1. Device World: The Basics SR and NSR Determinations Expanded 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 2

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 3

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) 4

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 5

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 novelenters the market as substantially equivalentinherits 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 approval process A positive response to a 510k application is a clearanceFDA 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 codifiedsubstantially 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 approvalIRB makes that determination

12. 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 determinationand 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 sponsors 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/guida nces/ucm126418.pdf Conventional Gastroenterology and Urology Endoscopes and/or Accessories Conventional General Hospital Catheters (long-term percutaneous, implanted, subcutaneous and intravascular) Conventional Implantable 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. Expanded Access

27. From FDA website: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/H owtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm05134 5.htm#treatmentuse http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/H owtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm05134 5.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 Clinical Care: Compassionate Use Clinical Care: Emergency Use Clinical Care: Humanitarian Use Clinical Care: Emergency or Off Label Use of an HUD Clinical Care: Treatment Use Clinical Care: Continued Access Research BackgroundUse for patient or small group who do not meet protocol inclusion criteria. Treating physician feels device will help patient(s). Allowed before or during a clinical trial Subject does not meet inclusion criteria, clinical trial is not open at the institution, life threatening situation and no time to get IRB approval Allowed before or after start of clinical trial Device that would be used in less than 4000 patients /year in the US. ( Orphan Device) If use meets criteria for emergency use see Emergency Use column. Off label use: Follow same criteria as Humanitarian Use. Provides access to investigational devices early in development process. Allowed during a clinical trial Allows patients access to device after clinical trials are completed- awaiting FDA approval. Use of an investigational device for research purposes Other IssuesMust first identify patient, then sponsor submits IDE application to FDA, then submit application to IRB. May only use as emergency use one time at each institution- then must have a compassionate use protocol. Within 5 days of use submit notification to IRB. Sponsor cannot submit data as part of an FDA application. Called: Humanitarian Use Device (HUD) OR Humanitarian Device Exemption (HDE) Sponsor must have HDE designation from FDA. For Off Label Use FDA recommends patient sign a consent form and that the PI has a plan to protect the patient. PI should submit summary report to IRB following the use. Must report AE's to IRB. For patients with serious or life threatening condition- may receive outside of a clinical trial. Sponsor must obtain a Treatment use IDE from FDA. May use outside IRB. IRB must determine if device is exempt from IDE regulations. If not exempt, must determine if device is significant risk. Considered Research? No- however FDA requires an IDE# and IRB Concurrence No- but use must be reviewed by full board AFTER USE. No, however IRB review required. No, however IRB review required. Yes ProtocolYes-submit sponsors protocol only NoNo, but need to submit Investigators Brochure No, but for off- label use, need some type of plan of methods to protect patient. Yes- submit sponsors protocol only Yes- may submit per local protocol template or sponsors protocol ConsentYes-submit and use sponsors consent Yes-use sponsors consent if patient able to consent. No- may provide patient with product information Yes, may use sponsors template. YES- use local research template to develop consent Yes-may use local research template or one approved by outside IRB. Yes-use local research template to develop consent unless waiver approved TrainingNo Yes Review TypeIRB Chair onlyFull Board- AFTER use Initial – Full Board Continuations- Expedited Initial – Full Board Continuations- Expedited Full Board ResponseLetter of Concurrence from IRB Chair Letter of Concurrence from IRB IRB Assurance Form

30. Clinical Care: Compassionate Use Back ground Other issues Research?ProtocolConsentTrainingReview Type Response Use for patient or small group who do not meet protocol inclusion criteria. Treating physician feels device will help patient(s). Allowed before or during a clinical trial. Must first identify patient, then sponsor submits IDE applicatio n to FDA, then submit applicatio n to IRB. No- however FDA requires an IDE# and IRB Concurrence Yes- submit sponsors protocol only Yes- submit and use sponsors consent NoIRB Chair only Letter of Concurren ce from IRB Chair

