Transcript Slide 1

IRB Review of Device
Research and
Other Clinical Uses of Devices
Marian Serge, R.N.
Nurse Consultant
Division of Bioresearch Monitoring
Office of Compliance, CDRH, FDA
(240) 276-0250
[email protected]
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Disclaimer
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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. The Food and Drug Administration will
not be bound by any of the comments or
information contained in this presentation.
Topics
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Background – FDA’s review
IRB Review
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Significant Risk Devices
Non-significant Risk Devices
Exempt Devices
Humanitarian Use Devices
Emergency use
Custom Device
Compassionate Use
IRB and Clinical Investigator Non-compliance
Background
FDA’s Investigational Device Exemption (IDE)
Review
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Pre-IDE meeting (sponsor and FDA)
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Protocol design may be decided upon
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IF IRB makes changes - strongly suggest CDRH input
IDE application (sponsor submits research plans to FDA)
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FDA acknowledges the date it received the IDE
FDA determination within 30 days
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Approve, approve with modifications, disapprove
“Condition of approval letter”
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Study may start, while sponsor responds to the conditions
IRB review of an IDE study
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IRBs may review an IDE study before FDA approval
but with the following risks:
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IRB might review again after FDA’s changes and approval
The investigator might start study before FDA approval
Standard practice: IRB review after FDA approval
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Ensure IDE application is approved by FDA
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Ask for a copy of FDA approval, or condition of approval
letter
Ensure letter states study can start
FDA-Regulated Research
Human Subject Protection & Data Integrity
Sponsor
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IRB
and
Institution
Clinical
Investigator
and
Research
Team
Significant Risk Device Study
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Significant Risk Device Study
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Significant risk device means an investigational
device that presents a potential for serious risk to the
health, safety or welfare of a subject and is
– an implant;
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for use in supporting or sustaining human life;
for substantial importance in diagnosing, curing,
mitigating, or treating disease or preventing
impairment of health; or
the device study presents serious risk to health,
safety, or welfare of a subject
Significant Risk Device
IRB Initial Review Considerations
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Initial Review – gathering the information
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Protocol, informed consent document, device
description, previous research, etc. reviewed at
convened meeting
Most IRBs have standard forms for completion by
clinical investigators at initial review –
Significant Risk Device
IRB Initial Review Considerations
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More questions to ask:
 Monitoring plans? How often will the site be
monitored?
 Who will implant/use the device?
 Who will conduct the informed consent
process?
 Are there subinvestigators – what activities?
 What are the responsibilities of the research
team – research activities; CRF completion;
device accountability?
 What are the Field Clinical Engineer activities?
Significant Risk Device
IRB Review Considerations During Study
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Unanticipated adverse device effect
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Clinical investigators must make UADE reports to
sponsor and IRB within 10 working days
IRBs may observe the consent process and
research [21 CFR 56.109(f)]
Review of Amendments/changes
Sponsor reports to the IRB at least yearly
Significant Risk Device
IRB Continuing Review
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Convened meeting
Review protocol, current informed consent,
adverse events, sponsor info, etc.
Review of IRB forms completed by CI
Also ask for monitoring reports,
accountability records, and ask who is
implanting the device, whether device
implanted outside the study, etc.
Questions so far?
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Non-significant risk device studies
IRB Review Considerations
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Non-Significant Risk Device
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FDA is not aware of NSR studies
IRB is only oversight body for NSR studies
Sponsor will make the initial NSR
determination
IRB Review
Non-Significant Risk Device
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IRB must determine whether the NSR device
research is NSR or SR
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How to make the determination
– Review the SR definition
– Review Sponsor’s brief explanation of why the
device is not a SR
– Review the proposed use of the device
– Review the additional procedures - surgical
– Ask FDA for assistance: 301-594-1190
IRB Review
Non-Significant Risk Device
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IRB determination of whether the NSR
device research is NSR or SR
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If NSR, IRB may continue their review for
implementation at the site. If approved, study is
considered to have IDE; it may start; must follow
abbreviated requirements at 812.
