1 Investigational Device Exemption (IDE) Best Practice for Preparation and Maintenance Jelena P. Berglund, PhD, RAC Regulatory Affairs Associate

2 Overview Definitions / classifications Marketing pathways Clinical investigation of medical device Abbreviated IDE IDE preparation IDE submission IDE maintenance Closing an IDE Additional types of device studies IDE exempt studies

3 What is a Medical Device? Its an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent or other similar or related article or component part or accessory which: - is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease - is intended to affect the structure or any function of the body - achieve it's primary intended purposes through physical action and NOT chemical or metabolic action - medical devices range from dental floss to an artificial heart valve

4 Medical Device Regulations 1976 - Medical Device Amendment - Prior to 1976, investigational devices were either not reviewed or were reviewed as drugs 1990 - Safe Medical Device Act (SMDA) - Post marketing surveillance, tracking of implants, injury reporting 1997- FDA Modernization Act (FDAMA) - Modifications to existing regulations to streamline device development and marketing 2002- Medical Device User Fee and Modernization Act (MDUFMA) - Combinatory product, user fees established

5 Medical Device Classification Devices are classified related to the: medical specialties: 16 groups (21CFR 862-892) 862 Clinical Chemistry and Clinical Toxicology 864 Hematology and Pathology 866 Immunology and Microbiology 868 Anesthesiology 870 Cardiovascular 872 Dental 874 Ear, Nose, and Throat 876 Gastroenterology and Urology 878 General and Plastic Surgery 880 General Hospital and Personal Use 882 Neurology 884 Obstetrical and Gynecological 886 Ophthalmic 888 Orthopedic 890 Physical Medicine 892 Radiology

6 Devices are classified related to the: risk associated with the use of the device Class I; lowest risk Class II; intermediate risk Class III; highest risk Class I and II are non-significant risk (NSR) devices Class III devices are significant risk (SR) devices Medical Device Classification

7 Medical Device Classification Class I - e.g. dental floss, medical scissors, dental syringe Class II – powered wheel chair, MRI, clinical mercury thermometer Class III - e.g. external defibrillator, replacement heart valves

8 Medical Device Classification Devices are classified based on the time of their marketing - pre-Amendments device – marketed prior to 1976 - post-Amendments device - marketed after 1976 - Transitional devices - those regulated as drugs prior to the ’76 Amendments, but subsequently as devices

9 Placing a device on the market

10 Market submission options PMA - premarket approval is required for class III devices. Focus on scientific and regulatory review of safety and effectiveness 510 (k) - device is at least as safe and effective, substantially equivalent, to a legally marketed device that is not subjected to PMA Exempt – most class I and few class II devices are exempt from the 510(k) regulations

11 Finding information about the device… http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/classification.cfm

12 Clinical Investigation of Medical Device

13 Clinical Investigation of Medical Device FDA regulation prohibit promotion and commercialization of an unapproved medical device Such device can be legally distributed for investigational purposes under an investigational device exemption (IDE) Clinical studies are usually conducted to support PMA Small percentage of 510 (k) require clinical study to support the application Although previously marketed, if device is used to asses safety or effectiveness of certain modifications or new intended use – it is considered investigational device

14 Clinical Investigation of Medical Device All clinical investigation of device must: - have an approved IDE (21 CFR 812.20) OR - be exempt from the IDE regulations (21 CRF 812.2 (c))

15 Who approves an IDE? FDA and IRB Significant risk (SR) device Investigation exempt from the informed consent FDA notifies the sponsor that IDE application is required Before starting a clinical trial IDE must be approved by: IRB (abbreviated IDE) Non-significant risk (NSR) device Not a banned device (21CFR 895.101) Must have informed consent

16 What are Significant Risk Devices? 21 CFR 812.3 (m) Significant Risk Device is investigational device that: - is intended as an implant and presents a potential for serious risk to the health, safety and welfare of a subject - is used to support or sustain human life - is substantial importance in diagnosing, curing, mitigating, or treating disease or otherwise preventing impairment of human health - otherwise presents a potential for a serious risk to the health, safety or welfare of human subject Guidance : http://tiny.cc/6EfEF

17 If investigational device is NSR device (21 CFR 812.2 (b)) Trial can be run under an abbreviated IDE…

18 Abbreviated IDE Obtain and maintain IRB approval of the investigation Make sure that the device is properly labeled Ensure that informed consents are obtained Maintain required records and reports Monitor the study to ensure compliance with the protocol and protect the human subject The promotional practices are NOT permitted

19 Obtaining an IRB approval Sponsor makes initial significant or non-significant risk study determination Submit to the IRB required documents: - explanation why you believe that the device is NSR device - report of prior investigation - proposed investigational plan - other If IRB agrees with sponsor, study can be conducted under the IRB oversight only

20 If IRB disagree? FDA and IRB Significant risk (SR) device Investigation exempt from the informed consent FDA notifies the sponsor that IDE application is required Before starting a clinical trial IDE must be approved by: IRB (abbreviated IDE) Non-significant risk (NSR) device Not a banned device Must have informed consent IRB “shopping” is NOT allowed!

