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Lynn Henley, M.S., M.B.A. IDE and HDE Programs Food and Drug Administration

Contents of the IDE Application NHLBI June 24, 2010. Lynn Henley, M.S., M.B.A. IDE and HDE Programs Food and Drug Administration. Objectives Today. IDE (Investigational Device Exemption) Exempt device study Significant Risk v. Non-Significant Risk Types of IDEs Contents of Application.

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Lynn Henley, M.S., M.B.A. IDE and HDE Programs Food and Drug Administration

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  1. Contents of the IDE ApplicationNHLBI June 24, 2010 Lynn Henley, M.S., M.B.A. IDE and HDE Programs Food and Drug Administration

  2. Objectives Today • IDE (Investigational Device Exemption) • Exempt device study • Significant Risk v. Non-Significant Risk • Types of IDEs • Contents of Application

  3. Investigational Device Exemption (IDE) • Purpose: • To encourage discovery and development of useful medical devices for human use, to the extent consistent with the protection of the public health and safety and with ethical standards, while maintaining optimum freedom for scientific investigators in their pursuit of that purpose

  4. Provisions of the IDE Regulation • All clinical investigations subject to FDA oversight must be approvedbefore they can begin • Assigns responsibilities to all participants in clinical investigation • All subjects in the investigation must give written informed consent

  5. Studies Subject to Device Regulation • If used to support a marketing application: PMA, HDE or 510(k), OR • Collection of safety and effectiveness information (e.g., for a new intended use of a legally marketed device), OR • Sponsor-investigator studies of unapproved devices or new intended use of approved device (even if no marketing application planned)

  6. Pre-1976 devices 510(k)-cleared and HDE- or PMA-approved devices, if used in accordance with approved label Certain diagnostic devices Consumer preference testing of marketed device Combinations of legally marketed devices Custom devices (NARROWLY defined) Foreign Studies; Declaration of Helsinki Studies Exempt from Device Regulation (no IDE needed)

  7. Exempt Diagnostic Devices • Noninvasive; • Do not require an invasive sampling procedure that presents significant risk; • Do not introduce energy into the patient; and • Is not used as diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product.

  8. Need to assess whether proposed study of device is considered SIGNIFICANT RISK (SR), or NONSIGNIFICANT RISK (NSR) IRBs can and do make this assessment most of the time FDA can assist IRBs and/or investigators by making risk determinations; determination is final See IRB Information Sheet on SR/NSR: http://www.fda.gov/oc/ohrt/irbs/devices.html#risk If NOT Exempt from Device Regulation, Then…

  9. Significant Risk (SR) Study Presents a potential serious risk to the health, safety, and welfare of a subject and is: • an implant (usually 30 days); or • used in supporting or sustaining human life; or • of substantial importance in diagnosing, curing, mitigating, or treating disease or preventing impairment of human health

  10. Significant Risk (SR) Study Examples • Evaluation of temporary pacing leads in pediatric open heart surgery • Off-label stent registry • Evaluation of implantable echocardiogram • Evaluation of minimally invasive mitral valve repair • Evaluation of extracorporeal membrane oxygenation

  11. Significant Risk IDEs • Sponsor submits application to FDA • FDA approves, conditionally approves or disapproves IDE within 30 calender days • Sponsor obtains IRB approval • After both FDA and IRB approve the investigation, study can begin

  12. Non-significant Risk IDEs • Sponsor presents protocol to IRB and a statement why investigation does not pose significant risk • If IRB approves the investigation as NSR, it can begin • Abbreviated IDE requirements (labeling, IRB, consent, monitoring, reporting, prohibition on promotion) • No IDE submission to FDA needed

  13. Non-significant Risk Study Examples • Most functional MRI studies • Study of non-invasive blood pressure measuring device • Pediatric EKG study • Imaging blood velocity

  14. Types of IDEs • Feasibility study • May provide support for a future pivotal study or may be used to answer basic research questions • Not intended to be the primary support for a marketing application • Endpoints and sample size generally not statistically driven • Often required by FDA prior to pivotal study to assess basic safety and potential for effectiveness • Generally ~10-40 patients but may be larger • FDA review is primarily focused on safety

  15. Types of IDEs • Pivotal study • Generally intended as the primary clinical support for a marketing application • Endpoints and sample size statistically driven • Designed to assess both safety and effectiveness • FDA review is much more complex

  16. FDA’s Feasibility IDE Review • Focused on safety • Critical issues • Reasonable study conceptually? • Adequate preclinical validation of device? • Appropriate mitigation of potential risks? • Appropriate enrollment criteria? • Patients adequately informed? • Sample size appropriate?

