Drafting Experts (in alphabetical order)
Bai Nan, General Hospital of the Chinese People's Liberation Army (PLA)
Cao Yu, The Affiliated Hospital of Qingdao University (QUH)
Chen Xiaoyun, Longhua Hospital of Shanghai University of Traditional Chinese Medicine (SUTCM)
Fan Xingfang, Bayer Healthcare Company Limited (BHC)
Fan Qiaoyu, RDPAC PV. RDPAC PV Working Group/Pfizer
Jiang Yifeng, Shanghai First People's Hospital
Liu Haitao, Swiss Wesson Pharmaceutical Consulting
Lu Qi, Renji Hospital, Shanghai Jiaotong University School of Medicine
Shen Yifeng, Shanghai Mental Health Center
Sheng Aijuan, Beijing You'an Hospital of Capital Medical University
Tang Xue, RDPAC PV Working Group/Pfizer
Fan Xingfang, Bayer HealthCare Co. Pfizer Pharmaceuticals
Wan Bangxi, Tai Mei Medical Technology
Wang Jing, RDPAC PV Working Group/Bayer Healthcare
Wu Lei, RDPAC
Xia Yusong, RDPAC PV Working Group/Novartis Pharmaceuticals
Xu Chongyuan, Nanfang Hospital of Southern Medical University
Yue Miao, Bayer HealthCare Co. > Reviewing experts (in alphabetical order)
Chen Yongchuan, Southwest Hospital of the Third Military Medical University
Ji Ping, Shenzhen Biomedical Ethics Review Committee
Jiang Faye, Guangdong Provincial People's Hospital
Wang Xiuqin, Jiangsu Provincial People's Hospital
Wang Meixia, Beijing You'an Hospital, Capital University of Medical Sciences
Xiong Ningning, Nanjing Hospital of Chinese Medicine University
Xiong Ningning, China Affiliated Hospital of Nanjing University of Traditional Chinese Medicine
Chapter I General Considerations
According to the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (hereinafter collectively referred to as: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals According to the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (hereinafter collectively referred to as ICH) and the 2020 edition of China's Good Clinical Practice (hereinafter collectively referred to as the 2020 edition of GCP), sponsors, investigators, clinical trial organizations and ethics committees have the responsibility to protect the safety of subjects. The relevant parties should pay attention to the safety of subjects through communication and review of safety information. The sponsor, as the main responsible person of the clinical trial, should take the protection of the rights and safety of the subjects as the basic consideration of the clinical trial; the ethics committee has the right to suspend or terminate the clinical trial that is not carried out in accordance with the relevant requirements, or where the subjects have unanticipated serious damage; the investigator and his/her clinical trial organization are the main body responsible for the protection of the rights and interests of the subjects.
In the 2020 version of GCP, for safety reporting, it is adjusted from the old version of GCP, in which the investigator promptly reports to the sponsor, the clinical trial organization, the ethics committee, the drug supervision and management department, and the department in charge of health care after discovering the Serious Adverse Event (hereinafter collectively referred to as "SAE"), to the investigator reporting the SAE to the sponsor, and then the sponsor evaluates the SAE, and then reports the SAE to the drug supervision and management department. The sponsor will evaluate the SAE, and then report the evaluated Suspected Unexpected Serious Adverse Reaction (hereinafter collectively referred to as SUSAR) to all participating investigators, their clinical trial organizations, ethics committees, and the national drug supervision and management departments and health authorities in an expeditious manner. department and health care authorities. The investigator should sign and read the relevant safety information of the clinical trial provided by the sponsor in a timely manner after receiving it, and should report the SUSAR report provided by the sponsor to the ethics committee.
In this context, clinical trial organizations and ethics committees must consider updating their processes for collecting, reviewing, analyzing, and examining safety information, in order to guide sponsors, investigators, and investigators of investigator-initiated projects (e.g., cellular, immunotherapy, and other clinical trials) of drug registration reporting projects to submit safety reports to clinical trial organizations and ethics committees in a timely manner.
