CCHRPP Expert * * * Knowledge

Drafting experts (in alphabetical order)

China People's Liberation Army Bainan General Hospital

Caoyu Affiliated Hospital of Qingdao University

Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Chen Xiaoyun

Fanbaier medicine health care co., ltd

Fan Qiaoyu RDPAC Photovoltaic Working Group/Pfizer

Jiang Yifeng First People's Hospital

Liu Haitao Swiss Weisen Medicine Consulting Company

Luqi Renji Hospital affiliated to Shanghai Jiaotong University School of Medicine

Shenyifeng Shanghai Mental Health Center

Sheng Aijuan Beijing You 'an Hospital affiliated to Capital Medical University

Tang Xue RDPAC Photovoltaic Working Group/Pfizer

Wanbang Xi taimei medical technology

Wang Jing RDPAC Photovoltaic Working Group/Bayer Healthcare

Leo RDPAC

Xia RDPAC PV working group/Novartis pharmaceutical

Southern Hospital of Xu Zhongyuan Southern Medical University

Yue Miao Bai er medicine health care co., ltd

Audit experts (in alphabetical order)

Chen Yongchuan Third Military Medical University Southwest Hospital

Shenzhen Biomedical Ethics Review Committee

guangdong general hospital

Wangxiuqin Jiangsu Provincial Hospital

You 'an Hospital Affiliated to Wang Capital Medical University

Xiong Ningning Affiliated Hospital of Nanjing University of Traditional Chinese Medicine

Chapter I Overall consideration

According to the relevant guiding principles of the International Council for Harmonisation of Technical Requirements of Human Drugs (hereinafter collectively referred to as ICH) and the 2020 version of the Management Specification for Clinical Trials of Drugs in China (hereinafter collectively referred to as GCP 2020). Sponsors, researchers, clinical trial institutions and ethics committees have the responsibility to protect the safety of subjects. Relevant parties should pay attention to the safety of subjects through communication and review of safety data. As the main person in charge of clinical trials, the applicant should take the protection of subjects' rights and interests and safety as the basic consideration of clinical trials; The Ethics Committee has the right to suspend or terminate clinical trials that are not implemented according to relevant requirements, or the subjects have unexpected serious damage; Researchers and their clinical trial institutions are responsible subjects for protecting the rights and interests of subjects.

In the 2020 edition of GCP, the researchers of the old version of GCP reported to the applicant, clinical trial institutions, ethics committees, drug supervision and administration departments and health authorities in time after discovering serious adverse events, and were adjusted to report SAE to the applicant for evaluation. Then report the suspected unexpected serious adverse reactions (hereinafter referred to as SUSAR) after evaluation to all the researchers who participated in the clinical trial, their clinical trial institutions and ethics committees, and report them to the state drug supervision and administration department and the competent health department. After receiving the safety data related to the clinical trial provided by the sponsor, the researcher should sign for it in time and report the SUSAR report provided by the sponsor to the Ethics Committee.

In this context, clinical trial institutions and ethics committees should consider updating their safety information collection, review, analysis and review processes to guide sponsors, researchers and researchers of drug registration applications (such as clinical trials such as cell and immunotherapy) to submit safety reports to clinical trial institutions and ethics committees in a timely manner.

Therefore, the Organizing Committee of China Summit Forum on Improving Clinical Research Capability and Protecting Subjects (CCHRPP) and the Drug R&D Industry Committee of China Association of Enterprises with Foreign Investment (RDPAC) convened industry experts to set up a working group, referring to ICH-GCP-E6(R2), GCP version 2020, ICH E2B(R3) safety message processing and case safety reporting technical specifications, and rapid safety data during drug clinical trials.

The following figure outlines the path of the security report.

Note: 1) In this example, the applicant submits SUSAR to the researcher, and the researcher submits ethics and system as the main line (solid line), and the applicant directly submits ethics and system as the auxiliary line (dotted line). For more suggestions on submission methods, please refer to section 4. 1 of this knowledge.

The researcher needs to report all saes to the sponsor and receive the SUSAR report evaluated by the sponsor to evaluate whether it is necessary to take relevant measures to protect the rights and interests of the subjects. Clinical trial institutions, as the main body responsible for the protection of subjects' rights and interests in drug clinical trials, should confirm whether relevant measures are implemented and whether subjects' rights and interests are properly protected through researchers.

The sponsor shall effectively transmit meaningful safety information, and provide comprehensive research drug safety information to researchers, their clinical trial institutions and ethics committees as far as possible on the basis of ensuring information blindness. The importance of conclusive information of risk and benefit is greater than the simple description of a single event.

