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Post-marketing Drug Safety Surveillance:
Pharmacovigilance in MFDS
Action plans for the regulatory harmonization in Pharmacovigilance
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What we do…
• Evaluate the safety of drug products
• Advance public health by detecting and analyzing safety signals
• Enforce appropriate regulatory actions, including labeling changes, Re-
examination, Re-evaluation, Risk Management Plan(RMP), ADR
Relief Program, etc.
• Support and Supervise the following affiliated institution
• Korea Institute of Drug Safety and Risk Management(KIDS)
• Communicate relevant safety information
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The “Six Toos”
too few subjects ..... 적은 임상시험 증례수
too simple design ..... 합병증, 병용약이 없는 임상시험 대상
too median-aged population ..... 소아·고령자는 피험자에서 제외
too narrow range of exposure ..... 임상시험계획서에 따라서만 사용
too brief period of observation time ..... 임상시험은 짧은 투여기간
too indirect surrogate ..... Surrogate vs. Desired endpoint
(Brian L. Strom. Pharmacoepidemiology. John Wiley & Sons. England, 2000.)
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The science and activities relating to the detection,
assessment, understanding , and prevention of
adverse effects or any other drug-related problems.
- WHO
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The ability to study the following:
• Low frequency reactions(not identified in clinical trials)
• High risk groups
• Long-term effects
• Drug-drug/food interactions
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Article 37-3(Post-Marketing Safety Control of Drugs)
(1) A person who has obtained marketing approval of drugs shall employ a physician,
pharmacist, or oriental medicine pharmacist to perform the duties of post-marketing safety
control, such as re-examining new drugs, etc., re-evaluating drugs, and reporting side effects,
as prescribed by Ordinance of the Prime Minister. That a person who has obtained marketing
approval of a drug to be used for animals only may perform the duties of post-marketing safety
control after employing a veterinarian.
(2) A person who performs affairs of safety control under paragraph (1) (hereinafter referred to as
a “safety control manager”, shall comply with the matters prescribed by Ordinance of the Prime
Minister, regarding the safety control of drugs in distribution.
...... 안전관리책임자 제도 도입(‘07.10.17.)
...... 교육 의무화(‘14.10.10.)
...... GVP(‘16.10.28.)
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The ability to study the following:
• Low frequency reactions(not identified in clinical trials)
• High risk groups
• Long-term effects
• Drug-drug/food interactions
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1975
1988
19952012
2015Risk Management Plan
Drug Re-evaluation
Spontaneous
AE Reporting
Re-examination
on new drug
Establishment of KIDS
• Korea Institute of Drug Safety and Risk Management(KIDS)• Aims to provide evidence to promote public health through
advancement in drug safety & risk management system
2014
ADR Relief Program
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Overview of pharmacovigilance in MFDS
Spontaneous ADR ReportingPlanning
of RMP
for NME
Approval
RMP
Use-result Surveillance
Special Surveillance
PM Clinical Trial
Re-
examinati
on
Re-
evaluation
If necessary
•••
4~10 years
Periodic Safety Update Report(PSUR)
•••
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To ensure safety, efficacy, equivalence of already-approved drug based on up-
to-date medical and pharmacological standard
Pharmaceutical company should submit the predetermined number of safety
data on the new drug after 4 or 6 years since it was approved to be marketed
from the government.
