FDA, EMA and other regulatory agencies routinely perform both announced and unannounced phase I clinical investigator inspections, in order to verify the accuracy and reliability of data that has been submitted to the agency, and to provide real-time assessment of the investigator’s conduct of the trial to ensure human safety. Preparing for a clinical inspection involves making sure that all aspects of your clinical trial are up to code. This includes being able to provide all required documents that prove that your trial is GCP compliant. A short summary of SGS CPU experience in ensuring site compliance prior to/during an agency inspection, as well as the importance of conducting site internal quality management is presented in this presentation. For more information visit: https://www.sgs.com/exprimo and contact us at: clinicalresearch@sgs.com Follow us on LinkedIn: https://www.linkedin.com/company/sgs

1. FDA/EMA INSPECTION READINESS
ANTICIPATE AND BE READY FOR GROWING
REGULATORY EXPECTATIONS IN EARLY PHASE
CLINICAL TRIALS
ANNICK VAN RIEL

2. 2
SGS BIOPHARMA DAY – OCTOBER 25, 2016
FDA – EMA GCP INSPECTIONS
CHALLENGES
 GCP inspection
Clinical inspection of registration trials submitted in support
of marketing application of new drug products, to ensure
 data integrity
 subject’s safety
 Challenges
 Globalisation of clinical trials - same trials used to support
• Marketing Authorization Application (MAA) to EMA
• New Drug Application (NDA) and Biologics License Application
(BLA) to FDA

3. 3
SGS BIOPHARMA DAY – OCTOBER 25, 2016
FDA – EMA GCP INSPECTIONS
SIMILARITIES AND DIFFERENCES 1/2
Topic FDA EMA
General BIMO program - since 1977
Routine (80%) ~ NDA
For cause (20%) ~ IND
GCP inspections since 1997
Routine
Triggered
GCP FDA CDER Title 21 CFR parts
11/50/54/58/312/314
Less details vs ICH GCP
ICH Topic E6
Directive 2005/28/EC
Clinical Trial Directive 2001/20/EC
Local requirements
Announcement Announced / unannounced Formal announcement letter
Preparation Inspection plan
documents from application dossier
Central / local inspection plan
Site to provide documents
Conduct Data reliability/subject protection Systems / processes to obtain data
/ ensure subject protection

4. 4
SGS BIOPHARMA DAY – OCTOBER 25, 2016
FDA – EMA GCP INSPECTIONS
SIMILARITIES AND DIFFERENCES 2/2
Topic FDA EMA
Reporting Closing meeting
Observations in 483
General classification
(NAI – VAI – OAI)
Negative inspection
- rejection of data
- Disqualification of investigator
Closing meeting
no written summary
Grading per finding (critical, major,
minor)
Negative inspection
-Negative opinion
-Rejection of data
-Restrictions on SPC
-Refusal MAA
NAI (No action indicated) – VAI (Voluntary action indicated) – OIA (Official action indicated)

5. 5
SGS BIOPHARMA DAY – OCTOBER 25, 2016
FDA – EMA GCP INSPECTIONS
JOINT INSPECTIONS BECOMING ‘STANDARD’
 More ‘joint’ inspections FDA + EMA
 Identify gaps in processes
 Expand outside US / EU
 Focus sponsors and CRO as well as sites
 Focus on triggered inspections
 More ‘parallel’ inspections with exchange of inspection
reports
* Report on the Pilot EMA-FDA GCP initiative, September 2009 – March 2011 (EXT/INS/GCP/56289/2011)

6. 6
SGS BIOPHARMA DAY – OCTOBER 25, 2016
ICH E6 (R2) - HOT TOPICS
REFLECTING RECENT GCP INSPECTION FINDINGS 1/2
 Sponsor Risk Management at the core of Quality
 To implement for QMS and Monitoring
 To incorporate risk science, ALCOA communication, record
keeping
 Risk based monitoring
 Closing the loop of significant non-compliance
 Identification / Root cause analysis / correction and
prevention
 Human Factor Analysis
 Oversight by investigators
 Delegation oversight
 Quality and control at all times of data and documents
provided to sponsor

7. 7
SGS BIOPHARMA DAY – OCTOBER 25, 2016
ICH E6 (R2) – HOT TOPICS
REFLECTING RECENT GCP INSPECTION FINDINGS 2/2
 Technology
 Paper access control, data perenniality and ALCOA at the
basis
 Validity, longevity, fidelity of data
 Standard processes to avoid that real-time data influence trial
outcomes early in the process
 Control by site of the generated data
 Vendor oversight by sponsor
 Sponsor oversight of tasks delegated to CROs
 CRO to ensure transparency of data and tasks
 Final guideline by November 2016

8. 8
SGS BIOPHARMA DAY – OCTOBER 25, 2016
EU CLINICAL TRIAL REGULATION 563/2014
CLINICAL RESEARCH WITH HIGH PATIENT SAFETY
 What’s New?
 No more national interpretation of Directive
 Single trial application covering all EU countries involved
 SUSAR reporting coordinated across EU
 Predictable application timelines
 Transparent clinical trial reporting
 Flexibility in TMF content and monitoring
 Trial registration in database
• prior to start (<-> FDA : 21 days after FPFV)
• Phase I registration (<-> FDA : exempted)
• US trials to adhere
 Applicable in 2017/2018

9. 9
SGS BIOPHARMA DAY – OCTOBER 25, 2016
HOW CAN WE BE PREPARED ?

