Date :
16 May 2023, Tuesday

Time :
15:00 – 16:00 China
17:00 – 18:00 Sydney
05:00 – 06:00 EST
09:00 – 10:00 CET

Upcoming complimentary webinars in May & June 2023:

• 21-Jun-23 Post-marketing Pharmacovigilance in China

Date :
17 April 2023, Wednesday

Time :
15:00 – 16:00 China
17:00 – 18:00 Sydney
05:00 – 06:00 EST
09:00 – 10:00 CET

Upcoming complimentary webinars in May & June 2023:

• 16-May-23 Drug Registration Overview in China
• 21-Jun-23 Post-marketing Pharmacovigilance in China

The Responsible Person for Pharmacovigilance (RPPV) is the Chinese equivalent of the Qualified Person Responsible for Pharmacovigilance (QPPV) in EU and other countries. Like QPPV, the primary role of an RPPV in China is to ensure the pharmacovigilance system is following regulations and for the safety of the marketed products and serve as the primary contact for regulatory authorities.

In China, RPPV plays an essential part in the Good Pharmacovigilance Practice (hereinafter “China GVP”) and the Inspection Guideline for Pharmacovigilance (hereinafter “PV Inspection Guideline”), both were released by National Medical Products Administration (NMPA) in May 2021 and April 2022 respectively.

This article will guide you through the key regulatory requirements for RPPV in three areas: 1) RPPV Qualification, 2) RPPV Responsibilities, and 3) key functions.

This webinar is about China Drug Master Filing (DMF) versus EU and U.S DMF. Accestra will provide an overview of the DMF registration systems covering Active Pharmaceutical ingredients (APIs), Excipients & Packaging Materials. Thanks to global harmonization efforts, the Chinese DMF regulatory system is becoming more similar with US DMF, EU ASMF, CEP and Japanese DMF requirements. However, local regulations and differences still exists and it is essential to understand these to minimize risks and issues further down the line with DMF submissions to China CDE & NMPA.

China CDE director vows more support for drug review & approval in the coming years.

The director of China’s Center for Drug Evaluation (CDE) has delivered a speech on Improving the Efficiency and Quality of Drug Review & Approval at the 2022 DIA China Annual Conference, with a retrospective summary of the last 5 years’ work and an outlook for the future.

Substantial Growth in the past 5 year, both the received drug registration applications and the completed registration cases have seen consecutive increase. From 2017 to 2021, the number of drug applications have increased from 4839 to 11658, an average annual increase by 24.59%. The number of completed registration applications significantly increased by 14.12% from 7124 to 12083 applications, according to Kong Fanfu, the director of CDE.

CDE director also noted that the 4 “accelerated pathways” for drug approvals include:

1. Breakthrough therapy drugs
2. Conditional approval
3. Priority review & approval
4. Special review & approval

These 4 pathways have contributed significantly to the growth in speed of application. The time limit for drug registration applications via the accelerated pathways has been expedited from 200 days to 130 days now.

More support in future. To go beyond the achievement, Mr. Kong has promised that the CDE will take concrete measures in multiple aspects as summarized below:

• To improve and accelerate the registration procedures
• To facilitate multi-channel communication mechanisms,
• To advance the process-oriented management system,
• To optimize the standard system of review & approval
• To boost more new and good drugs into the market.

To provide strong technical support for the R&D as well as review & approval of drugs, CDE will make 300 new or revised technical guidelines within 2021-2025. It is expected that by 2025, the total number of technical guidelines for drugs will surpass 600.

As the zero-COVID policy retreats and more support taps into the review & approval system, there is enough reason to believe that China’s drug market will see a steady and rosy picture in the near future.

Contact Us

For help to determine whether your drug product qualifies for accelerated pathway or queries related to China regulations and registration, please contact: info@accestra.com

Signal management in Pharmacovigilance is an important part in China’s Good Pharmacovigilance Practice (hereinafter “China GVP”), which was released by National Medical Products Administration (NMPA) in May 2021.

