FDAs IDE Decisions and Communications Owen Faris Ph

FDA’s IDE Decisions and Communications Owen Faris, Ph. D. Deputy Director Division of Cardiovascular Devices

Overview What is an IDE? FDASIA (changes in the law) FDA decisions and communications Take home points

Investigational Device Exemption (IDE) Established in 21 CFR Part 812 FDA approval of an IDE is required for US human study of a significant risk device which is not approved for the indication being studied. Exempts sponsor from certain provisions of FD&C Act Requirements for informed consent, labeling, monitoring of the study, records/reporting Requires approval by Institutional Review Board (IRB)

FDA’s IDE Review Decisions Approval Approves the trial for a specified number of patients and investigational centers Approval with Conditions 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

FDA’s Draft Guidance on IDE Decisions Originally issued in draft on November 10, 2011 Explained each of FDA’s decisions and provided examples on the reasons that could support IDE disapproval or approval with conditions.

FDASIA Section 601 Amends Section 520(g)(4)(C) of the FD&C Act FDASIA was signed into law on July 9, 2012 FDA shall not disapprove an IDE because: the investigation may not support a substantial equivalence or de novo classification determination or approval of a device; the investigation may not meet a requirement, including a data requirement, relating to the approval or clearance of a device; or an additional or different investigation may be necessary to support clearance or approval of the device.

FDASIA Section 601 This means that an IDE cannot be disapproved on the basis of FDA’s belief that the study design is inadequate to support a future PMA, 510(k), HDE, or de novo classification. Note that the standard for market approval (PMA) or clearance (510(k)) has not changed.

FDASIA Section 601 FDA implementation approach has included establishment of a working group to: Develop IDE decision policy Re-Draft “IDE Decisions” guidance Modify IDE boilerplate letters Consider changes to FDA’s regulations needed because of conflicts with the modified statute Consider other mechanisms to encourage sponsors to work with FDA to develop pivotal trials that are appropriately designed to support marketing applications

IDE Decision Letter Changes Feasibility vs. pivotal study Clarify meaning of IDE Approval Clarify meaning of Approval with Conditions* Clarify whether FDA agrees with study design Communicate concerns regarding study design as “study design considerations” Staged approval option (approval of limited initial patient cohort)* *Not discussed in detail today

IDE Approval letter “FDA has reviewed your IDE application to conduct a [1. feasibility / 2. pivotal study] for a significant risk device. ” “FDA has determined you have provided sufficient data to support initiation of a human clinical study; this means that there are no subject protection concerns that preclude initiation of the investigation. Your application is therefore approved. ” For pivotal studies, one of the following will be communicated: A. FDA believes the study design provided in your submission is adequate and may support a future marketing approval or clearance, if it is successfully executed and meets its stated endpoints without raising unforeseen safety concerns. B. Although the proposed study meets the regulatory requirements of Section 520(g)(4) of the FD&C Act, FDA believes that additional modifications as outlined in “Study Design Considerations” below are needed for your study design to support a marketing approval or clearance.

IDE Approval letter Please note that approval of an IDE application [Option, if applicable] and agreement with the study design [End option] does not ensure that the results of this investigation will provide reasonable assurance of the safety and effectiveness of your device or assure a determination of clearance/approval for your premarket submission. Study Design Considerations: “FDA believes that additional modifications are needed in order for your study design to support marketing approval or clearance. We recommend, but do not require, that you modify your study to address the following issues: ”

Typical Study Design Considerations Primary & important secondary endpoints, study success criteria Randomization, control, and blinding Follow-up duration and assessments Statistical plan, including Sample size and power Missing data handling Type-1 error control Interim analyses and stopping rules Poolability Case report forms Enrollment criteria Core labs and Independent adjudication committees

IDE Disapproval Primary distinction is presence or absence of safety concerns Typical disapproval deficiencies include: Concerning or inadequate preclinical safety data Inadequate demonstration of potential for benefit to justify risks Investigational protocol is not adequate to protect study subjects Background medical care not consistent with standard of care Not monitoring for an expected adverse event Enrollment of high risk subgroup

How do we get to the “right” study? FDA is considering new ways to best work with sponsors to address IDE approval/disapproval issues as well as Study Design Considerations prior to the IDE submission: Pre-Submission process Focused discussion on a particular element of the IDE submission Not based on a comprehensive FDA review Pre-Decisional IDE process New concept not yet implemented Interactive and comprehensive pre-review of the IDE so that sponsors can anticipate FDA’s concerns and submit an IDE that addresses those concerns Described in more detail in the upcoming draft guidance

Take home points FDA approval or approval with conditions of an IDE means that FDA believes: The device is appropriate to be used in a clinical study from a riskbenefit perspective. The study is appropriately designed to protect subjects enrolled in the study. For IDE’s approved with conditions, FDA does not believe it is necessary that those conditions be addressed prior to initiation of study enrollment.

Take home points FDA approval or approval with conditions of an IDE does not necessarily mean that FDA believes the study design is appropriate to support the sponsor’s study goals in terms of a future marketing application or study. FDA’s decision letters will communicate our perspective on study design.

Discussion FDA appreciates the opportunity to discuss the challenges surrounding clinical trials and the IDE process We welcome your suggestions for better communication between FDA, study sponsors, and other important stakeholders to ensure appropriate patient protections and the conduct of valid and robust clinical trials.

Contact Information Owen Faris owen. faris@fda. hhs. gov (301) 796 -6356