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

13

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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Contact Information

Office: (952) 882-4083

E-mail: paul@pbelow-consulting.com

Web: www.pbelow-consulting.com