“To conduct efficient activities of signal detection and assessment” is listed as a fundamental requirement for quality management in Pharmacovigilance and one of the key responsibilities of The Market Authorization Holders (MAH) in the China GVP. The timeliness of signal detection and assessment is considered as one of the critical indicators of quality control. China GVP requires the MAH to ensure the timeliness of signal detection and assessment throughout the entire pharmacovigilance system.

In the China GVP, a signal is defined as information arising from one or multiple sources which indicates a potentially new association or a change in a known association between a drug and the event. Any information considered necessary for further assessment of associations shall be deemed as signal too.

Signal management and detection in China GVP can be summarized in 4 parts: 1) Method, 2) Frequency, 3) Prioritization and 4) Assessment.

1. Methods of Signal Detection
   The MAH shall carry out signal detection on suspected adverse drug reactions (ADR) collected from relevant channels in order to find out new safety risks in the drug in a timely manner.
   • To adopt appropriate, scientific, and effective methods for signal detection. The MAH should take into consideration its own conditions and the characteristics of the very drug when adopting detection methods. Different methods are often applied, including manual detection methods like reviewing the individual ADR reports, assessing case series, and analyzing case reports; and computer-assisted methods such as data mining.
2. Frequency of Signal Detection
   • To maintain a reasonable frequency of signal detection. The MAH should take into account relevant factors of a drug including the time to market, its characteristics, risk characteristics, etc. and keep a reasonable frequency of the signal detection.
   • For newly marketed drugs, improved new drugs, and other varieties required by drug regulatory authorities at or above provincial level or by ADR monitoring institutions, the frequency of signal detection should be increased.
3. Prioritization of Signals
   To achieve a productive signal detection, the following factors are normally required to consider in order to prioritize the signals:
   • Seriousness, severity, outcome, reversibility, and preventability of ADR
   • Patient exposure and expected frequency of ADR
   • Exposure of patients in high-risk group and of patients in groups with different uses of medication
   • Impact of treatment interruption on patients as well as accessibility of other treatment options
   • The anticipated measures for risk-control
   • Signals applicable to other similar drugs
4. Assessment of Detected Signals
   The MAH should collect relevant information—as comprehensive and extensive as possible—to make an informed judgment as whether the signal makes up a new risk of the drug safety. In addition, when necessary, the MAH may also conduct post-marketing safety studies to obtain more information.
   The relevant information often includes the following:
   • Individual ADR report, including feedback reports from ADR monitoring institutions
   • Research data from clinical trials
   • Literature reports
   • ADR information or its epidemiological information
   • Non-clinical research information
   • Information from medical & pharmaceutical databases
   • Relevant information released by drug regulatory authorities or ADR monitoring institutions

Tips & Tricks for MAH

The following key points should be paid attention to by MAH for signal detection in China:

• Adverse drug reactions not mentioned in the package insert, particularly serious ADR.
• ADR mentioned in the package insert, but the occurring frequency and severity of the ADR increase significantly.
• Suspected new ADR caused by interactions between drugs, between drugs and medical devices, or between drugs and food.
• Suspected new special groups using the drug or changes in the drug use of known special groups.
• Suspected ADR is showing signs of clustering and the correlation of the suspected ADR with drug quality cannot be ruled out.

Conclusion

Signal detection is one of the major responsibilities of MAH in China GVP. It not only determines the quality of the ensuing activities like risk assessment, but also directly relates to the quality of pharmacovigilance activities throughout the full life cycle of the product. Failure or insufficient compliance with the regulations in signal detection could result in penalty or punishment of the MAH by the Chinese authorities. Therefore, it is necessary for MAH to attach great importance to signal detection requirements and compliance.

Our Services

For advisory on complying with China’s GVP and support with signal management and other pharmacovigilance activities, Accestra Consulting is your professional and reliable PV & RA outsourcing partner in China.