21 If FDA approval is needed… 21 CFR 812.20 http://tiny.cc/uxH9X

22 IDE Content 21 CFR 812.20 (b) 1. Cover Sheet – form 3514

23 1. Cover Sheet – Form 3514 used voluntarily same form is used for IDE, 510(k), PMA, meetings, 513(g) etc. captures the following information: - original submission, amendment or supplement (section A) - information about the sponsor (section B, C) - reasons for submission (section D2) - product information/data included in the submission (section F) - product classification if known (section G)

24 IDE Content 21 CFR 812.20 (b) 1. Cover Sheet – form 3514 2. Name and Address of the Sponsor 3. Report of Prior Investigations

25 3. Report of Prior Investigation (21 CFR 812.27) General - prior clinical, animal and laboratory testing Specific - bibliography of all publications - summary of all unpublished information - if laboratory studies are referenced, statement whether such a studies have been done according to the GLP

26 IDE Content 21 CFR 812.20 (b) 1. Cover Sheet – form 3514 2. Name and Address of the Sponsor 3. Report of Prior Investigations 4. Investigational Plan

27 4. Investigational Plan (21 CFR 812.25) - Purpose – name and intended use - Protocol - Risk Analysis - Description of the Device - Monitoring Procedures - Additional Records and Reports

28 IDE Content 21 CFR 812.20 (b) 1. Cover Sheet – form 3514 2. Name and Address of the Sponsor 3. Report of Prior Investigations 4. Investigational Plan 5. Manufacturing Information 6. Investigators Agreement

29 6. Investigators Agreement (21 CFR 812.43) Who is the investigator? -Investigator is an individual who actually conducts a clinical investigation, i.e., under whose immediate direction the investigational device is administered, dispensed to, or used - In the event of an investigation being conducted by a team of individuals, "investigator" refers to the responsible leader of that team

30 6. Investigators Agreement (21 CFR 812.43) CV of the investigator Statement of investigator’s relevant experience If investigator was involved in the investigation that got terminated, explain the circumstances Financial disclosure information Statement of investigators commitment to: -conduct the investigation according to the agreement - supervise all testing - ensure that requirements for obtaining of the IC are met

31 IDE Content 21 CFR 812.20 (b) 1. Cover Sheet – form 3514 2. Name and Address of the Sponsor 3. Report of Prior Investigations 4. Investigational Plan 5. Manufacturing Information 6. Investigators Agreement 7. Investigators Certification

32 IDE Content 21 CFR 812.20 (b) 8. IRB Information 9. Name and Address of Investigators Institution 10. Financial Claims 11. Environmental Assessment 12. Labeling 13. Informed Consent 14. Additional Information

33 IDE Content 21 CFR 812.20 (b) 1. Cover Sheet – form 3514 2. Name and Address of the Sponsor 3. Report of Prior Investigations 4. Investigational Plan 5. Manufacturing Information 6. Investigators Agreement 7. Investigators Certification 8. IRB Information 9. Name and Address of Investigators Institution 10. Financial Claims 11. Environmental Assessment 12. Labeling 13. Informed Consent 14. Additional Information

34 IDE submission Send original and 2 copies of your application State clearly that it is an original IDE application IDE should be sent to: Food and Drug Administration Center for Devices and Radiological Health (CDRH) Document Mail Center (HFZ-401) 9200 Corporate Boulevard Rockville, Maryland 20850-3223

35 What happens after IDE submission? Sponsors are notified of the date that FDA received the original application IDE number is assigned (e.g., G096000) Project manager is assigned

36 Within 30 calendar days of the day the application has been received, FDA may: - Approve the investigation as proposed - Approve it with modifications - Disapprove it An IDE application is considered approved 30 days after it has been received by FDA What happens after IDE submission?

37 Reasons for disapproval Risk associated with the study outweigh the benefits There are untrue statements in the applications Failure to respond to the request for additional information Inadequacy of monitoring, reviewing, manufacturing, packaging etc.

38 Once you have an active IDE… http://tiny.cc/uxH9X

39 Registering trial on ClinicalTrial.gov Introduced by FDAAA in 2007 Do not need to send a 3674 form to the FDA with your IDE submission Do need to register “applicable trial” on ClinicalTrial.gov

40 What is the “applicable clinical trial”? Defined in the 402(j) of the PHS Act - prospective study with the health outcomes - compares an intervention with a device against a control in human subject - the studied device is subjected to 510(k), 515 or 520(m) - its OTHER then a small clinical trial to determine a feasibility of device, or a clinical trial to test prototype device when the primary outcome relates to feasibility and not to health outcomes

41 Deadline(s) for Registering Trials ICMJE Policy – Study must be registered prior to enrollment of first subject PHS Act – No later than 21 days after enrollment of the first subject Post through the Duke Office of Research Support Wesley G. Byerly, PharmD Send email to rebeka.branagan@duke.edu

