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)

2. 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. The Food and Drug Administration will not be bound by any of the comments or information contained in this presentation.

3. Topics Background – FDA’s review IRB Review Humanitarian Use Devices
Significant Risk Devices
Non-significant Risk Devices
Exempt Devices
Humanitarian Use Devices
Emergency use
Custom Device
Compassionate Use
IRB and Clinical Investigator Non-compliance

4. Background FDA’s Investigational Device Exemption (IDE) Review
Pre-IDE meeting (sponsor and FDA)
Protocol design may be decided upon
IF IRB makes changes - strongly suggest CDRH input
IDE application (sponsor submits research plans to FDA)
FDA acknowledges the date it received the IDE
FDA determination within 30 days
Approve, approve with modifications, disapprove
“Condition of approval letter”
Study may start, while sponsor responds to the conditions

5. IRB review of an IDE study
IRBs may review an IDE study before FDA approval but with the following risks:
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
Ensure IDE application is approved by FDA
Ask for a copy of FDA approval, or condition of approval letter
Ensure letter states study can start

6. FDA-Regulated Research
Human Subject Protection & Data Integrity
Sponsor
Clinical
Investigator
and
Research
Team
IRB
and
Institution
HSP is not just an IRB function
Joint effort
CI/Sponsor responsibilities
Sponsors are in an unique position through their monitoring responsibilities to ensure CI compliance with HSP
IRB approval
ADRs
CFs
Continuing Rvw
FDA and the regs hold all parties accountable

7. Significant Risk Device Study

8. Significant Risk Device Study
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;
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

9. Significant Risk Device IRB Initial Review Considerations
Initial Review – gathering the information
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 –

10. Significant Risk Device IRB Initial Review Considerations
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?

11. Significant Risk Device IRB Review Considerations During Study
Unanticipated adverse device effect
Clinical investigators must make UADE reports to sponsor and IRB within 10 working days
IRBs may observe the consent process and research [21 CFR (f)]
Review of Amendments/changes
Sponsor reports to the IRB at least yearly

12. Significant Risk Device IRB Continuing Review
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.

13. Questions so far?

14. Non-significant risk device studies IRB Review Considerations

15. Non-Significant Risk Device
FDA is not aware of NSR studies
IRB is only oversight body for NSR studies
Sponsor will make the initial NSR determination

16. IRB Review Non-Significant Risk Device
IRB must determine whether the NSR device research is NSR or SR
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:

17. IRB Review Non-Significant Risk Device
IRB determination of whether the NSR device research is NSR or SR
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.

18. 21 CFR 812.2(b) Non-significant risk device studies
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

19. Non-significant risk device studies Sponsor responsibilities
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

20. 21 CFR 812.2(b) Non-significant risk device studies
Clinical Investigator responsibilities
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

21. Research exempt from 21 CFR 812 but not from parts 50 (consent) & 56 (IRB)
Several categories of exempt research
510(k) devices used according to labeling
If the testing is not for determining safety or effectiveness and subjects not at risk
Consumer preference testing
Testing of a modification
Testing of two devices in commercial distribution
Diagnostic devices, if it meets the following

22. Diagnostic devices exempt, if the testing
Research exempt from 21 CFR 812 but not from Parts 50 (consent) and 56 (IRB)
Diagnostic devices exempt, if the testing
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

23. Informed consent process Important for device studies
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

24. IRB Review and Informed Consent
FDA has no waiver of
informed consent
(except for emergency use)

25. Questions so far?

26. Humanitarian Use Device

27. 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

28. Humanitarian Use Device Humanitarian Device Exemption
HUD – Office of Orphan Products Development
HDE – Office of Device Evaluation

29. HDE application review by CDRH
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

30. What are the HDE holder responsibilities? (Federal Register)
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.

31. What are the IRBs responsibilities
IRB activities – follow Part 56
Approval before HUD-HDE administered!
Initial review – convened meeting
Continuing review
Withdrawal of approval

32. Federal Register – IRB review of an HUD-HDE
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.
(i.e., No special IRB written procedures are needed to review an HUD – use the approval criteria at )

33. Federal Register – IRB review of HDE
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

34. Federal Register – IRB review of HDE
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

35. Federal Register – IRB review of HDE
IRB requirement to withdraw approval
Failure to follow IRB or FDA requirements
Unexpected serious harm to subjects

36. What are physician responsibilities?
Physician and Institution Activities
Report serious adverse events using Medical Device Reporting system 21 CFR 812 Subpart H
Information to Patients
Regulations do not require informed consent
IRB and Institution may require consent
Most HUDs have information for patients

37. Humanitarian Use Device Research and off label use
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.

38. Questions so far?

39. Emergency use of an unapproved device

40. Emergency Use of unapproved device Points for IRBs to Remember
Unapproved device (usually under IDE)
Either for new use or
by a physician not part of the research study
Physician must determine:
Life-threatening situation or serious disease/condition
No other treatment available
Used once; if potential for more uses -- IDE required and IRB review

41. Emergency Use of unapproved device
FDA does not have to concur before it is used.
Physician makes report to the IRB and sponsor within 5 working days after use
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)

42. Emergency Use and NO Informed Consent - 21 CFR 56.23
What are HSP requirements if NO consent?
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

43. Questions so far?

44. Custom Device

45. Custom Device All of the following criteria must be met:
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

46. Custom Device IRB Awareness
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

47. Three Examples when a device was NOT a Custom Device
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)

48. Questions so far?

49. Compassionate Use

50. Compassionate Use Compassionate use Single patient or small group
Serious disease or condition
No alternative available

51. Compassionate Use Physician duties - guidance
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

52. Compassionate Use and Patient Protection Measures Guidance
Physician obtains uninvolved physician’s assessment of compassionate use
Physician obtains IRB chair concurrence
(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

53. Questions so far?

54. IRB Deficiencies Fiscal Years 1998 - 2005FY
1998
1999
2000
2001
2002
2003
2004
2005
Inadequate initial &/or
continuing review
80%
64%
56%
39%
24%
25%
50%
37%
Inadequate minutes
61%
42%
35%
11%
28%
17%
Lack of or incorrect SR/NSR determination
52%
58%
57%
10%
16%
34%
22%
Inadequate SOPs
36%
33%
26% 9%
19% 7%
Inadequate membership roster
32%
31%
30%
13%
20%
21%
12%

55. To Improve compliance institutions should:
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

56. Investigator Deficiencies Fiscal Years 1998 - 2005
1999
2000
2001
2002
2003
2004
2005
Failure to follow investigational plan/regs
32%
46%
47%
44%
51%
54%
50%
Protocol deviations
21% 8%
26%
40%
20%
38%
16% 9%
Inadequate subject protection/IC
24%
19%
28%
29%
Inadequate device accountability
17%
27%
18%
14% 7%
Lack of FDA &/or IRB approval
11% 5%
13%
10%

57. Areas where clinical investigators or research team did not comply . . . .
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

58. Areas where clinical investigators or research team did not comply . . . .
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.

59. Areas where clinical investigators or research team did not comply . . . .
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.

60. Areas where clinical investigators or research team did not comply . . . .
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

61. Questions so far?

62. Summary IRB Review Humanitarian Use Devices Emergency use
Significant Risk Devices
Non-significant Risk Devices
Exempt Devices
Humanitarian Use Devices
Emergency use
Custom Device
Compassionate Use
IRB and Clinical Investigator Non-compliance