What Are the FDA Requirements for Submitting an IDE? Andrew Farb, MD and Dorothy Abel, BSBME Interventional Cardiology Devices Branch Division of Cardiovascular Devices Center for Devices and Radiological Health (CDRH) The Essentials of Clinical Research CRT 2013 Washington, DC February 25, 2013 Will not talk about IND’s 1

I/we have no real or apparent conflicts of interest to report. Andrew Farb, MD I/we have no real or apparent conflicts of interest to report.

The Investigational Device Exemptions (IDE) Regulations and Clinical Studies Practice of medicine and off-label use The IDE regulations Applicability to clinical studies Exempted investigations Significant risk studies IDE basics IDE decision-making Case studies for sponsor-investigators: Is an IDE required? 3

Practice of Medicine Section 1006 of the Food, Drug and Cosmetic Act specifically states that: Nothing in this Act shall be construed to limit or interfere with the authority of a health care practitioner to prescribe or administer any legally marketed device to a patient for any condition or disease within a legitimate health care practitioner-patient relationship. 4

Off-Label Use Considerations Definitive data from appropriately designed and conducted clinical studies are needed to guide informed treatment decisions. The FDA approves a device for marketing for a specific use or uses. Off-label is a term applied to the use of an approved device under the practice of medicine, outside of the instructions for use. Off-label use of an approved device is not necessarily inappropriate or unstudied , but is typically supported by less information than with on-label use. 5

The Investigational Device Exemptions (IDE) Regulations The purpose of the IDE regulations is to encourage development of useful devices while providing protection of public health and safety. Clinical studies (i.e., any standardized, systematic collection of safety and/or effectiveness data) performed in the US are subject to the IDE regulations Regardless of whether the data would be used to support a marketing application. 6

Applicability of the IDE Regulations Some clinical studies are exempted from the IDE regulations, for example: The study of approved devices that are being used on-label The testing of a modification to a device or of a combination of two or more legally marketed devices if the testing does not put subjects at risk and is not for the purpose of determining safety or effectiveness A clinical study of a significant risk device, subject to the IDE regulations, requires prior FDA approval through the submission of an IDE application to FDA, and IRB approval, before initiating study subject enrollment. 7

Significant Risk Determination Significant risk devices are those that present the potential for serious risk to the health, safety, or welfare of a subject. A significant risk device may be: an implant; a life supporting or life sustaining device; or a device of substantial importance in diagnosing curing, mitigating, or treating disease, or in otherwise preventing impairment of human health. 8

IDE Basics An IDE approval is issued by the FDA to allow the use of significant risk investigational devices in human subjects. An approved IDE provides protection to human subjects (e.g., informed consent), study monitoring, and allows shipping of devices. An approved IDE exempts sponsors from certain provisions of the FD&C Act. Clinical study data collected under an IDE can be used to support a marketing application [PMA or 510(k)]. IDE submissions have a 30-day FDA review period. 9

Definitions Sponsor: A person or other entity that initiates, but does not actually conduct the investigation. Investigator: An individual who actually conducts a clinical investigation, i.e., under whose immediate direction the investigational device is administered, dispensed, or used. Sponsor-Investigator: Individual who both initiates and actually conducts, alone or with others, a clinical investigation, i.e., under whose immediate direction the investigational device is administered, dispensed, or used. 10

IDE Application The information to be included in an IDE application is listed in the regulations. The IDE sponsor needs to provide: sufficient information to justify the proposed study based on reports of prior investigations of the device; an appropriate investigational plan; adequate patient protection measures; and other required elements that address records and reports, study monitoring, and manufacturing information. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm046164.htm 11

IDE Decision-Making IDE approval: No outstanding issues that must be addressed to support the initiation of the clinical study IDE approval with conditions: FDA has identified issues, but these issues do not raise concerns that preclude study initiation Issues must be addressed within 45 days from the date of FDA’s decision letter IDE Disapproval Outstanding issues that may lead to approval with conditions include: Issues related to data analysis methods and handling if the corrections will occur prior to the gathering of important study data; Issues related to late stage follow-up procedures and assessments, if the corrections are made prior to beginning any late-stage procedures or assessments; Minor divergences from what FDA considers appropriate study endpoints, design assumptions, or key definitions; Issues related to the informed consent document that must be corrected before enrolling subjects but can be reviewed by FDA after study initiation; Requests for additional information or data involving non-clinical testing issues that do not need to be resolved prior to study initiation; Other minor clarifications, corrections, or modifications that do not need to be resolved prior to review completion

