Preparing for an IDE Application

1. Preparing for an IDE Application John McLane, Ph.D. COO & Vice President Clinical and Regulatory Affairs Clinquest, Inc. jmclane@clinquest.com

2. Importance of Medical Devices • 11,000,000 Americans have at least one medical device implant • In the U.S. annually: • >290,000 hip replacement surgeries • >300,000 knee reconstructive implants • >151,000 pacemaker implants • >2,000,000 lens implant surgeries Hippocrates

3. IDE Preparation • Do your homework • CYA – avoid possible liabilities • Budget appropriately for R&D • Lawsuits cost more • Form a solid team of experts – • Scientific advisory Board

4. Differences between Drugs and Devices Pharmaceuticals • Molecular entities • Limited shelf life • Long life cycle • Long development time • Potential for interactions with other drugs • Wrong drug/dose issues Devices • Complex components • Many = durable equipment • Short product cycles – “tweaking” of design • Device malfunctions • User errors

5. FDA 1976 Medical Device Regulations • Prompted by Dalkon Shield IUD contraceptive device – caused injury, miscarriage, infertility • Established three classes of medical devices • Required safety and efficacy of all medical devices including diagnostic products • Required manufacturers to register with FDA and follow quality control procedures • Required pre-market approval for devices

6. Classification Basis • Classification depends on intended use and indications for use, and level of risk • Intended use- What disease, symptom, or condition is the device intended to treat? How will the device be used? • Indications for use- What kinds of patients should this be used on? Can be based on age, disease state, medical history, allergies, etc. • Level of risk-Is the device life-saving? Is the device life-sustaining? Is there an unreasonable risk of illness or injury associated with use of the device?

7. Device Classification Class I • Safety & effectiveness are well-established • Subject only to “General Controls” (registration, device listing, GMPs) Class II • Need “Special Controls” (guidances, postmarket surveillance, labeling, preclinical testing) Class III • General and special controls are insufficient to assure safety and effectiveness • Devices that are life-sustaining, life-supporting, or present unreasonable risk of illness or injury

8. General Routes for FDA Approval For a new device: • Pre-market Approval or PMA: • Manufacturer must show safety and effectiveness of new device • Laboratory and Animal Research • Clinical Research For a “Me Too” device: 510(k) Notification: • Manufacturer must show substantial equivalence to marketed device

9. Valid scientific evidence • Well-controlled investigations • Human factor testing • Animal testing • Component testing • Partially controlled studies or studies without matched controls • Well-documented case histories by qualified experts • Reports of significant human experience with a marketed device

10. Why an IDE? • Studies on “significant risk” devices require an Investigational Device Exemption (IDE) (21 CFR 812) • Sponsors must usually complete bench, animal testing before proceeding to human IDE trials • An IDE helps assure good study design • Data from IDE studies are used to support PMAs and sometimes 510(k)s

11. Medical Device Clinical Paths

12. Studies Exempt from IDE Regulation • Legally marketed device when used in accordance with its labeling • Diagnostic device if it complies with the labeling requirements in §809.10(c) and if the testing: • Noninvasive • Does not require an invasive sampling procedure • Does not introduce energy into a subject • Has “back-up” approved confirmatory diagnostic tests • Consumer preference testing, testing of a modification, or testing of a combination of devices if the device(s) are legally marketed device(s) • Device intended solely for veterinary use or laboratory animal use

13. Type of IDE Devices: Risk Based • Significant Risk (SR) Devices (21 CFR 812.3M) • Requires FDA approval • Presents potential for serious risk • Use for support or sustain life • Substantial importance diagnosing, or treating • Non-significant Risk Devices (812 and 812.2(b) • Abbreviated IDE • Sponsor to provide rationale for NSR • IRB can act as FDA surrogate • IRB usually asks FDA for ruling on SR/NSR • FDA Guidance

14. Test for Safety • Biocompatibilty • ISO 10993 • Rabbit epidural study • Implant – Tissue interface • Mechanical Performance • ASTM testing • Biomechanical Performance • Cadaveric, animal?? • Expulsion, subsidence, catastrophic failure

15. Example: Implant Assessments • Static / Fatigue – endurance – 10M • Wear debris – amount & characterization • Long term creep • Quantity of Motion • Quality of Motion • How much work does the implant have to do – will affect lifespan of implant • Interface with tissue

16. Pre IDE FDA Meetings • Informal Guidance Meeting • Meeting with ODE to discuss • IDE development plans • Significant and non-significant categories • ODE team • Formal Guidance Meetings • Determination Meeting • Broad outline of clinical design • Agreement Meeting • Request and summary information • On-going preclinical programs • Protocol design • Risk assessments

17. FDA Meeting Preparation • Prepare a target product profile • Key efficacy and safety objectives • Potential pt and user group description • Plan on submission questions • Keep questions focused • Don’t ask question of what you can easily find in the regulations • Can ask question to clarify approach to a regulation • Plan on providing support documentation • Evidence-based information most persuasive • Be prepared

18. Non-significant Risk Device IDE Applications • Abbreviated IDE application submitted to IRB: • Device Labeling : • CAUTION - Investigational Device. Limited by Federal (or United States) law to investigational use • Informed Consent –Investigators must obtain and document informed consent from each subject • Monitoring - All investigations must be properly monitored to protect the human subjects and assure compliance • Records and Reports - Sponsors and Investigators are required to maintain specific records and make certain reports as required by the IDE regulation • Prohibitions –Commercialization, promotion, test marketing, misrepresentation of an investigational device, and prolongation of the study are prohibited (§812.7)

