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

2. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 11 Medical Device Clinical Paths

12. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 22 Quality System Regulations

23. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 34 IDE Supplements Required if changes 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. Fulfilling the Promise of Medicine Together 35 5-Day FDA Notice to Protocols Additional measurements More targeted subject criteria More frequent follow-ups Change in secondary endpoints

36. Fulfilling the Promise of Medicine Together 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. Fulfilling the Promise of Medicine Together 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