How to Put Together an IDE Application Clinical Investigator Training Course Silver Spring, MD November 9, 2016 Véronique Li Clinical Trials Program Center for Devices and Radiological Health Good morning. My name is Veronique Li, and I am with the Clinical Trials Program in the Center for Devices and Radiological Health at FDA. Today, I will provide an overview of how to put together an IDE application and briefly discuss applicable regulations. To get into the meat of these would take days.

Investigational Device Exemption An IDE is a regulatory submission that, when approved, permits clinical investigation of certain medical devices. This investigation is exempt from some regulatory requirements. The name “Investigational Device Exemption” stems from this description in 21 CFR 812.1: “An approved investigational device exemption (IDE) permits a device that otherwise would be required to comply with a performance standard or to have premarket approval to be shipped lawfully for the purpose of conducting investigations of that device.” You may be wondering what exactly is meant by “Investigational Device Exemption.” The term refers to a regulatory submission that permits clinical investigation of devices. This investigation is exempt from some, but not all, regulatory requirements for medical devices. The name stems from the following description: “An approved investigational device exemption (IDE) permits a device that otherwise would be required to comply with a performance standard or to have premarket approval to be shipped lawfully for the purpose of conducting investigations of that device.” www.fda.gov

Law (Food, Drug & Cosmetic Act)  Regulation Code of Federal Regulations (21 CFR): Part 812: IDE Regulation Part 50: Protection for Human Subjects, Informed Consent (IC) Regulation Part 54: Financial Disclosure of Investigators Part 56: Institutional Review Boards (IRBs) Regulation The Federal Food, Drug, and Cosmetic Act, referred to as the FD&C Act, is the statutory law passed by Congress. The Code of Federal Regulations is a codification of the rules published in the Federal Register by Federal agencies, including FDA. The Code is divided into 50 titles which represent broad areas subject to Federal regulation. Title 21 covers Food and Drugs, which pertain to the Food and Drug Administration. The parts of 21 CFR listed here are those with the most relevance to IDE regulation: Part 812, which outlines the IDE regulations; Part 50, which deals with human subject protection and informed consent, Part 54, which describes how investigators should disclose their financial interests; and Part 56, which delves into the responsibilities of Institutional Review Boards. As you proceed with your clinical investigation, you may need to refer to these sections of the CFR. www.fda.gov

All Device Investigations Studies Subject to the IDE Regulation Studies Exempt from the IDE Regulation SR Investigations NSR Studies This chart helps determine how to determine whether your study is subject to an IDE and, if so, whether your study is significant risk or non-significant risk. First you must determine whether your study is subject to the IDE regulation. If it is exempt, you do not need to send in an IDE. If it is subject to the IDE regulation, you need to determine whether it is significant risk (SR) or non-significant risk (NSR). If the IRB or sponsor do not want to make the risk determination, FDA can assist with the process. However, if FDA makes the determination, that decision is final. Significant risk studies are subject to the full requirements of the IDE regulations, whereas non-significant risk studies are subject to abbreviated requirements. Please note that study risk determinations take into account not only the device but how the device is used in the study and other procedures in the study which may increase the overall risk of the study. Studies which are subject to the IDE regulation are those intended to support a marketing application, those for collection of safety and effectiveness information, and sponsor-investigator studies of an unapproved device or a new intended use of an approved device, even if no marketing application is planned. Studies that are exempt from the need for an IDE include pre-amendment or pre-1976 devices; 510(k)-cleared or PMA-approved devices, if used in accordance with approved labeling; in vitro diagnostic devices (most of the time); consumer preference testing; combinations of legally marketed devices; and custom devices, which are rarely granted this exemption. CDRH’s Office of Compliance can assist sponsors with determining whether a device meets the custom device criteria. The criteria may be found in 21 CFR 812.3. Full Requirements Abbreviated Requirements 4 www.fda.gov

Process Significant Risk IDEs Non-Significant Risk IDEs Full IDE requirements apply Sponsor submits IDE application to FDA FDA approves, approves with conditions or disapproves IDE within 30 calendar days Sponsor obtains IRB approval After both FDA and IRB approve the investigation, study can begin 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 In the case of significant risk studies, the sponsor submits the IDE application to FDA. FDA then approves, approves with conditions, or disapproves the IDE within 30 calendar days. If FDA does not respond within 30 days, the IDE is “deemed approved.” The sponsor then obtains IRB approval. After both FDA and the IRB approve the investigation, the study may begin. In the case of non-significant risk studies, the sponsor presents the protocol to the IRB and a statement as to why the investigation does not pose significant risk. If the IRB approves the investigation as NSR, the study may begin. Abbreviated IDE requirements apply in this situation, including labeling, IRB approval, informed consent, monitoring, reporting, and prohibition of promotional activities. No IDE submission to FDA is necessary. www.fda.gov

