The Clinical Investigator: Responsibilities in Medical Device Clinical Trials

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The Clinical InvestigatorResponsibilities in
Medical Device Clinical Trials
Presented by Catherine Parker, RN
Consumer Safety Officer Division of Bioresearch
Monitoring Office of Compliance Center for
Devices and Radiological Health
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Disclaimer

• The contents of this presentation are my own,
  and do not necessarily reflect the views and/or
  policies of the Food and Drug Administration or
  its staff as per 21 CFR 10.85.

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Presentation Topics

• Introduction to Medical Devices
• Introduction to BIMO
• CI Responsibilities
• Lessons Learned

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FDAs Mission is to Protect and Promote
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CDRH Devices and Rdx Emitting Products
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What is a Medical Device?

• An instrument, apparatus, implement, machine,
  contrivance, implant, in vitro reagent, or other
  similar article, including any component, part,
  or accessory which is
• Recognized in the official National Formulary, or
  the United States pharmacopeia, or any supplement
  to them
• Intended for use in the diagnosis of disease or
  conditions, or in the cure, mitigation,
  treatment, or prevention of disease in man or
  other animals
• Intended to affect the structure or any function
  of the body of man or other animals
• Which does NOT achieve its primary intended
  purposes through chemical action within or on the
  body of man or other animals and which is NOT
  dependent upon being metabolized for the
  achievement of its intended purposes.

• Definition of Device
• Food Drug and Cosmetic Act 201 (h)

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The Important Points

• Device definition excludes products that
• Achieve their primary intended purpose through
  chemical action within the body
• Are dependent upon being metabolized for the
  primary achievement of their primary intended
  purposes

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Medical Devices are Classified by Risk
21 C.F.R. 888
Class I
Class II
Class III

• Medical devices are classified and regulated
  according to their degree of risk to the public

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Medical Device Marketing Applications

• Premarket Approval Application (PMA)
• New Use, Technology, or Class III
• Premarket Notification (510(k))
• Substantial equivalence (SE)
• Humanitarian Device Exemption (HDE)
• Similar to Orphan Product

21 C.F.R. Part 814
21 C.F.R. Part 807
21 C.F.R. 814.100
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Research Applications
21 C.F.R. Part 812

• Investigational Device Exemption (IDE)
• approved by an IRB
• If the study involves a significant risk device,
  the IDE must also be approved by FDA
• informed consent from all subjects
• labeling for investigational use only
• monitoring of the study and
• required records and reports
• Permits a device to be shipped lawfully

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Device Clinical Research

• Significant Risk (SR)
• IDE Submission
• Non-Significant Risk (NSR)
• Abbreviated Requirements
• IDE Exempt

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SR vs. NSR Determination

• Decision based on use of device in study
• Sponsor makes initial assignment
• IRB makes determination
• FDA can disagree

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Significant Risk Definition
21 C.F.R. 812.3(m)

• Device that presents potential for serious risk
  to health, safety, or welfare of a subject
• Implant
• For use in supporting or sustaining life
• Of substantial importance in diagnosing curing,
  mitigating, or treating disease, or otherwise
  preventing impairment of human health

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Non-Significant Risk (NSR)

• No IDE application to FDA
• Considered to have IDE
• Abbreviated requirements only

21 C.F.R. 812.2(b)
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Abbreviated Requirements

• Labels device
• Obtains IRB approval
• SR vs. NSR determination
• Ensures informed consent
• IRB may waive if minimal risk
• Monitors study

• Maintains records
• Makes reports
• Ensures investigators maintain records make
  reports
• Refrains from promotion and other practices

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IDE Exempt Device Research
21 C.F.R. 812.2(c)

• In commercial use before May 28, 1976
• Substantially equivalent to device in commercial
  use before May 28, 1976 and used or investigated
  for labeled indication
• In vitro diagnostics (IVDs)
• Consumer preference testing
• Solely for veterinary or lab animal use

