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Ema fda joint inspections
1. FDA /EMA Inspection Collaborations
What Sponsors Need to Know
Presented by
Vaska Toné
2. FREEDOM OF INFORMATION
FDA OVERSEAS INSPECTIONS
FOREIGN ARRANGEMENTS
INSPECTION COLLABORATION
FDA, Foreign Inspections
& Collaborations
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3. FDA
Sponsor’s share price can be influenced by information about
product safety, quality or efficacy entering the public domain
§ Freedom of Information Act (FOI) is effective globally
http://www.fda.gov/RegulatoryInformation/FOI/default.htm
§ FDA Warning Letters
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters
/default.htm
§ Clinical Investigator’s Investigator Inspection List (CIIL)
http://www.accessdata.fda.gov/scripts/cder/cliil/
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4. FDA – Foreign Offices
Asia-Pacific office = Maryland, USA
Latin American offices (3) – Costa Rica; Chile; Mexico
Europe offices (3) – Maryland USA; EMA UK; Parma Italy
India offices (2) – New Delhi and Mumbai
Middle East – Jordan (1) – Amman
China offices (3) – Beijing, Shanghai, Guangzhou
South Africa (1) - Pretoria
Note: Since 2009 FDA Inspections expanded further into the
Middle East and South Africa
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5. FDA – Overseas Inspection
There are no inspection fees for FDA inspections (fees are collected
as part of the Prescription Drug User Fee Act (PDUFA)
- 2010 it was $1,400,000
- 2012 it was $1,842,000
- 2014 it will be $2,169,100
FDA has no legal international authority, however, their actions are
administrative which can result in significant monetary losses to the
company:
• Refusal to approve an application
• Recall of an existing product (same product being inspected)
• Possible fines on US affiliates
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6. FDA – Overseas Inspections
• FDA has been conducting international inspections since
1955 as a result of the Federal FD&C Act (Food, Drugs, and
Cosmetics Act)
• Section 201 of the FD&C Act defines interstate commerce as
"commerce between any state and any place outside thereof.“
• Section 704 of the FD&C Act allows the issuance of the FDA
Form 483 to list the “…observations of objectionable
conditions and practices listed on the front of this form…”
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7. FDA – Foreign ‘Arrangements’
FDA has “confidentiality” arrangements in place with its foreign
regulatory counterparts:
106 agreements in place within the last 5 years and growing
29 countries - including Australia, India, China, Mexico, Japan
18 agreements within the EU/EEA (UK, Germany etc...)
with the World Health Organization (WHO)
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8. FDA – EMA Inspection Collaboration
EMA & FDA updated their “arrangement” Jul-2009 to last for 18
months to allow for joint GCP inspections.
The agreements allow for the sharing of human, scientific and
investigation resources and knowledge.
The collaboration is continuing today.
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9. Report on the Pilot EMA FDA GCP Initiative:
September 2009 - March 2011
http://www.fda.gov/downloads/InternationalPrograms/FDABeyondOurBordersForeignOffice
s/EuropeanUnion/EuropeanUnion/EuropeanCommission/UCM266259.pdf
FDA – EMA Inspection Collaboration
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10. Total of 13 collaborative inspections between the agencies
● 7 joint GCP inspections
Sponsors = 3 (2 in USA, 1 in France)
CRO = 1 (in Canada)
Investigator sites = 3 (2 in USA, 1 in Germany)
Inspectors from: USA, UK, Germany, Spain,
Denmark & France (host country was the lead
inspector)
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FDA – EMA Inspection Collaboration
11. ● 6 Observational inspections:
3 US FDA inspections observed by EU inspectors:
• US = 2 CROs
• US = 1 Sponsor
3 EU inspections observed by US inspectors:
• UK = 1 Sponsor
• Ireland = 1 CRO
• Sweden = 1 Investigator Site
Showed a difference in the inspectional STYLE by the
different regulatory inspectorates
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FDA – EMA Inspection Collaboration
12. ■ Inspection procedures:
● Before the inspection – shared info; i.e. EMA
inspection requests, FDA assignments
● Close-out Meetings: Each agency followed its own
procedures:
EMA provided verbal feedback
FDA provided verbal feedback and a Form 483
● Reporting: Each agency followed their own procedures
for reporting the inspection and further follow-up
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Inspection Collaboration Procedures
13. Type of inspection
o Routine or “For Cause” / “Triggered”
Inspection request
o Scope of the inspection
Inspection Preparation
Conduct:
o Opening meeting
o Review of trial related documents
o Document deficiencies observed
o Close-out meeting
Reporting
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Inspection Similarities
14. Inspection approach:
o EU = System
o FDA = Data
Inspectors involved “qualification”
o EU = Clinical Trial expertise
o FDA = Generalist
Experience in working as a team
o EU familiar working as a team approach
o FDA inspectors often work alone
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Inspection Differences
15. Continuity of inspections
o EU – at least 1 team member involved in all inspections
o FDA – work out of their districts and rarely do several
inspections for same application
Number of findings:
o EU can cite against ICH-GCP
o Fewer findings by FDA – can only cite CFR
Close-out meetings:
o EU give oral feedback of systematic issues, details are in
the reports
o FDA provides written 483 “report” at close-out
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Inspection Differences
16. Grading of findings
o EU grades every finding:
• Critical
• Major
• Minor
o FDA gives an overall grade no individual findings:
• NAI
• VAI
• OAI
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Inspection Differences
17. FDA vs. EMA Inspection STYLES
FDA:
FDA Sponsor inspections are more focused on data
review and verifying the submitted data in the NDA
application
CSR results are the primary variable of inspection focus
Systems and processes are reviewed, but as a secondary
objective not as primary
Personnel training and experience are not a main focus
unless critical issues are noted
CSV is rarely reviewed during general sponsor inspections
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18. FDA vs. EMA Inspection STYLES
EMA:
EMA Sponsor inspections are Systems focused
● Pre-inspection Dossier completion is requested and
includes:
o Description of your QMS including PV and a list of
SOPs
o Requests a list of all of your ongoing trials
o Requests an organogram of your company
o Etc…
NOTE: Dossier completion can take up to a month for large
organizations.
