The EMA Inspection ProcessProcedures, Timelines & Expectations

Presented byVaska Toné

TYPES OF INSPECTIONS

EMA DEFINITIONS & PROCEDURES

EMA INSPECTION TIMELINES

EMA INSPECTION PREPARATION

DOSSIER REQUEST

SITE SELECTION

INSPECTION SELECTION

INSPECTION PROCESSES

GCP Inspections

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GCP Inspections

Systems Inspections● Look at all relevant SYSTEMS for CTIMPs

o CTIMP = Clinical Trial of Investigational Medicinal Product

● Check that the expected process is used in practice

Study Specific Inspections● Carefully review the study data● Is it real, reliable and trustworthy?● Reduced reliance on interviews● But site staff will/may be interviewed

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Inspection Reason

Mainly based on questions raised by assessors reviewing the submitted dossier

But can be caused by intelligence obtained relating to potential problems within clinical trials

EMA has no inspectors – they “subcontract” inspecting to the individual member states to perform the inspection according to the EMA SOPs

Each member state has its own inspectorate and inspects in its own territory independently

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EMA Definitions

Reporting Inspectorate (RI)● The inspectorate member state designated by the EMA to

manage the inspection and timelines and writing the Integrated Inspection Report

Reporting Inspector● The Inspector at the RI with responsibility for the inspection

Lead Inspector (LI)● The inspector leading the conduct of an inspection and writing

the Inspection Report. The LI is based in the member state where the inspection is performed

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EMA Definitions

Inspection Report (IR)● The report produced after each site inspection by the Lead

Inspector. Should responses not be provided in the expected timeframe this fact is documented in the report by the LI.

Integrated Inspection Report (IIR)● Prepared by the RI based on each of the IRs for the whole

inspection. Contains an evaulation of the quality of the data and GCP compliance. Signed by all LIs who have written IRs for the overall inspection. Includes recommendations for follow-up and further inspections

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EMA Inspections

EMA has no inspectors – they “subcontract” inspecting to the individual EU member states to perform the inspection according to the EMA SOPs

Each member state has its own inspectorate and inspects in its own territory independently

All EMA procedures are documented and in the public domain

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EMA Procedures

All EMA procedures are documented and in the public domain

Located on the EMA website under:o EMA Home Regulatory → Human Medicines → Inspections →

GCP Compliance → Inspections Procedure

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000140.jsp&mid=WC0b01ac05800296c6

This documents all the EMA SOPs relating to GCP inspection processes

Each SOP can be opened and is readable

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EMA Procedures9

EMA Procedures10

EMA Timelines11

Dossier

Dossier request – usually 30 days prior to inspection• Can be very helpful to get to know your own company better and for

QA to be “In the Loop”• Takes a long time to complete with participation of many

departments• Listing of systems in use for the trials and those outsourced• List of trials taken place over a period of years• Plan – inspector prepares with input from the inspectee• Studies are pre-selected by the inspectors• Generally more than one study selected

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Dossier

Dossier Details: There are 2 sections that need to be completed:

• Section 1 has 6 required items to be provided:• Item 1: Organizational Charts• Item 2: List of Clinical Trial Processes (SOPs, etc)• Item 3: Adverse Event Reporting Systems & Procedures• Item 4: List of Computer Systems & Validation Status• Item 5: For non-commercial organizations only• Item 6: List of clinical trials (use the provided spreadsheet)

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Dossier

Section 2 has 3 items:• Item 1 & 2: Names and addresses of all facilities involved in the

clinical trials, including:o Vendors (i.e. labs, drug depots) o CROs (full scope, niche i.e.: DM, Stats, Safety)o Support services (readers: ECG, CT/MRI/Bone

Scan imaging, etc)

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Dossier

Section 2 has 3 items:• Item 3: Summary information of your organization’s clinical trial

systems (info on 1 side of paper for each department)

1. Contract and Agreement Preparation

2. Quality System (including training)

3. Clinical Quality Assurance

4. Project Management

5. Clinical Trial Monitoring

6. Pharmacovigilance (including medical expertise)

7. Regulatory Affairs

8. Computer Systems

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Dossier

Item 3 continued: 9. Investigational Medicinal Products (IMP)

10. Data Management & Statistics

11. Clinical Trial Reporting

12. Trial Master File

13. Archiving

14. Clinical Facilities

15. Laboratories

16. Equipment Maintenance

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Investigator Site Selection

EMA• Can be selected by the EMA or the assessors of the

data depending on the information and intelligence held about each investigator site

• The inspectors may add in more or change the investigator sites after review of the data

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Inspection Process

• Usually site inspection AFTER the Sponsor/CRO inspection but NOT always

• If the Inspection is based on a marketing application, more emphasis will be placed on data credibility and assurance that data exists and is true at the site

• Less interview, more data review• CRA should be present to provide assistance to the

inspectors• Documents may be requested during the inspection

(requested using a request form)

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Inspection Topics

System inspections• Look at any issues seen in monitoring visit reports• Issues with safety, data or site knowledge of GCP or the protocol• Not always the highest recruiter

Study Inspections• Depends on the issues that the assessor has noted within the

submitted dossier• It may be an issue relating to credibility of site data• It may be a company data management issue• The investigator site provides the data so are key inspection

areas for both types of inspection

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Inspector Selection

• Two member states present if EMA requested, the host member state plus one other member state

• The lead inspector will contact the site to arrange the dates for the inspection

• But the dates need to be acceptable to both member states attending the inspection

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General Inspection Process

• Review of documentation and interview with staff members

• Interviews can be by video/telecon if necessary• Documents will be requested using a request form• Further unannounced studies can be requested• Review of areas where the research is managed• Inspectors can go “off-plan” if there is a need

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On Site Inspection Conduct

• Inspection hours – from 9am to 5pm but can be longer if necessary

• Opening meeting – to explain the purpose of the inspection

• Inspected company provides a SHORT relevant presentation to the inspectors

• Have ALL requested documentation ready from the beginning

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Expectations & Close Out

• Document review sessions – leave the inspectors alone unless they request assistance

• Don’t offer more info than necessary – if TMF is paper leave it at that, if you have online access to it, the inspector will want the same

• Inspectors closed meeting to collate findings and prepare for closing

• Closing meetingo to provide the observations noted and the grading of

those observationso to inform inspectee of the selected investigator sites

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Any Questions?24

LaVaPharm Consulting25

Vaska TonePresident & CEOLaVaPharm Consulting LLC

Email: vaska.tone@lavapharm.com

US Office Phone: +1-951-240-5635

European Office: +389-75-417-417