Good Clinical Practices andFDA Inspections

Patricia Holobaugh

Chief, Bioresearch Monitoring Branch

Division of Inspections and Surveillance

Office of Compliance and Biologics Quality

Agenda

• Define Good Clinical Practices

• Describe FDA’s Bioresearch Monitoring Program for on-site inspections of clinical and animal studies

• Explain when and how inspections are performed

• Describe common deficiencies and what happens after the inspection

Good Clinical Practices

GCP is a standard for the design, conduct, performance monitoring auditing, recording, analysis, and reporting of clinical trials.

www.fda.gov/oc/gcp/

Regulations

Investigational Application21 CFR Part 312 IND drugs and biologics

21 CFR Part 812 IDE21 CFR Part 809 IVD

Marketing Application21 CFR Part 601 BLA biologics21 CFR Part 314 NDA drugs21 CFR Part 814 PMA devices

Regulations

21 CFR 50 Protection of Human SubjectsInformed ConsentSafeguards for Children

21 CFR Part 56 Institutional Review Boards

21 CFR Part 11 Electronic Records; Electronic

Signatures

Examples of GCP Guidance Documents

Guideline for Monitoring Clinical Investigations (1998)

Information Sheets for IRBs and Clinical Investigators (1998)

ICH GCP Consolidated Guideline E6 (1997)

Regulations Guidance

FDA’s Bioresearch Monitoring Program (BIMO)

Clinical Investigators

Sponsor/Monitor/Contract Research

Organizations

Institutional Review Boards

Nonclinical Laboratories

When are BIMO Inspections conducted?

• Submission of BLA / PMA• Referrals from CBER staff• Referrals from other Centers/ORA• Complaints from sponsor, IRBs, and

consumers• Routine surveillance of ongoing

studiestarget 50 pediatric sites this FY

Profile of CBER BIMO InspectionsFY04-05 (thru 3/9/05)

189 Assignments issuedBLA 45 PMA15

CI surveillance 102IRB 22GLP 12Complaints 12

True or False???

Clinical investigator: “I’m only doing phase 1 and 2 studies – I’ll never be inspected by FDA.”

True or False???

Clinical investigator: “I’m only doing phase 1 and 2 studies – I’ll never be inspected by FDA.”

FALSEClinical investigators of studies in all

phases may (and are) inspected by FDA....

And ALL GCP regulations apply.

CBER continues its program toinspect ongoing studies under

IND/IDE“Real-time” surveillance of phases

1/2/3

• Cell therapies• Gene transfer• Vaccines • Blood products• Devices

For FY 2005, we issued assignments to inspect 50 sites enrolling pediatric subjects

History of CBER Surveillance Program

• Started in 2000 following Gelsinger’s death in gene therapy study

• Expanded to cell therapies, and then to all CBER IND/IDEs

Surveillance – Cross-Section of Sponsors (FY00-05)

Individuals 64NIH + DOD 29**Hospitals +

universities 11“Big” companies 48“Small” companies 84

Inspections for BLA / PMA

How Many Sites per BLA/PMA?

Usually 3 to 5 study sites...but sometimes more

Will inspect foreign sites when needed:

No US study or sitesForeign data are critical

Inspections for BLA / PMA

Factors in Site Selection

• Distribution of subjects

• Distribution of subjects whose data are

excluded

from S&E analyses

• Inspection history of investigators

• Inconsistent data for one site

increased efficacy

decreased incidence of adverse events

Inspections for BLA / PMA Factors in Site Selection

GCP problems reported by sponsor

Randomization cannot be reconstructed

Number of sub-investigators / sub-sites*

Pending workloads in FDA Districts

FDA Inspection “101”

• Inspections are performed by ORA by specially-trained investigators

Center reviewers may participate

• Most inspections are pre-announced

• Interview: who did what, and how• Review of records• Closing discussion & issue Form FDA

483

Comparison of Data in BLA / PMA to Source Data

Data in BLA/PMA

Sponsor

Source Data

CRF

Where is “Source Data” Defined?

NOT defined in 312 or 812

See GLP regs 21 CFR 58.3(k) – “raw data”21 CFR 58.130(e) – describes how

data are to be recorded, corrected, and describes automated systems.

Elements of Data Quality = ALCOA

Attributable

Legible/readable

Contemporaneous

Original

Accurate

After the Inspection

• Inspected party may respond in a letter - send to address on the Form FDA-483.

• May also ask the FDA investigator for the HQ Center address

• The inspection report is written by the FDA investigator and sent to the Center.

After the Inspection (2)

• The Center evaluates the report, and determines the corrective action.

• Classifications• NAI – No Action Indicated• VAI – Voluntary Action Indicated• OAI – Official Action Indicated

• We write a letter following most inspections

Most Common CI Violations

Failure to follow the protocol

example: Required testing is

incomplete

Recordkeeping errors

Informed consent problems

Most Significant Violations

• Enrollment of ineligible subjects• Violation of protocol affecting safety• Extensive data corrections and

questionable changes • Inadequate oversight of study personnel

Inappropriate delegation of authority Poor oversight of satellite sites

• No Informed consent• Failure to communicate with IRB

Significance of Violations

Do the violations

...affect rights, safety, or welfare of subjects?

...directly impact integrity of data set?

...indicate systemic problems within the study? sponsor problems?

Did the sponsor report the problems to FDA?

...indicate that other studies at that site might be impacted? investigator problems

Inappropriate delegation to subinvestigators

Investigator – individual who actually conducts an investigation (i.e., under whose immediate direction the drug is administered or dispensed to subjects.

How many miles (or states!) away ????

Sponsor should assure that the CI controls the study

Possible Administrative Actions

• Warning Letter• Determine if the data are reliable

• Complete and accurate?

• Delay approval of BLA/PMA• Clinical hold• Disapproval of IDE Initiate termination of IND Initiate disqualification of investigator Initiate Application Integrity PolicyRefer to Office of Criminal Investigations

Your Questions for CBER

Can case report forms be source documents?

Yes – protocol should specify how data are to be captured and records are to be maintained.

Are diaries, questionnaires, photos subject to inspection?

Yes –these need to be maintained by CI per 21 CFR 312.62(c)

Your Questions for CBER

What data points should be captured on case report forms?

What data should be entered into a database for analysis?Data critical to determining safety and efficacy endpoints. Protocol is roadmap for required tests. Consult FDA review team.

Your Questions for CBERDoes FDA audit systems & databases to ensure

they are validated?FDA does not audit computerized systems for clinical

trials.Sponsor is responsible for QA of computerized systems

used by the sponsor, and for determining whether systems used by investigator sites are suitable for their study.

See FDA Guidance “Computerized Systems Used in Clinical Trials”

http://www.fda.gov/ora/compliance_ref/bimo/ffinalcct.htm

Your Questions for CBERFor clinics without medical records system in place, howshould study records and source documents bemaintained when subjects participate in one or more studies?

Do you recommend that subject source records andhealth information be maintained in a central file, withstudy-specific CRFs maintained separately?

No regulation for this. Records should be retrievableand meet 312.62(c) retention requirements. Recordsmust be maintained at site if clinical investigatordeparts. Recommend SOPS explaining how an alternaterecord system is utilized.

If You have GCP Questions......

• Contact CBER’s Bioresearch Monitoring Branch --

Pat Holobaugh 301-827-6347 holobaugh@cber.fda.gov

OR

• Contact your IND/IDE reviewer