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19. Difficulties noted for Joint Inspections
Inspection dates and number of days at each site
(scheduling a common time in the calendars of 4 - 5 busy
people is not easy)
Availability at the inspected site of adequate rooms
Coordination of the distribution of tasks within the team
Coordination of the requests for documents and keeping
track of copies
Ability to look at the files "together"
Concentration during the inspection (as it can get very
noisy with so many people involved)
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20. Lessons Learned
Assignment of a lead inspector
Agreed upon pre-inspection plan with same inspectional
approach for the group
Don’t do many break-out sessions. 2 teams are feasible
Scope of inspections is the same (in one case EMA
reviewed 2 trails, FDA covered 3)
Sharing of inspection procedures (prep, conduct,
reporting)
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21. Lessons Learned
These joint inspections are more resource consuming
than other inspections
Gathering feedback from the inspectors to improve inter-
agency processes
Gathering feedback from inspectees
Staff assigned should be willing to do joint inspections and
develop a joint inspection plan
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22. Positive Results
• Initiative has been judged as a success in meeting
and/or exceeding the expectations of the pilot
o Improved communications between the agencies
o Strengthened each agency’s trust in the other’s
inspection efforts
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23. Expectations - Recommendations
• To carry out more inspections, in a joint-inspection
capacity
o Will help identify and fill-in gaps of the inspection
processes
o Mutual acceptance of inspectional findings
• To perform more observational inspections
o Gather feedback for a more analysis-friendly mechanism
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24. Expectations - Recommendations
• To expand the joint inspections beyond the US and EU
• To focus inspections on sponsors and CROs rather
than sites – Quality Systems approach
• Focus on triggered inspections as joint opportunities
• Parallel inspections for parallel submissions
• Harmonize pre-defined metrics to assess GCP
compliance and reliability
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25. Expectations - Recommendations
■ Develop common system for tracking info and
procedures for handling large amount of info exchange
■ Assign more resources at both agencies
■ Expand into BA/BE studies in generic applications
■ Expand into FDA’s CBER division
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So what does this have to do with Global GCP you might ask? Well let’s see why FOI is so important
FOI is available to anyone and everyone globally.
- There is online access to whether FDA did or didn’t approved a drug, biologic or device.
- There are warning letters posted,
- and the Clinical Investigator’s Inspection List even lists out which doctor’s have been
inspected and those results (although this last one is not always up to date)
And for a small fee ($26, $43, $86) anyone can gain more information than what is already available on line
OK so this is what FDA has available, but you can’t find this sort of info readily available for EMA or other areas of the world. So what is happening?
FDA staff are assigned overseas and then local staff are hired and trained to perform inspections in their region. Its no longer a given that the FDA person coming to do the inspection is from the US.
Therefore, products from foreign countries and the firms producing them are considered to be interstate commerce
And since FDA has the rights to inspect outside its boundaries there was a need to have agreements in place with foreign governments to share information which lead to bilateral agreements and also a need for a global standard which led to ICH GCPs So we’ll start with the agreements and then move on to GCPs
It basically means that FDA can and usually will share the audit outcomes with their regulatory counterparts to promote cooperation and vice versa
FDA also has invited the EMA and local inspectors to share in the audit process (but not always)
What is really important to understand is that there are significant difference between the inspectors and the final reports/outcomes of the inspections FOR NOW – but this is expected to change over time
