japanese guidance and pmda’s experiences in …marketing database study for drugs (february 2018)...
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Japanese guidance and PMDA’s experiences in utilizing real world data for drug safety assessment
Dr Yoshiaki Uyama
Director, Office of Medical Informatics and Epidemiology
Pharmaceuticals and Medical Devices Agency (PMDA)Visiting Professor, Graduate School of Medicine, Chiba University
Visiting Professor, Graduate School of Medicine, Nagoya University
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Disclaimer /免责声明
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Data sources for post-market safety assessment of a drug
Spontaneous
ADR report
DBSafety
measure
DPC DB
Risk
communi
cation
Literatures
Overseas
regulatory
actions
Presentation in
Academic
Conference
etc
Claims
DB
Electronic
Healthcare Data
PMDA
Conventional
Information Sources
MHLW Medical
institutions
Launched in 2009
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PEpi Assessment in PMDA
In pre-approval
– Review Risk Management Plan
– Propose appropriate post-marketing studies etc.
In post-approval
– Conduct PEpi studies utilizing EMRs database for drug safety assessment
– Review PEpi data/reports submitted by industries etc.
Office of Safety
(I and II)Office of Medical
Informatics and
Epidemiology Office of New Drug
(I - V)
Role of Pharmacoepidemiologist
Linkage
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EPPV : Early Post-marketing Phase Vigilance (6 months intensive monitoring)
RMP : Risk Management Plan
Re-EX : Re-examination
Post-Market Clinical Trial (If necessary)
Planning of RMP
Considerations
on Post-market
Requirements
Re-EX
Spontaneous ADR Reporting
EPPV
4-10 years
Real-world use survey (Usually needed)
(Primary and/or secondary data collection)
ApprovalNDA
1 year
Overview of the regulatory schemes of pharmacovigilance in Japan
GPSP
GVP(Good Vigilance Practices)
GPSP
(Good Post-Marketing Study Practices)
Routine Pharmacovigilance Spontaneous reports, Periodic reports, etc
NDA Review
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Revised GPSP
Good Post-marketing Study Practice(The Ministerial Ordinance, Implemented on April 1st 2018)
Intervention
Primary datacollection
“Post marketing
clinical trial”
Observation
DB
“Post marketing
database study”
Observation
Primary datacollection
“Drug use
result survey”
Study frames in GPSP
Newly created
Revised GPSP clearly mentions that safety study based on database is
acceptable for re-examination under the Japanese Pharmaceuticals and
Medical Devices Law
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Related Guideline
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https://www.pmda.go.jp/safety/surveillance-analysis/0011.html
Many related guidelines focusing on Real World Data utilization
were recently published in synchronization to the GPSP revision
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 of a drug (January 2018)
Points to consider for ensuring data reliability on post-
marketing database study for drugs (February 2018)
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General steps for considering a plan of post-market studies (January 23, 2018)
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Step 1. What is a concern to be clarified in post-
approval?
Step 2. What is a suitable approach(i.e.; routine or
additional PV)? If additional, what is the
research question and suitable data
source?
Step 3. If additional, which GPSP frame must be
complied with?(clinical trial, observational study
with primary data collection, database)
Step 4. If additional, creating a study protocol
Afte
r ap
pro
val
ND
A re
vie
w
Step 1~4 per each safety specification
Describes basic
principle on how to
plan a post-market
study under Japanese
pharmaceutical
regulation
• Four steps approach
to plan an appropriate
post-market study
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-More details, More timely-
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MID-NET® Project
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The Medical Information Database Network in Japan for a
real-time assessment of drug safety (currently >4M patients).
