United States Food and Drug Administration

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United States Food and Drug Administration

• FDA Conduct of Clinical Investigator Inspections
  Denver, CO
• June 8, 2009

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DISCLAIMER

• The content of this presentation is my own and
  does not necessarily reflect the views and/or
  policies of the Food and Drug Administration or
  its staff. The Food and Drug Administration will
  not be bound by any of the content or information
  contained in this presentation.

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OBJECTIVES

• Understand the purpose of the FDA's bioresearch
  monitoring program in regards to clinical
  investigators.
• Understand the federal regulations covering
  clinical research and clinical investigator
  obligations.
• Understand and discuss what to expect during and
  after an FDA inspection.
• Discuss specific problems seen during recent FDA
  inspections at clinical sites.
• Discuss various methods that can be used to
  ensure compliance with federal regulations and
  study protocol requirements.

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TOPICS

• BIMO Program
• Regulations
• Inspection
• Observations
• Compliance
• Resources

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BIMO PROGRAM

• FDAs Bioresearch Monitoring Program
• A comprehensive program of on-site inspections
  and data audits designed to monitor all aspects
  of the conduct and reporting of FDA regulated
  research.

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BIMO PROGRAM

• Program Objectives are
• Protect the rights and welfare of human animal
  research subjects
• Verify the quality and integrity of bioresearch
  data

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BIMO PROGRAM

• Good Clinical Practices (GCP)
• Institutional Review Boards (IRBs)
• Clinical Investigators (CIs)
• Sponsor-Monitors, CROs
• Good Laboratory Practices (GLP)

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CLINICAL INVESTIGATOR PROGRAM

• Provides for study specific inspections and
  audits of physicians, veterinarians, and other
  investigators conducting clinical trials of new
  human and veterinary drugs, medical devices,
  biologicals, etc.

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TYPES OF INSPECTIONS

• Routine
• New Drug/New Animal Drug Applications
  (NDAs/NADAs) (drugs)
• Pre-Market Applications (PMAs) (devices)
• Surveillance
• Directed
• Investigate problems that have been identified at
  the Investigational New Drug (IND) or
  Investigational Device Exemption (IDE) stage.
• Investigate complaints that have been reported to
  the FDA
• Compliance follow-up for previous deficiencies.

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BIMO REGULATIONS

• 21 CFR 314 New Drug Applications (NDA)
• 21 CFR 312 Investigational New Drug Exemption
  (IND)
• 21 CFR 814 Pre-Market Approval Applications
  (PMA)
• 21 CFR 812 Investigational Device Exemption (IDE)

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BIMO REGULATIONS

• 21 CFR 511 New Animal Drugs for Investigational
  Use
• 21 CFR 50 Protection of Human Subjects
• 21 CFR 56 Institutional Review Boards
• 21 CFR 58 Good Laboratory Practice for
  Non-Clinical Laboratory Studies

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BIMO GUIDANCE DOCUMENTS

• http//www.fda.gov/oc/gcp/guidance.html
• These guidances and information sheets represent
  the Agency's current guidance on good clinical
  practice and the conduct of clinical trials. They
  do not create or confer any rights for or on any
  person and do not operate to bind FDA or the
  public. An alternative approach may be used if
  such approach satisfies the requirements of the
  applicable statute, regulations, or both.
  However, in many places throughout these
  documents, specific regulations are cited and the
  requirements of the regulations are reiterated.
  The regulations are enforceable.

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GUIDANCES, cont.

• FDA Information Sheet Guidances for Institutional
  Review Boards, Clinical Investigators and
  Sponsors
• FDA/NCI MOU Regarding Common Standards-based Data
  Repository
• Financial Relationships and Interests in Research
  Involving Human Subjects Guidance for Human
  Subject Protection
• Guidance for Clinical Investigators, Sponsors,
  and IRBs Adverse Event Reporting to IRBs-
  Improving Human Subject Protection

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GUIDANCES, cont.

• Process for Handling Referrals to FDA under 21
  CFR 50.54
• Computerized Systems Used in Clinical
  Investigations
• Financial Disclosure by Clinical Investigators
• Guideline for the Monitoring of Clinical
  Investigators
• Guideline for the Study and Evaluation of Gender
  Differences in the Clinical Evaluation of Drugs
• Use of Clinical Holds Following Clinical
  Investigator Misconduct

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FY08 Sponsor Deficiencies

• Monitor study
• Secure investigator compliance
• Analyze and report AE/UADE
• Inform investigators, FDA, or IRB
• Control of inv devices
• Obtain signed Inv Agreement
• Informed consent

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FY08 Investigator Deficiencies

• Follow investigational plan, investigator
  agreement, or protocol
• Document case hx/device exposure
• Obtain adequate informed consent
• Control of inv. device
• Report UADEs
• Obtain FDA/IRB approval to conduct study

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FY08 IRB Deficiencies

• Inadequate initial or continuing review
• Frequency of review
• Expedited review
• SR determination
• Inadequate records
• Minutes
• Membership roster
• Study documentation
• Inadequate or failure to follow written
  procedures
• SR determination
• Quorum
• Report non-compliance
• Frequency of review
• Inadequate membership roster

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CLINICAL INVESTIGATOR OBLIGATIONS
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CLINICAL INVESTIGATOR OBLIGATIONS

• Follow the approved protocol or investigational
  plan.
• Obtain Informed Consent prior to conducting any
  study-related procedures.
• Maintain adequate and accurate records.

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CLINICAL INVESTIGATOR OBLIGATIONS

• Administer test article only to consented
  subjects under control of the Investigator.
• Ensure Adverse Events are appropriately reported.
• Ensure adequate IRB review.