31. Clinical Care: Emergency Use Back Ground Other IssuesResearch?ProtocolConsentTrainingReview Type Response Subject does not meet inclusion criteria, clinical trial is not open at the institution, life threatening situation and no time to get IRB approval Allowed before or after start of clinical trial May only use as emergency use one time at each institution- then must have a compassionate use protocol. Within 5 days of use submit notification to IRB. Sponsor cannot submit data as part of an FDA application. No- but use must be reviewed by full board AFTER USE. NoYes-use sponsor s consent if patient able to consent NoFull Board- AFTER use Letter of Concurre nce from IRB

32. Clinical Care: Treatment Use BackgroundOther IssuesResearch?ProtocolConsentTrainingReview Type Response Provides access to investigation al devices early in development process. Allowed during a clinical trial For patients with serious or life threatening condition- may receive outside of a clinical trial. Sponsor must obtain a Treatment use IDE from FDA. Different from Compassionate Use: do not need to identify patient before IRB approval. YesYes- submit sponsors protocol only YES- use local research template to develop consent YesFull Board IRB Assurance Form

33. Clinical Care: Continued Access BackgroundOther Issues Research?ProtocolConsentTrainingReview Type Response Allows patients access to device after clinical trials are completed- awaiting FDA approval. May use outside IRB. Differenc e between Treatmen t Use : does not have to be life threateni ng or serious disease. YesYes- submit sponsors protocol only Yes-may use local research template or one approved by outside IRB. YesFull BoardIRB Assurance Form

34. Clinical Care: Humanitarian Use BackgroundOther Issues Research?ProtocolConsentTrainingReview Type Response Device that would be used in less than 4000 patients /year in the US. ( Orphan Device) Called: Humanitarian Use Device (HUD) OR Humanitarian Device Exemption (HDE) Sponsor must have HDE designation from FDA. No, however IRB review required. No, but need to submit Investiga tors Brochure No- may provide patient with product informatio n NoInitial – Full Board Continuat ions- Expedited IRB Assurance Form

35. Clinical Care: Emergency Use or Off Label Use of an HUD BackgroundOther Issues Research ? ProtocolConsentTrainingReview TypeResponse If use meets criteria for emergency use- see Emergency Use column. Off label use: Follow same criteria as Humanitarian Use. For Off Label Use FDA recommends patient sign a consent form and that the PI has a plan to protect the patient. PI should submit summary report to IRB following the use. Must report AE's to IRB. No, however IRB review required. No, but for off- label use, need some type of plan of methods to protect patient. Yes, may use sponsors template. No Initial – Full Board Continuatio ns- Expedited IRB Assurance Form

36. Research BackgroundOther Issues Research ? ProtocolConsentTrainingReview Type Response Use of an investigational device for research purposes IRB must determine if device is exempt from IDE regulations. If not exempt, must determine if device is significant risk. Yes Yes- may submit per local protocol template or sponsors protocol Yes-use local research template to develop consent unless waiver approved YesFull BoardIRB Assurance Form

37. Device Review Decision Tree 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? ) Is the device a Research Use Only Device (RUO)? Does the device being used have FDA approval for any indication? 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 Will results be used to diagnose or treat subjects? Yes NO Do all other procedures fit under an expedited criteria? YES Is study minimal risk? Yes To Full Board for Review NOTE: FB does NOT determine SR/NSR status NO Expedite under category # 4 and any other applicable categories. (RUO devices not considered a medical device.) Yes NO Is study exempt from IDE Regulations ? Answer NO if an In-vitro diagnostic device. Expedite under category # 1 Yes: FDA Regs apply 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 ) Yes Send full protocol to IRB for review. No Do all other procedures fit under an expedited criteria Is study minimal risk? Send protocol to full board for review and SR/NSR Determination Send study to full board to make SR/NSR Determination. Yes No Yes No Yes 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. NSRSR No: FDA Regs DO NOT apply Is the device an in-vitro diagnostic device? No Yes 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.