Clinical Pharmacovigilance (PV) in China

CDE – Regulatory Authority Responsible for China Clinical Pharmacovigilance Activities

The Clinical Trials Management Office, which is subordinated to China Center for Drug Evaluation (CDE), is specifically responsible for the reception, analysis and evaluation of suspected and unexpected serious adverse reactions (SUSAR) during clinical trials conducted in China, as well as development safety update reports (DSURs) during the research and development of relevant drugs. Following the guidelines of ICH E2A, E2B and E2F, among others, China CDE has published a series of technical standards and normative documents based on the actual situation in China which includes an electronic reporting system for SUSAR cases during clinical trials.
Pharmacovigilance in clinical trials is the process of monitoring and assessing the safety of investigational drugs or therapies during the clinical trial. This is essential to ensure that the benefits of the treatment outweigh any potential risks or adverse effects. The principle goal of China pharmacovigilance systems in clinical trials is to identify and prevent any adverse reactions or unexpected events related to the investigational product.
China Clinical Pharmacovigilance activities typically include the following:
  • Design and implementation of a China pharmacovigilance plan: This plan outlines the strategies for collecting and reporting adverse events (AEs) and serious adverse events (SAEs) during the clinical trial.
  • China pharmacovigilance adverse event reporting and management: All AEs and SAEs that occur during the clinical trial must be reported and managed according to regulatory requirements.
  • Safety monitoring: Regular safety monitoring is conducted to identify any potential safety issues that may arise during the clinical trial.
  • Risk management: Strategies are implemented to mitigate the risks associated with the investigational product and to ensure the safety of the trial participants.
  • Safety reporting in China: All safety data and analyses are compiled and reported to regulatory authorities, ethics committees, and other relevant stakeholders.
China pharmacovigilance in clinical trials plays a crucial role in ensuring the safety of study participants and in providing reliable safety data for regulatory approval of new drugs or therapies. It also helps to build trust between the pharmaceutical industry, regulatory agencies, and the general public.

Navigating SUSAR Reporting in China

China CDE began to receive SUSAR reports from drug registration sponsors on May 1, 2018. In China SUSAR reporting stands for “Suspected Unexpected Serious Adverse Reaction” reporting. It refers to the requirement for sponsors of clinical trials to report any serious adverse reactions that occur during the trial to the relevant regulatory authorities.
In China serious adverse reaction is defined as any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defect.
If such an adverse reaction is considered to be unexpected (i.e. not consistent with the product’s known safety profile), the sponsor is required to report it to the China regulatory authorities as a SUSAR. The purpose of SUSAR reporting is to ensure that the safety of trial participants is monitored and that any potential risks associated with the investigational product are identified and communicated to the relevant authorities.

China SUSAR Reporting

The specific guideline for China SUSAR reporting is “The Standards And Procedures for Expedited Reporting of Safety Data during Clinical Trials” which serves as the official guidline document published on 27 Apr 2018, Effective date 1st May 2018.
The applicant must report any unexpected and serious adverse reactions that are assessed as certain or suspected to be related to the investigational drug. If the applicant and investigator cannot come to an agreement on the causality assessment between the adverse event and the drug, and neither party can rule out a relationship to the investigational drug, then a expediated reporting should proceed.
The following scenarios generally do not need to be reported as expediated reporting:
  1. non-serious adverse events,
  2. serious adverse events that are not related to the investigational drug
  3. serious adverse reactions that are expected, and
  4. when the primary efficacy endpoint is a serious adverse event, the applicant is not advised to report it as a case safety report (ICSR) to the national drug regulatory agency.
The applicant is responsible for determining whether to report serious adverse reactions related to a positive control drug to other drug manufacturers and/or directly to the China drug regulatory agency. The applicant must report such events to the drug manufacturer or directly to the regulatory agency. Adverse events related to a placebo generally do not meet the criteria for an adverse reaction and do not need to be reported.

Adaptation to ICH-E2B(R3)

The content of case safety reports for unexpected serious adverse reactions should follow the requirements outlined in the ICH “E2B(R3): Management of Clinical Safety Data – Data Elements for Transmission of Individual Case Safety Reports” and use the ICH “M1: MedDRA” to code relevant terms.
The applicant is responsible for monitoring the safety information of clinical trials and reporting serious adverse events. The applicant must appoint a dedicated person to be responsible for clinical trial safety information monitoring and serious adverse event report management, establish standard operating procedures for clinical trial safety information monitoring and serious adverse event reporting, and train all relevant personnel. The applicant must also be aware of the latest safety information during the clinical trial process, conduct timely safety risk assessments, inform relevant trial stakeholders of relevant information, and be responsible for reporting unexpected serious adverse reactions in a timely manner.

