Device World: The Basics SR and NSR Determinations Expanded Access

1. Device World:The Basics SR and NSR DeterminationsExpanded Access Susie Hoffman University of Virginia Margaret Foster Riley, J.D. University of Virginia, School of Law, School of Medicine, Batten School of Leadership and Public Policy

2. Definition of Device §201(h) • “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part or accessory, which is • …(2)intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment or prevention of disease

3. Definition of Device §201(h) • “(3)intended to affect the structure or function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animlas and which is not dependent upon being metabolized to achieve its primary intended purposes”

4. Medical Devices • Vast number • Tongue depressor, stethoscope, stents that hold blood vessels open • Vary in complexity and risk as well as benefit • Characterized by “on the spot” innovation • FDA interprets the statute broadly and claims authority over many articles that may not seem to be devices: e.g. reagents for assays, genetic tests and software (even maybe medical records)

5. Line between device and drug not clear • Saline • Contrast imaging agents • Can be either but must treat them consistently • Combination products • E.g. Clot busting stents • Office of combination products at FDA

6. Devices are Different • Not just in “substance” but in regulation • Different pathways (different statutory roots) • Devices can be confusing because there are a number of different types of “risk assessment”—need to be clear on what question is being asked

7. Three Classifications based on Risk • I bedpans, crutches, • II blood pressure cuffs, catheters, wheelchairs, heating pads, and x-ray film processing machines • III defibrillators, heart valves, and implanted cerebral stimulators

8. Marketing Pathways for New Devices • New and novel automatically class III; go through PMA (device analog to drug NDA) process unless they are reclassified • New and not novel—enters the market as “substantially equivalent”—inherits the classification status of the device that it emulates-- “the 510k process”

9. 510(k) process: The new and not novel • This is a notification process, not an approvalprocess • A positive response to a 510k application is a “clearance”—FDA makes no representation that the device is “safe and effective for its intended use(s).” • 98% of all post-1976 devices have entered the market through this mechanism

10. Substantial Equivalence • Must have same intended use as a predicate device. • “Piggy backing” now codified—substantially equivalent to a device that was substantially equivalent to a pre-1976 device

11. Investigational Devices • IDE similar to IND for drugs, except not all IDEs require FDA approval • If pose no significant risk, just require IRB approval—IRB makes that determination

12. Device World Significant Risk/Non-Significant Risk Determinations

13. What is Significant Risk? • Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject; • Is purported or represented to be for a use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject; • Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or • Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject. (21 CFR 812.3(m))

14. Likely Significant Risk (SR) devices • Many devices that are obviously SR will be submitted to FDA for IDE approval • Most of those devices are submitted to IRB review after FDA has made that determination • An SR device must meet all FDA IDE regulations and must have FDA approval before enrolling • IRBs do not have to make the SR or NSR determination if FDA has already made the risk determination. • IRB role is then to confirm the issuance of the IDE

15. Likely Non-Significant Risk (NSR) Devices • Here the sponsor does not need to submit to FDA and FDA leaves the determination to the IRB • In most of these cases, FDA will have no role in the risk determination—and will not even be aware of the study

16. IDE Exempt • If using an investigational device in research must first determine if the device is exempt from IDE regulations.

17. IDE Exempt Devices • Consumer preference testing • Testing of a device modification • Testing of two or more devices in commercial distribution if the testing does not collect safety or effectiveness data, or put subjects at risk. • Studies of an already cleared medical device in which the device is used or investigated in accordance with the indications in the cleared labeling • If the study is looking at a new use, it is not exempt

18. IDE Exempt Devices • A diagnostic device if the testing: • Is noninvasive • Does not require an invasive sampling procedure that presents significant risk • Does not by design or intention introduce energy into a subject AND • Is not used as a diagnostic procedure without confirmation by another medically established diagnostic product or procedure.

19. Not Exempt? • If a device is determined to NOT be exempt from an IDE, the full IRB must determine if the device meets the criteria of Significant Risk

20. Exempt from IDE requirements does not mean that the device study is exempt from other IRB/FDA requirements for clinical research study

21. IRB Considerations of NSR Determination • The sponsor’s description of why the study is not SR • Whether the proposed NSR research study meets the definition of “significant risk” • The proposed use of the device as well as any protocol related procedures and tests, not just the device (test article) alone. (This process is different and separate from the typical IRB review of risk) • Whether the subject will undergo additional procedures • Additional information from the sponsor, if needed.