Overview of pharmacovigilance in MFDS
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Planning
of RMP
for NME
Approval
RMP
4~10 years
Spontaneous ADR Reporting
Use-result Surveillance
Special Surveillance
PM Clinical Trial
Re-
examinati
on
Re-
evaluation
If necessary
•••
Periodic Safety Update Report(PSUR)
•••Foreign
Regulatory
Agency
Safety
alerts/letter
Label change
Withdrawal/
Recall
Forbidden or
restricted for
sale
Healthcare
professionals
Patients,
Consumer
MFDS
Industry
KIDS
(KAERS)
Spontaneous ADR Reporting
27 RPVCs
AE/ADR reporting AssessmentRegulatory
Actions
• Korea Adverse Event Reporting System (KAERS)a database that contains information on AE/ADR reports submitted to KIDS
Overview of pharmacovigilance in MFDS(Continued)
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· Seoul National Univ. Hospital· Asan Medical Center· Samsung Medical Center· Severance Hospotal· Seoul St. Mary`s Hospital· Korea University Guro
Hospital· Chung-Ang Univ. Hospital· Hanyang Univ. Hospital
Seoul
· Keimyung Univ. Dongsan Medical Center· Kyungpook Univ. Dongsan Medical
Center
Daegu, Kyungpook
·Gyeongsang National Univ. Hospital· Keimyung Univ. Dongsan Medical Center· Dong-A Univ. Hospital· Pusan National Univ. Hospital· Inje Univ. Pusan Paik Hospital
Pusan, Ulsan, Kyungnam
Gwangju, Jeolla
· National Medical Center· Korea Pharmaceutical Association
Nationwide
· Jeju National Univ. Hospital
Jeju
· Hallym Chuncheon Sacred Heart Hospital
Gangwon
· Dankook Univ. Hospital· Chungbuk National Univ. Hospital
· Chunnam Univ. Hospital· Chunnbuk Univ. Hospital· Chosun Univ. Hospital
Gyeonggi-Inchun
· Dongguk Univ. Ilsan Hospital· Ajou Univ. Hospital· Inha Univ. Hospital· Hallym Univ. Sacred Heart Hospital
Daejeon, Chungcheong
27 Regional Pharmacovigilance Centers
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1. Collection & causality assessment on spontaneous ADRs
2. Education on the importance of PV
– Medicinal experts: doctors, pharmacists, nurses, etc.
– Consumer
3. Drug information center
– Consult patients who (or who’s families) are experienced ADR
– Provide drug safety information
4. Required Office and Staff
– Office and counseling area
– Healthcare professionals
– Computerized ADR report system
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Report
Report
Report
Report
Report Ranking of ICSRs to VigiBase
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1. 현황
Year ~2012 2013 2014 2015 2016 2017 2018
ICSRs 92,375 183,260 183,554 198,037 228,939 252,611 257,438
ICSR cumulative 295,373 478,633 662,187 860,224 1,089,163 1,341,774 1,599,212
1988 1998 2006 2009 20122011
20063 Regional PV center 2,467
200915 Regional PV center
201120 Regional PV center
2012KIDS was established
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27,010
74,657
21 290
2018
257,438
Number of Adverse Event Reports Entered into KAERS
201827 Regional PV center
(Dec 31, 2018)
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1. 현황
Year 2015 2016 2017 2018
LabelChanges
Based on Safety information from Korea
17 21 32 34
Based on Safety information from Foreign Regulatory
Agency88 157 91 93
(Dec 31, 2018)
Regulatory Actions
Safety Information from Korea (from KEARS)
Source of Possible Safety Signal
(Serious AE,Frequent reported AE,
Other safety issues etc)
Epidemiology studies
Regulatory Actions
(Label Changes,
Communicating
Safety Issues to the
Public,
Dear Healthcare
Professional Letters
etc)
Evaluations
Safety Information from Foreign
Regulatory Agency
Process of Regulatory Actions
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• As MFDS joined ICH Regulatory Member in November 2016, ICHGuidelines should be implemented for international harmonization
• ICH Guideline : Efficacy(E) E2B(R3) Clinical Safety Data Management E2C(R2) Periodic Benefit-Risk Evaluation Report E2D Post-Approval Safety Data Management Definitions and Standards
Expedited Reporting E2E Pharmacovigilance Planning
M1 MedDRA
Enhance International Harmonization and Post-marketing Safety management efficiency
Introductions
Implementation(until 2021)
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MedDRA (Medical Dictionary for Regulatory Activities)
• A rich and highly specific standardised medical terminology(code) to
facilitate sharing of regulatory information internationally for medical
products used by humans
• MedDRA is available to all for use in the registration, documentation
and safety monitoring of medical products both before and after a
product has been authorised for sale. (about 100,000 terms,
Multilingual)
M1(MedDRA)
※ Source : www.meddra.org
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• Under the oversight of the ICH MedDRA Management Committee, MSSO(Maintenance and Support Service Organization) maintain, distribute, and support MedDRA
• MedDRA Release : March, September (Twice a year) with Multilingual English, Chinese, Czech, Dutch, French, German, Hungarian, Italian, Portuguese,
Japanese, Russian, and Spanish
• Essential supporting documents is maintained each release
• MedDRA being an integral part of the ICH e-submission standard :
e-CTD(ICH M8), ICH E2B
M1(MedDRA)(2)
※ Source : www.meddra.org 23
MedDRA Subscription Rates
※ Source : www.meddra.org
M1(MedDRA)(3)
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E2B(R3)
E2B(R3)?
