2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing1
The recent progress ofGCP inspection in Japan
Yoshiko Komuro, Ph.D
Deputy Inspection Director, Office of Non-clinical and Clinical Compliance
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing2
Agenda
1. Introduction of our office
2. Trends of clinical trials and approved drugs utilizing MRCTs
3. GCP inspection procedure in Japan
4. GCP on-site inspection
5. International cooperation
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing3
Pharmaceuticals and Medical devices Agency
3
Kansai Branch
Date of Establishment : April 2004
Scientific review for drugs & Medical devices
GCP, GLP, GMP inspection
Consultation on clinical trials
Safety measures
Relief services
Major services
Tokyo
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing4
PMDA’s safety triangle
ReviewReduction in risk
Safety
Continuous risk
mitigation efforts
ReliefRelief measures
for health damagecaused by
risk factors
Japanese citizens
*GLP: Good Laboratory Practice, GCP: Good Clinical Practice, GPSP: Good Post-marketing Study Practice
GMP: Good Manufacturing Practice, QMS: Quality Management System
Consultations Drug reviews Medical device reviews GLP/GCP/GPSP inspections * GMP/QMS inspections * Standards development
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing5
Organizational chart of PMDA
Office of Review Management
Office of Standards and Guidelines Development
Office of Vaccines and Blood Products
Office of New Drug I-V
Office of Medical Devices I-III
Office of OTC/Generic Drugs
Office of Non-clinical and Clinical Compliance
Office of Safety I, II
Office of GMP/QMS Inspection
Offices of General Affairs / Office of Financial Management / Office of Planning and Coordination
Auditor
Auditor
Office of Review Administration
Chief Relief Officer
Office of International Programs / International Liaison Officers
Senior Executive Director
Executive Director
Executive Director
Directorof Center
for Product Evaluation
Associate Executive Director
Associate Center
Director
Associate Center
Director
Associate Center
Director
Chief Safety Officer
Chief Executive
Office of Cellular and Tissue-based Products
Principal Senior Scientist / Senior Scientists
AuditOffice
Chief Management Officer
Deputy Executive Director
Associate Executive Director
Office of Regulatory Science
Office of Relief Funds
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing6
Regulatory authority in Japan
Scientific review for drugs & medical devices
GCP, GMP inspection
Consultation on clinical trials
etc.
Final authorization of applications
Publishing guidelines
Advisory committee
Supervising PMDA activities
PMDAMHLWPharmaceuticals and Food Safety Bureau, MHLW Pharmaceuticals and Medical Devices Agency
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing7
Trends of MRCT-related clinical trial notifications in Japan
508 524560
632689
556601 601
657
3882
113 134 123 137173 181
276
7.5
15.6
20.2 21.217.9
24.6
28.8 30.1
42.0
0.0
10.0
20.0
30.0
40.0
50.0
0
200
400
600
800
Total MRCT % of MRCT
Nu
mb
er
of
CTN
s
%
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing8
Trends of approved new drugs based on MRCTs in Japan
81 79
107114
130 134 138
119 115
1 0 4 712
19 2232
23
1.20.0
3.7
6.1
9.2
14.215.9
26.9
20.0
0.0
10.0
20.0
30.0
0
50
100
150 %
Total MRCT Bridging Strategy % of MRCT
Nu
mb
er
of
app
rove
d d
rugs
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing9
Approved new drugs based on MRCTs in Japan
• 123 applications were approved as of March 31, 2016
Red : Asian Trials
2012
DenosumabAripiprazoleOlanzapineExenatideCrizotinibBudesonide/FormoterolEsomeprazoleFormoterolAxitinibBudesonide/FormoterolAtomoxetineAfliberceptInsulin -DegludecGlycopyrroniumPazopanibEverolimusFesoterodineApixabanInsulin-degludec+Aspart
PaclitaxelPregabalinTofacitinibRegorafenibOfatumumabBevacizumabPertuzumabLixisenatideRanibizumabRegorafenibIndacaterol/GlycopyrroniumPaliperidoneVilanterol/FluticasoneBevacizumabAflibercept
2013 2014
RiociguatTadalafilAfatinibTuroctocog alfaRanibizumabPazopanibGoserelinEverolimusTolvaptanFavipiravirTapentadolTofogliflozinAlogliptinSorafenibAnti-Inhibitor-Coagulant-ComplexUmeclidinium/VilanterolDelamanid
SirolimusRuxolitinibEftrenonacog alfaEfinaconazoleLamotrigineAflibercept (PM)Edoxaban (AF)Edoxaban (VTE)BosutinibSuvorexantAflibercept (DME)TiotropiumDarbepoetin alfaEmpagliflozinElosulfase alfaSecukinumabInsulin glargine(BS1)Nonacog gamma Efraloctocog alfa
2015 2016
EvolocumabLevetiracetamSebelipase alfaAsenapinePerampanelMepolizumabCeritinibOsimertinibRurioctocog alfa pegolOctocog beta
RiociguatLenvatinibEliglustatGadobutrolAripiprazoleUmeclidiniumTrifluridine / TipiracilRamucirumabCatridecacogAfliberceptBortezomibInsulin-glargineAsfotase alfaNintedanibPanobinostatInsulin-degludecLamotrigineRuxolitinibDutasterideOmarigliptinTiotropium/OlodaterolLapatinib
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing10
Office of Non-clinical and Clinical Compliance
Office Deputy Director
GCPon-site
Inspection
Document-based
Inspection
GLPInspection
GPSPInspection
Office Director
DevicesInspection
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing11
Two types of inspection in Japan
GCP on-site Inspection
Source documents (medical record,
patient diary, etc.)
