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Transcript of The PMDA’s GCP Inspection Methods, the Current State · PDF fileThe PMDA’s GCP...
The PMDA’s GCP Inspection Methods,the Current State of Overseas GCP
on-site inspections by PMDA
• Emiko KONDO
• Director, Office of Conformity Audit, PMDA Japan
1. PMDA outline2. Conformity Audit Program and the PMDA’s
GCP Inspection Methods3. Document-based Conformity Inspection and
GCP on-site Inspection4. Current State of Overseas GCP on-site
inspections
5. From Recent Topics
ContentContent
2
Pharmaceuticals and Medical Devices Agency
Introduction of PMDA
Established in April 2004Number of permanent staff
256 (Apr.’04) 341 (Apr.’07) 648 (Apr.’11) 751 (by the end of FY 2013)
PMDA submits performance report to MHLW annually.
3
Office of Review Administration
Office of Review Management
Office of Medical Devices I - III
Office of New Drug I - V
Office of Biologics I - II
Office of OTC/Generic Drugs
Office of Conformity Audit
Office of Relief Funds
Office of GMP/QMS Inspection
Office of Planning and Coordination
GLP GCP
GPSP
SeniorExecutive Director
Chief Executive
Auditor
Chief Safety Officer
Executive Director
Executive Director
Office of Regulatory Science
Office of International Programs
Chief Relief Officer
(As of November 2011)
Audit Office
Information Technology Promotion Group
Chief management Officer
Chief Actuary
Associate Executive director
AssociateCenter director
AssociateCenter director
Director ofCenter for Product
Evaluation
AssociateCenter director
AssociateExecutive director
International Liaison Officers
Senior Scientists
GMP/QMS
4
Auditor
Office of Safety I - II
Office of General Affairs
Office of Financial Management
Office of Standards and Guidelines Development
Organization Chart of PMDA
5
GCP On-siteInspection
Document-based
ConformityInspection
GLPInspection
GPSPInspection
Office Director
Office of Conformity Audit, PMDA
2. Conformity Audit Program and the PMDA’s GCP Inspection Methods
6
Outline of Approval Review Process
7
Applicant
PMDAPMDA○○Scientific ReviewsScientific Reviews○○Conformity AuditsConformity Audits( GLP/GCP/GMP etc. )
External Experts
Expert Discussion
Pharmaceutical Affairsand Food Sanitation CouncilMinisterMinister
MHLWMHLW Consultation
Advice
ApprovalApplication
Review Report
Good Clinical Practice(J-GCP)
■Article 80-2Clinical Trial NotificationReview before trial
■Article 80-2For Cause Inspection
■Article 14 para.3Standard for Application
■Article 14 para.5New Drug ApplicationReview & InspectionApproval
The PharmaceuticalAffairs Act, Enforcement
Regulations
Pharma-ceutical
Affairs Act
Legal BasisLegal Basis
Administration of the Enforcement of the Ordinance
Regarding Good Clinical Practice
■Article 43Standards for Documents Submitted in Application
Standards for Conducting Clinical Trial
Operation Procedures of J-GCP
8
9
Article 80-2 of The Pharmaceutical Affairs Act
If necessary, MHLW may Request “necessary reports” from sponsor,
medical institute, etc. Inspect the related structure (the hospital, clinic or
veterinary clinic, factory, office, etc) Question the employees or other personnel
concerned.
Legal Basis for “For Cause Inspection” in Japan
Article 14, Paragraph 3, of The Pharmaceutical Affairs Act
If a clinical trial is conducted for application submitted to MHLW, the sponsor must conduct a clinical trial in compliance with the standards provided in the MHLW Ordinance.
Article 43 of The Pharmaceutical Affairs Act, Enforcement Regulations
Reliability Criteria of Application Data are below.GCP, GLP, GPSP/GPMSPAccuracy/ Completeness, Comprehensiveness/ Retention
Legal Basis for Standard of Clinical Trials for Application in Japan(1)
10
11
The quality, efficacy and safety of the product (drug or medical device) shall be reviewed based on documents that are submitted with marketing approval applications of medicinal products.
A document-based inspection or an on-site inspection shall be performed to determine whether or not documents were created in compliance with the standards provided in the MHLW Ordinance.
Article 14, Paragraph 5(& Article 19, Paragraph 2), of The Pharmaceutical Affairs Act
Legal Basis for Standard of Clinical Trials for Application in Japan(2)
12
Our office conducts two types of inspection for documents for application.
Document-based conformity inspectionGCP on-site inspection
What is “GCP on-site inspection”?What is “Document-based conformity inspection”?
Source documents (medical records,
ECG, CT film, patient diaries, etc.)
Documents from all medical Institutions and Sponsor’s records
(Case Report Form, monitoring reports, etc.)
