1. 1 THE UNIQUE ROLES OF IRB IN MEDICAL DEVICE CLINICALL TRIAL Chiu Lin, Ph.D. CITI, May, 2009 CITI, May, 2009

2. 2 The World of Medical Device Industry Venture Oriented Venture Oriented Diverse Diverse - > 20,000 firms world wide - Produce > 80,000 brand products Rapidly Expanding Rapidly Expanding Becoming very innovative and high- tech Becoming very innovative and high- tech

3. 3 Medical Device Industry Exponential Growth Dun & Bradstreet Medical Device Firm Data Number of Manufacturers by Year

4. 4 4

5. 5 DEVICES ARE NOT DRUGS DRUGS ARE DISCOVERED DRUGS ARE DISCOVERED DEVICES ARE DESIGNED DEVICES ARE DESIGNED

6. 6 Development of Products - Clinical Investigations DEVICES (IDE) ( ̴̴ 20% clinical trials) DEVICES (IDE) ( ̴̴ 20% clinical trials) - Effectiveness and/or safety pivotal trial (one phase) DRUGS AND BIOLOGICS (100% clinical trials) (IND) - Dose limiting toxicity (Phase I) - Safety and efficacy (Phase II & Phase III)

7. The complexity and need for clinical data is growing… Embolic protection devices Vascular anastomosis devices for CABG Image-guided bronchoscopes Combination product Glaucoma shunts Daily wear contact lenses CPAP devices for apnea … requiring more in-depth assessment of safety and assessment of safety andeffectiveness…….

8. 8 Perspectives of Device Clinical Trials – Compared to Drugs Devices vary greatly on type, intended use population, and risk posed Devices vary greatly on type, intended use population, and risk posed FDA device regulation recognizes these differences by classifying devices into 3 classes: Class I (low risk), Class II (intermediate risk), and Class III (high risk) FDA device regulation recognizes these differences by classifying devices into 3 classes: Class I (low risk), Class II (intermediate risk), and Class III (high risk) FDA does not automatically require clinical trials as part of its approval process for all devices (only about 20% devices require clinical trials) FDA does not automatically require clinical trials as part of its approval process for all devices (only about 20% devices require clinical trials)

9. 9 Premarket Submission Requirements of Medical Devices Premarket Notification [510(k)] –Class I & Class II Premarket Notification [510(k)] –Class I & Class II Premarket Approval (PMA) – Class III Premarket Approval (PMA) – Class III

10. 10 PREMARKET NOTIFICATION 510(K) Data to demonstrate the new device is as safe and effective (substantially equivalent, SE) as a legally market (predicate) device Only in few cases, a clinical data is needed to support SE determination.

11. 11 PREMARKET APPROVAL (PMA) The most stringent marketing application The most stringent marketing application PMA must contain sufficient information to reasonably assure the safety and effectiveness of the proposed device. PMA must contain sufficient information to reasonably assure the safety and effectiveness of the proposed device. Valid scientific evidence must be provided to demonstrate that the device is safe and effective for its intended use. Valid scientific evidence must be provided to demonstrate that the device is safe and effective for its intended use.

12. 12 Valid Scientific Evidence (21 CFR 860.7) Well-controlled clinical investigation Well-controlled clinical investigation Partially controlled clinical studies Partially controlled clinical studies Studies and objective trials without matched control Studies and objective trials without matched control

13. 13 Regulation of Medical Device Clinical Investigation 21 CFR Part 812 - Investigational Device Exemption, IDE (IND – 21 CFR Part 312) 21 CFR Part 812 - Investigational Device Exemption, IDE (IND – 21 CFR Part 312) 21 CFR Part 50 - Informed consent – drugs, devices, and biologics 21 CFR Part 50 - Informed consent – drugs, devices, and biologics 21 CFR Part 56 - Institutional Review Boards (IRB) – drugs, devices, and biologics 21 CFR Part 56 - Institutional Review Boards (IRB) – drugs, devices, and biologics

14. 14 Clinical Investigations Subject to IDE Regulation To support marketing application [PMA, or 510(k)] To support marketing application [PMA, or 510(k)] Collection of safety and effectiveness information for unapproved device Collection of safety and effectiveness information for unapproved device Sponsor-investigator studies Sponsor-investigator studies

15. 15 Clinical Investigation Under IDE To determine safety and effectiveness of an investigational device To determine safety and effectiveness of an investigational device No phases in clinical investigation No phases in clinical investigation Distinction between significant risk (SR) devices and non-significant risk (NSR) devices in approval process Distinction between significant risk (SR) devices and non-significant risk (NSR) devices in approval process Different approval procedures for SR and NSR studies Different approval procedures for SR and NSR studies

16. 16 Significant Risk (SR) Investigation A study that presents a potential for serious risk to the health, safety, or welfare of a subject A study that presents a potential for serious risk to the health, safety, or welfare of a subject Require FDA and IRB approval before clinical investigation can begin Require FDA and IRB approval before clinical investigation can begin