  17. FDA’s Pivotal IDE Review • Focused on safety and plan for collecting and evaluating study data • Additional critical issues • Trial endpoints • Randomization, blinding, etc • Study conduct and monitoring • Statistical analysis plan

  18. Basic Submission Elements, All IDEs • Background of medical issue, the study goals, and why this study will further the science • Detailed description of the device under study • Previous studies (preclinical and clinical) • Summary of available data • Why is a clinical study needed at this stage? • What evidence supports the safety of this study/device and the potential for the study data to be meaningful? • Are there outstanding safety questions that could be addressed with preclinical data?

  19. Basic Submission Elements, All IDEs • Risk analysis • What are the potential risks to the patient? • Does the study mitigate the risks where possible? • Patient monitoring and follow-up plan • Inclusion and exclusion criteria • Informed consent document • Sample size and number of investigational centers, with justification

  20. Submission Elements, Pivotal IDEs • Primary and secondary endpoints • Discussion of appropriateness of endpoint parameters, hypotheses, and success criteria • Basic trial design • Controlled? If not, why not? • Randomized? If not, why not? • Blinded? If not, why not?

  21. Submission Elements, Pivotal IDEs • Trial conduct and study monitoring • Data handling and adjudication process • Sponsor blinding • Independent committees • Case report forms • Is the right information being gathered to support the study endpoints and are investigators adequately prompted to report adverse events?

  22. Submission Elements, Pivotal IDEs • Statistical analysis plan • Type-1 error and multiplicity • Missing data handling • Sample size calculations and assumptions • Assessment of critical covariates • Adaptive design plans • Interim analyses and early stopping rules • Data handling

  23. Submission Elements, Pivotal IDEs • Statistical analysis plan Provide enough detail to avoid ambiguity once the trial has started.

  24. FDA’s IDE Review Decisions • Approval • Approves the trial for a specified number of patients and investigational centers • Conditional Approval • Allows sponsor to begin the trial if the sponsor agrees to address the conditions (deficiencies) from the conditional approval letter within 45 days • Disapproval • Trial may not start until sponsor addresses the deficiencies from the letter, submits this information to FDA, and receives approval

  25. FDA Deficiency • Statement of FDA’s concern • Brief summary of how sponsor addressed (or did not address) this concern • Explanation for why this is inadequate • Discussion of what FDA believes is needed in order to have the concern addressed

  26. Common Pitfalls • Feasibility Study • Inadequate detail regarding the device under study or the methods used in the study • Inadequate preclinical data to assess basic safety • Inadequate procedures in place (or discussion of those procedures) to maximize patient safety • Inadequate informed consent document

  27. Informed Consent Common Pitfalls • Not explaining which procedures are experimental • Minimizing the risks involved • Promoting uncorroborated “benefits” • Not explaining that participation is voluntary and subject can withdraw participation at any time.

  28. Common Pitfalls • Pivotal Study • Trial design not adequately rigorous in terms of control, blinding, randomization, or duration • Inadequate justification for endpoints or success criteria • Inadequate detail in statistical plan or sample size calculations • Inadequate case report forms

  29. Process Suggestions • Early discussion with FDA through the preIDE process (to be discussed later today). • In response to conditional approval or disapproval: • Address deficiencies individually • Point to specific changes in the protocol or specific additional data that addresses the concern • Provide red-lined documents to facilitate review

  30. Review Timeline • 30-day review clock for all IDE original submissions and supplements • 45-day period for sponsors to respond to a conditional approval (extension may be requested) • “5-day notice” submission allowed for some minor changes to an ongoing IDE

  31. Thank youQuestions: Lynn.Henley@fda.hhs.gov 301-796-6120

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