Postmarketing Regulations in Japanand 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 Devices Agency, Japan
3rd India - Japan Medical Products Regulation Symposium 2018
Introduction
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!
Comparison of median review time of NMEs among 6 agencies
To put innovative products into practice in Japan first in the world
Designation Criteria
- 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
Designation Advantage
1. Prioritized
Consultation
[Waiting time:
2 months→1 month]
4. Review Partner
[PMDA manager as a
concierge]
5. Substantial Post-Marketing
Safety Measures[Extension of
re-examination period]
2. Substantialized Pre-
application Consultation
[de facto rolling submission
before application]
3. Prioritized Review
[12 months → 6
months]
Designation Procedure
SAKIGAKE (forerunner)Review Designation System
1. Initiation by applicant 2. Initiation by the MHLW 4
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 consistent with 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
5
Benefit & Risk Assessment during the product lifecycle
and Safety: “What to do for safety?”
Reactions to booming “Sakigake” approaches in the review
Early patient access & post-marketing safety vs.
sustainable and cost-effective product development
Nationwide Adverse Drug Reaction/EventReporting System
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-
Exam
ina
tion
Spontaneous ADR Reporting
EPPV
4-10 years
Real-world use survey (Usually needed)
(Primary and/or secondary data collection)
ApprovalNDA1 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
6 months
Release of safety information
ADR reports
Latest research(scientific
reports etc.)
SituationsOverseas
‘trigger’
MAHs
Review of safety measures
Tendency of ADRs
Release of safety informationRevision of precautions in labeling, etc.
PMDA-ATC Pharmacovigilance Seminar 2017 (APEC Center of Excellence Workshop)8
MHLW
Spontaneous ADR and Infection Reports
0
10000
20000
30000
40000
50000
60000
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
件数
年度
企業報告数
4ワクチン報告数
医療機関報告数
企業報告義務化(1980)
モニター病院の拡大(1988)
感染症報告義務化(1997)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
(2003)
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)
Voluntary MAH reporting
/ monitor hospital system
Mandatory
MAH reporting
Expansion of monitor
hospitals
Infection Report introduction
Monitor hospital system abolished
Legally binding
Health Professional Report
MAH reporting
Vaccine reporting
Health Professional reporting
Vaccine AE
reporting under
immunization
regulation
Classification of spontaneous reports from MAHs
Types of MAHs who report ADRs
FY2014 FY2015 FY2016
No. % No. % No. %
JPMA companies 42,614 86.5% 43,303 84.8% 47,528 85.2%
Other than JPMA
companies6,666 13.5% 7,762 15.2% 8,288 14.8%
Total 49,280 51,065 55,816
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
approval4,640 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
Consideration should be given to the environmental change surrounding
the safety of pharmaceuticals, such as the spread of generic medicines
in recent years, the occurrence of adverse events associated with
polypharmacy in the elderly.
Collaboration among medical professions in 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.
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.
（Summary）
（Points）
11
Administrative communication issued on July 10 2017.
Incentive (fee) for pharmacy to support AE reporting was covered by Medical Fee Revision 2018
Risk communication activities
Scientific evaluationfollowed by consideration of proper safety measures
Collection of safety information including ADRs
Information provision in a timely manner
12
MAHs
MHLW
HCPs
Public
Labeling change orders from MHLW/PMDA : Pharmaceuticals
FY2014 FY2015 FY2016
Pharmaceuticals within re-
examination (exclusivity)
periods
45 48 49
Pharmaceuticals after re-
expiry of examination
(exclusivity) periods
47 34 96
Total 92 82 145
Regulatory Output : Labeling change regulatory actions
13
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
Labeling change orders from MHLW/PMDA :
Medical Devices and Regenerative Medical Products
Ref) http://www.pmda.go.jp/english/service/precautions.html14
Issued monthly basis
Communications through PMDA
General overview of risk communication provided by MHLW
PMDA-ATC Pharmacovigilance Seminar 2017 (APEC Center of Excellence Workshop)15
Target user HCPs
Preparation MHLW
Frequency 10 times/year
English version available? Yes
• A summary of cases served as the basis for revisions of precautions is also included
• Published 1-2 months after Instructionsfor Revision of Precautions
• Cases which require continuous alert repeatedly is also introduced.
