Good Clinical Practices and FDA Inspections

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Good Clinical Practices andFDA Inspections

• Patricia Holobaugh
• Chief, Bioresearch Monitoring Branch
• Division of Inspections and Surveillance
• Office of Compliance and Biologics Quality

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Agenda

• Define Good Clinical Practices
• Describe FDAs 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

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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/

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Regulations

• Investigational Application
• 21 CFR Part 312 IND drugs and biologics
• 21 CFR Part 812 IDE
• 21 CFR Part 809 IVD
• Marketing Application
• 21 CFR Part 601 BLA biologics
• 21 CFR Part 314 NDA drugs
• 21 CFR Part 814 PMA devices

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Regulations

• 21 CFR 50 Protection of Human Subjects
• Informed Consent
• Safeguards for Children
• 21 CFR Part 56 Institutional Review Boards
• 21 CFR Part 11 Electronic Records Electronic
• Signatures

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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)

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Regulations Guidance
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FDAs Bioresearch Monitoring Program (BIMO)

• Clinical Investigators
• Sponsor/Monitor/Contract Research
• Organizations
• Institutional Review Boards
• Nonclinical Laboratories

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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 studies
• target 50 pediatric sites this FY

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

• 189 Assignments issued
• BLA 45 PMA 15
• CI surveillance 102
• IRB 22
• GLP 12
• Complaints 12

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True or False???

• Clinical investigator Im only doing phase 1
  and 2 studies Ill never be inspected by FDA.

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True or False???

• Clinical investigator Im only doing phase 1
  and 2 studies Ill never be inspected by FDA.
• FALSE
• Clinical investigators of studies in all phases
  may (and are) inspected by FDA....
• And ALL GCP regulations apply.

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CBER continues its program toinspect ongoing
studies under IND/IDEReal-time surveillance of
phases 1/2/3

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

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

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History of CBER Surveillance Program

• Started in 2000 following Gelsingers death in
  gene therapy study
• Expanded to cell therapies, and then to all CBER
  IND/IDEs

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Surveillance Cross-Section of Sponsors (FY00-05)

• Individuals 64
• NIH DOD 29
• Hospitals
• universities 11
• Big companies 48
• Small companies 84

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Inspections for BLA / PMAHow Many Sites per
BLA/PMA?

• Usually 3 to 5 study sites
• ...but sometimes more
• Will inspect foreign sites when needed
• No US study or sites
• Foreign data are critical

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Inspections for BLA / PMAFactors in Site
Selection

• Distribution of subjects
• Distribution of subjects whose data are excluded
• from SE analyses
• Inspection history of investigators
• Inconsistent data for one site
• increased efficacy
• decreased incidence of adverse events

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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

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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

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Comparison of Data in BLA / PMA to Source Data

• Data in
• BLA/PMA
• Sponsor

Source Data
CRF
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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.

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Elements of Data Quality ALCOA

• Attributable
• Legible/readable
• Contemporaneous
• Original
• Accurate

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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.

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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

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Most Common CI Violations

• Failure to follow the protocol
• example Required testing is incomplete
• Recordkeeping errors
• Informed consent problems

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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

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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

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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

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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 Policy
• Refer to Office of Criminal Investigations

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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)

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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.

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Your Questions for CBER

• Does 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/ffinalc
  ct.htm

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Your Questions for CBER

• For clinics without medical records system in
  place, how
• should study records and source documents be
• maintained when subjects participate in one or
  more
• studies?
• Do you recommend that subject source records and
• health information be maintained in a central
  file, with
• study-specific CRFs maintained separately?
• No regulation for this. Records should be
  retrievable
• and meet 312.62(c) retention requirements.
  Records
• must be maintained at site if clinical
  investigator
• departs. Recommend SOPS explaining how an
  alternate
• record system is utilized.

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If You have GCP Questions......

• Contact CBERs Bioresearch Monitoring Branch --
• Pat Holobaugh 301-827-6347
• holobaugh_at_cber.fda.gov
• OR
• Contact your IND/IDE reviewer