New drug/ medical device
application for approval
GCP on-site inspection
Document-based conformity inspection
Implementation system(including IRB and
SMO)
Implementation system(including CRO)
Clinical site Sponsor
Our office ensures conformity of the data of clinical trial13
Model Schedule of Inspection
Selection for CT and CS
GCP-Inspection(Clinical Site) GCP-Inspection
(Sponsor)
NDA Approval
Submit the Preliminary Documents
Document-based conformity inspection
(as needed)Inquiries/Reply
Notification of Inspection Results
4.5months
6.9months5.7months
※Performance of Document-based conformity inspection in 2010 (average)New Pharmaceutical Drug, classification No. 1 to 9, conducted on the same day inspection (excluding
additional Inspection) 14
• Study Selection (Document-based, GCP on-site)– Extract pivotal studies in application for approval
• Clinical Site Selection (GCP on-site)– New active pharmaceutical ingredients : Approximately 4
institutions (except in case of priority/prompt review )
– Orphan drugs and other application categories:Approximately 2 institutions
– Number of subjects, result of previous inspection and etc. will be considered
Selection of Study, Clinical Site and Subject (1)
Consultation for decision between Office of Conformity Audit and Office of Drug Evaluation
15
• Subject selection
– (Document-based) Sampling rate is dependent on importance of study (Sampling rate: up to 20% per 1 site)
– (GCP on-site) All subjects in the site
16
Selection of Study, Clinical Site and Subject (2)
• At any situation do we conduct inspection for foreign site?– If the case of pivotal clinical trials are conducted in
overseas (global clinical trials including Japan, bridging study)
– Approval in overseas and experience of Inspection(s) by Foreign Authorities will be considered
• Selection of Clinical Site– Same rule as inspection of clinical site in Japan
Inspection for Foreign Site
Consultation for decision between Office of Conformity Audit and Office of Drug Evaluation
17
• Warning/Critical findings
• No warning letter
18
Conclusion of Document-based conformity inspection
Need inquiry response and improvements are indicated Need inquiry response but improvements are not indicated No Inquiries
Conclusion of GCP on-site InspectionCompliance :
accepted as application dossier(Voluntary, improvements are indicated )
Compliance with condition : the violation of GCP was confirmed for a part of the subjects → accepted as application dossier after deleting the data
from NDA package.
Non-compliance : the violation of GCP was found generally and systematically
→ no reliability → whole clinical trial data should be deleted
19
20
3. Document-based Conformity Inspection and GCP on-site Inspection
Reviews of new Drugs
21
0
5
10
15
20
25
0
20
40
60
80
100
120
140
FY2006 FY2007 FY2008 FY2009 FY2010
Number of applications
Number of approved applications
Total review time(standard review products)
Total review time(priority review products)
Number Month
145159
92106
0
50
100
150
200
FY '07 FY '08 FY '09 FY '10
22
1) New Pharmaceutical Drug, classification No.1 to 92) Number of issued completion notice of inspection per year (applicant unit)
Number of Document-based conformity inspection for New Drug
Conclusion of Inspection for New Drug Document-based conformity inspection
【FY2009-2010, N=198】
23
No Inquiries156 cases (79%)
Warning / Critical findings5 cases (2%)
Need inquiry responseand improvements are indicated17 cases (9%)
Need inquiry responsebut improvements are not indicated20 cases (10%)
Note: In case of “No inquiries”, there are examples of application dossiers modification occurs.
14 cases (20%)
12 cases (18%)
12 cases (18%)
6 cases (9%)
5 cases (7%)
19 cases (28%)
Signature for CRF
Inadequate retention of raw source data with implementation of electronic archiving
Inconsistent Data
Response to deviation
Others
24*Number of issued inquiries of inspection (Total number), release to 41 application (applicant unit)
Data Management / Statistics Analysis
Issued inquiries of Inspection for New Drug Document-based conformity inspection
【FY2009-2010, N=68】
68
80
100
84 84
1 03 6 7
0
20
40
60
80
100
120
251) Number of issued completion notice of inspection per year (applicant unit)2) Including inspection for Foreign Sites
FY ‘10FY ‘09FY ‘08FY ‘07FY ‘06
Total number of inspection 1)2)
Number of inspection for foreign sites 1)
Number of GCP On-site inspection for New Drug
Conclusion of GCP On-site Inspection for New Drug
No non-compliance
• Compliance
・ Voluntary, improvements are indicated
・No indication
• Compliance with condition
• Non-compliance
26
39 cases (47%)
44 cases (52%)
1 case (1%)
Compliance(improvements
are indicated)
Compliance with condition
Compliance(No indication)
【FY2010, N=84】
27
0
50
100
150
200
250
FY2006 FY2007 FY2008 FY2009 FY2010
Sponsor
Clinical site
Number of GCP On-site inspection for New Drug
28
146 68 88 63 36
44
2140
25
24
41
7
18
1
