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1. Postmarketing Regulations in Japan
and Real World Data Utilization
for Drug Safety Assessment
Daisaku Sato, Ph.D.
Chief Management Officer
& Associate Centre Director for Advanced Evaluation, Medical Informatics
and Epidemiology
Pharmaceuticals and Medical DevicesAgency, Japan
3rd India - Japan Medical Products Regulation Symposium 2018

2. Introduction

3. Comparison of median review time of NMEs among 6 agencies
Median approval time for NASs approved by ICH agencies
by approval year 2007-2017
FDA and PMDA NAS median approval times converged in 2007-2016, with PMDA
the fastest of the three agencies for a third year in a row. But in 2018!

4. Designation Criteria
Designation Advantage
Designation Procedure
SAKIGAKE (forerunner)Review Designation System
 To put innovative products into practicein Japan first in the world 

- Medical products for diseases in dire need of innovative therapy
- Applied for approval firstly or simultaneously in Japan
- Prominent effectiveness can be expected based on non-clinical
study and early phase of clinical trials
1. Prioritized
Consultation
[Waiting time:
2 months→1 month]
4. Review Partner
2. Substantialized Pre-
application Consultation
[de facto rolling submission
before application]
3.PrioritizedReview
[12 months → 6
months]
[PMDA manager as a
concierge]
1. Initiation by applicant 2. Initiation by the MHLW
5. Substantial Post-Marketing
Safety Measures[Extension of
re-examination period]

5. Reactions to booming “Sakigake” approaches in the review
Benefit & Risk Assessment during the product lifecycle
and Safety: “What to do for safety?”
 As Product Life Cycle Regulations, “effective and sustainable post-
marketing benefit and risk assessments”will contribute to expediting
early patient access while enhancing post-marketing safety.
 Under such regulations, risk management including optimal use
promotion should be more emphasized.
① Regulatory Reform, in consistentwith regulatory support during R&D
process
② Improve regulatory environment for quality assurance, considering
global supply chain
③ Promote benefit-risk assessment throughout the product lifecycle, with
particular emphasis on the post-marketing process
Early patient access & post-marketing safety
vs.
sustainable and cost-effective product development

6. Nationwide Adverse Drug Reaction/Event
Reporting System

7. Overview of the regulatory schemes of
pharmacovigilance in Japan
NDA 1 year Approval
6 months 4-10 years
Spontaneous ADR Reporting
Planning of RMP
Considerations
on Post-market
Requirements
EPPV
Routine Pharmacovigilance
 Spontaneous reports,
 Periodic reports, etc
GVP(Good Vigilance Practices)
Real-worlduse survey (Usually needed)
(Primary and/or secondary data collection)
Post-Market Clinical Trial (If necessary)
GPSP
(Good P
G
oP
stS
-M
Parketing Study Practices)
EPPV : Early Post-marketing Phase Vigilance (6 months intensive monitoring)
RMP : Risk Management Plan
Re-EX : Re-examination
Re-
Examination

8. Latest
research
(scientific
reports etc.)
MHLW MAHs
Release of safety information
‘trigger’
Review of safety measures
8
PMDA-ATC Pharmacovigilance Seminar 2017 (APEC Center of Excellence Workshop)
ADR
reports
Situations
Overseas
Tendencyof
ADRs
Release of safety information
Revision of precautions in labeling, etc.