• Clinical Safety Data Management : Data Elements for Transmission of individual Case Safety Reports (ICSR)
Revision of E2B(R2) Guideline in 2003 and a revised E2B(R3) was released for
public consultation in May 2005
Reached Step 4 in November 2012 (Now Step5)
Recent updated publication of the IG(Implementation guideline) package in
June 2018
• ICSR?
A report of information describing adverse event(s)/reaction(s)
experienced by an individual patient
※ Source : Implementation Guide for Electronic Transmission of ICSRs E2B(R3) Data Elements and Message Specification 25
E2B(R3)(2)
Purpose of E2B(R3)
• To standardise the definitions of the data elements used in the electronic transmission of different types of ICSRs, regardless of source and destination For both the pre- and post-authorisation periods, adverse drug
reaction reports and adverse event reports
• Assist reporters and recipients in implementing systems to construct transmittable ICSR messages
• Focus on technical implementation (Not intended to serve as a
reference for proper pharmacovigilance practices)
※ Source : Implementation Guide for Electronic Transmission of ICSRs E2B(R3) Data Elements and Message Specification 26
E2B(R3)(3)
Code Sets, Terminologies and Vocabularies for E2B(R3)• ISO Identification of Medicinal Products (IDMP)
• MedDRAⓇ - Medical Dictionary for Regulatory Activities
• ICH Maintained Code Sets
• International Standard Code Sets
• nullFlavor
ICH E2B(R3) Data Elements- N.1 and N.2.r (the Wrapper information)
- C.1 - Identification of the Case Safety Report
- C.2 - Primary Source(s) of Information
- C.3 - Information on Sender of Case Safety Report
- C.4 - Literature Reference(s)
- C.5 - Study Identification
- D - Patient Characteristics
- E - Reaction(s) / Event(s)
- F - Results of Tests and Procedures Relevant to the Investigation of the Patient
- G - Drug(s) Information
- H - Narrative Case Summary and Further Information
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E2B(R3)(4)
Regulation on Safety of Pharmaceuticals, etc. Annex 4-3
6. Reporting safety reports(AE/ADR)A. Doctors, dentists, oriental medical doctors, nurses, pharmacists, oriental medicinepharmacist , or related organizations may report to Minister of Ministry of Food and Drug Safety or the president of Institute of Drug Safety and Risk Management inaccordance with the form No.77-2 for the Adverse Event or Drug Adverse Reactionthat occurred or became aware of while taking or using the medication.
B. The patient or consumer may report to the head of Ministry of Food or Drug Safety or A person who has obtained marketing approval, in accordance with the formNo.77-3 for Adverse Event or Adverse Reaction that occurred or became aware of while taking or using the medication.
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E2C(R2)
Regulation on Safety of Pharmaceuticals, etc. Annex 4-3
8. Periodic update safety reports for medicines submitted risk management plans
A. The person who obtains the marketing approval submitted with the riskmanagement plan shall periodic update safety report the results of the safety assessment or benefit and risk assessment, such as the analysis of the clues, to the collected safety information to the Ministry of Food and Drug Safety in accordance with the form No. 77-4.
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E2D
• Regulation on the Safety of Pharmaceuticals etc. Article 84 and Annex 4-3
15-day Alert reports: Serious and unexpected adverse experience from all
sources(domestic and foreign)
1. Cases which cause death or threaten a person's life;
2. Cases which require hospitalization or the extension of hospitalization period;
3. Cases which cause continuous or serious disabilities or hypofunction;
4. Cases which cause congenital deformations or abnormalities;
5. Cases which require treatment due to medically serious situations such as drug
dependence and abuse, or blood disorders, etc.
