

Standard operating procedures (SOPs) for vaccine clinical trials

I. SOP for clinical trials of vaccines

SOP for SOP

2. Organization chart developed and updated SOP

3. Select the test site SOP

4. Develop (review) and revise the SOP of the test plan

5. Develop (review) SOP for summary report

6. Develop (review) an SOP for the researcher's manual

7. Develop (review) SOP for informed consent

8. Test feasibility assessment SOP

9. SOP for Contract Signing

10. SOP for Ethical Application

11. ethics follow-up application and report SOP

12. SOPs subject to audit, inspection and inspection

13. Researcher Training SOP

14. SOP for Researcher Division of Labor

15. Blind SOP

16. Case report form review and recovery SOP

17. Subject's SOP for Financial Compensation

18. SOP for biological sample preservation and transfer

19. SOP for Instrument Registration and Management

20. Temperature and Humidity Recorded SOP

21. Subjects diagnosed with SOP

22. Quality Assured SOP

23. SOPs to Prevent Conflicts of Interest

24. SOP for Complaints

25. Archive Management SOP

26. SOP for Data Archive and Access

27. Check SOP for raw data and case report form

Second, the SOP of the trial site vaccine clinical trial

SOPs for personnel duties

2. Personnel qualification SOP

3. Staff training SOP

4. Training SOP before the start of the test project

5. Test Data Management SOP

6. SOP for equipment registration and management

7. SOPs operated by various test instruments

8. SOP for various rescue equipment operations

9. Rescue operation and SOP of green channel

10. SOP for oxygen cylinder

11. SOP Called by Ambulance

12. SOP for Ambulance Management

13. Recruitment SOP

14. Subject Screening and Selected SOPs

15. Subject shed treatment SOP

16. Subject Informed Consent SOP

17. Subject's SOP

18. Collect SOPs from subject biological samples

19. Subject's SOP Sample SOP

20. SOP for Biological Sample Processing

21. Temperature and Humidity Recorded SOP

22. Biological sample preservation SOP

23. SOP for Biological Sample Transport

24. Subjects observed SOP after vaccination

25. Subject Training and Education SOP

26. Subject's SOP filled in

27. SOP for Adverse Reaction Investigator Training

28. SOPs for the Evaluation and Management of Adverse Events and Serious Adverse Events

29. SOP for Serious Adverse Events Reporting

30. Emergency envelope management and blind SOP

31. Electronic Data Recording SOP

32. SOP recorded in case report form

33. SOP for Source Record

34. Test Protocol Deviation / Violation Report and Recorded SOP

35. SOP filled in test data questionnaire

36. SOP for Confidential Test Data

37. Cold Chain Equipment Management SOP

38. SOPs for Vaccine Reception, Return and Inventory

39. SOP for vaccine preparation and vaccination

40. Start-up and shutdown SOPs at the test site

41. Quality Control SOP

42. SOPs to Prevent Conflicts of Interest

43. SOP for Complaints

44. SOP for vaccine damage management

Major work of vaccine clinical trial sponsors

Table 1 Work before the test

Job name	Implementation content
Evaluate and determine responsible institutions, test sites	According to the trial design, determine the corresponding implementation conditions and requirements, conduct a comprehensive field assessment of the vaccine clinical trial agency and all trial sites, and write an evaluation report.
Preparation of test documents	The sponsor completes the preparations for the trial, formulates and prepares the trial protocols, case report forms, informed consent and other necessary documents for the trial. Register clinical trials and disclose information to drug regulatory agencies as required.
Hold a kickoff meeting	Organize a meeting before the trial to introduce researchers to clinical trial protocols, specific test procedures, test vaccine characteristics, informed consent process, completion of case report forms, surveillance plans, vaccine management, adverse event and serious adverse event reporting procedures, Requirements for first aid measures and preservation of test documents. Ensuring that researchers are adequately trained in GCP, clinical trial protocols, and corresponding job responsibilities.
Distribution of test supplies	Distribution of test vaccines, related items and documents.
Confirm the signature	Confirm that all tasks have been completed before enrollment, confirm that the clinical trial institution is ready to enroll subjects through the notice of initiation; submit to the main investigator and sign for confirmation.