9. 行政指導による企業報告開始(1967)
モニター病院制度開始(1967)
企業報告義務化(1
モニター病院の拡大(1988)
感染症報告義務化(1997) (2003)
モニター病院制度廃止し、
全医療機関・薬局に拡大(1997)
医療機関報告義務化
企業報告数
4ワクチン報告数
医療機関報告数
Spontaneous ADR and Infection Reports
60000
50000
MAH reporting
Vaccine reporting
Health Professional reporting
Legally binding
Health Professional Report
40000
Infection Report introduction
30000
20000
Voluntary MAH reporting
/ monitor hospital system
Expansion of monitor
hospitals
Vaccine AE
reporting under
immunization
regulation
10000
Mandatory
MAH reporting
980)
0
67 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 14
年度
件
数

10. Classification of spontaneous reports from MAHs
 ADR reports of products : period from approval
FY2014 FY2015 FY2016
No. % No. % No. %
During EPPV
（within Six months after
launch）
1,974 4.0% 2,089 4.1% 1,254 2.2%
Within 2 years after
approval
4,640 9.4% 5,611 11.0% 7,338 13.1%
Others 42,666 86.6% 43,365 84.9% 47,224 84.6%
Total 49,280 51,065 55,816
 Types of MAHs who reportADRs
FY2014 FY2015 FY2016
No. % No. % No. %
JPMA companies 42,614 86.5% 43,303 84.8% 47,528 85.2%
Other than JPMA
companies
6,666 13.5% 7,762 15.2% 8,288 14.8%
Total 49,280 51,065 55,816

11. Administrative communication issued on July 10 2017.
Adverse event reporting guidance of health
professionals (Gist)
• The gist of guidance was compiled by Health Labor Science Special Research
Project (FY2016).
• The reports from medical institutions and reports made in collaboration between
medical institutions and pharmacies are encouraged and promoted when adverse
events are suspected to be associated with ethical drugs.
• The guidance gist was published to be used as a reference of health professionals.
• The guidance will be further improved based on the researches to be conducted in
the consecutive years.
Consideration should be given to the environmental change surrounding
the safety of pharmaceuticals,such as the spread of generic medicines
in recent years, the occurrenceof adverse events associatedwith
polypharmacy in the elderly.
Collaboration among medical professionsin medical institutions,and
between facilities including out-patient pharmacies is important.
Health professionals’duty of effort to report adverse event is laid down
under Article 68-10 sec. 2 of PMD Act. 11
Incentive (fee) for pharmacy to support AE reporting was covered by Medical Fee Revision 2018

12. Information
provision in a
timely manner
Scientific evaluation
followed by consideration
of proper safety measures MHLW
Risk communication activities
MAHs
HCPs
Public
12
Collection of
safetyinformation
including ADRs

13. Regulatory Output : Labeling change regulatory actions
Labeling change orders from MHLW/PMDA: Pharmaceuticals
FY2014 FY2015 FY2016
Pharmaceuticals withinre-
examination (exclusivity)
periods
45 48 49
Pharmaceuticals after re-
expiry of examination
(exclusivity) periods
47 34 96
Total 92 82 145
Labeling change orders from MHLW/PMDA:
Medical Devices and Regenerative MedicalProducts
FY2014 FY2015 FY2016
Medical Devices*1 4 28 6
Regenerative Medical
Products*2
0 0 0
*1 Based on each generic name of the product
*2 Number after implementation of PMD Act on 25 November 2014
13

14. Issued monthly basis
Communications through PMDA
Ref) http://www.pmda.go.jp/english/service/precautions.h14
tml

15. General overview of risk communication
provided by MHLW
• A summary of cases served as the basis
for revisions of precautions is also
included
• Published 1-2 months after Instructions
for Revision of Precautions
• Cases which require continuous alert
repeatedly is also introduced.
MHLW PMDSI
MHLW
Pharmaceuticals and
Medical Safety
Information
https://www.pmda.go.jp/english/
safety/info-
services/drugs/medical-safety-
information/0014.html
15
PMDA-ATC Pharmacovigilance Seminar 2017 (APEC Center of Excellence Workshop)
Target user HCPs
Preparation MHLW
Frequency 10 times/year
English version available? Yes

16. Product specific Risk Management Plan
and
Pharmacoepidemiology

17. “Optimal use”, at each stage, from pre-marketing to post-marketing,
Post-market
Pre-market
Keep agreeable benefit-risk balance in the lifecycle
Consistent risk management
From rigorous CTs To complex real world after product launch
CT start NDA Approval
Clinical Safety
Data
Pre-approval
Clinical
Effectiveness
Data
Post
-approval
Clinical Trial
Phase
Real world, day to day
medicine