Contact Us

For more information or request for support please email: info@accestra.com

On December 19, 2018, China’s NMPA released the Guideline for Collecting and Reporting of Individual Case of Adverse Drug Reactions (hereinafter “the Guideline”). Aiming to standardize the collection and reporting throughout the Adverse Drug Reaction (hereinafter “ADR”) monitoring and processing, this Guideline provides for the Market Authorization Holder (MAH) a “5+3” instruction —5 consecutive procedures including: 1) “collection”, 2) “record, transfer, and verification”, 3) “confirmation”, 4) “evaluation”, and 5) “submission”; 3 important aspects throughout the process covering: 1) “quality control”, 2) “follow-up and investigation”, and 3) “data management”.

Accestra Consulting has digested the relevant regulations and compiled key points for you.

5 Consecutive Procedures

1. Collection of Individual ADR Case
   The MAH shall establish effective information channels for doctors, pharmacists, patients, and others, to actively collect ADR information related to clinical use, clinical studies, market projects, academic literature, etc. Effective channels often involve Medical Institutions, Drug Distributors, Hotline & Complaints, Academic Literature, Internet, Post-marketing Research & Projects, and Regulatory Authorities.
   1. Medical Institutions
      • The MAH may collect the clinical ADR information from the medical personnel regularly by means of daily visit, e-mail, telephone, fax, etc., make detailed records, and establish archives of ADR information.
      • The MAH or its distributor shall make the medical institutions fully aware of the responsibility of reporting ADR and encourage medical personnel to report ADR when signing the drug purchase and sale contract with them.
   2. Drug Distributors
      • The MAH shall establish an effective and direct channel for Drug Distributors to report ADR information.
      • The MAH shall regularly evaluate the capability of the Distributor to perform its information collection responsibilities and take necessary measures to ensure the quantity and quality of the collected information.
      • The MAH shall have a designated person to answer phone calls, collect and record ADR information reported by patients and others (e.g.,doctors, pharmacists, lawyers).
      • The MAH shall inform the consumer in an effective manner of the ways to report ADR.
      • The MAH shall report any ADR received through legal litigation channels, whether the report has been submitted to regulatory authorities by others or not.
   3. Academic Literature
      • Academic literature is one of the high-quality sources to collect ADR information. The MAH shall research regularly and report the individual ADR cases found in academic literature.
      • The literature screening shall be conducted at least every two weeks for new drugs first marketed or imported within 5 years, and once a month for other drugs in principle. Alternatively, the frequency could be adjusted according to the risk of the drug.
      • The time frame of the searched literature shall be continuous as long as product is marketed.
      • The MAH shall search on widely-used literature databases, including databases in China—such as China National Knowledge Infrastructure (CNKI), CQVIP database, Wanfang Data—and outside China like
        PubMed, Embase, Ovid and others.
      • It is required to search at least two databases simultaneously in domestic and foreign literatures respectively.
      • The MAH shall have a reasonable search strategy to ensure the comprehensiveness of search results and minimized omissions. For example, using the international nonproprietary name (INN)/active
        ingredient of the drug as keywords for searching, or using a combination of generic names, trade names and other common names of the drug approved by the drug regulatory authorities.
   4. Internet and Relevant Channels
      • The MAH shall regularly visit its websites—whether launched or managed—to collect potential ADR cases.