PMDA
Hospital
Hospital
HospitalHospital
HIS dataDB
DB
DBDB
23 hospitals
In closed network
Hospital
Database
Claims data
DPC data
An integrated real time EMRs database with high quality
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Data categories in the MID-NET® system
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Database
Claims data
DPC data
HIS data
・Patient identifying data
・Medical examination history data
(including admission , discharge data)
・Disease order data
・Discharge summary data
・Prescription order/compiled data
・Injection order/compiled data
・Laboratory test data
・Radiographic inspection data
・Physiological laboratory data
・Therapeutic drug monitoring data
・Bacteriological test data
HIS data
Contents Standard Code
Disease ICD-10
Drug YJcode, HOT9
Laboratory test JLAC10
Bacteriological test JANIS
Example of standard code
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HospitalsHospitalsHospitals
Data integration method of MID-NET
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Central data centerOnsite Center
⑦View & Analysis
②Request for running program
individual leveldata
Summarized
data
①Create program
⑥Send data
User
Labo test data
Original databases
StandardizationAnonymizition
④ Output
Medical record
Claims Others
Common data model database
for MID-NET
Hospitals
SAS®etc
③Approve the request
Technical stafffor MID-NET
SAS®etc
⑤Approve to send data
individual leveldata
Summarized
dataSAS®
etc
Summarized
data
OR
⑧ Output
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Data Quality of MID-NET®
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Disease order data
Prescription order data
EMR MID-NET
Laboratory test data
compare
99.1%
67.0%
55.8%
Disease order data
Prescription order data
EMR MID-NET
Laboratory test data
compare
99.9%
100%
100.0%
PMDA has worked with cooperative hospitals
for assuring data quality of MID-NET®.
Before quality
managementAfter quality
management
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A pilot study of MID-NETⓇ
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At the post-market, the label change and
warning letter were issued for awaking the risk
of hypocalcemia associated with denosmab
Launched(2012.4.17)
Spontaneous ADR reports
・32 serious cases of hypocalcemiaincluding 2 death cases
(~2012.8.31)
MID-NET® pilot: Case 1
denosumab and severe hypocalcemia
Warning letter(Dear healthcare
professionals letter)
(2012.9.12)
A) More laboratory test on serum calcium etc.
B) Co-administration of calcium/vitamin D
C) Special caution to patients with severe
impairment of renal function
D) Prepare for emergency situation
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Monthly transition of the incidence of hypocalcemia
0.0
1.0
2.0
3.0
4.0
5.0
0.0%
20.0%
40.0%
60.0%
80.0%
100.0%
Ris
k r
ati
o
Inci
den
ce P
rop
orti
on
(%)
ランマークゾレドロン酸水和物リスク比
Blue
letterLabelling
change
Denosumab
Zoledronate
Risk ratio
MID-NET® pilot: Case 1
denosumab and severe hypocalcemia
・Calculate the incidence of hypocalcemia during 28 days from a prescription date.
・Perform segment regression analysis based on the incidence of hypocalcemia / month.
■ObjectiveTo examine impacts of label change and warning letter in clinical practice for the risk of hypocalcemia
associated with denosmab
Pilot studyUnpublished data
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Various kinds of data including laboratory test
results
High data quality (confirmed consistency with
the original data source)
Real-time data update (every 1-4 weeks)
Advantages and Limitation of MID-NET®
Advantages
• May be not enough sample size (currently 4M)
• No linkage of a patient among hospitals
• Need to consider data generalizability due to
limited cooperative organizations (mainly mid-
large size hospitals like University hospitals)
Limitations
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Lessons Learned in utilizing RWD
High data quality is pre-requisite in utilizing real world data such as claims and electronic medical records database.
To obtain clinically meaningful results, it is important to – understand characteristics of the database in details
– validate outcome definitions
– utilize appropriate methods for controlling confounding (e.g., propensity score matching)
– conduct sensitivity analysis
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Other recent activities
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Utilization of National Claims Database (NDB)
Claim data
Copayment
Claim
Patient$
National Claim Database (NDB)
Medical Information
Medical care
Claim
Claim data
MID-NET
InsuranceCard & ID
Medical Institution Insurer
National Institution forclaims review & paying agent
InsuranceFee
$
Payment$
Payment(as agent)
$
Health Insurance Association’s
Claim Database
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Characteristics of MID-NETⓇ and NDB
© 2018 DIA, Inc. All rights reserved
National Claims DB
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Data Type Electronic Medical Records Health Insurance Claims
Data Provider23 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
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Establishment of patients registries for regulatory purpose
Current patient registries mainly focuses on academic research for grasping patient backgrounds in clinical practice
– A lack of items for regulatory review
– Less interventional data (e.g.: prescription date, drug name, dose, prescription period etc.)