17. 17 Examples of SR Devices Cardiac catheters Cardiac catheters Surgical tissue adhesives Surgical tissue adhesives Vascular and arterial graft protheses Vascular and arterial graft protheses Dental endosseous implants Dental endosseous implants Cochlear implants Cochlear implants Implantable infusion pumps Implantable infusion pumps Implantable pacemaker Implantable pacemaker

18. 18 Examples of NSR Devices (Require only IRB approval for investigation) Bio-stimulation lasers for treatment of pain Bio-stimulation lasers for treatment of pain Daily wear contact lenses Daily wear contact lenses Glucose monitor Glucose monitor Blood pressure monitor Blood pressure monitor Magnetic resonance imaging (MRI) Magnetic resonance imaging (MRI) Pulse oximeter Pulse oximeter Ob/Gyn diagnostic ultrasound Ob/Gyn diagnostic ultrasound

19. 19 Approving Clinical Investigation of Medical Devices by IRB (21 CFR 812 Subpart D – IDE Regulation)

20. 20 IRB Review and Approval § 812.60 – IRB composition, duties, and function § 812.60 – IRB composition, duties, and function - An IRB reviewing and approving investigation shall comply with requirements of Part 56 in all respects, including its composition, duties, and function

21. 21 IRB Review and Approval § 812.62 – IRB Approval § 812.62 – IRB Approval - An IRB shall review and have authority to approve, require modifications, or disapprove all investigations under IDE. - If FDA finds that an IRB’s review is inadequate, a sponsor should submit an IDE application to FDA.

22. 22 IRB Review and Approval § 812.64 – IRB’s Continuing Review § 812.64 – IRB’s Continuing Review - The IRB shall conduct its continuing review of an investigation in accordance with Part 56.

23. 23 Determination of SR/NSR Study (21 CFR 812.66) Sponsor presents protocol to IRB and a statement why investigation does not pose significant risk (NSR study) Sponsor presents protocol to IRB and a statement why investigation does not pose significant risk (NSR study) If IRB agrees the study is NSR & approves the study, then, no formal IDE submission for FDA approval is needed. Investigation can begin (Abbreviated IDE requirements). If IRB agrees the study is NSR & approves the study, then, no formal IDE submission for FDA approval is needed. Investigation can begin (Abbreviated IDE requirements). If IRB disagrees, then, submit IDE application to FDA for approval (SR Investigation with full requirements) If IRB disagrees, then, submit IDE application to FDA for approval (SR Investigation with full requirements)

24. 24 Abbreviated IDE No formal FDA IDE approval is needed No formal FDA IDE approval is needed IRB is required to meet all aspects of: IRB is required to meet all aspects of: - 21 CFR Part 50 (protection of human subjects) – Informed consent - 21 CFR Part 56 (IRB) Labeling requirements Labeling requirements

25. 25 Comparison Between Device and Drug/Biologics Trials

26. 26 Regulatory Distinctions Device Classification – risk based Device Classification – risk based - Class I - Class II - Class III Drug and Biologics Drug and Biologics - All high risk - No Class I, II, and III classification

27. 27 Regulatory Distinctions * Devices: “Investigator agreement” generated by the sponsor [per 21 CFR 812.43(c)] * Drugs: “Statement of Investigator” - Form 1572

28. 28 Regulatory Distinctions Adverse Events  Devices: investigators shall submit the adverse effect report to the sponsor and IRB [21 CFR 812.150(a)(1)]  Drugs/Biologics: investigators shall submit the adverse effect report to the sponsor [21 CFR 312.64(b)]

29. 29 Regulatory Distinctions Device – Significant vs. non-significant risk trials Device – Significant vs. non-significant risk trials Drug – All significant risks Drug – All significant risks

30. 30 Research Distinctions Device Studies (vs. drug trials) Device Studies (vs. drug trials) - Small subject population (mostly 100s) - One phase trial - Blinding study is not common - “Controls” vary Can not do placebo Can not do placebo Sham, active, historical controls are common Sham, active, historical controls are common - CI training is critical (Human Factors) - IRBs play critical role

31. 31 Regulatory Similarities 21 CFR 50: Informed consent 21 CFR 50: Informed consent 21 CFR 54: Financial Disclosure of clinical investigator 21 CFR 54: Financial Disclosure of clinical investigator 21 CFR 56: IRB 21 CFR 56: IRB

32. 32 Regulatory Similarities  FDA approval required  IDE or IND  FDA regulations specify sponsor and clinical investigator responsibilities  21 CFR 812 and 21 CFR 312

33. 33 CONCLUSION The role of IRB in approving medical device clinical trial is identical to approving drug investigation The role of IRB in approving medical device clinical trial is identical to approving drug investigation Additional role in medical device trial is the differentiation of SR and NSR investigation Additional role in medical device trial is the differentiation of SR and NSR investigation

34. 34 THANK YOU FOR YOUR ATTENTION !! Question ?