18. Serious specified risk
Serious potential risk
Serious missing
information
安全性検討事項
Safety Specification
Concept of structured RMP
implementation in line with ICH-E2E guideline
安全性監視計画
Pharmacovigilance Plan
リスク最小化活動
Risk Minimization Action Plan
Additional measure
No
Yes
Vigilance
and / or
Additional Patient medication guide
Leaflet
Education programme
minimisation？
（evaluation）※
Additional minimisation
EPPV
Medicalexperiencesurvey
Distribution control
Labelling revision
 Limited medical
Additional vigilance
Controlled study
Pharmaco-epidemiology
study
institutions and limited
doctors
 Patient selection
criteria
Regular Labelling
Commentary
SpontaneousRep.
Literature survey
2010/07/08
Regular
review

19.  RMPs have been published to share them with health
professionals to promote implementation and to strengthen
measures
 The number of PMPs published since August 2013 was 333 items
as of the end of March 2018.
RMPs have been published on PMDA website

20. Pragmatic clinical trials using registries of
medical/health records
N Engl J Med 2016; 375:454-463 August 4, 2016
An attractive alternativeto trials in which electronic health records
are used can be found in trials of alternativeinterventions involving
patients who are already enrolled in disease-specificor intervention-
specific registries that incorporate detailed patient phenotypesand long-
term follow-up data. This framework provides an efficient and low-
cost opportunity for conducting pragmatic trials
http://www.nejm.org/doi/full/10.1056/NEJMra1510059?query=featured_clinical-trials

21. Can compare frequency of
ADR occurrence drugs in
the same class
Can ascertain whether
the occurrence of a
certain symptom is
increased by
administration of a drug
Can compare to see whether
implementation of safety
measures actually results in
a change in ADR frequency
Verification of effects
of safety measures
Rate of occurrenceof ADRs
(symptoms/number of patients
who used the drugs)
Before safety After safety
measures measures
Rate of occurrenceof
symptoms
(symptoms/number of patients
who used the drugs)
Treated with
Drug A Treated without
Drug A
underlying disease
Comparison with
symptoms due to
Drug A
Drug B
Treated with
Rate of occurrenceof ADRs
(ADRs/number of patients who
used the drugs)
Treated with
Comparison with
other drugs
What will become possible by utilizing a large-scale
medical information database?

22. • Speedy, efficient and low cost PMS and clinical studies using medical real world data
 PMDA’s MID-NET starts full operation from FY 2018, aiming at efficient and scientifically sound
PMS for safety measure.
 Patient registries of ＮＣs（ National Advanced MedicalResearch Center ）as real world database will
be promoted and available for regulatory purposes
（e.g. ）Rwd as substitution of clinical trials for genomic cancer therapies for regulatory submission.
• In response to innovative drugs R&D, PMDA will perform organizational strengthening and review
quality improvement.
PMDA’s review quality for reform
Regulatory Reform to reduce cost and improve efficiency
(December 2017)
●Reform the pharmaceutical regulations for improve access and productivity in terms of
promoting and developing innovative products, though considering safety and appropriate use
「Conditional & Accelerated Approval」&「”Sakigake” designation」 to be
stipulated in the legislation
• Clarify the early regulatory pathway and predictability of R&Ds for innovative pharmaceuticals with
higher clinical benefit
• PMDA’s support(such as consultations) for efficient development and higher predictability.
Exploratory
Trial
Conditional
Accelerate
d Approval
Confirmation of
effectiveness and
safety, using
post-marketing
data, e.g. real
Confirmation of
Approved
maters
・
Release
commitments
・
Sakigake designation
Designate the product developed
ahead of the world for Japanese
market with prominent clinical benefit
for regulatory support to expedite the
Conditional AcceleratedApproval world evidence Expand
indications
process (ex.review time : 6 months）
Real world Data utilization 5.1 M$ for FY2018
18M$ for FY 2018
Post-marketing

