IRB Review of Device Research and Other Clinical Uses of Devices

1. IRB Review of Device Research andOther Clinical Uses of Devices Marian Serge, R.N. Nurse Consultant Division of Bioresearch Monitoring Office of Compliance, CDRH, FDA (240) 276-0250 Marian.Serge@fda.hhs.gov

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 • 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

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 56.109(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 studiesIRB 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 ReviewNon-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: 301-594-1190

17. IRB ReviewNon-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 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. 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 56.111)

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 mayspecify 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 • 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.

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 DeviceIRB 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 240-276-0125

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