If SR, IRB reports its determination to the CI and
where appropriate the sponsor and wait for the
sponsor to obtain an IDE before approving the
research study at the site.
21 CFR 812.2(b)
Non-significant risk device studies
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Sponsor responsibilities [21CFR 812.2(b)]
– Label: “Caution-Investigational device limited by
Federal law to investigational use.
– Ensure IRB approval after presenting the IRB
with explanation of why device is NSR.
– Ensures Investigators obtain informed consent
– Monitoring
– Maintains records: name and use of device;
explanation of NSR; name and address of CIs;
name and address of each IRB; GMP statement,
and adverse effects & complaints
Non-significant risk device studies
Sponsor responsibilities
Sponsor responsibilities
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Reports to IRBs and FDA:
unanticipated AEs;
withdrawal of IRB approval;
withdrawal of FDA approval;
at least yearly submit progress reports;
recalls (return, repair, disposal);
submit final report w/i 6 mo;
lack of informed consent to FDA; and
the IRB’s SR determinations to FDA.
Ensures CIs maintain records and reports
No promotion of the NSR device
21 CFR 812.2(b)
Non-significant risk device studies
Clinical Investigator responsibilities
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Obtain and document informed consent
Report unanticipated adverse device effects
to IRB and sponsor in 10 working days
Report any information about the research to
IRB and FDA upon request
Research exempt from 21 CFR 812 but
not from parts 50 (consent) & 56 (IRB)
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Several categories of exempt research
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510(k) devices used according to labeling
If the testing is not for determining safety or
effectiveness and subjects not at risk
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Consumer preference testing
Testing of a modification
Testing of two devices in commercial distribution
Diagnostic devices, if it meets the following. . . .
Research exempt from 21 CFR 812 but not
from Parts 50 (consent) and 56 (IRB)
Diagnostic devices exempt, if the testing
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Is non invasive (simple venepuncture is okay)
Sampling procedure does not present significant risk
Will not introduce energy into the body
Is confirmed by another established diagnostic
procedure
Otherwise the diagnostic study must follow 812
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Informed consent process
Important for device studies
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Ensure language understandable
Ensure there is no exculpatory language
Ensure patient given opportunity to consider whether
or not to participate
Ensure possibility of coercion or undue influence is
minimized
Ensure patient is given adequate opportunity to read it
before it is signed and dated
IRB: ask about the process at initial and continuing review
IRB Review and Informed Consent
FDA has no waiver of
informed consent
(except for emergency use)
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Questions so far?
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Humanitarian Use Device
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What is a Humanitarian Use Device?
An HUD is a device that is intended to benefit
patients in the treatment or diagnosis of
diseases or conditions that affect or are
manifested in fewer than 4,000 individuals in
the US per year.
An HUD is a significant risk device
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Humanitarian Use Device
Humanitarian Device Exemption
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HUD – Office of Orphan Products
Development
HDE – Office of Device Evaluation
HDE application review by CDRH
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Bench and animal testing
Clinical experience: may be data, literature,
investigation(s), marketing experience
Approval based on probable benefit outweighs risk
of injury from its use (not reasonable assurance of
safety and effectiveness – as in PMA approval)
HDE label states “the effectiveness of this device
for this use has not been demonstrated”
The HDE allows the HUD to be sold
What are the HDE holder
responsibilities? (Federal Register)
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The HDE holder is responsible for ensuring
that the HUD is not administered to or
implanted in a patient prior to obtaining IRB
approval at the health care facility.
An HDE holder may wish to enforce this
requirement by not shipping the HUD to the
facility until it has received confirmation of
IRB approval.
What are the IRBs responsibilities
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IRB activities – follow Part 56
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Approval before HUD-HDE administered!