23. Data sources for post-market safety
assessment of a drug
PMDA MHLW Medical
institutions
Conventional
Information Sources Electronic
Healthcare Data
Spontaneous
ADR report
DB
Overseas
Claims
DB
Safety
measure
Risk
communi
cation
Literatures regulatory
actions
DPC DB
Presentation in
Academic
Conference
etc Launched in 2009

24. s
 Promote safety measuresby pharmaco-epidemiological method using medicalinformation
database.
 MHLW/PMDA have established a medicalinformation database for collecting large-scale
medicaldata at sentinel site hospitals and have constructed analytical systems at PMDA
since FY 2011.
Researcher, MAHs DB Sentinel site
hospitals
site
DB
Collaboration
PMDA
Data
analysis Claim Data
DPC
EHR
Networking 10
sentinel sites of
23 hospitals
safety information collection and
analysis
Prompt safety
Data
Lab. test
Tohoku U, Tokyo U, Chiba U,
site
DB
action
Expected Outcome：
4,000,000
patients included
NTT Hosps、Kitasato Hosps,
Hamamatsu M U, Tokushukai
Hosp Group, Kagawa U,
Kyushu U, Saga U. ite
Promptand precisesafety actions
site
DB DB
【History and way forward】
●April 2010 ：「Revision of pharmaceutical administration etc. to prevent recurrence of pharmaceutical
disasters (final recommendation) 」
● April 2011 - ： Start construction of MID-NET system
● April 2013 - ： Start data quality validation to assure precision and comprehensivenessof the collected data
● April 2015 - ： Start trial operations by PMDA and sentinel sites
● April 2015 - ： Setting utilization rules for full-scale operation and framework of operation cost / userfees.
● April 2018- ： Full scale operation, enable MAHs and researchersto use MID-NET
Medical Information Database Network（MID-NET）

25. Common Data Model of the MID-NET®
HIS data
・Patient identifying data
Example of standard codes
・Medical examination history data
(includingadmission , discharge data)
・Disease order data
・Discharge summary data
・Prescription order/compiled data
・Injection order/compiled data
・Laboratorytest data
・Radiographic inspection data
・Physiological laboratorydata
・Therapeutic drug monitoringdata
・Bacteriological test data
Database
HIS data
Claims data
DPC data
Contents Standard Code
Disease ICD-10
YJ, HOT9
Drug (JP specific codes)
JLAC10
Laboratory test (JP specific codes)

26. High data quality as well as appropriate analysis are pre-
requisite in utilizing real world data for providing scientifically
interpretable results
Importance of Data Quality Management
Inappropriate
analysis
Appropriate
analysis
Uninterpretable
results
Uninterpretable
results
Reliable Data
Appropriate
analysis ＝Interpretable
results
Reliable Data
Unreliable
Data
＝
＝

27. Before quality
management
After quality
management
Data Quality of MID-NET®
PMDA has worked with cooperative hospitals
for assuring data quality of MID-NET®.
EMR MID-NET EMR MID-NET
compare compare
Disease order data
99.1%
Disease order data
99.9%
Prescription order data
67.0%
Prescription order data
100%
Laboratory test data
55.8%
Laboratory test data
100.0%

28. Clinical Trial
population
Post-marketing safety measures using MID-NET
Real world data population
Patients of various medical
background; Anamnesis,
liver and renal dysfunctions,
elderly….
So far:
• Post-marketing use result surveys have
been performed
→long term and huge research budget
necessary
Realize ICT based efficient PMS
One of the biotech / venture supporting measures
 Substitute current ways of PMDA by
MID-NET
→rapid and efficient collection of large
scale real world data of the patients with
various medical background
→huge reduction of cost of MAHs and
medical institutions for PMS
Improve quality of safety measure
and promote R&D