Researchers and their clinical trial institutions should focus on all safety incidents in the center; The Ethics Committee focuses on SUSAR and safety events that may affect the safety of subjects, the implementation of clinical trials and the approval of the Ethics Committee. At the same time, researchers, clinical trial institutions and ethics committees also need to pay attention to the SUSAR—— of the same drug in non-centers-paying attention to the safety of the same research drug in all centers means paying attention to the overall safety of the research drug.

In chapter 2, the researcher fills in the SAE report.

2. 1 Time limit and requirements

The researcher shall immediately report serious adverse events to the sponsor in writing, usually within 24 hours, unless otherwise agreed in the research plan.

When making a written report, it shall ensure the completeness and accuracy of the contents of the report so as to provide evaluation for the applicant. If a patient report contains multiple SAE events, the characteristics (severity, start and end time, correlation judgment, etc. A detailed description of).

2.2 Correlation judgment

We should follow the provisions of the plan, make a scientific judgment on the correlation between "drugs" and "events" and provide a basis. Common binary classification of relevance and irrelevance, or multiple classification of definitely relevance, probably relevance, probably irrelevance and definitely irrelevance. Based on the conservative principle, we should judge irrelevance/possible irrelevance more carefully.

2.3 Use standardized forms

In 2020, GCP requires applicants to report SUSAR to all researchers involved in clinical trials, clinical trial institutions, ethics committees, drug regulatory authorities and health departments. In order to reduce the burden and improve efficiency, it is suggested to use standardized forms that meet E2B requirements (covering all fields as much as possible). See attached template of SAE/SUSAR report form. If possible, serious adverse events report, electronic case report or pharmacovigilance system can be integrated. Attention should be paid to the use of anonymous information of subjects.

Chapter III Handling of Security Incidents by Sponsors

The principle of data collection and reporting should comply with the relevant requirements of GCP 2020 and the standards and procedures for rapid reporting of safety data during drug clinical trials.

After receiving the safety-related information from any source, the applicant shall immediately analyze and evaluate it, and make a scientific and independent judgment based on the facts, including the seriousness, correlation with the test drug and whether it is an expected event.

3. 1 Handling of different opinions

When evaluating the seriousness and relevance of an event, if there are different opinions with the researcher, especially opinions that belittle the researcher's judgment (for example, judging the event that the researcher judges as relevant as irrelevant), the applicant must give reasons. If no agreement can be reached on the judgment of correlation, neither party can rule out the correlation with the experimental drug, and should also report it quickly.

3.2 Conservative principle

When writing an evaluation report, the applicant needs to make clear the basis for judging the relevance. We should judge the relevance carefully, and tend to judge it as relevant when there is no conclusive basis to judge it as irrelevant.

Chapter IV SUSAR Report Submission Ethics

SUSAR report submission mentioned in this section refers to a separate SUSAR report.

4. 1 process

See the above figure-the path of safety report. Repeated reports tend to cause unnecessary confusion. In related practice, FDA also made it clear that sponsors and researchers do not need to report repeatedly. Therefore, it is suggested to choose the submission mode of mainly scientific researchers and supplemented by applicants (applicants can not submit directly); It can also be agreed that the applicant's submission is the main one, supplemented by the researcher's submission, or both.

In practice, it is necessary to obtain the receipt of the other party, including the receipt of the applicant from the researcher and the receipt of the researcher from the ethics Committee. Among them, the latter can be used as the proof submitted by the applicant to the ethics Committee.

4.2 Cross-center and Cross-project Submission

When sending SUSAR reports to researchers and their clinical trial institutions, the applicant should pay special attention to sending reports from any center in all research projects of the same experimental drug to all researchers, clinical trial institutions and ethics committees participating in the clinical trial of the drug.

4.3 Start and End Time

Pre-marketing clinical research, starting from the date of approval of clinical trials/the date of tacit approval by the national drug evaluation agency; Commitment to research after listing, the start time is the official start time of the experiment.

The end time is the end date of the last subject's follow-up in China. The researcher shall report to the applicant the SAE that occurred after the end of the clinical trial or the follow-up of the evaluation conclusion and the approval conclusion. If it is an unexpected serious adverse reaction, it shall also report it in time.

4.4 time limit

The quick reporting requirements of 7 days and 15 days shall be followed, namely:

(1) For fatal or life-threatening unexpected serious adverse reactions, the applicant should report them as soon as possible, but not more than 7 days, and report and improve the follow-up information within the next 8 days. (The date of notifying the applicant for the first time is day 0)

(2) For non-fatal or life-threatening unexpected serious adverse reactions, the applicant should report them as soon as possible, but not more than 15 days.