IDE Decision-Making IDE Disapproval is appropriate when: Probable risks to the subjects are not outweighed by the anticipated benefits to the subjects and the importance of the knowledge to be gained Safety concerns related to the device/procedure Often that nonclinical testing does not provide adequate safety information Unacceptable risks to subjects in the proposed study Inadequate potential for benefit OR The study does not pose a reasonable scientific question and/or is not designed to collect data related to that scientific question

FDASIA Section 601 Amends Section 520(g)(4)(C) of the FD&C Act 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.

IDE Decision-Making in Plain Language An FDA evaluation that concludes that the study is not adequate to support a subsequent marketing application cannot be used as the basis for IDE disapproval as long as: the probable risks of the study are not outweighed by the anticipated benefits and the importance of the knowledge to be gained; and the study is scientifically sound CDRH is developing new procedures to facilitate agreement between FDA and industry sponsors on a study design that both parties consider reasonable to support a marketing application.

When is an IDE Required? Example 1 The investigator-initiated research involves the use of an approved covered stent for treating intimal hyperplasia at the venous anastomosis of two different manufacturers’ cleared A-V access grafts to determine whether the results are affected by the graft type. All three devices are FDA approved/cleared and are being used in accordance with their labeling. But the specific brand of graft with which the covered stent can be used with is not specified in the product labeling. The investigator intends to publish the results in a peer-review journal. 16

Determining the Need for an IDE Submission Questions to Address Determining the Need for an IDE Submission YES NO Does the research constitute a clinical study?   If YES, proceed to next question. If NO, then an FDA approved IDE is not required.    Does the study involve: a) an off-label use of a medical device that has been approved/cleared by the FDA; or b) an Investigational Device?   17

An IDE is Not Needed The research constitutes a clinical study because the investigator plans to systematically collect safety and effectiveness data. The devices are being used in accordance with their labels, so no IDE submission is required. NOTE: The prior clinical studies of each of the devices to be used in the new study did require IDEs, as they involved the use of significant risk investigational devices. 18

When is an IDE Required? Example 2 The investigator intends to compare the performance of two approved coronary drug-eluting stents in the treatment of stenotic saphenous vein bypass grafts. The stents are FDA-approved for the treatment of native coronary artery lesions. The investigator intends to publish the results in a peer-review journal, and the manufacturer of one of the DES may use the data to support a change in their product’s labeling. 19

Determining the Need for an IDE Submission Questions to Address Determining the Need for an IDE Submission YES NO Does the research constitute a clinical study?   If YES, proceed to next question. If NO, then an FDA approved IDE is not required.    Does the study involve: a) an off-label use of a medical device that has been approved/cleared by the FDA; or b) an Investigational Device? 20

Determining the Need for an IDE Submission Questions to Address Determining the Need for an IDE Submission YES NO Is the Investigational Device a Significant Risk (SR) Device (per 21 CFR 812.3(m) and 812.20(a)(1)? (a) Is the investigational device intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject? (b) Is the investigational device purported or represented to be for a use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject? (c) Is the investigational device for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject? (d) Does the investigational device otherwise present a potential for serious risk to the health, safety, or welfare of a subject?  If YES to any of questions (a) - (d), the study utilizes a Significant Risk Device and therefore requires IDE approval prior to study initiation.      N/A 21

An IDE is Needed The research constitutes a clinical study because the investigator plans to systematically collect safety and effectiveness data. Although the devices are commonly used off-label for the treatment of stenotic SVGs, the proposed prospective clinical study of these significant risk devices requires IDE and IRB approval prior to initiation. 22

Parting Thoughts IDE approval is needed for some clinical research studies, depending on: the device’s approval status; the intended clinical use; and whether the device is a significant risk or nonsignificant risk device. If there is any doubt with respect to the answers to the questions in deciding whether an IDE is needed, contact FDA. Early contact with the appropriate Division of Cardiovascular Devices branch chief is highly recommended to discuss the entire IDE process Early contact can help sponsors determine what’s needed to meet IDE administrative requirements and avoid wasted steps. 23