19. Complete IDE Application • Name and address of sponsor • Complete report of prior investigations of device • Summary and completed investigational plan • Description of methods, facilities, and controls used for manufacture, processing, packaging, storage , installation of device (Quality System Regulations) • Example of investigator agreements • Names and addresses of investigators • List of names, address, and chairperson IRB • Institution(s) participating • Investigational labeling for device • Reimbursement charges for device • Patient informational materials and forms provided to patients to obtain consent • Clinical protocol

20. Reports of Prior Investigations • Provide all data that is relevant (whether adverse of supportive) • Including laboratory/animal data • Provide data on previous versions (models) of the device. • Explain what conclusions where reached from the clinical experience with previous device designs. • For each clinical investigation: • Rationale for subject selection • Statistical justification for N • Description of the study methods and endpoints • Efficacy and safety results (summary table AEs)

21. Good Manufacturing Processes and Systems • Material controls • Design controls • Production and process • Equipment and facility controls • Records, documents, and change controls • Risk assessments • Hazard Identification • Risk management programs

22. Quality System Regulations

23. Investigational Plan • Purpose • Protocol • Risk analysis • Description of device • Label to be on device • Monitoring Procedures • CRF • Patient information materials • Informed consent template

24. Device Description • Description of each important component, property and principle of operation of the investigational device • Identify Human Factor tests • If applicable, state any anticipated change(s) in the investigational device during the course of the study • Identify potential device-related risks • Differentiate from clinical risks • Investigational use instructions

25. Feasibility IDE clinical Study • Simple trial design to provide • Support for a future pivotal study • Answer basic research questions • Often not primary support for a marketing application • May be required by FDA prior to pivotal study to assess basic safety and potential for effectiveness • Endpoints and sample size generally not statistically driven • N=10-50 subjects

26. Pivotal study • Generally intended as the primary clinical support for a marketing application • Endpoints and sample size statistically driven • Assess both safety and effectiveness • Reasonable study conceptually? • Adequate preclinical validation of device? • Appropriate mitigation of potential risks? • Appropriate enrollment criteria? • Patients adequately informed? • Sample size appropriate?

27. Key Components of Clinical Protocol • General study design • Proposed subject population • Anticipated number of subjects • Inclusion criteria • Exclusion criteria • Screening procedures • Study treatment (allocation, breaking the blind) • Follow-up assessment methods including the schedule of testing

28. Biometrics Sections of Protocols • Identify primary effectiveness endpoint • Avoid composite or ambiguously defined terms • Describe how measured • How will safety be assessed and monitored (safety endpoint) • Not just well tolerated • Objective performance criteria • Sample size determination • Data and Safety Monitoring Committee

29. Objective Performance Criteria • Type of comparison in medical device trials • Requires statistical pooling of prior investigations • Underlying disease and pt population well described and stable • Fixed Target(s) Positive Tx effect expected • Objective and Meaningful Standard • Provides Comparison in Evaluating Safety and Effectiveness • Usually a Rate • Surrogate for Control Group • Benchmark for Minimally Acceptable • Values • Not a Control Group

30. Statistical Analysis Plan • Justification for sample size calculations • Type-1 error and multiplicity • Missing data handling • Assessment of critical endpoint covariates • Interim analyses and early stopping rules • Data handling • Contingency analysis • Provide enough detail to avoid ambiguity

31. Anticipated and Unanticipated Safety Events • Use prior studies to clearly identify potential and anticipated risks • Similar devices • Engineering, animal, and human factor testing • Define how study design mitigates risk • Clinical training necessary? • Define how different safety events to be reported • Patients • Patient’s Investigator and all investigators • IRB • FDA

32. Shared regulations with drugs • Part 50 – Protection of Human Subjects • Part 56 – Institutional Review Boards • Part 54 – Financial Disclosure by Clinical Investigators • Part 58 – Good Laboratory Practices for Nonclinical Laboratory Studies • Part 11 – Electronic Records; Electronic Signatures

33. Adequate Monitoring • Trained monitors • Qualified investigator sites • Following the written procedures in the protocol • Collection of essential documents • Obtaining a signed investigator agreement from each participating investigator (can use FDA form 1572) • Provide investigators with the information they need to conduct the investigation properly • Documented training of all study personnel • Delegation log • Ensuring subjects sign informed consent form • Device quality check and accountability

34. IDE Supplements • Required ifchanges significantly affect: • Validity of data • Scientific soundness of study • Rights, safety, or welfare of subjects Examples: • Different type of study control • Alternative primary endpoint • Reduction in study population size • Change in method of evaluation • Early termination of the study

35. 5-Day FDA Notice to Protocols • Additional measurements • More targeted subject criteria • More frequent follow-ups • Change in secondary endpoints

36. Protocol Deviations • CFR 812.150(a)(4) require prior approval from the sponsor of all planned deviations, including administrative and minor deviations.  • Planned deviations requested of a sponsor must be submitted for IRB review as a “Change in Research” prior to instituting any IDE research planned deviations • For device research, the PI must keep on file a copy of the written approval document from the sponsor and IRB when a deviation is granted.

37. Conclusion • Consider the IDE as a comprehensive process • Get Experts (Reliance Medical Association) • Know your target product profile • Be prepared • Have the evidence • Preclinical • QSR • Work with the FDA and IRBs • Be realistic on potential risks