China SUSAR Reporting Deadlines

After learning of a serious adverse event, the applicant should immediately conduct a comprehensive analysis, evaluation, and judgment of the event. According to the nature (category) of the serious adverse event, the applicant should report it to the Center for Drug Evaluation (CDE), NMPA quickly within the following time limits:
  • For unexpected serious adverse reactions that cause death or endanger life, the applicant should report as soon as possible after learning of it, but no later than 7 days, and report and improve follow-up information within the following 8 days.
Note: The day the applicant first learns of the event is Day 0.
  • For unexpected serious adverse reactions that do not cause death or endanger life, the applicant should report as soon as possible after learning of it, but no later than 15 days.
The start time for quick reporting is the approval date of the clinical trial/national drug regulatory authority’s implicit permission start date, and the end time is the date of the last follow-up of the last subject in the country. Serious adverse events that occur between the end of the clinical trial or follow-up and obtaining the evaluation and approval conclusion should be reported by the investigator to the applicant, and if they are unexpected serious adverse reactions, quick reporting should also be conducted.
After the first report, the applicant should continue to track serious adverse reactions and report new information or changes to the previous report in a timely manner in the form of follow-up reports. The reporting time limit is 15 days from obtaining new information.

Fatal or life-threatening SUSAR for China

In China for fatal or life-threatening SUSAR, the applicant should report as soon as possible but no later than 7 days after the first report is made and submit a follow-up report with as much information as possible within 8 days of the first report. For subsequent reporting of new information in the form of a follow-up report or changes to the previous report, the time limit for reporting is 15 days from the date the new information was obtained.
The Center for Drug Evaluation (CDE), NMPA receives the individual case safety reports submitted by the applicant during the drug clinical trial period in an e-submission format that complies with ICH E2B (R3), and conducts analysis and evaluation. When necessary, opinions on modifying the trial plan, suspending or terminating the drug clinical trial, etc. will be put forward according to relevant standards.
In addition to individual safety reports of unexpected serious adverse reactions, the applicant should also report other potential serious safety risk information to the national drug regulatory authority as soon as possible, and make medical and scientific judgments on each situation.
Generally speaking, information that obviously affects the drug risk-benefit assessment or may consider changing the drug use, or affects the overall drug development process, belongs to this category, such as:
  1. The occurrence rate of known serious adverse reactions has increased, and it is judged to be clinically important;
  2. There is a significant harm to the exposed population, such as the drug being ineffective in treating life-threatening diseases;
  3. Significant safety findings (such as carcinogenicity) in recently completed animal experiments.
The applicant should also report unexpected serious adverse reactions related to the trial drug and other potential serious safety risk information obtained from other sources to the Chinese drug regulatory authority quickly.

SUSAR Report in Chinese Language

Both domestic and foreign individual safety reports and reports of other potential serious safety risks should be reported in Chinese. The acceptance number of the drug application clinical trial should be clearly marked in both individual safety reports and reports of other potential serious safety risks.
Reference: 1.The Standards And Procedures for Expedited Reporting of Safety Data during Clinical Trials Announcement of the publication of the Standards and Procedures for Expedited Reporting of Safety Data during Drug Clinical Trials
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China DSUR Reporting

In China, DSUR also stands for Development Safety Update Report. China CDE opened the DSUR reporting submission channel on its official website to receive DSUR reports from drug registration sponsors on April 26, 2019,.
In 2020, overall 1775 copies of DSUR reports were submitted to CDE by the sponsors.
DSUR in China is a required regulatory document that provides a comprehensive summary of the safety profile of a drug under investigation during a clinical trial. The DSUR is submitted at regular intervals to the CDE and is intended to be a tool for ensuring that the safety of trial subjects is being appropriately monitored and that any emerging safety concerns are being addressed.
The China DSUR includes a description of any adverse events or safety issues that have been identified during the reporting period, along with an assessment of their severity and potential impact on the study or the overall safety profile of the drug. It also includes information on any changes that have been made to the trial protocol or study design, as well as any actions taken to address safety concerns or manage risks to study participants.
The DSUR is typically required for all clinical trials of investigational drugs, and may be requested by regulatory authorities at any stage of the clinical trial process. The contents are reviewed by the Chinese authorities as part of their ongoing assessment of the safety and efficacy of the drug, and may be used to inform decisions about whether to allow the clinical trial to continue or whether to require additional safety measures.

RMP (Risk Identification, Evaluation & Control) in China

RMP outlines the potential risks associated with a medicinal product and the measures that are in place to minimize or manage those risks. The purpose of an RMP is to identify, characterize, and assess the known and potential risks of a medicinal product, and to determine whether additional measures are necessary to mitigate these risks.