Documents from all medical Institutions and sponsor’s records
(case report form, monitoring reports, etc.)
New drugapplication
for approval
Implementation system
(including IRB and SMO)
Implementation system(including CRO)
Medical Institution Sponsor
We verify conformity of the data of clinical trials in application dossier
Document-based Inspection
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing12
Typical flow chart of review and inspection
Document-based
GCP on-site
PMDA
NDA
MHLW
Approval
Simultaneous implementation of document-based and on-site inspection is under way
Inspection result
Sponsor
Medical institutions
Inspection
Inspection result
Review report& Result
■Site/studyselection■Scheduling
NDA review
Discussion with review team before
the inspection
Pharmaceutical Affairs and Food
Sanitation Council
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GCP on-site inspection- Overview -
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing14
Overview of GCP inspection
Data collection system
Systemfor Analysis
Patient data listing
Table/Figure
CSR
Data ManagementSystem
CRFpaper
Program
Input or description
Loading (mainly)
Input to “EDC”
eCRF(PDF)
Clinical data
Result Report Data
Collect clinical trial data
On-site inspection Document-based inspection
CRF:Case Report Form, eCRF:electronic Case Report Form, CSR:Clinical Study Report
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Outline of GCP on-site inspection
1. Select medical institutions/clinical trials for inspection
2. Fix inspection schedules of sponsor and medical institutions
3. Establish an inspection team
4. Send notifications to sponsor and medical institutions
5. Receive pre-submitted documents from sponsor and medical institutions
6. Conduct inspections
7. Write an inspection report
8. Evaluate compliance based on GCP at monthly meetings
9. Send notifications of inspection results to sponsor
and medical institutions
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing16
Typical schedule of inspection
Selection
NDAPre-submitted
documents (as needed)Inquiries/Reply
Notification of inspection results
Approval
On-site Inspection**
Notification of conducting inspection
1.5(Months)
0 4 5 - 5.5 7 12
Close communicationwith applicant*
**Domestic sites → Foreign sites → Foreign sponsors → domestic sponsors * Arrangement of inspection schedule, F2F meeting
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing17
Selection of clinical trials and medical institutions to be inspected(point to consider)
Clinical trials
Medical Institutions
Priority in the clinical data package for J-NDA (e.g. pivotal trial, bridging trial)
Sampling number• The drugs with new active pharmaceutical ingredients (Excluding the drugs of quick/priority review, the orphan drugs)
→Approximately 4 institutions • Others
→Approximately 2 institutions The number of subjects Results of previous inspections
• Clinical trials and medical institutions to be inspected are decided on after discussing them with NDA reviewer.
• Additional institutions will be inspected if there are problems identified during review/inspection process.
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing18
Selection of clinical trials and medical institutions in oversea inspection
Conduct oversea inspection?
Points to be considered
(Pivotal trial in the package) was conducted in foreign countries?
(Product) already approved by foreign authorities?
(Trial/Institution) already inspected by foreign authorities?
Others (total ratio/number of subject in Japanese sites, etc.)
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing19
Selection of Clinical trials and Medical Institutions in oversea inspection (cont.)
Which country/medical institutions to be inspected ?
Points to be considered
Conducted clinical trials at the site
The number of subjects
Results of previous inspections
Future inspection plan
Inspection of foreign authorities
Others (security situation, etc.)
Usually 2 medical institutions in 1 country are selected.