Table 2 Monitoring work in clinical trials

Job name	Implementation content
Check the test process and progress	Discuss the trial progress and safety events with the main investigator and other investigators; follow up with the progress of the group, check the routine procedures of the trial, and discuss the solutions with the relevant investigators when major problems are found, and develop a plan to prevent similar incidents from happening again; The safety information is delivered to researchers in a timely and accurate manner.
Check regulations and ethical implementation	Ensure timely submission by major investigators and timely approval by ethics committees, such as trial protocols, informed consent and amendments, adverse event reports, safety reports, mid-term or annual progress reports of trials, etc .; timely submission of safety reports to drug regulatory authorities, Changes in registration information, etc. Check the implementation and compliance of the scheme, timely discover and report the violation of the scheme, and ensure that the test operation is carried out in accordance with the scheme.
Check informed consent sign	Ensure that all subjects and researchers sign and sign the complete informed consent form approved by the ethics committee, the subject holds a copy of the informed consent form, and the researcher keeps the original; ensure that the signed date on the informed consent form matches the original Keep records consistent.
Verify researcher qualifications and effectiveness of facilities and equipment	Verify the qualifications and authorizations of the researchers in the test, and whether the test facilities and equipment can complete the corresponding test operations continuously and effectively.
Periodic inspection of test supplies	During the test, the quantity, validity period, storage status, and related records of test vaccines and test supplies are regularly checked to ensure that all vaccines are distributed, recovered, stored, and destroyed in accordance with the test plan.
Check the collection and storage of biological samples	Understand the collection and storage of biological samples, check the relevant records, and inventory the collected biological samples.
Site inspection during vaccination	Check, check, and record whether the researcher's vaccination process is performed according to the requirements of the test protocol and SOP.
Check the handling of adverse events	Check whether the investigator has recorded all adverse events during the trial, whether all subjects with serious adverse events have received the necessary medical assistance, investigate the results of the treatment, and have all submitted to the sponsor, ethics committee, and drug regulatory authority within the prescribed time report.
Regularly review and update test related documents	Regularly review and update the test files stored in the researcher's office to ensure that all relevant test files are recorded and archived.
Check the original records and the logicality of the report file in the test	Check the original record and the case report form (CRF) to ensure that the data is accurate and consistent, and there are no logical contradictions; ensure that all serious adverse events (SAE) and medical events such as pregnancy are timely and accurately recorded on the case report form and reported as required Ensure that all research information of the subject is accurately and timely recorded on the original file; each case report form is signed and dated by the principal investigator.
Complete the audit report and give feedback to researchers in a timely manner	Immediately after the inspection, major incidents, safety incidents, and other conditions that would affect the progress of the trial should be reported to the main investigator to ensure that these issues can be resolved correctly and in a timely manner. Complete the audit report as required, and summarize the problems and suggestions found during the audit to the researchers.

Table 3 Monitoring work after completion of the test

Job name	Implementation content
Checking the transport of biological samples	Check whether the transportation of biological samples is consistent with the requirements of the test protocol and archive relevant documents.
Urge researchers to complete research reports	Urge researchers to compile clinical trial summary reports and submit database CD-ROMs and laboratory-related documents to sponsors.
Examine files archived by researchers	Check whether the trial documents kept by the investigator are complete, such as informed consent, investigator documents, subject identification form, vaccine release records, original documents, etc.
Explain to researchers the role after the trial	Explain to the investigator his responsibilities after the trial, including preparing for possible audits, providing continued treatment to the subject, and publishing a trial summary report.
Test off	At the end of the trial or early termination, it is responsible for closing the research site in accordance with the SOP and test requirements and completing the monitoring report; recovering the remaining vaccine and making records to check the consistency of the usage and the remaining amount; completing the confirmation letter for closing the research site and submitting the main research By.
Inform the sponsor	Sign the end-of-trial report and inform the sponsor of the end of the trial.