MHLW PMDSIMHLW Pharmaceuticals and Medical Safety Information
https://www.pmda.go.jp/english/safety/info-services/drugs/medical-safety-information/0014.html
Product specific Risk Management Planand
Pharmacoepidemiology
Clinical Safety
Data
CT start NDA Approval
Pre-approvalPost
-approval
Keep agreeable benefit-risk balance in the lifecycle
Real world, day to day medicine
Clinical TrialPhase
“Optimal use”, at each stage, from pre-marketing to post-marketing,
Pre-market Post-market
Consistent risk management From rigorous CTs To complex real world after product launch
Clinical
Effectiveness
Data
2010/07/08
リスク最小化活動Risk Minimization Action Plan
安全性監視計画Pharmacovigilance Plan
Regular
Additional
安全性検討事項Safety Specification
Serious specified risk
Serious potential risk
Serious missing
information
Additional measure
No
Yes
Concept of structured RMPimplementation in line with ICH-E2E guideline
Spontaneous Rep.
Literature survey
Labelling
Commentary
EPPV
Medical experience survey
Controlled study
Pharmaco-epidemiology
study
Patient medication guide
Leaflet
Education programme
Distribution control
Labelling revision
Vigilance
and / or
minimisation？（evaluation）※
Additional vigilance
Additional minimisation
Re
gu
lar re
vie
w
Limited medical
institutions and limited
doctors
Patient selection
criteria
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
19
An attractive alternative to trials in which electronic health records
are used can be found in trials of alternative interventions involving
patients who are already enrolled in disease-specific or intervention-
specific registries that incorporate detailed patient phenotypes and long-
term follow-up data. This framework provides an efficient and low-
cost opportunity for conducting pragmatic trials (e.g., the TASTE
trial)http://www.nejm.org/doi/full/10.1056/NEJMra1510059?query=featured_clinical-trials
Pragmatic clinical trials using registries of
medical/health recordsN Engl J Med 2016; 375:454-463 August 4, 2016
What will become possible by utilizing a large-scale medical information database?
Comparison with
other drugs
Comparison with
symptoms due to
underlying disease
Verification of effects
of safety measures
Can compare frequency of
ADR occurrence drugs in
the same class
Rate of occurrence of ADRs
(ADRs/number of patients who
used the drugs)
Treated with
Drug A
Treated with
Drug B
Rate of occurrence of
symptoms
(symptoms/number of patients
who used the drugs)
Treated with
Drug A Treated without
Drug A
Can ascertain whether
the occurrence of a
certain symptom is
increased by
administration of a drug
Rate of occurrence of ADRs
(symptoms/number of patients
who used the drugs)
Before safety
measures
After safety
measures
Can compare to see whether
implementation of safety
measures actually results in
a change in ADR frequency
• 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 Medical Research 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.
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
・ 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.
Sakigake designationDesignate the product developed
ahead of the world for Japanese market with prominent clinical benefit for regulatory support to expedite the process (ex.review time : 6 months）
Real world Data utilization
PMDA’s review quality for reform
• In response to innovative drugs R&D, PMDA will perform organizational strengthening and review quality improvement.
「Conditional & Accelerated Approval」&「”Sakigake” designation」 to be stipulated in the legislation
5.1M$ for FY2018
18M$ for FY 2018
Exploratory
Trial
Conditional
Accelerate
d Approval
Confirmation of
effectiveness and
safety, using
post-marketing
data, e.g. real
world evidence
Confirmation of
Approved
maters
・Release
commitments
・Expand
indications
Innovative products that
reasonably predict higher
clinical benefit
Post-marketing
Conditional Accelerated Approval
Data sources for post-market safetyassessment 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
Collaboration
Expected Outcome：Prompt and precise safety actions
PMDAsafety information collection and
analysis
Researcher, MAHs
Prompt safety
action
site
sitesite
DB
DB
DBDB
Networking 10
sentinel sites of
23 hospitals
Data
analysis
Tohoku U, Tokyo U, Chiba U,
NTT Hosps、Kitasato Hosps,
Hamamatsu M U, Tokushukai
Hosp Group, Kagawa U,
Kyushu U, Saga U.
site
DBSentinel site
hospitals
EHRClaim Data
DPC
DataLab. test
Medical Information Database Network（MID-NET）
【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 comprehensiveness of 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 / user fees.
