magi's clinical trial agreements, budgets & regulatory conference fda inspections of...
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MAGI's Clinical Trial Agreements, Budgets & Regulatory Conference
FDA Inspections of Investigator Sites
Paul BelowClinical Research Consultant
P. Below Consulting, Inc.
2MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference
Learning Objectives
Describe the FDA’s Bioresearch Monitoring Program (BIMO)
Define the BIMO inspection activities during an investigator inspection
Describe how inspections are classified
Identify resources available on the FDA website to obtain inspection findings
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BIMO Program Overview
Established in 1977 and expanded in 1992
Comprehensive program of on-site inspections and data audits to monitor all aspects of the conduct and reporting of FDA regulated research
Each FDA Center has its own BIMO program staff with overall coordination by the Office of Regulatory Affairs
Implemented domestically and internationally resulting in over 1000 inspections annually
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Who is Inspected?
Clinical Investigators
Sponsors/Monitors/CROs
Institutional Review Boards
Non-Clinical Labs (aka GLP)
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Inspections by FDA Center (2006)
Inspected Entity CDER CBER CDRH
Sponsor 32 5 53
Investigator 408 108 200
IRB 71 8 59
TOTAL 511 121 312
Source: Compiled from BIMO presentations and statistics on the FDA website
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Inspection Triggers
Marketing application submission (majority)
Novel technology
Vulnerable population
“Investigator-oriented” or “For cause” inspections usually done when suspicion of integrity or human subject protection issue (often on-going studies)
Complaints
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Investigator Inspections – Preliminaries
Assigned by HQ BIMO staff
FDA field inspectors from 19 district offices conduct inspections. They do all kinds of inspections (i.e., GCP, manufacturing, lab)
For routine “study-oriented” inspections, scheduled with site within 2 weeks
Inspectors show credentials (photo ID) and “Notice of Inspection” form (FDA Form 482)
Permission or authorization to inspect of investigator sites is not required. FD&C Act provides criminal penalties for refusal to permit inspections
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Investigator Inspections – On-Site Activities
Inspection Areas: Protocol compliance
Informed consent
Facilities
Test article accountability
Data audit
Regulatory document review
Detailed procedures for inspections contained in Compliance Program Guidance Manual for Clinical Investigators (7348.811) http://www.fda.gov/ora/compliance_ref/bimo/
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Investigator Inspections – Completion
End inspection with an exit interview with the investigator
Findings of non-compliance are reported on an FDA Form 483
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Most Common Investigator Deficiencies
Failure to follow the investigational plan
Protocol deviations
Inadequate recordkeeping
Inadequate accountability for the investigational product
Inadequate subject protection – including informed consent issues
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Inspection Follow-up Process
After inspection, FDA field inspector writes an establishment inspection report (EIR)
After district office review, the completed EIR package is sent to the FDA
Once the EIR is received, it is assessed and classified by FDA
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Inspection Classifications
No Action Indicated (NAI) = the FDA field inspector did not identify objectionable practices or identified only minor issues that did not justify further action
Voluntary Action Indicated (VAI) = indicates that objectionable practices were uncovered during the inspection, but were not significant
Official Action Indicated (OAI) = inspection uncovered significant objectionable practices, which could affect data reliability or compromise human subject protection. Generally results in the issuance of a Warning Letter or some other higher-level compliance action
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NAI
VAI
OAI
MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference
Investigator Inspection Classification 2006
All Centers (n = 595)
4%
51%44%
Source: “FDA Regulation of Pharmaceuticals and Devices” FDA presentation by Jean Toth-Allen, June 2007
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Inspection Classifications
Long-term OAI rates:
CDRH = 13%
CDER = 3%
In general, OAI classification results in issuance of a warning letter about ~70% of the time
Investigator warning letters issued in 2007:
CDRH = 16
CDER = 6
CBER = 2
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CDER “Investigator-Oriented” Inspections
Inspection Type 2004 2005 2006
Routine 241 312 350
For Cause110
(31%)70
(18%)58
(14%)
Total 351 382 408
Source: Compiled from BIMO presentations and statistics on the FDA website
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Clinical Trial Complaints to CDER
9
106 118
210
266
325
0
50
100
150
200
250
300
350
1998
1999
2000
2004
2005
2006
Source: Compiled from BIMO presentations and statistics on the FDA website
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Clinical Trial Complaints to CDER
Complaints lead to on-site inspections approximately 30% of the time
Most of the complaints are being submitted by drug sponsors and monitors, followed by private citizens
The complaints most likely to trigger FDA inspections are being made by clinical trial subjects
CDER views complaints as an increasingly important element of its emerging risk-based GCP compliance effort. Reporting information available at www.fda.gov/oc/gcp/complaints.html
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Office of Criminal Inspections
Part of Office of Regulatory Affairs
Conduct FDA criminal investigations
Agents have law enforcement training
Collaborate with US Attorney and Department of Justice for prosecution
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FDA Resources
Warning Letters available on the FDA website at www.fda.gov/foi/warning.htm
Some 483s (sponsor and IRB) available at www.fda.gov/ora/frequent/default.htm
Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) Letters atwww.fda.gov/foi/nidpoe/default.html
Clinical Investigator Inspection List available at www.fda.gov/cder/regulatory/investigators/default.htm
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Clinical Investigator Inspection List
Source: www.fda.gov/cder/regulatory/investigators/default.htm
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This presentation and related references are posted on my corporate website at:
www.pbelow-consulting.com/fda-inspections.html
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