42 More information on registering clinical trial http://prsinfo.clinicaltrials.gov/ElaborationsOnDefinitions.pdf http://research.musc.edu/orsp/Clinical%20Trials%20Registration.pdf http://www.icmje.org/faq_clinical.html

43 Modification in the active IDE Changes that DO NOT require prior approval inform the FDA within 5 working days Emergency change Non-significant design changes Protocol changes that increase patient safety Changes that require prior approval Indication Type or nature of study control Primary end point Statistical methods for evaluation Expanding the study Significant design changes Early termination Guidance: http://tiny.cc/1VfGN

44 IDE Reports to the FDA 21 CFR 812.150 At least yearly At least yearly Progress report * Every 6 month Investigator list 5 working days 5 working days Withdrawal from FDA / IRB approval 24 hours if death; 5 working days if reportable and serious; 10 working days for all other events 10 working days Unanticipated adverse device effects Duke - IRB FDA

45 IDE Reports to the FDA 21 CFR 812.150 6 months - report 30 working days – notification 6 months - report Final Report * 5 working days 5 working days Significant Risk Determination 30 working days 30 working days Recall and device disposition 24 hours if death; 5 working days if reportable and serious; 10 working days for all other violations 5 working days Informed Consent violation 5 working days or pre-approval 5 working days or pre-approval Deviation from the Investigational Plan Duke - IRB FDA

46 Progress/Final Report 1. Basic information 2. Study Progress - Brief summary of the study progress - Number of investigators/investigational sites - Number of subjects enrolled - Number of devices shipped - Disposition of all device shipped - Brief summary of results - Summary of anticipated and unanticipated adverse effects - Description of any deviations from the investigational plan (since last progress report)

47 Progress/Final Report 3. Risk Analysis - Summary of any new adverse information (since the last progress report) that may affect the risk analysis - Reprints of any articles published from data collected from this study - New risk analysis, if necessary, based on new information and on study progress 4. Other Changes - Summary of any changes in manufacturing practices and quality control - Summary of all changes in the investigational plan not required to be submitted in a supplemental application 5. Marketing Application or Future Plans

48 Terminating/Closing an IDE If IDE is still not yet approved – request a withdrawal If you have an active IDE, but no subject enrolled – request a withdrawal, but state why and account for all the device If subjects have been enrolled – you need to complete follow-up of already enrolled subjects If you completed the study – notify FDA within 30-days and send Final Report within 6 months

49 Additional Types of Device Studies

50 Additional Types of Device Studies Emergency Use of Unapproved Medical Device An IDE might or might not have been approved Life-threatening situation that needs immediate treatment There is no generally acceptable alternative for treating the patient There is no time to use existing procedures to get FDA approval Must be reported to FDA, IRB within 5 days Guidance: http://tiny.cc/EPPna

51 Additional Types of Device Studies Single Patient or Compassionate Use Serious condition for which device is the only option Patient do not meet inc/exc criteria Prior approval of FDA and IRB is required Time-frame: during clinical trial Guidance: http://tiny.cc/EPPna

52 Additional Types of Device Studies Treatment IDE (21 CFR 812.36) - For serious or life-threatening condition No alternative therapy An appropriate level of safety and efficacy has been shown in clinical studies Prior approval of FDA and IRB is required

53 Additional Types of Device Studies Continued Access - trail is completed and marketing application is being prepared - there is a public health need for the device preliminary evidence shows that device is likely to be effective and no significant safety concerns have been identified Difference:Treatment IDE vs Continued Access - For Treatment IDE you can apply earlier - Treatment has more narrow patient population

54 Additional Types of Device Studies

55 Clinical Investigation of Medical Device All clinical investigation of device must: - have an approved IDE (21 CFR 812.20) OR - be exempt from the IDE regulations (21 CRF 812.2 (c))

56 IDE exempt investigations Device is used according to the approved label A diagnostic device if: Is not invasive Does not require an invasive sampling procedure that presents a significant risk Does not by design or intention introduce energy into a subject Is not used as a diagnostic procedure without confirmation of the diagnosis by another medically established diagnostic product or procedure

57 IDE exempt investigations A device undergoing a consumer preference testing, testing of modification or testing of a combination of two or more devices in commercial distribution if the testing is not for the purpose of determining safety or effectiveness A device intended for veterinary use only A device for research on or with laboratory animals A custom device

58 Useful websites: CDRH Learn Course List http://www.fda.gov/Training/CDRHLearn/ucm162015.htm Device Advice: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/default.htm

59 How to Reach Us. . . You can contact us on any IDE or regulatory issue at: bruce.burnett@duke.edu or (919) 668-7178 jelena.petrovic@duke.edu or (919) 668-4639 erin.oreilly@duke.edu or (919) 668-4635 sue.avery@duke.edu or (919) 668-8685 OR regulatorydtmi@mc.duke.edu