● April 2018- ： Full scale operation, enable MAHs and researchers to use MID-NET
Promote safety measures by pharmaco-epidemiological method using medical information
database.
MHLW/PMDA have established a medical information database for collecting large-scale
medical data at sentinel site hospitals and have constructed analytical systems at PMDA
since FY 2011.
4,000,000
patients included
Common Data Model of the MID-NET®
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
YJ, HOT9
(JP specific codes)
Laboratory test
JLAC10
(JP specific codes)
Example of standard codes
Reliable DataInappropriate analysis ＝ Uninterpretable
results
Importance of Data Quality Management
Unreliable Data
Appropriate analysis ＝ Uninterpretable
results
Reliable DataAppropriate analysis ＝ Interpretable
results
High data quality as well as appropriate analysis are pre-
requisite in utilizing real world data for providing scientifically
interpretable results
Data Quality of MID-NET®
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
Post-marketing safety measures using MID-NET
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
Real world data population
Clinical Trial 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
28Improve quality of safety measure
and promote R&D
One of the biotech / venture supporting measures
Monthly transition of the incidence of hypocalcemia
29
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
ort
ion
(%
) 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:denosumab and severe hypocalcemia
Pilot study
・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
30
MID-NET® pilot:Risk of Acute Myocardial Infarction Associated with Anti-
Diabetes Drugs
Pilot study
Incidence Rateper 1,000 Person-years
Adjusted Rate Ratio
（95%CI）
AdjustedHazard Ratio
（95%CI）Non-sulfonylurea insulin
secretagogues2.4 1［ref］ 1［ref］
DPP-4 inhibitors 2.10.86
(0.25-2.90)0.93
(0.08-10.80)
Table. Adjusted rate ratio and adjusted hazard ratio for AMI in the standardized population.
Objective Cardiovascular events associated with anti-diabetes drugs are
common risk in post-marketing phase To compare the risk of acute myocardial infarction (AMI)
associated with DPP-4 inhibitors monotherapy to other anti-diabetes drugs monotherapy.
Exposed GroupDPP-4 inhibitors
(n=2,578)
MID-NET®
(2010～2015）
DPP-4 inhibitors（n=2,952）
Cohort：New users of anti-diabetes drugs monotherapy
Propensity score standardization
(SMRW)
■Outcome definition（AMI）
Definitive diagnosis of AMI, Admission* and Elevation of cardiac biomarker values*（CK or CK-MB：≧URL ×2 or Troponin T：≧0.1ng/mL）
*during 30 days before and after the diagnosis date of AMICases of AMI Cases of AMI
Occurrence of AMI
Control groupGlinides
(n=2,717.2)
Glinides(n=237)
Characteristics of MID-NETⓇ and NDB
© 2018 DIA, Inc. All rights reserved
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
National Claims DB
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
Risk evaluation of atypical antipsychotics (AAP) for Hyperlipidemia: A Sequence Symmetry Analysis
Risperidone
Aripiprazole
Olanzapine
Number of days since an initial administration of AAP
Takeuchi Y et al, Drug Saf (2015)38: 641-650
Adjusted sequence ratio (95 % CI)
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
Use Result surveyPost-marketing
clinical studyPost-marketing
Data base survey
Specific Use
Result survey
Post-marketing
Study
General Use Result
survey
Orange cells are added by the expected Ordinance revision
GPSP Ordinance Revision
Use Result
controlled survey
April 2018 Implementation
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)
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
PMDA Regulatory Science Center
Active utilization of e-DATA
38
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
Coordination
Officer for
Evaluation of
Advanced
Science and
Technology
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
Office of Safety
Office 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.
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
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）
41
PMDA web site
http://www.pmda.go.jp/english/index.html
Thank you very much for your kind attention !!
