Signal Management in China: An Overview of Regulatory Requirements


Overview of Signal Management

Signal Management is a set of activities performed to determine whether, based on an examination of individual case safety reports (ICSRs), aggregated data from active surveillance systems or studies, scientific literature information or other data sources, there are new risks associated with an active substance or a medicinal product or whether known risks have changed, as well as any related recommendations, decisions, communications, and tracking.The Signal Management consists of

  • Signal Detection
  • Signal Validation
  • Signal Prioritization
  • Signal Assessment

Regulatory Guidance of Signal Management

According to China GVP1, the scope and requirement for signal management is listed below:
Chapter V Risk Identification and Assessment Section 1 Signal Detection
Article 55 The holders should carry out signal detection on the suspected adverse drug reaction information collected through various channels to discover new drug safety risks in a timely manner.
Article 56 The holders should select an appropriate, scientific, and effective signal detection method according to its own situation and product characteristics. The signal detection methods can be manual detection methods such as individual adverse drug reaction report review, case series evaluation, and case report summary analysis, or computer-aided detection methods such as data mining.
Article 57 The frequency of signal detection shall be reasonably determined according to relevant factors such as the time of drug marketing, drug characteristics, and risk characteristics. For newly marketed innovative drugs, improved new drugs and other varieties that attention required by the drug regulatory authorities or drug adverse drug reaction monitoring authority, at or above the provincial level, the frequency of signal detection shall be increased.
Article 58 When carrying out signal detection, the holders should pay special attention to the following signals:
  1. Adverse drug reactions not mentioned in the drug package insert, especially serious adverse drug reactions.
  2. Adverse drug reactions mentioned in the drug package insert, but the frequency of occurrence、 severity,etc. have increased significantly.
  3. Suspected new adverse drug reactions caused by drug-drug, drug-device, and drug-food interactions.
  4. Suspected new medications in special populations or changes of medications in known special populations.
  5. Suspected adverse reactions show clustering characteristics, and the correlation with drug quality cannot be ruled out.
Article 59 The holders shall determine the priority of signals, and prioritize the evaluation of signals that may affect the benefit-risk balance of the product or have an impact on public health. The following factors can be considered for signal priority determination:
  1. The seriousness, severity, outcome, reversibility, and preventability of adverse drug reactions;
  2. Patient exposure status and expected frequency of adverse drug reactions;
  3. Patient exposure in high-risk populations and populations with different medication modes;
  4. The impact of interruption of treatment on patients and the availability of other treatment options;
  5. Anticipated risk control measures that may be taken;
  6. Signals applicable to other same class drugs.
Article 60 The holders shall comprehensively summarize relevant information, evaluate the detected signals, and comprehensively determine whether the signals constitute a new drug safety risk. Relevant information includes individual adverse drug reaction reports ((including feedback reports from adverse drug reaction monitoring agency), clinical study data, literature reports, epidemiological information on adverse drug reactions or diseases, non-clinical study information, medical database information, relevant information released by drug regulatory authority or adverse drug reaction monitoring agency, etc. If necessary, the holders can obtain more information by conducting drug post-marketing safety studies, etc.
Article 61 If the holders aware of or discovers that multiple suspected adverse reactions with similar clinical manifestations in the same batch of the same drug (or adjacent batches) in a short period of time, presenting clustering characteristics, a case analysis and investigation shall be carried out in a timely manner.
Reference: 1. China Good Pharmacovigilance Practice Announcement of the NMPA on the Publication of China Good Pharmacovigilance Practice (No. 65 of 2021)
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