Initial review – convened meeting
Continuing review
Withdrawal of approval
Federal Register –
IRB review of an HUD-HDE
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FDA believes that the approval criteria set
forth in the IRB regulations can and should
be interpreted to include consideration of the
patient’s need for the HUD and the likelihood
that the device is appropriate for the patient’s
condition or disease state.
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(i.e., No special IRB written procedures are needed to review
an HUD – use the approval criteria at 56.111)
Federal Register – IRB review of HDE
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An IRB may approve the use of the HUD
– in general, for HUD patients
– for groups of patients (with the serious
HUD disease or condition) that meet
certain criteria
– under a treatment protocol for the HUD
– on an HUD case by case basis
Federal Register – IRB review of HDE
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An IRB may specify limitations on the use of
the HUD based upon
– one or more measures of disease
progression
– prior use and failure of any alternative
treatment modalities
– reporting requirements to IRB or IRB chair
– appropriate follow up precautions and
evaluations
– any other criteria it determines appropriate
Federal Register – IRB review of HDE
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IRB requirement to withdraw approval
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Failure to follow IRB or FDA requirements
Unexpected serious harm to subjects
What are physician responsibilities?
Physician and Institution Activities
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Report serious adverse events using Medical
Device Reporting system 21 CFR 812 Subpart H
Information to Patients
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Regulations do not require informed consent
IRB and Institution may require consent
Most HUDs have information for patients
Humanitarian Use Device
Research and off label use
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Research
– If safety and effectiveness data are being
collected on the exact use described in
approved labeling – IDE may not needed
– If research is intended to prove safety or
effectiveness for a new use – IDE needed
Off label use of HUD
– FDA recommends compassionate use provision,
which includes prior FDA and IRB concurrence
before use.
Questions so far?
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Emergency use of an
unapproved device
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Emergency Use of unapproved device
Points for IRBs to Remember
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Unapproved device (usually under IDE)
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Physician must determine:
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Either for new use or
by a physician not part of the research study
Life-threatening situation or serious
disease/condition
No other treatment available
Used once; if potential for more uses -- IDE
required and IRB review
Emergency Use of unapproved device
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FDA does not have to concur before it is
used.
Physician makes report to the IRB and
sponsor within 5 working days after use
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Uninvolved physician’s assessment
Informed consent (if no consent - next slide)
Institutional clearance, if required
IRB chairperson’s concurrence (if time)
Authorization from the sponsor (if under an IDE)
Emergency Use and
NO Informed Consent - 21 CFR 56.23
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What are HSP requirements if NO consent?
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Physician and an uninvolved physician certify that
 The patient has life-threatening situation
 Patient is unable to communicate
 Time is not sufficient to obtain consent from
patient or LAR
 No alternative method of approved or generally
recognized therapy that provides likelihood of
saving the life
If time not sufficient to find uninvolved physician,
then Physician must make above determinations
Questions so far?
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Custom Device
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Custom Device
All of the following criteria must be met:
1)
2)
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4)
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Necessarily deviates from performance standard or PMA
requirements
Not generally available in finished form for purchase or
dispensing upon prescription
Not offered through labeling or advertising
Not generally used by other physicians, dentists
Specific patient form (the device is formed to the individual
patient’s physiological needs) or special needs of a
practioner
Custom Device
IRB Awareness
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Rule of thumb
– Device is only available through special order for an
individual patient
– Physician requests special design from manufacturer for
unique situation
– Patient’s name on manufacturer’s order form
– Tools for use by specific physician or dentist in medical
practice
Used by physicians or dentists
No IRB review is required. No IDE needed.
Institutional policy may require IRB review
Report misuse to FDA at 240-276-0125
Three Examples when a device was
NOT a Custom Device
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Hydrocephalic shunts made of some other
material than silicone because patients allergic
to silicone. (IDE needed)
Cranial helmets for miss-shaped new-born
heads. The helmets were shaped or sized i.e.