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Periodic Adverse Events Reports: Domestic spontaneous adverse events that are:
• Serious and expected
• Non-serious and unexpected
• Non-serious and expected
• Quarterly reported to KIDS
E2E
• Guideline for work on Risk Management Plan
2. Pharmacovigilance methodsTo evaluate whether the monitoring of medicines is being carried out well according to
their purpose,The following are the methods for pharmacovigilnace: characteristics,
indications, groups of targets for treatment, and the latest and most appropriate and
applicable medicines in the drug based on safety issues, etc.
It is desirable to select and utilize the monitoring method. For a detailed description, see
the Guidelines for the pharmacovigilance Plan.
Drugs subject to submission of a risk management plan are subject to one of the
following active or comparative studies….
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In-Process : MedDRA
• (2013) Start MedDRA Korean ver. translation project- Advancement of drug safety management such as global clinical trials and exchange
of safety information
• (Dec.2013) ICH officially approved MedDRA Korean ver. translationproject
- Authorized by the MedDRA Steering Committee subject to copyright delegation
• (Jun.2014) Attend the ICH Meeting (MedDRA Steering Committee)- Share MedDRA Korean ver. Translation project, Suggest MedDRA education, etc.
• (Dec.2016) Draft MedDRA Korean ver.
- Draft Korean version of MedDRA 19.0 and send ICH
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In-Process : MedDRA(2)
• (Nov.2017) Agreement on Transfer of Korean ver. of MFDS to ICH
• (May.2018~) Company selection for MedDRA Korean ver. translation
- Cooperated with MSSO to evaluate four translation company
• (~Dec.2018) Prepare translation rule and synonym list(MedDRA)
• (Jan.2019) Issued Regional guidance for E2B(R3) implementation- Republic of Korea Implementation Guide: Electronic Transmission of Individual Case Safety
Reports E2B(R3) Data Elements and Message Specification
• (Feb.2019) MFDS conducted a pilot testing for E2B (R3) implementation with Adverse events reporting system
- Testing with MedDRA English ver.
In-Process : E2B(R3)
A pilot testing system for E2B(R3) implementation
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In-Process : E2B(R3)
A pilot testing system for E2B(R3) implementation
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MedDRA Special License(1)
MedDRA Special License?
• MSSO supports the use of MedDRA by providing special MedDRAlicenses to regulatory authorities
Intended to help government and other governmental agencies worldwide to
give access to MedDRA coding for non-commercial users and small commercial
organisations with low revenue and often limited IT resources
• Special licenses allow MedDRA’s use without charge in a non-downloadable format within agency electronic (software) tools
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Approximately 350 Pharmaceutical companies(61%) save up to 2.8billion(KRW) annually in Korean
Introduction Process of MedDRA Special License
Nov.2018 Nov.2018 Jun.2019 Sep.2019 Nov. 2019
ICH MFDS
MFDS(KIDS)
Application of Special
License
ICH Review and Approval
Internal SOPfor approval and renewal process of MedDRASpecial License
ReleaseMedDRA
Korean ver.
ApplyMedDRASpecial
License to pilot testing
systemMFDS ICH ICH 〮 MSSO
MFDS(KIDS)
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MedDRA Special License(2)
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MedDRA ↔ WHO-ART bridge file☞ Provide bridge file for compatibility between WHO-ART and MedDRA
MedDRA Korean Version Synonym List
☞ Provide synonym information available in the Korean version of MedDRA
Revision of Adverse Events Report Form according to E2B(R3) (2020)
☞ Regulation on Safety of Pharmaceuticals, etc. Annex4-3 (Form No.77-2, No.77-3)
Provide Training programs for industries to prepareMedDRA, E2B(R3) adoption (Continued)
☞ Training of Safety Control Manager etc
Action Plans (2019~)
Action Plans (Continued)
Release MedDRA Korean version (Sep.2019)
☞ MedDRA Korean ver. will be applied to a pilot testing for E2B (R3) (Nov.2019~)
Establish MedDRA special license approval process (Sep.2019)
☞ Notice Application Procedure for industries (through MFDS homepage etc)
Apply MedDRA to drug development, clinical trials, and post-marketing surveillance (~2021)
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Thank you!