29. ランマーク
ゾレドロン酸水和物
リスク比
■Objective
 To examine impacts of label change and warning letter in clinical practice for the risk of hypocalcemia
associated with denosmab
MID-NET® pilot:
denosumab and severe hypocalcemia
Monthly transition of the incidence of hypocalcemia
29
5.0
4.0
3.0
2.0
1.0
0.0
100.0%
80.0%
60.0%
40.0%
20.0%
0.0%
Labelling
change
Blue
letter
Denosumab
Zoledronate
Risk ratio
・Calculate the incidence of hypocalcemia during 28 days from a prescription date.
・Perform segment regression analysis based on the incidence of hypocalcemia / month.
Pilot study
Incidence
Proportion
(%)
Risk
ratio

30. MID-NET®
(2010～2015）
Cohort：Newusers of anti-diabetes
drugs monotherapy
Control group
Glinides
(n=2,717.2)
Glinides
(n=237)
Exposed Group
DPP-4 inhibitors
(n=2,578)
MID-NET®
pilot:
Risk of Acute Myocardial InfarctionAssociated with Anti-
Diabetes Drugs
Propensity score
standardization
(SMRW)
Occurrence of AMI
Cases of AMI Cases of AMI
Table.Adjusted rate ratio and
adjusted hazardratiofor AMIin
the standardized population.
30
■Outcome definition（AMI）
 Definitivediagnosis ofAMI,
 Admission* and
 Elevation ofcardiacbiomarker values*
（CK or CK-MB：≧URL ×2 or Troponin T：≧0.1ng/mL）
*during30 daysbefore andafterthe diagnosis date of AMI
Adjusted Adjusted
IncidenceRate Rate Ratio Hazard Ratio
per 1,000 Person-years
（95%CI） （95%CI）
Non-sulfonylurea insulin
secretagogues 2.4 1［ref］ 1［ref］
DPP-4 inhibitors 2.1
0.86 0.93
(0.25-2.90) (0.08-10.80)
Objective
 Cardiovascular events associatedwith anti-diabetes drugs are
common risk in post-marketingphase
 To compare the risk of acute myocardial infarction (AMI)
associated with DPP-4 inhibitors monotherapy to other anti-
diabetes drugs monotherapy.
DPP-4 inhibitors
（n=2,952）
Pilot study

31. National Claims DB
Characteristics of MID-NETⓇ and NDB
Data Type Electronic Medical Records Health Insurance Claims
Data Provider
23 hospitals of 10 Medical
institutions
All health insurers in Japan
Covered patients
People provided medical
service by each institution (~4
Million)
Entire Japanese population
(120 Million)
Obtainable Health
Information
Detailed information in
medical practices by each
institution
Standardized information
relevant to reimbursement
Diagnosis YES YES
Medical procedure YES YES
Pharmacy Dispensing YES (on-site pharmacy) YES
Laboratory test result YES NO
OTC Drug NO NO

32. $
Insurance
Card & ID
Insurance
Fee Claim
data
Health Insurance
Association’s
Claim Database
Insurer
Patient
Medical Institution
Claim
Payment
(as agent)
$
Payment
$
Claim
Utilization of National Claims Database (NDB)
Medical care
$
Medical
Information
Copayment
Claim
data
National Claim Database (NDB)
National Institution for
claims review & paying agent
MID-NET

33. Risperidone
Risk evaluation of atypical antipsychotics (AAP) for
Hyperlipidemia: A Sequence Symmetry Analysis
Adjusted sequence ratio (95 % CI)
Number of days since an initial
administration of AAP
Takeuchi Y et al, Drug Saf (2015)38: 641-650
Aripiprazole
Olanzapine