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing20
Main points in the checklist of medical institution
Checklist (Only Japanese) is available in the PMDA websitehttp://www.pmda.go.jp/files/000205701.doc
Outline of clinical trialsRequirement of Medical institute
Control of Clinical Trials
InvestigatorRequirement, work information
transfer to the staffs
IRBOrganization, Management,
review process to result notification
SubjectsSelection of the subjects
Informed consent
Case reportConsistency to the source documents, Investigator’s
confirmation
Control of clinical trialsAE information, Investigational drugs control, Record keeping
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing21
Main points in the checklist of sponsor
Checklist (Only Japanese) is available in the PMDA websitehttp://www.pmda.go.jp/files/000205702.doc
Clinical trial management Preparing clinical trials
Selection of medical institute,Principal investigator
AuditContract of CT
Protocol, Investigator’s brochure
Record keeping
MonitoringSafetyinformation
Control ofIMPs
Compensation
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing22
GCP on-site inspection- Performance -
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Trend in GCP on-site inspection 1)
FY’ 11 FY’ 12 FY’ 13 FY’ 14 FY’ 15
Number of drugs
84 99 125 110 106
Number of sponsors
80(8)
Total:88
97(5)
Total:102
120(6)
Total:126
103(7)
Total:110
108(6)
Total:114
Number of medical
institutions
175(13)
Total:188
190(9)
Total:199
233(7)
Total:240
218(10)
Total:228
213(12)
Total:225
( ): The number of inspections in overseas
1) New Molecular Entities, except generic
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing24
Detail of GCP on-site inspection in overseas
Breakdown by nations
The number of IPs inspected
681)
The number of sponsors inspected
(including CROs)
662)
USA 20 Swiss 2 Netherlands 1Germany 7 Poland 2 Philippines 1
China 6 Belgium 2 France 1Korea 5 Spain 2 Czech 1
UK 4 Brazil 1 Italy 1Taiwan 4 Romania 1 Canada 1Austria 3 India 1
The number of medical
institutions inspected
92
USA 21 Canada 4 Brazil 2China 12 Czech 2 Ukraine 1Korea 8 India 2 Netherlands 1
Taiwan 7 Hungary 2 Belgium 1Germany 6 Philippines 2 Australia 1
UK 4 Austria 2 Poland 1Spain 4 France 2 Ukraine 1
Romania 4
1) Counted based on the notification published during Apr. 2008~Mar. 20172) 9 cases are coincident inspection of GCP on-site inspection and document-based inspection
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing25
Result of GCP on-site inspection for new drug (FY2014) 1,2)
Compliance(Voluntary actions to improve indicated)
22 cases, 21%
Compliance(no indication)82 cases, 77%
Compliance with condition 2 cases, 2%
A total of 106 cases 3)
1) The products for which the inspection result notification was issued from Apr. 2014 to Mar. 2015.
2) There were no “non-compliance” cases in FY 2014. 3) Number of inspection result notifications issued (per applicant), except sponsor-investigator.
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing26
Findings for sponsors in Japan (FY2014) 1)
N=28 cases2)
1) The products for which the inspection result notification was issued from Apr. 2014 to Mar. 2015.
2) Number of findings for sponsors(Except the Sponsors in Overseas, sponsor-investigator)
Details of findings for monitor’s responsibility (N=14 cases)
Monitor’sResponsibility14 cases, 50%
Safety information reporting
6 cases, 21%
Others8 cases, 29%
Protocol Deviation
8 cases, 57%
Discrepancyof CRF
4 cases, 29%
Selection of subjects
2 cases, 14%
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing27
Findings for sponsors in overseas (FY2014) 1)
Monitor’s
responsibility
27 cases
Others
5 cases
Details of findings for monitor’s responsibility
N=27
Protocol deviation
10 cases
Discrepancy
of CRF
9 cases
Deficiency of
Subinvestigator’s
designate
3 cases
Others
5 cases
(N=32 cases)
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing28
General findings for medical institutions(FY2014 for Japan, FY2008 – 2014 for overseas)
Japan
IRB‘s review11 cases
Contract of outsourcing etc,
9 cases
Investigational product control
2 cases
PI/Sub-PI etc2 case
Insufficient description of contract
1 case
Safety information reporting1 cases
(N=26 cases)
Overseas
Investigational product control
7 cases
PI/Sub-PI etc,6 case
Informed
consent form
2 cases
Contract of outsourcing
1 case
(N=17 cases)
Contract of clinical trial
1 case
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing29
Findings for individual subjects (medical institutions)(FY2014 for Japan, FY2008 – 2014 for Overseas)
Protocol Deviations35 cases
Informed consent5 cases
CRF4 cases
Record keeping3 cases
(N=51 cases)
Protocol Deviations35 cases
CRF16 cases
Informed consent7 cases
Selection of subjects5 cases
Record keeping3 cases
(N=71 cases)
Japan Overseas
Selection of subjects4 cases
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International cooperation in GCP area
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Globalization challenges
• Increasing number of MRCTs • Resource challenges, Inspection coverage• Need for synergies and avoidance of duplication
Regulatory authorities should work closely to secure the quality of the result of clinical trial and protection of subject all over the world
• Promote confidence building with other regulatory authorities- Mutual understanding on GCP regulation in each region- Confirmation on the practical GCP inspection level
• Make a platform to exchange information of GCP inspection
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing32
• Participate in the inspection of Japanese site by foreign inspectors
• Sharing information of inspection etc. with FDA and EMA
• Acceptance of foreign regulators as trainees for inspector training by PMDA
• Asia training center (ATC)
Recent communication with foreign regulatory agency
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Training seminar for inspectors from foreign regulatory agencies
2017 Sep 7th-8th 3rd Asia QA Forum Conference in Beijing34
• PMDA websitehttp://www.pmda.go.jp/english/index.html
• Information of GLP / GCP / GPSP Compliance Assessments(English)http://www.pmda.go.jp/english/review-services/glp-gcp-gpsp/ 0001.html(Japanese)http://www.pmda.go.jp/review-services/inspections/0001.html
• International activitieshttp://www.pmda.go.jp/english/int-activities/index.html
Reference
Thank you for your attention.
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