Ema fda joint inspections

FDA /EMA Inspection CollaborationsWhat Sponsors Need to Know

Presented byVaska Toné

FREEDOM OF INFORMATION

FDA OVERSEAS INSPECTIONS

FOREIGN ARRANGEMENTS

INSPECTION COLLABORATION

FDA, Foreign Inspections & Collaborations

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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 globallyhttp://www.fda.gov/RegulatoryInformation/FOI/default.htm§ FDA Warning Lettershttp://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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FDA – Foreign Offices

Asia-Pacific office = Maryland, USALatin American offices (3) – Costa Rica; Chile; MexicoEurope offices (3) – Maryland USA; EMA UK; Parma Italy India offices (2) – New Delhi and MumbaiMiddle East – Jordan (1) – AmmanChina offices (3) – Beijing, Shanghai, GuangzhouSouth Africa (1) - Pretoria

Note: Since 2009 FDA Inspections expanded further into the Middle East and South Africa

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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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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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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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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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Report on the Pilot EMA FDA GCP Initiative: September 2009 - March 2011

http://www.fda.gov/downloads/InternationalPrograms/FDABeyondOurBordersForeignOffices/EuropeanUnion/EuropeanUnion/EuropeanCommission/UCM266259.pdf


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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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● 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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■ 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

Type of inspection o Routine or “For Cause” / “Triggered”

Inspection request o Scope of the inspection

Inspection Preparation Conduct:

o Opening meetingo Review of trial related documentso Document deficiencies observedo Close-out meeting

Reporting

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Inspection Similarities

Inspection approach:o EU = System o FDA = Data

Inspectors involved “qualification”o EU = Clinical Trial expertiseo FDA = Generalist

Experience in working as a teamo EU familiar working as a team approacho FDA inspectors often work alone

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Inspection Differences

Continuity of inspectionso EU – at least 1 team member involved in all inspectionso FDA – work out of their districts and rarely do several inspections for same

application

Number of findings:o EU can cite against ICH-GCPo Fewer findings by FDA – can only cite CFR

Close-out meetings:o EU give oral feedback of systematic issues, details are in the reportso FDA provides written 483 “report” at close-out

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Grading of findingso EU grades every finding:

• Critical• Major• Minor

o FDA gives an overall grade no individual findings:• NAI• VAI• OAI

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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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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 SOPso Requests a list of all of your ongoing trialso Requests an organogram of your companyo Etc…

NOTE: Dossier completion can take up to a month for large organizations.

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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 teamCoordination 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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Lessons Learned

Assignment of a lead inspectorAgreed upon pre-inspection plan with same inspectional

approach for the groupDon’t do many break-out sessions. 2 teams are feasibleScope 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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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 inspecteesStaff assigned should be willing to do joint inspections and

develop a joint inspection plan

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Positive Results

• Initiative has been judged as a success in meeting and/or exceeding the expectations of the piloto Improved communications between the agencieso Strengthened each agency’s trust in the other’s

inspection efforts

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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 inspectionso Gather feedback for a more analysis-friendly mechanism

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• 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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■ 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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Any Questions?26

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Vaska TonePresident & CEOLaVaPharm Consulting LLC

Email: [email protected]

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Ema fda joint inspections