To this end, the organizing committee of the China Clinical Research Capability and Subject Protection Summit (CCHRPP), together with the China Association of Enterprises with Foreign Investment (CAEFI) Pharmaceutical Research and Development Committee (RDPAC), has convened a working group of experts from the industry to develop and implement a new set of safety reports in accordance with the ICH-GCP-E6(R2), GCP-2020, ICH E6(R2), and ICH E6(R2), 2020 GCP, ICH E2B(R3) "Technical Specification for Safety Message Processing and Individual Safety Reporting", "Standards and Procedures for Rapid Reporting of Safety Data during Drug Clinical Trials", etc., to form this working guideline for the reference of industry colleagues.
The following diagram summarizes the pathway for safety reporting.
Note: 1) The example of this diagram is based on the sponsor's submission of SUSAR to the investigator, the investigator's submission to the ethics and organization as the main line (solid line), and the sponsor's direct submission to the ethics and organization as the secondary line (dotted line). Please refer to section 4.1 of this ****nowledgement for further submission pathway suggestions.
Investigators are required to report all SAEs to the sponsor and receive a completed SUSAR report that the sponsor evaluates for the need to take steps to protect subject rights. The clinical trial organization, as the responsible party for the protection of subjects' rights and interests in drug clinical trials, should confirm through the investigator that the relevant measures have been implemented and that subjects' rights and interests have been properly protected.
Sponsors should effectively communicate meaningful safety information, and on the basis of ensuring information blinding, provide comprehensive information on the safety of the investigational drug to the investigator and his/her clinical trial organization and ethics committee as far as possible. Conclusive risk-benefit information is more meaningful than a simple description of a single event.
Investigators and their clinical trial sites should focus on all safety events in their centers; ethics committee members should focus on SUSARs occurring in their centers, as well as safety events that may affect the safety of subjects, may affect the implementation of the clinical trial, and may change the consent of the ethics committee. At the same time, investigators, clinical trial sites and ethics committee members also need to focus on SUSAR of the same drug occurring in non-native centers - focusing on the safety of the same investigational drug in all centers is to focus on the safety of the investigational drug as a whole.
Chapter 2 Completion of the SAE report by the investigator
2.1 Timeframes and requirements
An investigator should report an SAE in writing to the sponsor as soon as he or she is notified of it, usually within 24 hours, unless otherwise agreed in the study protocol.
When reporting in writing, the report should be complete and accurate to provide the sponsor with an assessment. If a single case (copy) of the patient report contains multiple SAE events, the characteristics of each SAE (severity, start and end time, relevance judgment, etc.) need to be clearly described.
2.2 Judgment of relevance
The scientific judgment of drug-event relevance should be followed and supported by the protocol. The binary categorization of "relevant" and "irrelevant", or "definitely relevant" and "probably relevant", is common, "Possibly relevant", "Probably irrelevant", "Definitely irrelevant", and so on. Based on the principle of conservatism, the determination of irrelevant/possibly irrelevant should be more cautious.
2.3 Use of Standardized Forms
The 2020 edition of GCP requires sponsors to report SUSARs rapidly to all participating investigators in clinical trials and to clinical trial sites, ethics committees, as well as to drug regulators and health authorities. To reduce the burden and improve efficiency, it is recommended to use a standardized form (covering as comprehensive fields as possible) that meets the E2B requirements, see the annexed SAE/SUSAR Reporting Form template, and integrate SAE uploading with electronic case reporting or pharmacovigilance systems where available. Attention needs to be paid to the use of subject anonymization information.
Chapter 3: Handling of safety events by sponsors
The principles of data collection and reporting should be in accordance with the 2020 version of GCP and the relevant requirements of the Standards and Procedures for Rapid Reporting of Safety Data during Pharmaceutical Clinical Trials.
Upon receipt of safety-related information from any source, sponsors should immediately analyze and evaluate it, and make scientific and independent judgments based on the facts, including the severity, relevance to the trial drug, and whether it is an expected event.
3.1 Handling of Differences of Opinion
Sponsors who disagree with the investigator in assessing the severity and relevance of an event, particularly if there is a downgrading of the investigator's judgment (e.g., an event judged by the investigator as relevant is judged as irrelevant), must include a rationale for the disagreement. When agreement cannot be reached in the judgment of relevance, either party's judgment cannot rule out relevance to the test drug, should also be reported quickly.
