Risk Assessments in 510K Clinical Studies

1. Risk Assessments in 510K Clinical Studies John McLane, Ph.D. COO & Vice President Clinical and Regulatory Affairs Clinquest, Inc. jmclane@clinquest.com

2. Clinical Trial Preparation • Do your homework: • Start with the regs • Literature • Budget appropriately for R&D • Form a solid team of experts – • Scientific Advisory Board • Clinical Expertise • Careful Planning and Conduct are Key to Obtaining Useful Data and Assuring Human Subject Protections

3. Medical Device Risk Regulations • Medical Devices Directive (MDD), 93/42/EC – covers all general medical devices except: • Active Implantable Medical Devices (AIMD), 90/385/EC –in humans • In Vitro Diagnostic Devices (IVDD), 98/79/EC • ISO regulations • ISO 14155 (clinical) • ISO 14971 • 21 CFR Parts 812, ICH GCP, • Japan GCPs, GHTF guidelines • EU MEDDEVs (2.7.1)

4. ISO 14971 Risk Management • Risk Management standard • Must have that particular defined and documented RM Process that addresses • risk analysis • evaluation and control, • collection of production • post-production data to validate or change previous risk determinations

5. ISO 14155:2011 Newly Released • Harmonize the ISO standard with the ICH-GCPs and MedDev guidances on clinical trials • Clarify the responsibilities of investigator, sponsor, monitor, and IRB/EC more thoroughly and consistently • Clarify risk and risk assessment with regard to the subject rather then device design • Update the literature review section to match MedDev and any developing GHTF documents: Investigator’s Brochure • Clarify the responsibilities of sponsors, monitors, investigators, institutions, IRBs/ECs, DSMB, auditors, and other parties • Clarify details of the Investigator ‘s Brochures, final report, adverse event handling, case report forms, and data mgmnt • Distinguish between adverse events, devise deficiencies, and deviations

6. ISO 14155: 2011 key items • Definition of Clinical Data not included • Development of clinical data is in Annex A • Risk of Use Error (ref: ISO 14971) includes training • Use of selected literature allowed if meets similarity requirements • Intended use • Population • Conditions of use • Note: similarity differs from MDD “demonstration of equivalency” (Article 1) • Requires assessment of significance and weight of studies including published and unpublished studies • Note: FDA PMA require unpublished and published data • All AE (not just SAE) to be reported to all countries where trial conducted

7. ISO 14155 Med Device Clinical • Step-by-step methodology, record-keeping, and reporting requirements • Ethical and legal approval requirements • Steps to construct a protocol • Risk assessment • Case report (data collection) forms • Instructions for preparing a final report

8. Global Harmonization Task Force (GHTF) • Study Group 5 • Harmonize clinical definitions • Review applicable GHTF & ISO/ICH documents, to assure terminology is consistent and interfaces are clear • Develop guidance on how to conduct and document the clinical evaluation • Harmonise the content and format for clinical investigation reports.

9. GHTF Essential Principles • Essential Principles of Safety and Performance of Medical Devices (Summary Technical Document (STED) • Classification and complexity of the device; • If it incorporates novel technology • If it is an already marketed device type that w/ intended use different from original use • If it is new to the manufacturer • Device type associated w/ significant number of adverse events/ user errors, novel or potentially hazardous materials, or raises specific public health concerns

10. STED Premarket Use • General description and list specific features • Set of labels and language variants • Summary tech docs and design • Essential principles checklist • Risk analysis and control summary • Summary of V&V • Clinical Evaluation Report

11. Are Essential Principles met? Principles of GHTF SG5 MORE NO YES REQUIRED - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Outputs Clinical investigation Literature searching Clinical use CLINICAL EVALUATION Processes • CLINICAL INFO • - Literature • Clinical experience • Clinical Investigations • Other? DECLARATION OF CONFORMITY REPORT CLINICAL EVIDENCE ISO14155 S T E D NON CLINICAL EVIDENCE

12. Clinical Design • Clear statement of objectives • Appropriate subject population(s) • Minimization of bias • randomization, blinding • Confounding factors • concurrent medications, co-morbidities • Appropriate controls • cohort, sham, historical • Design configuration • parallel, crossover, factorial • Type of comparison • superiority, non-inferiority, equivalence

13. Conclusion • Consider the Clinical Trial 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

14. GHTF Documents to Consider • SG1/N011:2008 Summary Technical Documentation for Demonstrating Conformity to the Essential Principles of Safety and Performance of Medical Devices (STED) • SG1/N029:2005 Information Document Concerning the Definition of the Term “Medical Device” • SG1/N041:2005 Essential Principles of Safety and Performance of Medical Devices • SG1/N040:2006 Principles of Conformity Assessment for Medical Devices • SG1/N43:2005 Labelling for Medical Devices • SG5/N1R8:2007 Clinical Evidence – Key definitions and Concepts • SG5/N2R8:2007 Clinical Evaluation

15. Backup slides

16. 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?

17. 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

18. 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.

19. Medical Device Clinical Paths

20. Core Principles • When is Clinical Data Needed To Assure That Essential Principles are Met? • Clinical Evaluation Process • Justification for Clinical Investigation • What Type / Design of Clinical Investigation is Appropriate?

21. 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

22. 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)

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

24. 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

25. 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

26. 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)

27. 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

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

29. Feasibility 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

30. 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

31. 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?

32. 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

33. 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

34. 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

35. 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

36. 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

37. Unanticipated Adverse Device Events (UADE) • UADEs must be reported by investigators to sponsors and reviewing IRBs as follows: • As soon as possible, but in no event later than 10 working days after the investigator first learns of the event • Sponsors must immediately conduct an evaluation of a UADE and must report the results of the evaluation to FDA, all reviewing IRBs, and participating investigators within 10 working days after the sponsor first receives notice of the effect • Guidance for Clinical Investigators, Sponsors, and IRBs. Adverse Event Reporting to IRBs—Improving Human Subject Protection Jan 2009

38. 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

39. 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

40. Questions for audience • Does “risk analysis”mean risks of the device or the risks of study participation? • •Is it always necessary to keep records of all the potential subjects screened? • •Must all data be copied into or collected in Case Report Forms vs. hospital records? • •Must marketed products that are studied for new uses have “Investigational”labeling? • How to integrate quality assurance for the study into the overall quality system of the Sponsor? Investigator or CRO?