      • The MAH shall collect ADR information from the company’s portal website, such as establishing a special report channel for ADR on the website, providing guidance on reporting pathways, report forms and report content, and publishing complete and up-to-date product instructions.
      • Print media, digital media, social media/platforms under control of the MAH are also sources of individual ADR information, e.g., collection through corporate WeChat public accounts, microblogs, forums/bbs, etc.
   5. Post-marketing PV Research and Projects
      • Individual ADR found in post-marketing studies initiated by enterprises (including studies abroad), or organized data collection programs shall be reported to regulatory authorities as required, such as clinical trials, non-interventional epidemiological studies, drug focus monitoring, patient support programs, market research or other marketing promotion projects.
   6. Chinese Regulatory Authorities
      • The ADR report feedback from the domestic regulatory authorities to the MAH is mainly used for safety analysis and evaluation of the product.
      • The MAH shall react to the feedback report within the required time limit, such as readjusting terminology, evaluating the seriousness and expectation, conducting relevance evaluation and others.
2. Record, Transfer, and Verification of Individual ADR Case
   • Recording. The first person of MAH or its entrusting partner known of an individual ADR case is referred to as “the first recipient”.
   • The first recipient shall try to obtain the ADR information as much as possible, including the patient’s condition, the reporter’s situation, the suspected combination use of drug, the occurrence of ADR.
   • The ADR information received from various channels, such as emails, letters, phone calls, doctor interviews, etc., shall have original records.
   • In addition to the reporter, other relevant persons providing the information of the case report shall be recorded as well to ensure that the information provider is identifiable
   • The records shall be true, accurate and objective, and shall be kept properly
   • Transferring. In the process of transferring the original records of individual ADR to the pharmacovigilance department by the first recipient, the authenticity and integrity of the records shall be maintained without deletion or omission. The transferring time shall be limited to ensure the timeliness of the report.
   • Verifying. The MAH for China shall evaluate the authenticity and accuracy of the individual ADR information. And it shall try to verify the information when in doubt
3. Confirmation of Individual ADR Case
   • Contents to be confirmed mainly include: whether it is a valid report, whether it is within the scope of the report, whether it is a repeated report.
   • 4 Elements of a valid report: A valid report should include the following 4 elements: 1) identifiable patients, 2) identifiable reporters, 3) suspected drugs, and 4) details of the ADR.
   • If the 4 elements are incomplete, the report shall be deemed as invalid and shall be supplemented before reporting.
   • The scope of the report includes:
     a) the ADR occurring under the normal dosage of the drug;
     b) the harmful reactions occurring under off-label drug use, such as off-indicated drug use, overdose, use with contraindications, etc.;
     and
     c) harmful reactions suspected to be caused by drug quality problems.
4. Evaluation of Individual ADR Case in China
   • After receiving individual ADR reports (including feedback reports from regulatory authorities), personnel responsible for pharmacovigilance activities shall evaluate the report, including judgement of new adverse reactions and serious adverse reactions, as well as evaluating the relevance between drugs and adverse reactions.
   • The judgment of causality, also known as causality assessment, evaluates the correlation between the suspected drug and the adverse reaction/event of the patient.
   • According to relevant guidelines by World Health Organization (WHO), causality assessment is classified into 6 terms—certain, probable/likely, possible, unlikely, conditional/unclassified, and unassessable/unclassifiable, see the table below:

