Clinical Studies Involving an Investigational Device

1
Clinical Studies Involving an Investigational
Device

• Jelena P. Berglund, PhD, RAC
• Regulatory Affairs Associate

2
Overview

• Definitions/classifications
• Marketing pathways
• Clinical investigation of Medical Device
• Abbreviated IDE
• IDE preparation/submission
• IDE maintenance
• Closing an IDE
• IDE exempt studies

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What is a Medical Device?

• Its an instrument, apparatus, implement, machine,
  contrivance, implant,
• in vitro reagent or other similar or related
  article or component part or
• accessory which

- is intended for use in the diagnosis of
disease or other conditions, or in the cure,
mitigation, treatment, or prevention of disease
- is intended to affect the structure or any
function of the body - achieve it's primary
intended purposes through physical action and NOT
chemical or metabolic action - medical devices
range from dental floss to an artificial heart
valve
4
Medical Device Regulations

• 1976 - Medical Device Amendment
• - Prior to 1976, investigational devices were or
  not reviewed or reviewed as drugs
• 1990 - Safe Medical Device Act (SMDA)
• - Post marketing surveillance, tracking of
  implants, injury reporting
• 1997- FDA Modernization Act (FDAMA)
• - low risk exempt from 510(k)
• 2002- Medical Device User Fee and Modernization
  Act (MDUFMA)
• - Combinatory product, user fees established

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Medical Device Classification

• Devices are classified related to the risk
  associated with the use of the device
• Class I lowest risk
• Class II intermediate risk
• Class III highest risk
• Class I and II are non-significant risk (NSR)
  devices
• Class III devices are significant risk (SR)
  devices

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Medical Device Classification

• Class I - e.g. dental floss, medical disposable
  scissors
• Class II - e.g. automated cell counter, oxygen
  masks, MRI
• Class III - e.g. tracheal prostheses, replacement
  heart valves

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Medical Device Classification

• Devices are classified based on the time of
  their marketing
• - pre-Amendments device marketed prior to 1976
• - post-Amendments device - marketed after 1976
• - Transitional devices - those regulated as
  drugs prior to the 76 Amendments, but
  subsequently as devices

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Placing a device on the market
9
Market submission options

• 510 (k) - device is at least as safe and
  effective, substantially equivalent, to a legally
  marketed device that is not subjected to PMA
• PMA - premarket approval is required for all
  class III devices. Focus on scientific and
  regulatory review of safety and effectiveness
• Exempt most class I and few class II devices
  are exempt from the 510(k) regulations (e.g. some
  pre-amendment device not significantly changed)

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Clinical Investigation of Medical Device
11
Clinical Investigation of Medical Device

• FDA regulation prohibit promotion and
  commercialization of an unapproved medical device
• Such device can be legally distributed for
  investigational purposes under an investigational
  device exemption (IDE)
• Clinical studies are usually conducted to support
  PMA
• Small percentage of 510 (k) require clinical
  study to support the application
• Although previously marketed, if device is used
  to asses safety or effectiveness of certain
  modifications or new intended use it is
  considered investigational device

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Clinical Investigation of Medical Device

• All clinical investigation of device must
• - have an approved IDE (21 CFR 812.20)
• OR
• - be exempt from the IDE regulations
• (21 CRF 812.2 (c))

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Who approves an IDE?

• Before starting a clinical trial IDE must be
  approved by

• FDA and IRB
• Significant risk (SR) device
• Investigation exempt from the informed consent
• FDA notifies the sponsor that IDE application is
  required

• IRB (abbreviated IDE)
• Non-significant risk (NSR) device
• Not a banned device
• Must have informed consent

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What are Significant Risk Devices?

• Significant Risk Device is investigational device
  that
• - is intended as an implant
• - is used to support or sustain human life
• - is substantial importance in diagnosing,
  curing, mitigating, or treating disease or
  otherwise preventing impairment of human health
• - otherwise presents a potential for a serious
  risk to the health, safety or welfare of human
  subject
• Guidance http//tiny.cc/6EfEF

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If you have a NSR device(21 CFR 812.2 (b))

• You can have an abbreviated IDE

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Abbreviated IDE

• Obtain and maintain IRB approval of the
  investigation
• Make sure that the device is properly labeled
• Ensure that informed consents are obtained
• Maintain required records and reports
• Monitor the study to ensure compliance with the
  protocol and protect the human subject
• The promotional practices are NOT permitted

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Obtaining an IRB approval

• Sponsor makes initial significant or
  non-significant risk study determination
• Submit to the IRB required documents and
  explanation why you believe that the device is
  NSR device
• If IRB agrees with sponsor, study can be
  conducted under the IRB oversight only

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If IRB disagree with you?