4.5 format

SUSAR report shall be submitted together with standardized and structured information, such as SAE/SUSAR report form and International Council of Medical Scientific Organizations (hereinafter collectively referred to as CIOMS) form. Structured information should be provided at the time of submission for ethical statistics; The full text of the report can be sent as a PDF attachment for easy reading.

4.6 Death

In addition to meeting the general requirements of SUSAR, researchers should also provide other necessary information to the applicant and the ethics committee, such as autopsy report and final medical report.

4.7 language

In principle, the report should be in simplified Chinese. For the report with original materials in English, in order to realize E2A quick report, the English version of the report can be submitted at the first time, and the follow-up report can be submitted in English and Chinese.

4.8 Distinguish between center reports and non-center reports

In the actual review, the Ethics Committee decides the review method according to the situation: SUSAR report of our center focuses on the safety of subjects, follow-up treatment and correlation judgment; For non-central reports, focus on the overall trend of risk and benefit of experimental drugs.

Therefore, some methods can be used to identify whether SUSAR occurred in our center, such as the report itself or the cover letter.

4.9 Blind State Requirements

For blind projects, applicants should pay special attention to remain blind during the whole submission process when sending SUSAR reports; Under special circumstances (such as emergency blindness), the relevant parties can be informed according to the agreement of both parties.

Chapter V Institutions Submitting Sustainable Development Reports

Drug clinical trial institutions are responsible for protecting the rights and interests of subjects in drug clinical trials. The old version of GCP did not clearly stipulate to report SUSAR and other safety information to institutions, which led to different workflow and requirements of domestic institutions.

The 2020 edition of GCP stipulates that the sponsor shall promptly report suspected and unexpected serious adverse reactions to all researchers involved in clinical trials, their clinical trial institutions and ethics committees. The safety update report provided by the sponsor during the drug research and development period shall include the evaluation of the risks and benefits of clinical trials, and the relevant information shall be notified to all researchers involved in clinical trials, their clinical trial institutions and ethics committees. Colleges and universities should actively revise their own standard operating procedures according to the requirements of GCP 2020 to meet the new requirements.

Please refer to the process of submitting ethics in 4. 1 for the actual operation of SUSAR submission. It is suggested to choose the submission mode with researchers as the main part and applicants as the auxiliary part (applicants may not submit directly); It can also be agreed that the applicant's submission is the main one, supplemented by the researcher's submission, or both.

The institution shall designate a special person to be responsible for receiving and reviewing SUSAR reports and safety update reports.

After receiving the SUSAR report and safety report, the institution shall review and file it, communicate with the researcher on the contents and handling methods of the report when necessary, communicate with the ethics committee and coordinate them to handle the protection of subjects, and fill in the handover record or receipt.

Chapter VI Sponsor Submitting DSUR

The main purpose of developing the safety update report (hereinafter referred to as DSUR) is to comprehensively and deeply review and evaluate the safety information related to drugs under research (whether listed or not) collected during the reporting period.

6. 1 process

According to the requirements of GCP 2020, as a phased safety summary, the applicant needs to inform all researchers involved in clinical trials, their clinical trial institutions and ethics committees.

6.2 Contents and requirements submitted

6.2. 1 DSUR summary and conclusion information

According to the suggestion of ICH E2F, the applicant can submit the executive summary of DSUR, and supplement the list of serious adverse reactions according to the corresponding requirements, briefly explaining any changes in the effectiveness and safety information obtained by DSUR during the reporting period and the measures that have been taken or will be taken to solve the new safety problems in clinical research and development projects.

6.2.2 Provide complete DSUR information when required by the code of ethics.

The Ethics Committee may require the applicant to provide complete DSUR information when submitting.

For the specific requirements for writing and submitting DSUR, please refer to the requirements and management regulations of the upcoming R&D security update report issued by ICH-E2F and CDE, including but not limited to the following contents:

Preface, including report cycle and report serial number.

To study the mechanism of drug action, classification of treatment, indications, dosage, route of administration and dosage forms.

Indications and population of the study

Coverage of clinical trials

Briefly explain and explain the information not included in DSUR, and the reasons for submitting multiple DSURs for one study drug (if applicable).

Estimation of cumulative exposure of subjects

List Status (Global)

Summary of overall safety assessment

Overview of major risks

Measures taken for safety reasons, including major revisions to the researcher's manual.

