1. Humanitarian Device Exemptions (HDE) 101 Elizabeth Hillebrenner, MSE Biomedical Engineer IDE and HDE Program Staff Center for Devices and Radiological Health

2. Humanitarian Use Device device intended to benefit patients in the treatment and diagnosis of diseases or conditions that affect fewer than 4,000 individuals in the US designation of HUD status may be achieved through application to OOPD marketing approval of a device with HUD status may be achieved through application to CDRH or CBER 2

3. Marketing a HUD PMA PreMarket Approval Submission Does not require HUD designation from OOPD Requires demonstration of a reasonable assurance that the device is safe and effective for the proposed intended use No limitation on profit User fee (with exceptions) HDE Humanitarian Device Exemption Submission Requires HUD designation from OOPD Requires demonstration of a reasonable assurance that the device is safe and provides probable benefit for the proposed intended use Some profit limitations No user fee 3

4. Threshold for Approval PMA Effectiveness “There is reasonable assurance that a device is effective when it can be determined, based upon valid scientific evidence, that in a significant portion of the target population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warnings against unsafe use, will provide clinically significant results.” 21 CFR 860.7 HDE Probable Benefit “The device will not expose patients to an unreasonable or significant risk of illness or injury and the probable benefit to health from the use of the device outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment.” FD&C Act Section 520(m) (No regulatory definition) 4

5. Threshold for Approval PMA Effectiveness Data The valid scientific evidence used to determine the effectiveness of a device shall consist principally of well- controlled investigations 21 CFR 860.7 HDE Probable Benefit Data Summaries, conclusions, and results of all clinical experience or investigations (whether adverse or supportive) reasonably obtainable by the applicant that are relevant to an assessment of the risks and probable benefits of the device 21 CFR 814.104 5

6. HDE Profit Limitations Evolution over time –1990 SMDA: NO profit eligibility –2007 FDAA: profit eligibility for newly approved HDE devices labeled for pediatrics –2012 FDASIA: expansion of profit eligibility beyond pediatrics and to previously approved HDEs Determined by Annual Distribution Number (ADN) –Number of devices that can be sold per year at a profit 6

7. HDE Profit Eligibility FDAAA (2007) If the device is intended for the treatment or diagnosis of a disease or condition that occurs in pediatric patients or in a pediatric subpopulation, and such device is labeled for use in pediatric patients or in a pediatric subpopulation in which the disease or condition occurs. FDASIA (2012) If the device is intended for the treatment or diagnosis of a disease or condition that occurs in pediatric patients or in a pediatric subpopulation, and such device is labeled for use in pediatric patients or in a pediatric subpopulation in which the disease or condition occurs; or does not occur in pediatric patients; or occurs in pediatric patients in such numbers that the development of the device for such patients is impossible, highly impracticable, or unsafe. 7

8. HDE Profit Eligibility FDAAA (2007) Applies only to newly approved HDEs ADN capped at 3,999 ADN = product of: –# of devices reasonably necessary to treat, diagnose, or cure an individual –# of individuals affected by the disease or condition the HUD is intended to treat, diagnose, or cure and that are likely to use the device FDASIA (2012) May apply to previously approved HDEs ADN not capped ADN = product of: –# of devices reasonably necessary to treat, diagnose, or cure an individual –4,000 8

9. Submitting an HDE Submit to Document Mail Center (DMC) –Per FDASIA, must include e copy No user fee 75 day review time –May be placed on hold during this time if additional information is needed 9 U.S. Food and Drug Administration Center for Devices & Radiological Health Document Mail Center – WO66 – G609 10903 New Hampshire Ave. Silver Spring, MD 20993-0002 Document Control Center (HFM-99) Center for Biologics Evaluation & Research Food and Drug Administration 1401 Rockville Pike, Suite 200N Rockville, MD 20852-1448

10. HDE Submission Contents Statutory Requirements (520(m)) Letter from OOPD granting HUD designation Explanation why device would not be otherwise available Statement that no comparable device exists (through a 510(k) or PMA) Discussion of risks and benefits of currently available devices or alternative forms of treatment in the US Demonstration of safety and probable benefit 10

11. HDE Submission Contents Regulatory Requirements (814.104) 814.20 PMA requirements –Exception: Requirement for well controlled investigations as valid scientific evidence of effectiveness replaced with requirement for: “summaries, conclusions, and results of all clinical experience or investigations (whether adverse or supportive) reasonably obtainable by the applicant that are relevant to an assessment of the risks and probable benefits of the device” –Includes manufacturing information demonstrating compliance with QS regulations 11

12. HDE Submission Contents Regulatory Requirements (814.104) Labeling with the following statement: “Humanitarian Device. Authorized by Federal law for use in the [treatment or diagnosis] of [specify disease or condition]. The effectiveness of this device for this use has not been demonstrated” The amount to be charged for the device. –If >$250, verification that it does not exceed costs of the device's research, development, fabrication, and distribution. 12

13. HDE Post Approval Considerations IRB approval required at each institution prior to use –Exception: emergency use cases, approved IDE clinical studies Records maintenance (subject to inspection) –Facilities shipped to –IRB correspondence Modifications require prior approval of an HDE Supplement by FDA 13

14. HDE Post Approval Considerations Annual Reports –PMA annual reporting requirements –Annual incident reassessment re target population –Number of devices sold/used –Summary of clinical experience since approval –Summary of device changes Post Approval Study –if required as a condition of approval 14

15. HDE Post Approval Considerations Medical Device Reporting (MDR) of adverse events Annual review of adverse events related to pediatric devices by Pediatric Advisory Committee –Office of Pediatric Therapeutics Approval may be withdrawn if a PMA is approved for a different device with same indications 15

16. Common Points of Confusion HDE is marketing approval –Not investigational –Exempt from effectiveness requirements IRB approval required for all uses –IRB may also approve “off-label” uses Informed consent not required by FDA –May be required by state, local, institutional, or IRB requirement 16

17. Common Points of Confusion There can be multiple HDEs for the same indication from different sponsors Clinical trial for new indication requires an IDE if the device is SR (so far, all HDEs are SR) 17

18. Helpful References FD&C Act Section 520(m) http://www.gpo.gov/fdsys/pkg/USCODE- 2010-title21/html/USCODE-2010-title21-chap9-subchapV-partA- sec360j.htm 21 CFR Section 814 Subpart H http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CF RPart=814&showFR=1&subpartNode=21:8.0.1.1.11.7 Guidance Document (will be updated soon) http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidan ce/GuidanceDocuments/ucm110203.pdf Device Advice http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoM arketYourDevice/PremarketSubmissions/HumanitarianDeviceExemption/def ault.htm Summaries of Safety and Probable Benefit (SSPBs) of approved HDEs 18

19. HDE Contacts IDE/HDE Staff shelia.brown@fda.hhs.gov cindy.demian@fda.hhs.gov lynn.henley@fda.hhs.gov elizabeth.hillebrenner@fda.hhs.gov michael.marcarelli@fda.hhs.gov ellen.pinnow@fda.hhs.gov Review Branch/Division Leadership http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMe dicalProductsandTobacco/CDRH/CDRHOffices/ucm127 854.htm#ODE 19