• Before starting a clinical trial IDE must be
  approved by

• FDA and IRB
• Significant risk (SR) device
• Investigation exempt from the informed consent
• FDA notifies the sponsor that IDE application is
  required

• IRB (abbreviated IDE)
• Non-significant risk (NSR) device
• Not a banned device
• Must have informed consent

IRB shopping is NOT allowed!
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If you do need FDA approval21 CFR 812.20
http//tiny.cc/uxH9X
20
IDE Content 21 CFR 812.20 (b)

• 1. Cover Sheet 3514
• 2. Name and Address of the Sponsor
• 3. Report of Prior Investigations
• 4. Investigational Plan
• 5. Manufacturing Information
• 6. Investigators Agreement
• 7. Investigators Certification

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IDE Content 21 CFR 812.20 (b)

• 8. IRB Information
• 9. Name and Address of Investigators Institution
• 10. Financial Claims
• 11. Environmental Assessment
• 12. Labeling
• 13. Informed Consent
• 14. Additional Information

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3. Report of Prior Investigation (21 CFR 812.27)

• General
• - prior clinical, animal and laboratory testing
• Specific
• - bibliography of all publications
• - summary of all unpublished information
• - if laboratory studies are referenced,
  statement whether such a studies have been done
  according to the GLP

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4. Investigational Plan (21 CFR 812.25)

• - Purpose name and intended use
• - Protocol
• - Risk Analysis
• - Description of the Device
• - Monitoring Procedures
• - Labeling
• - IRB Information
• - Other Institution
• - Additional Records and Reports

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IDE submission

• Send original and 2 copies of you application
• State clearly that it is an IDE application
• IDE should be sent to
• Food and Drug Administration Center for
  Devices and Radiological Health (CDRH)
• Document Mail Center (HFZ-401) 9200 Corporate
  Boulevard Rockville, Maryland 20850-3223

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What happens after IDE submission?

• Sponsors are notified of the date that FDA
  received the original application
• IDE number is assigned
• Project manager is assigned

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What happens after IDE submission?

• Within 30 calendar days of the day the
  application has been received, FDA may
• - Approve the investigation as proposed
• - Approve it with modifications
• - Disapprove it
• An IDE application is considered approved 30 days
  after it has been received by FDA

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Reasons for disapproval

• Risk associated with the study outweigh the
  benefits
• There are untrue statements in the applications
• Failure to respond to the request for additional
  information
• Inadequacy of monitoring, reviewing,
  manufacturing, packaging etc.

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Once you have an active IDE
http//tiny.cc/uxH9X
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Modification in the active IDE

• Changes that DO NOT require prior approval
• Emergency change
• Non-significant design changes
• Some protocol changes inc/exc criteria, sec.
  end points
• - inform the FDA within 5 working days

• Changes that require prior approval
• Indication
• Type or nature of study control
• Primary end point
• Statistical methods for evaluation
• Expanding the study
• Significant design changes
• Early termination

Guidance http//tiny.cc/1VfGN
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IDE Reports to the FDA 21 CFR 812.150
FDA IRB
Unanticipated adverse device effects 10 working days
Withdrawal from IRB approval 5 working days
Withdrawal from the FDA approval 5 working days
Investigator list Every 6 month
Progress report No less then yearly
Check with your IRB
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IDE Reports to the FDA21 CFR 812.150
FDA IRB
Deviation from the Investigational Plan 5 working days
Informed Consent violation 5 working days
Recall and device disposition 30 working days
Significant Risk Determination 5 working days
Final Report 30 working days - notification 6 months - report
Check with your IRB
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Closing/Terminating an IDE

• If IDE is still not yet approved request a
  withdrawal
• If you have an active IDE, but no subject
  enrolled request a withdrawal, but state why
  and account for all the device
• If subjects have been enrolled you need to
  complete follow-up of already enrolled subjects
• If you completed the study notify FDA within
  30-days and send Final Report within 6 months.

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Clinical Investigation of Medical Device

• All clinical investigation of device must
• - have an approved IDE (21 CFR 812.20)
• OR
• - be exempt from the IDE regulations
• (21 CRF 812.2 (c))

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IDE exempt investigations

• Pre-amendment device in accordance with the
  indications in labeling in effect at that time
• Post amendment device in accordance with the
  indication on the labeling that FDA reviewed

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IDE exempt investigations

• A diagnostic device if
• - Its not invasive
• - Does not require an invasive sampling
  procedure that presents a significant risk
• - Does not by design or intention introduce
  energy into a subject
• - Is not used as diagnostic procedure without
  confirmation of the diagnosis by another
  medically established diagnostic product or
  procedure

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IDE exempt investigations

• A device undergoing a consumer preference
  testing, testing of modification or testing of a
  combination of two or more devices in commercial
  distribution if the testing is not for the
  purpose of determining safety or effectiveness
• A device intended for veterinary use only
• A device for research on or with laboratory
  animals
• A custom device

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How to Reach Us. . .

• You can contact us on any IDE or regulatory issue
  at
• bruce.burnett_at_duke.edu or [phone]
• jelena.petrovic_at_duke.edu or [phone]
• erin.oreilly_at_duke.edu or [phone]
• sue.avery_at_duke.edu or [phone]
• OR
• regulatorydtmi_at_mc.duke.edu

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Your UNC Regulatory ContactsNC TraCS Regulatory
Core
Maria Rape, RN Associate Director
mzeldin_at_med.unc.edu [phone] Amy
Franklin, BA IND Specialist amy_franklin_at_med.unc
.edu [phone] Diane Towle, RN Regulatory
Nurse towle_at_med.unc.edu [phone]