3.2 Conservatism
Sponsors need to be clear about the basis for the relevance judgment when writing the assessment report. Relevance should be judged cautiously, with a tendency to judge it as relevant when there is no solid basis for judging it as irrelevant.
Chapter 4: SUSAR Reporting Ethics
SUSAR reporting in this section refers to individual SUSAR reports.
4.1 Process
See the figure above - Pathways to Safety Reporting. Duplicate reports can cause unnecessary confusion, and the FDA has made it clear in relevant practice that sponsors and investigators do not have to duplicate reports. Therefore, it is recommended to choose the mode of submission by the investigator, supplemented by the sponsor (the sponsor may not submit directly); or agree that the sponsor should submit mainly, supplemented by the investigator, or both.
In practice, it is necessary to obtain the acknowledgement of receipt from the other party, including the acknowledgement of receipt from the researcher by the sponsor and the acknowledgement of receipt from the ethics committee by the researcher. Among them, the latter can be used as a proof of submission to the ethics committee by the sponsor.
4.2 Cross-center and cross-project submission
When sending SUSAR reports to the investigator and his/her clinical trial site, the sponsor should pay special attention to the fact that the report from any one of the centers of all the investigational projects of the same experimental drug should be sent to all the investigators who participated in the clinical trial of the drug, as well as to the clinical trial site and the ethics committee.
4.3 Starting and ending time
For pre-market clinical studies, the starting time is the date of approval of the clinical trial/starting date of the implied license from the National Institute for Drug Evaluation (NIDA), and for post-marketing commitment studies, the starting time is the time of official initiation of the trial.
The end time is the end date of the last subject follow-up in China. SAEs occurring at the end of the clinical trial or after the end of the follow-up until the conclusion of the review and approval is obtained shall be reported by the investigator to the sponsor, and shall also be reported rapidly if they are unanticipated serious adverse reactions.
4.4 Time Limits
The 7-day and 15-day rapid reporting requirements should be followed, i.e.
(a) For fatal or life-threatening unintended serious adverse reactions, the sponsor should report as soon as possible, but not more than 7 days after the first notification, and report, and complete the follow-up information, within the following 8 days. (Day 0 is the day on which the sponsor was first notified)
(ii) For unanticipated serious adverse reactions that are not fatal or life-threatening, the sponsor should report them as soon as possible, but not more than 15 days, after first notification.
4.5 Format
SUSAR reports should be submitted using standardized, structured information such as the SAE/SUSAR report form, the Council for International Organizations of Medical Sciences (hereafter collectively referred to as: CIOMS) form. The submission should have structured information to facilitate ethical statistics; the full report can be sent as a PDF attachment for easy reading.
4.6 Fatalities
The reporting of fatalities in SUSAR, in addition to meeting the general requirements of SUSAR, requires that the investigator provides the sponsor and the ethics committee with other required information such as autopsy reports and final medical reports.
4.7 Language
Reports should in principle be in simplified Chinese. For reports where the original information is in English, the English version of the report can be submitted in the first instance in order to achieve rapid E2A reporting, and then the English version can be used in conjunction with the Chinese version*** and the same report can be submitted subsequently.
4.8 Distinguish between SUSAR and non-SUSAR reports
In the actual review, the Ethics Committee decides the review method according to the situation: for SUSAR reports, the focus is on the safety of the subjects and the follow-up treatment, and the judgment of the relevance; while for the non-SUSAR reports, the focus is on the overall trend of the risk and benefit of the experimental drug.
Therefore, there are a number of ways to identify whether a SUSAR occurred at our center, such as a note in the report itself or in the cover letter.
4.9 Blinding Requirements
When sending SUSAR reports for blinded projects, sponsors should pay particular attention to maintaining blindness throughout the submission process; in special cases (e.g., emergency blinding), the relevant parties may be notified by mutual agreement.