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Intimidated at the thought of an FDA inspection?
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What Can You Do to Prepare?

• Dont panic!
• Have a plan for FDA Inspection
• Have documentation readily available
• Make sure copier is warmed up and tuned up
• Have space available for record review
• Coffee and donuts?

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HOW TO PREPARE FOR AN FDA INSPECTION

• When the FDA Investigator calls
• Be sure you understand the specific study that
  will be inspected.
• The FDA Investigator will tell you what records
  will be needed.
• The FDA Investigator will tell you how much time
  will be needed with the PI and/or other study
  staff.

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HOW TO PREPARE FOR AN FDA INSPECTION

• Be sure the PI will be available.
• Reserve a place for the FDA Investigator to work.
  
• Get the name and phone number of the FDA
  Investigator.
• Provide specific and clear directions to your
  site.

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HOW TO PREPARE FOR AN FDA INSPECTION

• Have ALL records related to the study available,
  including
• SOPs
• Regulatory records IRB approvals, protocols,
  investigator brochure, correspondence.
• CRFs, monitoring reports.
• Source records clinic charts, hospital records,
  x-rays, lab reports, subjects diaries, referrals.
• Test article accountability records.

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WHAT HAPPENS DURING AN FDA BIMO INSPECTION?

• Upon arrival, the FDA Investigator
• Shows FDA credentials to the most responsible
  person
• Issues a Form FDA 482 Notice of Inspection to
  the most responsible person
• Explains why FDA is there and what records and
  documents will be reviewed.

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WHAT HAPPENS DURING AN FDA BIMO INSPECTION?

• The FDA Investigator will ask some general
  questions of the study staff and the Principal
  Investigator.
• The bulk of the inspection will involve the FDA
  Investigator reviewing records.
• Photocopies of some records will be requested.
• Federal regulations allow the FDA to inspect and
  copy ALL records relating to a clinical
  investigation.

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How Long Will We Be There?

• Depends
• What study is covered
• Availability of records
• Extent of operations at facility
• Organization of records
• Cooperation of firm

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WHAT HAPPENS DURING AN FDA BIMO INSPECTION?

• Any deficiencies or observations found during the
  inspection will be discussed during the
  inspection and at the close-out.
• The PI or Study Coordinator should be available
  to answer questions and to provide records during
  the inspection.

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WHAT HAPPENS DURING AN FDA BIMO INSPECTION?

• The FDA Investigator will schedule a close-out
  meeting with the most responsible person.
• The site inspected may receive a Form FDA-483,
  Inspectional Observations.
• Observations may also be presented orally.
• The site may discuss all observations and issues
  with the FDA Investigator at the time of the
  close-out.

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DISCUSSION

• Arguing with an FDA Investigator is like
  wrestling with a pig after awhile, you realize
  the pig is enjoying it.

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Form FDA-483 Inspectional Observations

• Significant deviations from Regulations.
• Observations are based only on the FDA
  Investigators review of available records and
  information.

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COMMON BIMO OBSERVATIONS for CLINICAL
INVESTIGATORS

• Protocol Deviations/Violations.
• Failure to report Adverse Events.
• Poor record-keeping.
• Informed Consent issues.
• IRB issues.
• Test Article Accountability.
• Failure of the PI to adequately supervise the
  study.

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AFTER AN FDA BIMO INSPECTION

• The Principal Investigator should respond to the
  483 observations in writing.
• The study site should take corrective actions for
  any deficiencies, if possible.
• Provide documentation of the corrective and
  preventive actions with the response.

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AFTER AN FDA BIMO INSPECTION

• The FDA Investigator will write an Establishment
  Inspection Report (EIR) that contains all the
  information collected during the inspection,
  including attachments and exhibits.
• This report is forwarded to the Center that
  issued the assignment for review and final
  classification.

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AFTER AN FDA BIMO INSPECTION

• The assigning Center will classify the inspection
  as
• NAI no action indicated
• VAI voluntary action indicated
• OAI official action indicated

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AFTER AN FDA BIMO INSPECTION

• The inspected site will receive a copy of the EIR
  after the inspection is classified.
• The assigning Center will send a follow-up letter
  to the PI.

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AFTER AN FDA BIMO INSPECTION

• Possible consequences
• Untitled Letters
• Warning Letters
• Notice of Disqualification Proceeding and
  Opportunity to Explain (NIDPOE)
• Rejection of the study
• Prosecution
• Disqualification

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HELPFUL HINTS

• Keep files organized at all times.
• Keep ALL correspondence sponsor, IRB, monitors,
  study subjects.
• letters, faxes, e-mails, memos, phone contacts.
• Keep all test article accountability records
• Shipping receipts, enrollment logs, dispensing
  logs.

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HELPFUL HINTS

• Know your IRBs requirements.
• Know the sponsors Adverse Event reporting
  requirements.
• Know the protocol
• Inclusion/exclusion criteria, study windows,
  study procedures.
• Know each study staff members roles and
  responsibilities the PI is ultimately
  responsible.

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HELPFUL HINTS

• Have written procedures
• SOPs, Quality Policy, training procedures, job
  descriptions.
• Have a Corrective and Preventive Action Plan.
• Memos to File????
• DOCUMENT!!!

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HELPFUL HINTS

• Ask questions during the inspection to clarify
  misunderstandings/communication issues

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The Rewards of Preparation
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FOR MORE INFORMATION

• www.fda.gov
• www.fda.gov/cder/
• www.fda.gov/cber/
• www.fda.gov/cdrh/
• www.fda.gov/fdac/

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Questions and Answers

• What can I tell you?
• What can you tell me?