The Origin and Implementation of Pharmacovigilance Planning in China

As early as 12 November, 2019, the NMPA published a notice on 15 ICH guidelines (No. 88 of 2019), requiring that new drug marketing applications (NDAs) accepted three months after the date of publication, and new drug marketing applications approved six months after the date of publication starting to implement the ICH E2E: Pharmacovigilance Planning. The ICH E2E Guidelines focus on the submission of a Safety Specification and Pharmacovigilance Planning by the Regulatory Authority at the time of application for marketing authorization.

Safety Specification

The safety specification for China should be “a synopsis of important identified risks, important potential risks, and important missing information about the drug” and should begin with a summary of epidemiological information about the target indication.
Regardless of the indication and target population, a risk should be classified as important if it has the following characteristics:
  1. The risk leads to serious consequences when it occurs. such as death, disability or a serious impact on the quality of life of the person using the drug.
  2. requires a high proportion of clinical 1000 precautions.
  3. presents a significant challenge to current clinical practice. Significant risks may not affect all drug-using populations but are only highly prevalent in drug-users with certain characteristics. Applicants are advised to assess the risk causation scale, preventability and its impact on the benefit-risk balance and as an important reference for the development of risk control measures.
On July 1, 2020, the CDE published the “M4 Module 1 Administrative Document and Drug Information”, which explicitly requires applicants to submit NDA information “1.8.3 Risk Management Plan (RMP)”, including Pharmacovigilance Plan and Risk minimization Measures.
In the ICH E2E Guidelines and relevant Chinese laws, regulations, and guidelines, the terms “Pharmacovigilance Plan”, “Risk Management Plan”, and “Risk Analysis and Management Plan” are considered as one concept due to the refinement of laws and translation.

Pharmacovigilance Plan

Pharmacovigilance plans should include both:
  1. Routine pharmacovigilance activities
  2. Additional pharmacovigilance activities
If not specifically requested by the CDE, it is recommended that the first post-marketing evaluation of the pharmacovigilance programme/RMP be conducted approximately 2 years after the product is launched and may include, but is not limited to:
  1. The implementation of the pharmacovigilance plan and RMP.
  2. Whether the cumulative post-marketing data obtained influenced the judgement of product risk
  3. Whether the pharmacovigilance activities undertaken are adequate or no longer applicable
  4. The evaluation of the effectiveness of risk minimisation measures;
  5. Whether the pharmacovigilance plan and RMP affects the accessibility of the product or places an unnecessary burden on the healthcare system.
China Pharmacovigilance Plan China referencing ICH E2E as follows: Routine Pharmacovigilance Practices Routine pharmacovigilance should be conducted for all medicinal products, regardless of whether or not additional actions are appropriate as part of a Pharmacovigilance Plan. This routine pharmacovigilance should include the following:
  • Systems and processes that ensure that information about all suspected adverse reactions that are reported to the personnel of the company are collected and collated in an accessible manner;
  • The preparation of reports for Chinese regulatory authorities: Expedited adverse drug reaction (ADR) reports Periodic Safety Update Reports (PSURs)
  • Continuous monitoring of the safety profile of approved products including signal detection, issue evaluation, updating of labeling, and liaison with regulatory authorities;
  • Other requirements, as defined by local regulations.
Action Plan for Safety Issues The Plan for each important safety issue should be presented and justified according to the following structure:
  • Safety issue;
  • Objective of proposed action(s);
  • Action(s) proposed;
  • Rationale for proposed action(s);
  • Monitoring by the sponsor for safety issue and proposed action(s);
  • Milestones for evaluation and reporting.
Summary of Actions to be Completed, Including Milestones An overall Pharmacovigilance Plan for the product bringing together the actions for all individual safety issues should be presented. Whereas section 3.1.3 suggests presenting an action plan by ongoing safety issue, for this section the Pharmacovigilance Plan for the product should be organised in terms of the actions to be undertaken and their milestones. The reason for this is that one proposed action (e.g., a prospective safety cohort study) could address more than one of the identified issues.
It is recommended that milestones for completion of studies and other evaluations, and for submission of safety results, be included in the Pharmacovigilance Plan. In developing these milestones one should consider when:
  • Exposure to the product will have reached a level sufficient to allow potential identification/characterisation of the AEs/ADRs of concern or resolution of a particular concern; and/or
  • The results of ongoing or proposed safety studies are expected to be available.
These milestones might be aligned with regulatory milestones (e.g., PSURs, annual reassessment and license renewals) and used to revise the Pharmacovigilance Plan.
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