Chapter 5: SUSAR Report Delivery Organizations
Clinical trial organizations are responsible for protecting the rights and interests of subjects in drug clinical trials. The old version of GCP did not have clear provisions on the reporting of safety information such as SUSAR to the organization, which led to different workflow and requirements for each organization in China in practice.
The 2020 version of GCP stipulates that sponsors should report suspected and unanticipated serious adverse reactions (SUSARs) to all investigators participating in the clinical trial, as well as to their clinical trial organizations and ethics committees. The safety update report provided by the sponsor during drug development should include an assessment of the risks and benefits of the clinical trial, and the information should be communicated to all participating investigators, their clinical trial sites, and ethics committees. Institutions should take the initiative to revise their respective SOPs to meet the new requirements in conjunction with the 2020 version of GCP.
The actual operation of SUSAR submission can refer to the process of ethical submission in 4.1, and it is recommended to choose the mode of submission by the investigator, supplemented by the sponsor (the sponsor can not submit directly); or agree that the sponsor can submit mainly, supplemented by the investigator, or both.
Institutions should designate specialized personnel to be responsible for receiving and reviewing SUSAR reports and security updates.
After receiving the SUSAR report and safety report, the organization should review and archive the report, communicate with the investigator about the content of the report and the processing mode if necessary, communicate with the ethics committee and cooperate in dealing with the protection of subjects, and fill in the handover record or acknowledgement.
Chapter 6: Submission of DSUR by the Sponsor
The main purpose of the Development Safety Update Report (hereinafter collectively referred to as DSUR) is to provide a comprehensive and in-depth annual review and assessment of the safety information collected during the reporting cycle in relation to the drug under development (whether on the market or not).
6.1 Process
In accordance with GCP 2020, as a stage-by-stage safety summary, sponsors are required to communicate DSUR information to all participating investigators, their clinical trial sites, and ethics committees.
6.2 Submission Content and Requirements
6.2.1 DSUR Summary and Conclusion Information
In accordance with the recommendations of the ICH E2F, sponsors may use the DSUR executive summary for submission, supplemented by a list of Serious Adverse Reactions as required, outlining any changes to the efficacy and safety information obtained and any actions taken or to be taken during the DSUR reporting cycle. Changes and measures taken or to be taken to address emerging safety issues in the clinical development program.
6.2.2 Provision of complete DSUR information at the time of ethical request
The Ethics Committee may request the sponsor to provide complete DSUR information at the time of submission.
The specific requirements for DSUR writing and submission should refer to ICH-E2F and the forthcoming "Requirements and Regulations for Safety Update Reporting during R&D" issued by CDE, which are specific, but not limited to the following:
Preamble, including the reporting cycle and the report sequence number
Investigational drug - Mechanism of action, therapeutic classification, indications, dosage, route of administration, formulation
The investigational drug - mechanism of action, therapeutic classification, indication, dose, route of administration, and dosage form
Indications and populations studied
Coverage of clinical trials
Brief description and explanation of information not included in the DSUR, rationale for submitting multiple DSURs for a single investigational drug (if applicable)
Estimation of cumulative exposure to subjects
State of the art (worldwide)
Overall safety assessment of the drug Summary
Summary of Significant Risks
Actions Taken for Safety Consideration Including Significant Changes to Investigator's Manual
Conclusion, Risk-Benefit Related Conclusion
6.2.3 Handling of Unblinding Information in the DSUR
When a sponsor submits a DSUR to the drug regulatory authority, the Suspect Drugs column in the Row List may contain information about the drug used in the trial after blinding. When generating the Serious Adverse Reaction Row List for an investigator, care should be taken to omit the blinded bottom information. Ensure that the investigator is always blinded to the safety information.
6.3 Timeframe
The annual report should be submitted with reference to ICH-E2F and CDE's forthcoming "Requirements for Reporting and Management of Safety Updates during Research and Development", and in principle, the reporting cycle should not exceed one year.
Chapter VII Recommendations on Informatization Management
If the investigators, clinical trial sites and ethics committees adopt the informatization system for safety information management, it should be ensured that the informatization system is equipped with the following functions: uploading and receiving of safety information, reviewing of safety information, risk early warning, ethical review, and tracing records. If the informatization system can be docked with the sponsor's pharmacovigilance system for the interaction of safety information, the efficiency of safety information management will be further enhanced.