Drafting guidelines for vaccine clinical trial quality management guidelines (trial)

In order to further strengthen the quality management of vaccine clinical trials, promote the improvement of the quality of clinical trials, and protect the rights and safety of subjects, in accordance with the "Good Clinical Practice for Drug Clinical Trials" (GCP), combined with the World Health Organization (WHO) assessment of vaccine regulatory system With regard to relevant requirements, the State Food and Drug Administration has formulated the "Guiding Principles for the Quality Management of Vaccine Clinical Trials (Trial)" (hereinafter referred to as the "Guiding Principles"). The relevant situation is explained as follows:

Folding drafting guidelines for vaccine clinical trial quality management guidelines

Clinical vaccine trials are unique. First, the subjects of vaccine clinical trials are mostly healthy people and children. Second, the clinical trials of vaccines in China are usually organized by disease prevention and control agencies. According to the "Clinical Qualifications for Drug Clinical Trial Institutions (Trial)", one-off qualifications are required. Third, there are usually many clinical trial sites for vaccines, and different clinical trial sites are not fixed, which requires high quality management.

With the enhancement of China's independent research and development capabilities, more and more innovative vaccines have entered the clinical trial stage, unpredictable risks in clinical trials have increased, and higher requirements have been placed on quality management. In 2011, China's vaccine regulatory system passed the WHO assessment, but the WHO also put forward requirements for further strengthening the quality management of vaccine clinical trials. For this reason, in view of the particularity of vaccine clinical trials, it is urgent to strengthen the guidance and standardization of quality management.

Guidelines for vaccine clinical trial quality management

Guide all participants in vaccine clinical trials to standardize test behaviors, ensure the quality of trials, the rights and safety of subjects, and effectively perform quality management duties. At the same time, it provides specific guidance for one-time qualification declaration and strengthens the quality management and risk control capabilities of vaccine clinical trial participants.

Vaccine clinical trial quality management guidelines collapse drafting process

According to the relevant requirements of WHO's assessment of the vaccine clinical trial regulatory system, the former Drug Registration Department organized relevant departments to carry out a research project on vaccine clinical trial quality management. On this basis, in March 2013, the Commission's Drug Certification Management Center was commissioned to organize relevant experts to draft a discussion draft of the Guiding Principles. After several discussions and revisions, a draft of the Guiding Principles was formed. In August 2013, the Department of Drugs and Cosmetics Registration Management sought opinions from relevant direct units and some provincial drug regulatory agencies, vaccine clinical trial institutions, and vaccine research and development enterprises. A finalization meeting was organized in September 2013 to review each clause one by one, reach an agreement, and form a pilot draft of the Guiding Principles.

Guidelines for vaccine clinical trial quality management

The "Guiding Principles" are based on China's GCP, combined with the characteristics of China's vaccine clinical trials, formulated in accordance with relevant international regulations and the relevant requirements of the WHO vaccine clinical trial regulatory system evaluation, focusing on the requirements for the management and implementation of vaccine clinical trials, and further clarification Responsibilities of all parties involved. The Guiding Principles have twelve chapters, 53 articles, and 3 attachments.

Chapter I General Principles explain the purpose, basis, and scope of application of the guiding principles. The second chapter of the duty requirements emphasizes the duties of sponsors, ethics committees, and test institutions / researchers involved in vaccine clinical trials; the third chapter of the organizational conditions specifies the qualifications of vaccine clinical trial institutions and personnel, standard operating procedures, Requirements for test sites and facilities. Chapters 4 to 11 put forward the principle requirements of quality management for each step of the vaccine clinical trial process, including the test plan, organization and implementation, ethical review, test vaccine management, biological sample management, contract management, and data. Management and statistical analysis, quality management. Chapter twelve is the supplementary clause.

Annex 1 sets out the standard operating procedures that need to be developed for conducting clinical trials of vaccines; Annex 2 specifies the requirements for the functional division of vaccine clinical trial sites; Annex 3 lists the main features of vaccine clinical trial sponsors before, during and after the trial jobs.