10. 10
SGS BIOPHARMA DAY – OCTOBER 25, 2016
INSPECTION READINESS
A CULTURE OF COMPLIANCE
 Inspection readiness as “STATE OF BEING”
 not as preparation activity
 Management as active participant in a commitment to a
“Culture of Compliance”
 Quality Management / Control
 Digital solutions for data, document and quality
management
 eSource, CTMS, eTMF, QMS…
 Routine internal audits

11. 11
SGS BIOPHARMA DAY – OCTOBER 25, 2016
CASE STUDY
CPU QUALITY CONTROL - PURPOSE
 Continuous Quality Improvement
 Quality Data Collection performed according to
 Protocol
 ICH-GCP, GDP and local regulations
 SOP / WI
 Risk assessment
 Management enforcement

12. 12
SGS BIOPHARMA DAY – OCTOBER 25, 2016
CASE STUDY
CPU QUALITY CONTROL - APPROACH
 Plan
 Objectives / processes
 Do
 Implementation
 Check
 Monitor / evaluate
 testing the results against
objectives
 Act
 Apply actions necessary for
improvement if the results
require changes
Shewart Cycle (WE Deming)

13. 13
SGS BIOPHARMA DAY – OCTOBER 25, 2016
CASE STUDY
CPU QUALITY CONTROL - PROCESS
 A NEW DIRECTION
 100% QC  defining Critical QC Check Points
 “Spot check” activity
 Based on Risk Analysis
 Against GCP / GDP / protocol
 Electronic + manual
 Cross – functional
 Daily/weekly/Monthly
Protocol
Related
Guidelines
Ice
ECG rechecks
Drug screen
Centrifuge
setting …
GCP
Documentation
Version control
signatures
corrections
empty fields
black pen
…
GDP

14. 14
SGS BIOPHARMA DAY – OCTOBER 25, 2016
CASE STUDY
CPU QUALITY CONTROL – SPOT CHECKS
IQC SPOT CHECK
TACTILE
approach
OFFICE
Set-up IF
Signature process
All docs present
FLOOR
Screening, pre-dose – Dosing
FU – Samples – Lab –
Pharmacy
Drug screen
ECG – ICF
Prescription Log
Centrifuge settings…
PROCESS
approach
DAY -1 to Day 2
24h post-dose
Predose – Dosing
FU – Samples – Lab
Pharmacy
Drug screen
ECG – ICF
Prescription Log
Centrifuge settings…
Predefined # studies – randomly identified

15. 15
SGS BIOPHARMA DAY – OCTOBER 25, 2016
CASE STUDY
CPU QUALITY CONTROL – ELECTRONIC QC
 100% sampling and review
What Why Function Frequency
OOR values GCP PI Weekly
Time between ECG GCP CTN Monthly
Eligibility GCP PI Daily
Events pre-dose GCP PI Weekly
Heights GDP CTN / CLT / TOA Monthly
Lab centrifuge setting GCP CLT Monthly
Lab storage in time GCP CLT Monthly
Rescreening of a volunteer GDP RSO Monthly
Time on paper source same as in eSource GDP CTN / CLT / TOA Monthly

16. 16
SGS BIOPHARMA DAY – OCTOBER 25, 2016
CASE STUDY
CPU QUALITY CONTROL – TRENDING

17. 17
SGS BIOPHARMA DAY – OCTOBER 25, 2016
CASE STUDY
CPU QUALITY CONTROL - REPORTING
 Reporting tool
 Monthly QC meetings / minutes / actions
 Actions ~ Root Cause Analysis / CAPA
 Management commitment
Who Responsibility
Team lead GCP related actions / evidence
Management Team GDP related actions / evidence
IQC Collection of EVIDENCE
Senior Management GCP and GDP TRENDING
Outcome: Spot checks linked to risk modus

18. 18
SGS BIOPHARMA DAY – OCTOBER 25, 2016
CONCLUSION
QUALITY COMPLIANCE LEADS TO INSPECTION READINESS
Spot check
Manual QC
Electronic QC
Management
accountability
Trending
CULTURE OF COMPLIANCE

19. 19
SGS BIOPHARMA DAY – OCTOBER 25, 2016
Life Sciences van Riel Annick
Director CPU Antwerpen
SGS Phone:: + 32 (0) 3 217 25 60
Clinical pharmacology Unit Antwerpen Fax: + 32 (0) 3 217 25 81
Lange Beeldekensstraat 267 E-mail : annick.vanriel@sgs.com
B 2060 Antwerpen
BELGIUM Web : www.sgs.com/lifescience
THANK YOU FOR YOUR ATTENTION
+ 41 22 739 9548
+ 1 866 SGS 5003
+ 65 637 90 111
+ 33 1 53 78 18 79
+ 1 877 677 2667
+ 33 1 41 24 87 87

20. 20
SGS BIOPHARMA DAY – OCTOBER 25, 2016
QUESTIONS ?

21. 21
SGS BIOPHARMA DAY – OCTOBER 25, 2016