34. Study group for ethical issues for registries and relationships with industries
Utilizing registry data for promoting cost effective clinical
studies, accelerating drug development, and B/R assessment
Clinical Innovation Network (CIN)
MHLW PMDA AMED
CIN-Working Group About 20 members
ALS
Advice,
Cooperation
from New drugs &
Safety Offices
Muscular dystrophy
Registry
by NCNP
(Antilymphocytic
serum) Registry
By Nagoya Univ.
Cancer registry
By National Cancer
Center Japan
Cerebral surgery
By Japan
neurosurgical
society
Study group for epidemiological methods and data quality standards
Output

35. GPSP Ordinance Revision
Post-marketing
Study
Use Result survey
General Use Result
survey
Post-marketing
Data base survey
Post-marketing
clinical study
Specific Use
Result survey
Use Result
controlled survey
April 2018 Implementation
Orange cells are added by the expected Ordinance revision

36. Related guideline
 Guideline on pharmacoepidemiological study for drug
safety assessment based on medical information database
(March 2014)
 Basic Principles on the utilization of health information
databases for Post-Marketing Surveillance of Medical
Products (June 2017)
 General steps for considering a plan of post-market studies
(January 2018)
 Points to consider for ensuring data reliability on post-
marketing database study for drugs (February 2018)
Many related guidelines focusing on Real World Data utilization
were recently published in synchronization to the GPSP revision
https://www.pmda.go.jp/safety/surveillance-analysis/0011.html

37. PMDA Regulatory Science Center

38. Active utilization of e-DATA
Regulatory Science Center
Nurturing of talented experts, accumulating
scientific knowledge
Office of Research Promotions
Coordination and projectmanagement in
regulatory science research and publishing
guidelines (Governance office of Science board etc.)
Office of Advanced Evaluation with Electronic Data
Utilization of clinical trial data on CDISC
database (modeling & simulation, cross-productanalysis
for better benefit/risk assessment)
-CDISC data has been submitted by MAHs since October 2016
Office of Medical Informatics and Epidemiology
Utilization of EMR database for pharmaco-
epidemiological analysis (PEpi-study, cross-
productanalysis for better benefit/risk assessment)
3
8
- Implemented in 2016
Post-Approval
Continuous assessment on
Benefit/Risk of a drug (e.g.: proper
target population, doses, warning)
Maximal and effective utilization
of valuable data
Analysis for examining a causality
between safety/effectiveness and
candidate factors
Pre-approval
Analysis for identifying an
important factor on efficacy and/or
safety of drug(s)

39. Collaborative Functions of
Regulatory Science Center with other offices
Support advanced analysis,
Create disease model for
data evaluation etc. Office of New Drugs
For drug approval
Safetymeasures based
Office of
Advanced
Evaluation
with
Electronic
Data
Office of
Research
Coordination
Officer for
Evaluation of
Advanced
Science and
Technology
Office of
Medical
Support epidemiological
data evaluation and study
planning
on cross products
analysis etc.
Promotions Informatics
and
Epidemiology
Office of Safety
For safety measures
Safety measures based on
epidemiological analysis etc.

40. MHLW/PMDA
Industries
Medical Institutions
Public
Active utilization of EHR databases
toward advanced medical care
Regulatory decisions based on better scientific
evidences
• Proper safety assessment utilizing HER databases in
addition to the traditional approaches
RMP implementation utilizing EHR databases
• Efficient risk management
• Better quality of safety information
Provide leading-edge Medical Therapy with
ensuring Safety
• Scientific and speedy safety measure
Better quality of Medical Care
• Maximize benefit/riskratio

41. Our Goals
 Make new drugs and medical devices,
developed around the world, available to
patients available in a timely manner (maximize
benefits)
 Detect unknown risk emerged throughout from
development to post-marketing as early as
possible, to minimize the damage of the patient
as a result of timely action（minimize risk）
 Encourage efficient R&D with less waste of cost,
and improve safety measures, so as to promote
the medical innovations （cost optimization）

42. http://www.pmda.go.jp/english/index.html
 PMDA web site
Thank you very much for your kind attention !!