   Causality Term	If with time relationship to drug intake	If known	Response to withdrawal	Rechallenge	Other explanation
   Certain	+	+	+	+	–
   Probable/Likely	+	+	+	?	+
   Possible	+	±	±?	?	±?
   Unlikely	–	–	±?	?	±?
   Conditional/Unclassified	More data for proper assessment needed
   Unassessable/ Unclassifiable	Cannot be judged because necessary information is insufficient or unobtainable

5. Submission of Individual ADR Case
   • The MAH in China shall submit individual ADR report via the direct adverse drug reaction reporting system— a platform supervised by China’s National Center for ADR Monitoring, and timely update and maintain the registration information in the system.
   • The ADR reports shall be submitted within the following time limit:
     a) Serious ADR in China shall be reported within 15 calendar days, and death cases shall be reported immediately.
     b) Other non-serious ADR shall be reported within 30 calendar days.
     c) Serious ADR abroad shall be reported within 15 calendar days.

3 Important Aspects

• Quality Control
  • The MAH shall ensure that the contents of the report are true, complete, and accurate. The individual ADR shall be recorded in a true and detailed manner, and false reports are strictly prohibited.
  • The names of the drug, the disease, the ADR, and the unit shall be filled in accurately and normatively.
  • The names of the ADR as well as the disease, the diagnosis and the symptom shall be determined by referring to WHO Adverse Reactions Terminology (WHOART) or ICH Medical Dictionary for Regulatory Activities (MedDRA) and its supporting guidelines, such as MedDRA Term Selection: Points to Consider.
  • Indicators of physical signs and laboratory test results shall be unbiased as the original records.
• Follow-up and investigation
  • Follow-up. Individual ADR information received for the first time is generally incomplete. Thus, missing information should be followed up in the following priority order:
    a) new and serious ADR cases
    b) other serious ADR cases
    c) new and non-serious ADR cases.
  • Investigation of cases of death. The MAH shall investigate known death cases and complete the investigation report and submit it within 15 calendar days. The patient’s medical records and autopsy report shall be collected according to the actual situation.
  • The quality of the product shall also be reviewed during the investigation, and re-examined if necessary.
• Data Management
  • Data management shall run through the whole life cycle of the data. The management principles of truthfulness, integrity, safety, and traceability shall be adhered to from data collection, recording, transmission, processing, review, report, and storage to destruction.
  • All electronic and paper data shall be kept with security and confidentiality.
  • The ADR information of individual cases shall be well managed in the form of database for easy search, analysis, and evaluation, such as in Excel forms or a pharmacovigilance information system/platform of the MAH.
  • The submitted ADR report forms shall be traceable to the original records, follow-up records and investigation reports.
  • To implement strict access control to the database, the record of paper data shall be clear, readable, and understandable.
  • Paper data shall be classified and catalogued for convenience of future search.

China pharmacovigilance inspection is a critical part for ensuring enforcement of patient safety systems. On April 15 of 2022, China NMPA has released theGuideline for Pharmacovigilance Inspection [No. 17 of 2022]. It requires that the authority and institutions conducting the inspection shall follow the regulations in Measures for the Administration of Drug Inspection (Trial) [No. 31 of 2021].

Accestra Consulting has provided an overview of the authorities in China who are responsible for China pharmacovigilance inspections:

The overarching authority responsible for drug and pharmacovigilance inspections is China’s National Medical Products Administrations (NMPA).The pharmacovigilance audit and inspection work are conducted in groups formed by the Drug Inspection Institutions. The complete inspection is fulfilled with the support of the following 4 institutions:

1. Drug Testing Institutions
2. Center for Drug Evaluation (CDE)
3. Center for Drug Reevaluation (CDR)
4. National Center for ADR Monitoring.

In addition, the legal departments will be involved upon legal issues.

1. Authority for Supervision of Drugs
   • NMPA and Local MPA including Provincial, Municipal, and County level are responsible to set up and designate pharmaceutical and pharmacovigilance inspection institutions in accordance with law.
   • NMPA shall be responsible for forming annual supervision and inspection plan, arranging inspection tasks, or organizing inspections, and work according to the Report on Comprehensive Evaluation of Drug Inspection and relevant evidence materials.
   • NMPA shall set up a professional team of specialized drug inspectors, implement multi-level & classification system for inspectors, formulate the standards of duties and duties of inspectors at different levels as well as requirements for comprehensive capability, and establish strict criteria for relevant positions.
   • NMPA and the drug inspection institution is responsible for establishing inspector database and inspector information platform to realize the information sharing and coordination of inspectors at all levels from national to county-level.
2. Institutions for Drug Inspection
   • Drug inspection institutions carry out inspections according to China’s laws and regulations on drug supervision before issuing the Comprehensive Evaluation Report on Drug Inspection and be responsible for daily management of professional inspector team and implementation of inspection plans and tasks.
   • Other departments such as drug inspection, review, evaluation,and adverse drug reaction (ADR) monitoring established shall provide technical support during the inspection.
   • Drug inspection institutions shall establish a quality management system to continuously improve the quality of drug inspection work.
   • The drug supervision authority or drug inspection institution is responsible for establishing inspector database and inspector information platform to promote the information sharing and coordination of inspection within national, provincial, and county levels.
3. Drug Inspection Group
   • The inspection group should be set up by the pharmacovigilance inspection team to carry out the audit.
   • Usually, an inspection group consists of more than 2 qualified inspectors
   • The team leader is responsible for the inspection team. When necessary, experts in relevant fields can be selected to participate in the inspection