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Other Regulations that Apply

• 21 CFR Part 50 Protection of Human Subjects
• 21 CFR Part 54 Financial Disclosure
• 21 CFR Part 56 Institutional Review Boards
• 21 CFR Part 58 Good Laboratory Practice for
  Non-clinical Laboratory Studies

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Presentation Topics

• Introduction to Medical Devices
• Introduction to BIMO
• CI Responsibilities
• Lessons Learned

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BIMO Program Description

• A comprehensive agency wide 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 Objectives

• Protect the rights, safety, and welfare of human
  research subjects
• Assure the quality, reliability, and integrity of
  data collected
• Provide outreach and training to inspected
  parties (Center Objective)

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BIMO Compliance Programs

• Clinical Investigators
• Sponsors, Contract Research Organizations, and
  Monitors
• Institutional Review Boards
• Good Laboratory Practices

http//www.fda.gov/ora/cpgm/default.htmbimo
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What may Trigger a BIMO Inspection?

• New product or indication
• PMA or 510(k) submission
• New technology
• IDE
• Complaints
• Allegations of research misconduct

• Non-compliant history
• Previous OAI inspection
• Routine surveillance
• IRBs

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CDRH BIMO INSPECTIONSFiscal Years 2003 - 2008
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Compliance Classifications

• No Action Indicated (NAI)
• No objectionable conditions or practices
• Voluntary Action Indicated (VAI)
• Objectionable conditions or practices
• But not at threshold to take or recommend
  administrative or regulatory action
• Official Action Indicated (OAI)
• Serious objectionable conditions found
• Regulatory action recommended

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CDRH Clinical Investigator Compliance Rates
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FDA Regulatory Actions

• Rejection of data
• Deficiency letter
• IDE, 510(k), or PMA withdrawal
• Untitled letters
• Warning letters
• Consent Agreement
• Disqualification

• IRB restrictions
• No new studies or subjects
• Application Integrity Policy
• Civil Money Penalties
• Seizure / Detention
• Injunction
• Criminal Prosecution

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Presentation Topics

• Introduction to Medical Devices
• Introduction to BIMO
• CI Responsibilities
• Lessons Learned

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What is a Clinical Investigator (CI)?

• An individual who actually conducts a clinical
  investigation, under whose immediate direction
  the test article is administered, dispensed, or
  used.

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General Responsibilities
21 C.F.R. 812.100

• Follow the investigator agreement, the
  investigational plan, and applicable regulations
• Protect the rights, safety, and welfare of
  subjects
• Control devices under study
• Obtain informed consent

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Specific Responsibilities
21 C.F.R. 812.110

• Obtain IRB and FDA approval
• Follow investigator agreement, investigational
  plan, and conditions of approval imposed by IRB
  or FDA
• Supervise device use
• Disclose financial interests
• Financial Disclosure Guidance Document
• Dispose of device

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Disqualification
21 C.F.R. 812.119

• An investigators repeated or deliberate failure
  to comply with these requirements may result in
  disqualification from receiving investigational
  devices

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Investigator Records
21 C.F.R. 812.140(a)

• All correspondence with another investigator,
  Institutional Review Board (IRB), sponsor,
  monitor, or FDA

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Device Records
21 C.F.R. 812.140(a)

• Records of receipt, use, and disposition of
  device including
• Type and quantity of the devices, dates of
  receipt, and batch number or code mark
• Name of all persons who received, used, or
  disposed of each device
• Why and how many devices have been returned,
  repaired, or other wise disposed of

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Case Histories
21 C.F.R. 812.140(a)

• Exposure to the device
• CRFs and supporting data
• Informed consent documents
• Adverse device effects
• Any relevant observations

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On the second day the knee was better, and on
the third day it disappeared.
Case Histories
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Protocols
21 C.F.R. 812.140(a)

• All IRB approved amendments
• Including approvals
• Documentation of protocol deviations and IRB and
  sponsor approvals

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Record Retention
21 C.F.R. 812.140(d)

• Two years after study termination or completion
• Two years after records are no longer required to
  support marketing application

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Records Custody
21 C.F.R. 812.140(e)

• Withdraw responsibility to maintain records
• Transfer custody to any other person who will
  accept responsibility
• Notice of transfer to FDA not later than 10
  working days

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Documentation

• If it is not documented, it never happened!