7
0
50
100
150
200
250
1) Excluding inspections for Foreign Site
FY ‘10FY ‘09FY ‘08FY ‘07FY ‘06
Others
Safety Information
Monitor’s responsibility
Trend in Number of Findings at Sponsors(GCP on-site Inspection)1)
Changes in number of GCP on-site inspection for Clinical site(excluding inspections for foreign sites, clinical trials applied for New GCP only)
29*Data from notice of results issued each year (total number)
Number of Clinical site %
137
167
216
180 188
10083
98 9276
0
10
20
30
40
50
60
70
80
0
50
100
150
200
250
FY '06 FY '07 FY '08 FY '09 FY '10
Number of Clinical site
Number of Clinical site received warning Letter
% of Clinical site received warning letter
Changes in number of Findings to be improved- Inspection for Clinical sites - 1 of 2
30
(excluding inspections for foreign sites, clinical trials applied for New GCP only)
5420 44 27 36
14
7
1711 9
84
8372
27 13
50
2619
29 22
74
5063
7254
0
50
100
150
200
250
300 276
186215
166134
*Data from notice of results issued each year (total number)
FY ‘10FY ‘09FY ‘08FY ‘07FY ‘06
Number of cases
ProtocolCRFIRBRecord KeepingOthers
Changes in number of Findings to be improved- Inspection for Clinical sites - 2 of 2
31
113 97 9445 27
163
89121
121107
0
50
100
150
200
250
300
Individual subject
276
186215
166
134
(excluding inspections for foreign sites, clinical trials applied for New GCP only)
Number of cases
Framework of clinical trial
FY ‘10FY ‘09FY ‘08FY ‘07
*Data from notice of results issued each year (total number)
FY ‘06
Details of Findings to be improved in Clinical Site’s framework
32
13 cases (48%)
5 cases (19%)
9 cases (33%)
(Total 27 cases)
Outsourcing Duties
Control of Investigational Products
IRB
【FY2010, N=27】
33
9 cases (8%)
11 cases (10%)
43 cases (40%)
22 cases (21%)
20 cases (19%)
2 cases (2%)
Details of Findings to be improved in Clinical Site (Individual subject)
Selection of Subjects
Record Keeping Others
Informed consent
Case Report Form
Protocol Deviations
【FY2010, N=107】
34
4. Current State of Overseas GCP on-site inspections
35
※The total number of drugs and medical devices
Number of GCP onNumber of GCP on--site inspectionssite inspections(Institutions, Foreign countries)(Institutions, Foreign countries)
0
2
4
6
8
10
12
14
16
FY '06 FY '07 FY '08 FY '09 FY '10
Asia
AsiaAsia
36
Global Clinical Trials and GCP inspections
Basic Requirements• In compliance with the ICH-GCP in
all participating countries and clinical trial sites.
• All clinical trials sites accept GCP inspection from Japan.
Basic Principles on Global Clinical Trials, 28 Sep. 2007, MHLW Notification (No.0928010)
●MHW Ministerial Ordinance No.28 (Mar. 27, 1997)
●MHLW Ministerial Ordinance No.106(Jun. 12, 2003)
●MHLW Ministerial Ordinance No.72 (Mar. 31,2006)
●MHLW Ministerial Ordinance No.24 (Feb. 29,2008)
37
[Basic concept] - Harmonized with ICH-GCP
J-GCP
• Ethics quality
- Protect the rights, safety and well-being of trial subjects
• Science quality
- Accuracy and reliability of clinical trial data
- Accuracy and adequacy of evaluation
Points to be verified by Document-based Conformity Inspection and GCP on-site
Inspection
38
5. From Recent Topics
39
95
7154 52 63
4360 60 56
96105 107 109
119 121
722
500
406
391
463424 438
361414
497 504530
495553
616
0
100
200
300
400
500
600
700
800
0
50
100
150
200
250
300
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
J-GCPCT Activation Plan
Initial CT Notification (NCEs only)
CT notificationCT notificationInitial CT notification
J-GCP Enforcement
Larger Acceptance of
Foreign Clinical Data
40
5-year Strategy for Creating Innovative Medicines and Medical Devices
Trends in Trends in Notified CTNotified CT in Japanin Japan
• New 5-Year Clinical Trial Activation Plan
(2007-2011)
New Activation Plan will be published soon
41
Clinical Trials in Japan
42
1.Cost Costs are decreasing Overall costs are still high compare to US and Europe
2.Speed Overall, Japan’s level is comparable to US and Europe
3.Quality No significant issues were seen in the quality In general, the current level is sufficient It is important to maintain a certain level of quality,
but it is necessary for relevant parties to keep in mind not to go overboard in terms of quality
(Review Results of Working Group for the Streamlining of Clinical Trials, etc. 2010)
To ensure the reliability of the data more To promote more harmonization of J-GCP
and ICH-GCP To streamline clinical trial proceduresTo activate clinical trial by a person conducting
his or her own clinical trial
43
Revision of Notification on 24th October 2011
“Administration of the Enforcement of the Ordinance Regarding Good Clinical Practice
Ministerial Ordinance on GCP for Drug”
Smooth implementation of Clinical trials
Investigators IRB/EC
Sponsors(Pharmaceutical company, etc.)
Clinical trial office
Trial collaborators(CRC)
Subjects
Cooperation is indispensable.44
45
For patients’ prompt access to new and better drugs,
Thank you for your attention!