“fitted” for each subject. (IDE needed)
Thoracic Aortic Aneurysm graft ordered
individually for each patient (IDE needed)
Questions so far?
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Compassionate Use
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Compassionate Use
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Compassionate use
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Single patient or small group
Serious disease or condition
No alternative available
Compassionate Use
Physician duties - guidance
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Obtain FDA concurrence of the compassionate
use before it is used (FDA reviews the sponsor’s
protocol or IDE supplement)
Obtain IRB chair’s concurrence and follow IRB
procedures
Monitors the patient
Report adverse events to IRB
Follow-up report to sponsor (sponsor reports to
FDA)
 Summary information about patient
outcomes
Compassionate Use and
Patient Protection Measures Guidance
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Physician obtains uninvolved physician’s
assessment of compassionate use
Physician obtains IRB chair concurrence
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(chair should ask whether FDA concurred)
Institutional clearance
Physician provides the patient with info and obtains
consent for use
Physician monitors for problems
Physician makes a report
Questions so far?
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IRB Deficiencies
Fiscal Years 1998 - 2005
FY
1998
1999
2000
2001
2002
2003
2004
2005
80%
64%
56%
39%
24%
25%
50%
37%
Inadequate minutes
56%
61%
42%
35%
11%
42%
28%
17%
Lack of or incorrect
SR/NSR determination
52%
58%
42%
57%
10%
16%
34%
22%
Inadequate SOPs
36%
33%
28%
26%
9%
16%
19%
7%
Inadequate
membership roster
32%
31%
22%
30%
13%
20%
21%
12%
Inadequate initial &/or
continuing review
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To Improve compliance
institutions should:
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Provide training to IRB members & staff
Provide training to clinical investigators
Implement a quality assurance program
Correct & prevent problems before they
jeopardize subject safety and the
institution’s reputation
Focus institutional culture on ethics and
good clinical research practices
Investigator Deficiencies
Fiscal Years 1998 - 2005
1998
1999
2000
2001
2002
2003
2004
2005
Failure to follow
investigational
plan/regs
32%
46%
47%
44%
44%
51%
54%
50%
Protocol deviations
21%
8%
26%
40%
20%
38%
16%
9%
Inadequate subject
protection/IC
24%
19%
21%
28%
21%
21%
24%
29%
Inadequate device
accountability
17%
17%
21%
27%
26%
18%
14%
7%
Lack of FDA &/or
IRB approval
11%
9%
11%
5%
8%
13%
13%
10%
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Areas where clinical investigators
or research team did not comply . . . .
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Did not randomize subjects; put all subjects on the
investigational device
Implanted a patient not in the research study
Implanted a “custom” device by requesting it on a
“prescription pad”
Failed to obtain IRB approval for modifications or
amendments in protocol & IC
Enrolled subjects who did not meet eligibility criteria
Areas where clinical investigators
or research team did not comply . . . .
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Failed to report unanticipated adverse device effects.
Failed to complete CRFs, AE forms, and device
accountability records.
Failed to include all basic elements in the informed
consent document.
Failed to ensure completion of all protocol required
tests (i.e., 6-month angiograms).
Started research study before IRB approval.
Areas where clinical investigators
or research team did not comply . . . .
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Unapproved device implanted without an IDE.
CI failed to sign Investigator Agreement.
CI refused to give financial information to sponsor.
Patients did not sign an informed consent document.
Patients signed an informed consent from another
hospital IRB.
Areas where clinical investigators
or research team did not comply . . . .
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Patients signed an old version of Informed Consent
document
Clinical Investigator did not maintain correspondence
from IRB
No documentation about receipt of devices or
distribution to subjects
Lost devices
Questions so far?
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Summary
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IRB Review
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Significant Risk Devices
Non-significant Risk Devices
Exempt Devices
Humanitarian Use Devices
Emergency use
Custom Device
Compassionate Use
IRB and Clinical Investigator Non-compliance