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Investigator Reports
21 C.F.R. 812.150

• Unanticipated Adverse Device Effects
• Withdraw of IRB approval
• Progress reports
• Deviations from the investigational plan
• Informed consent
• Final report
• Other

Progress Report 2008
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Adverse Effect

• Any adverse medical occurrence that may or may
  not be related to the investigational device
• All adverse effects should be documented

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Unanticipated Adverse Device Effect
21 C.F.R. 812.3(s)

• Any serious adverse effect that is possibly
  caused by or related to the investigational
  device
• Not previously identified in nature, severity, or
  degree, or
• Any other unanticipated serious problem
  associated with a device

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CI Responsibilities-AEs and UADEs

• Report Unanticipated AEs to the sponsor and IRB
  within 10 working days
• Maintain records of all AEs (anticipated or
  unanticipated)
• Follow the sponsors requirements for reporting
  and recording of AEs and UADEs

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FDA Inspections
21 C.F.R. 812.145

• Occur at reasonable times and in a reasonable
  manner
• Permit records to be inspected and copied

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Study Deviations
21 C.F.R. 812.140(a)

• Document dates and reasons for any deviations
  from the study protocol
• Emergency deviations must be reported to the
  sponsor and IRB within 5 days
• Obtain prior approval from the sponsor, IRB, and
  FDA for changes or deviations from the
  investigational plan

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Presentation Topics

• Introduction to Medical Devices
• Introduction to BIMO
• CI Responsibilities
• Lessons Learned

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The 6 Virtues of the Researchers Creed

• I shall follow the investigational plan,
  investigator agreement, or protocol
• I shall document case hx/device exposure
  accurately, completely and currently
• I shall obtain adequate informed consent
• I shall control inv. devices
• I shall report UADEs
• I shall obtain FDA/IRB approval to conduct the
  study

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Adequate FDA 483 Response

• Submit a prompt written response
• Assess the root cause of the problem
• Evaluate the extent of the problem
• Explain actions to correct the problem
• Implement preventative actions to avoid
  recurrence
• Include supporting documentation
• Timelines for implementation

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Inadequate Response Example

• As to the (forged) signatures of four persons,
  out of eighty patients, suffice it to say we are
  talking of a margin of error of 5 this is well
  within recognized statistical limits.

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Adequate Response Example

• Failure to follow the investigational plan
• Response We prepared and adopted a written
  procedure that will help staff to assure
  compliance with written study protocols and the
  obligations we accept as clinical investigators
  for FDA-regulated trials. A copy of the approved
  SOP is attached. We have reviewed this new
  procedure at a meeting held on ___ with all
  research staff (attendance sign-in sheet
  attached) and implemented it on ___. After 3
  months, we will evaluate these new practices to
  determine if this corrective action assists with
  protocol adherence.

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References

• CDRH Homepage
• www.fda.gov/cdrh
• CDRH Learn
• http//www.fda.gov/Training/CDRHLearn/ucm162015.ht
  m
• Device Advice
• www.fda.gov/cdrh/devadvice

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In Closing

• A clinical investigator conducts a clinical
  investigation.
• CI responsibilities are designed to
• Protect human subjects
• Promote the collection of quality data

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Device Contacts for Questions

• Questions related to compliance
• Cathy Parker, Office of Compliance, Division of
  Bioresearch Monitoring, 301-796-5553
• Questions pertaining to SR/NSR
• Office of Device Evaluation
• Program Operation Staff 240-276-4040
• IRB or Human Subject Protections Marian Serge,
  301-796-5644