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

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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

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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)

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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

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• 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

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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

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• Warning/Critical findings

• No warning letter

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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

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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】

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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

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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

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13 cases (48%)

5 cases (19%)

9 cases (33%)

(Total 27 cases)

Outsourcing Duties

Control of Investigational Products

IRB

【FY2010, N=27】

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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】

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4. Current State of Overseas GCP on-site inspections

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※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

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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)

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[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

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5. From Recent Topics

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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

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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

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Clinical Trials in Japan

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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

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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

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For patients’ prompt access to new and better drugs,

Thank you for your attention!