22. Significant Risk Criteria (Review) • A device that presents a potential for serious risk to the health, safety, or welfare of a subject AND: • Is intended as an implant or • Is used in supporting or sustaining human life or • Is for use of substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents impairment of human health: or • Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.

23. Sometimes Examples provide the Most Insight NSR: • http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126418.pdf • Conventional Gastroenterology and Urology Endoscopes and/or Accessories • Conventional General Hospital Catheters (long-term percutaneous, implanted, subcutaneous and intravascular) • ConventionalImplantable Vascular Access Devices (Ports) • Digital Mammography • Externally Worn Monitors for Insulin Reactions • Urethral Occlusion Device for less than 14 days

24. Sometimes Examples provide the Most Insight--SR • http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126418.pdf • Catheters for General Hospital Use - except for conventional long-term percutaneous, implanted, subcutaneous and intravascular • Collagen Implant Material for use in ear, nose and throat, orthopedics, plastic surgery, urological and dental applications • Aortic and Mitral Valvuloplasty Catheters • Organ Storage/Transport Units • Cochlear Implants • Biliary Stents • Electrical Stimulation Devices for sperm collection • Antepartum Home Monitors for Non-Stress Tests • Cervical Caps • Condoms (for men) made from new materials (e.g., polyurethane) • Contraceptive In Vitro Diagnostics (IVDs) • Computer Guided Robotic Surgery

25. Effect of Decision • NSR • If the device does not meet the criteria of Significant Risk, then is by default a Non-Significant Risk Device • Do not need IDE from FDA to enroll subjects • SR • Must have IDE from FDA prior to enrolling subjects

26. Device World Expanded Access

27. From FDA website: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm051345.htm#treatmentuse

28. Ways to Access an Investigational Device for Clinical Care • Compassionate Use • Emergency Use • Treatment Use • Continued Access • * Humanitarian Use

29. Device Summary Table- see handout

30. Clinical Care: Compassionate Use

31. Clinical Care: Emergency Use

32. Clinical Care: Treatment Use

33. Clinical Care: Continued Access

34. Clinical Care: Humanitarian Use

35. Clinical Care: Emergency Use or Off Label Use of an HUD

36. Research

37. Does this study involve the clinical investigation to determine the safety and effectiveness of a device? ( e.g. – Are you evaluating the device for safety and efficacy? ) Yes: FDA Regs apply Device Review Decision Tree Is study exempt from IDE Regulations ? Answer NO if an In-vitro diagnostic device. No: FDA Regs DO NOT apply Is the device a Research Use Only Device (RUO)? No Yes Is the device an in-vitro diagnostic device? Yes Will results be used to diagnose or treat subjects? NO Yes Yes Do all other procedures fit under an expedited criteria Does the device being used have FDA approval for any indication? No Yes Will other procedures require study to be reviewed by full board? (e.g all procedures do not fit under expedited criteria or study is not minimal risk ) NO YES Is study minimal risk? No NO Do all other procedures fit under an expedited criteria? No Yes To Full Board for Review. As expedited criteria # 4 not applicable. DO NOT use Expedited Criteria # 1 as the device is not being evaluated therefore FDA regulations do not apply. NOTE: FB does NOT determine SR/NSR status but may determine if protocol is minimal risk, therefore allowing future continuations to be expedited via category # 9. Category # 9: Continuing review of research, not conducted under an investigational new drug application or investigational device exemption where categories (2) through (8) do not apply but the IRB has determined and documented at a convened full IRB meeting that the research involves no greater than minimal risk and no additional risks have been identified. NO Yes Expedite under category # 1 Send full protocol to IRB for review. No Yes NO To Full Board for Review NOTE: FB does NOT determine SR/NSR status Is study minimal risk? Send study to full board to make SR/NSR Determination. Send protocol to full board for review and SR/NSR Determination Yes Expedite under category # 4 and any other applicable categories. (RUO devices not considered a medical device.) NSR SR Study Involves Device: Overall Summary Use only/No evaluation of device: FDA regulations do NOT apply: expedited via category # 4 Evaluation of Device- FDA regulations DO apply- If device exempt from IDE regulations or NSR and protocol may otherwise be reviewed by expedited review procedures expedite via category # 1. Full Board determines study is SR: Full Board to review protocol . DO NOT expedite review of protocol. Full Board determines study is NSR- Expedite review of protocol under cat# 1.