7.1 Uploading of safety information
Investigators are able to fill in part or all of the information of the SAE report online, or upload the completed SAE report into the system.
Unless otherwise specified, Investigators will be able to complete the report using a standardized SAE template to ensure that the safety information is sufficiently complete.
Once the upload is complete, the researcher can send the SAE report to the sponsor through the system, and the system automatically prompts for a timeframe for sending the report.
7.2 Receipt of safety information
The investigator and his/her clinical trial organization and ethics committee can receive the SUSAR report from the sponsor, sign and read it, and keep a record of the signing.
7.3 Review of safety information
Clinical trial sites and ethics committees can use the system to review a list of all SUSAR reports and the specific details of each case. The system needs to be able to present a list of SUSAR events for each study in the center, with list fields containing the following information:
Report summary: subject number, study drug, name of adverse event
Management information: distinguishing between SUSAR reports in the center and those outside of the center
Clinical trial sites and ethics committees can open the corresponding SUSAR report table information from the list. report table information, conduct the review of a single SUSAR report, and accumulate review comments.
7.4 Compliance of electronic information storage and transmission
The transmission and storage process of the report should be encrypted to ensure data security.
7.5 Statistical analysis and risk warning
The information system should be able to perform statistics on the safety data in each clinical trial project, and give the analysis results and risk warning, such as: the number of various types of SUSAR reports in each project (SOC-PT), and also statistics on SUSAR reports of all projects involved in the center, so that the attention of the risky projects with the risky reports can be prompted. can prompt attention to risky items and drugs. Specific warning methods can be: when the number of events of concern reaches the set requirements (such as: the number of events, the frequency of occurrence), the system triggers an early warning signal, which can be sent by e-mail, SMS and other ways to warn, help timely assessment of the trial risk and the safety of the subjects.
7.6 Ethical Review
The information system should have the function of assisting the ethical committee to carry out review and improve efficiency.
For example, through statistical analysis and risk warning, the system identifies that the protocol or operational procedures of a clinical trial need to be evaluated or even changed, and the system can complete tasks such as organizing safety information, planning, arranging, summarizing, and summarizing ethical review meetings.
7.7 Audit trails
The information system needs to fully comply with GCP requirements for information technology systems, especially in electronic records and electronic signatures to meet the relevant regulatory requirements, according to the Good Automated Manufacturing Practice (GAMP) 5 to complete the validation of the system. The system is capable of recording submission traces, including the signature of the investigator and his/her clinical trial site. At the same time, the system is able to record records of all operations in the system, forming a complete chain of data, evidence, and ultimately ensuring investigator and sponsor compliance.
References:
1. "Drug Clinical Trial Quality Management Code", 2020, State Drug Administration, National Health and Wellness Commission
2. ICH E6 (R2) Good Clinical Practice,2016,ICH
3. ICH Technical Specification for Safety Message Processing and Individual Safety Reporting for E2B (R2),2018, State Drug Administration
4. "Rapid Safety Data During Drug Clinical Trials Standards and Procedures for Rapid Reporting of Safety Data during Drug Clinical Trials, 2018, State Drug Administration
5. Drug Evaluation Center issued the Notice on Matters Related to Standards and Procedures for Rapid Reporting of Safety Data during Drug Clinical Trials, 2018, Drug Evaluation Center of the State Drug Administration
6. ICH E2F Development safety update report, 2011, ICH
7.ICH E2A Clinical Safety Data Management:Definitions and Expedited Reporting, 1994, ICH
8.Guidance for Clinical Investigators, Sponsors, and IRBs. Adverse Event Reporting to IRBs - Improving Human Subject Protection, 2009, FDA
9. Measures for the Administration of Stem Cell Clinical Research (for Trial Implementation), 2015, National Health and Family Planning Commission, State Food and Drug Administration
10. Measures for the Administration of Clinical Research and Translational Application of Somatic Cell Therapy (for Trial Implementation) (Draft for Comment), 2019, National Health and Wellness Commission
Annex 1: SAE/SUSAR Reporting Template