– Less standardized data
– Non-coded data
– A lack of quality management
– Small sample size
It is highly needed to establish a patient registry which can be
utilized for regulatory purpose
Clinical Innovation Network (CIN)
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Clinical Innovation Network (CIN)
Study group for epidemiological methods and data quality standards
Study group for ethical issues for registries and relationships with industries
AMED
Advice,Cooperation
MHLW
Utilizing registry data for promoting cost effective clinical
studies, accelerating drug development, and B/R assessment
Output
PMDACIN-Working Group About 20 members
from New drugs & Safety Offices
Muscular dystrophyRegistry
by NCNP
ALS(Antilymphocyticserum) Registry
By Nagoya Univ.
Cancer registry
By National Cancer Center Japan
Cerebral surgery
By Japan neurosurgical
society
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PMDA Regulatory Science Center
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Regulatory Science Center (Organization Structure)
Director of Center for Regulatory Science
Associate Center Director Associate Executive Director
Office of
Medical Informatics
and Epidemiology
Office of
Advanced
Evaluation with
Electronic Data
Office of
Research
Promotion
Coordination
Officer for
Evaluation of
Advanced
Science and
TechnologyEMRs database
(RWD) CDISC database
(Clinical trials)
Big-Data analysis in regulatory science
Closely working together with Office of New Drugs, Office of Safety etc.
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Active utilization of e-DATA
Office of Research Promotions
Coordination and project management in
regulatory science research and publishing
guidelines (Governance office of Science board etc.)
Continuous assessment on
Benefit/Risk of a drug (e.g.: proper
target population, doses, warning)
Maximal and effective utilization
of valuable data
Nurturing of talented experts, accumulating
scientific knowledge
Regulatory Science Center
Utilization of EMR database for pharmaco-
epidemiological analysis (PEpi-study, cross-
product analysis for better benefit/risk assessment)
-Implemented in 2016
Office of Advanced Evaluation with Electronic Data
Utilization of clinical trial data on CDISC
database (modeling & simulation, cross-product analysis
for better benefit/risk assessment)-CDISC data has been submitted by MAHs since October 2016
Office of Medical Informatics and Epidemiology
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)
Post-Approval
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Coordination
Officer for
Evaluation of
Advanced
Science and
Technology
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Collaborative Functions of
Regulatory Science Center with other offices
Office of
Research
Promotions
Office of
Advanced
Evaluation
with
Electronic
Data
Office of
Medical
Informatics
and
Epidemiology
Offices of Safety
Offices of New Drugs
Support epidemiological
data evaluation and study
planning
Safety measures based on
epidemiological analysis etc.
Safety measures based
on cross products
analysis etc.
For drug approval
For safety measures
Support advanced analysis,
Create disease model for
data evaluation etc.
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Active utilization of EHR databases toward advanced medical care
RMP implementation utilizing EHR databases• Efficient risk management
• Better quality of safety information
Better quality of Medical Care
• Maximize benefit/risk ratio
Provide leading-edge Medical Therapy with
ensuring Safety
Regulatory decisions based on better scientific
evidences• Proper safety assessment utilizing HER databases in
addition to the traditional approaches
• Scientific and speedy safety measure
Medical Institutions
Public
Industries
MHLW/PMDA
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PMDA web site
http://www.pmda.go.jp/english/index.html
E-mail:[email protected]
Thank you very much for your kind attention !!
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?