Risk-benefit correlation conclusion

6.2.3 Processing of Blind Information in DSUR

When the applicant submits DSUR to the drug supervision department, the column of suspicious drugs in the list may contain information about the drugs tested after blindness. When generating a list of serious adverse reactions for researchers, we should pay attention to hiding blind information. Ensure that researchers always look at safety information blindly.

6.3 time limit

The annual report shall be submitted according to the requirements and management regulations of safety update report during R&D period issued by ICH-E2F and CDE. The reporting period shall not exceed one year in principle.

Chapter VII Information Management Suggestions

When researchers, clinical trial institutions and ethics committees use information systems to manage safety information, they should ensure that the information systems have the following functions: uploading and receiving safety information, safety information review, risk warning, ethical review and trace recording. If the information system can be connected with the pharmacovigilance system of the sponsor and interact with safety information, the management efficiency of safety information will be further improved.

7. 1 Upload security information

Researchers can fill in part or all of the information of SAE report online, or upload the completed SAE report to the system.

Unless otherwise specified, researchers can use standardized SAE templates to fill in reports to ensure the adequacy and completeness of safety information.

After uploading, the researcher can send the SAE report to the applicant through the system, and the system will automatically prompt the time limit for sending the report.

7.2 Receiving of Safety Information

Researchers, their clinical trial institutions and ethics committees can receive SUSAR reports from sponsors, sign for reading and keep the signing records.

7.3 Safety information review

Clinical trial institutions and ethics committees can systematically review the list of all SUSAR reports and the specific details of each report. The system needs to be able to present a list of SUSAR events for each research project in our center. The list fields contain the following information:

Summary of report: Subject number, study drug and name of adverse event.

Management information: distinguish between center and non-center SUSAR reports.

Clinical trial institutions and ethics committees can disclose corresponding report information through lists, review individual SUSAR reports and accumulate audit opinions.

7.4 Compliance of Electronic Information Storage and Transmission

The transmission and storage of reports should be encrypted to ensure data security.

7.5 Statistical Analysis and Risk Early Warning

The information system should be able to count the safety data in clinical trial projects, and give the analysis results and risk early warning, such as: count the number of various SUSAR reports in each project (SOC-PT), and also count the SUSAR reports of all projects involved in the center, so as to remind people to pay attention to risk projects and drugs. The specific early warning method can be: when the number of concerned events reaches the set requirements (such as the number of events and the frequency of occurrence), the system will trigger an early warning signal, which can be sent by email, SMS, etc. , which is helpful to timely assess the risk of examination and the safety of subjects.

7.6 ethical review

The information system should have the function of assisting the ethics committee to review and improve efficiency.

If, through statistical analysis and risk early warning, the system identifies that the scheme or operation process of a clinical trial needs to be evaluated or even changed, the system can complete tasks such as sorting, planning, arranging and summarizing safety information.

7.7 Audit trail

The information system needs to fully meet the requirements of GCP, especially in electronic records and electronic signatures, and complete the system verification according to GAMP) 5. The system can record the traces of contributions, including the receipt records of researchers and their clinical trial institutions. At the same time, the system can record all the operation records in the system, form a complete data and evidence chain, and finally ensure the compliance of researchers and bidders.

References:

1. Quality management standards for drug clinical trials, 2020, State Pharmaceutical Products Supervision and Administration, National Health and Wellness Committee.

2. Good clinical practice of 2.ICH E6 (R2), 20 16, ICH

3.ICH) Technical Specification for Safety Information Processing and Case Safety Reporting, 20 18, State Administration of Medical Products.

4. Standards and procedures for rapid reporting of safety data during drug clinical trials, 20 18, State Administration of Medical Products.

5. Notice of Drug Evaluation Center on Issues Related to Standards and Procedures for Rapid Reporting of Safety Data during Drug Clinical Trials, 20 18, Drug Evaluation Center of State Pharmaceutical Products Administration.

6.ICH E2F develops security update report, 20 1 1, ICH.

7.ICH E2A clinical safety data management: definition and quick report, 1994, ICH.

8. Guidelines for clinical researchers, sponsors and IRB. Reporting Adverse Events to IRB-Improving the Protection of Human Subjects, 2009, FDA

9. Administrative Measures for Stem Cell Clinical Research (Trial), 20 15, National Health and Family Planning Commission, China Food and Drug Administration.

10. management measures for clinical research and transformation of somatic cell therapy (for trial implementation) (draft for comments), 20 19, national health and wellness commission.

Attachment 1: SAE/SUSAR report template