IDE Application Administrative Checklist Required Elements Name and address of sponsor Report of prior investigations Investigational plan A description of the methods, facilities, and controls used for the manufacture, processing, packing, storage, and installation of device An example of the agreement to be signed by the investigators and a list of names and addresses of all investigators Certification that all investigators have signed the agreement, that the list of investigators includes all investigators participating in the study, and that the new investigators will sign the agreement before being added to the study A list of the names, addresses, and chairpersons of all IRBs that have or will be asked to review the investigation and a certification of IRB action concerning the investigation (when available) The name and address of any institution (other than those above) where a part of the investigation may be conducted The amount, if any, charged for the device and an explanation of why sale does not constitute commercialization Copies of all labeling for the device Copies of all informed consent forms and all related information materials to be provided to subjects as required by 21 CFR 50 All other relevant information that FDA requests for review of the IDE application Report of prior investigations refers to all the previous studies or bench/animal testing on the device. This report should include a bibliography including relevant preclinical and clinical studies, copies of all adverse information, copies of other requested publications, a summary of all other unpublished information, and a statement regarding whether the nonclinical studies were conducted in compliance with the Good Laboratory Practice regulations. The investigational plan should also include the purpose of the study, including the name and intended use of the device, the objectives of the investigation, a protocol, a risk analysis, and a description of the intended patient population. A description of the device should be provided. The investigational plan should describe the monitoring procedures as well as additional records and reports. A description of the methods, facilities, and controls used for the manufacture, processing, packing, storage, and installation of the device should also be included with the IDE. So that you don’t forget anything, I have included a link to the administrative checklist used by both internal and external stakeholders. IDE Application Administrative Checklist www.fda.gov

FDA Review of the Application FDA sends acknowledgment with IDE number GYYxxxx (e.g. G160001) IDE sent to appropriate review division based upon intended use Lead reviewer assembles team of experts to review the application, engage in interactive review with sponsor, and make decision with management concurrence within 30 days FDA issues a decision letter to the sponsor Once you have submitted your IDE application, you will receive an acknowledgment email identifying your IDE number beginning with the letter “G”. Your submission will be sent to the appropriate review division within ODE or OIR based upon the intended use of the device. Upon receipt, the lead reviewer assigned to the file will assemble a team of experts and engage in interactive review with you to arrive at a decision in consultation with FDA management. At the end of the 30 day review period, FDA will issue a decision letter. www.fda.gov

FDA Decisions Approval Approval with conditions Disapproval Approves the trial for specified number of sites and subjects Enrollment can begin once IRB approval is obtained Approval with conditions Approves the trial for specified number of sites and subjects provided conditions (deficiencies) are addressed within 45 days Disapproval Study may not begin Deficiencies will be listed Sponsor must address deficiencies and obtain FDA approval to start study The decision letter will indicate that your study is approved, approved with conditions, or disapproved. Approval means that your study may begin once IRB approval is obtained. Approval with conditions means that the study may begin, although deficiencies listed must be addressed within 45 days. After the deficiencies are resolved, the sponsor must obtain IRB approval and the study may begin. Disapproval means that the study may not begin. Once the sponsor adequately addresses the deficiencies and receives FDA approval, the sponsor must obtain IRB approval and then the study may begin. www.fda.gov

FDA Decisions for Investigational Device Exemption Clinical Investigations Clarifies FDA’s approach to IDE decisions Deficiencies Issues which must be addressed before study may proceed Study Design Considerations Those issues unrelated to subject safety that FDA believes should be addressed to meet sponsor’s stated goals Future Considerations Issues that FDA believes the sponsor should consider in preparing for a marketing application or additional clinical study but which are not necessary to address stated goals of the study The guidance outlines the types of decision letters that sponsors may receive. Deficiencies identified by FDA review of an IDE indicate issues that must be addressed before the study may proceed. Study design considerations include those issues unrelated to subject safety that FDA believes should be addressed to meet the sponsor’s stated goals. Future considerations consist of issues that FDA believes the sponsor should consider in preparing for a marketing application or a future study, but which are not necessary in order to address the stated goals of the study. www.fda.gov

FDA Submissions after Approval Amendments Any response to a deficiency is an Amendment to the submission for which the deficiency letter was sent Can be submitted to Supplements and Reports as well as the Original IDE Common amendment reasons: response to approval with conditions, response to disapproval Supplements Generally submitted by a sponsor to request something that requires an FDA decision Common supplement reasons: new study, change in protocol Reports Used to track all IDE reports May not be combined with any other submission Common report reasons: annual progress report; semiannual investigator list Submissions received after an Original IDE are assigned amendments, supplements, or reports based on their submission reason. Any response to a deficiency is an Amendment to the submission for which the deficiency letter was sent. Amendments can be submitted to Supplements and Reports as well as the Original IDE. Some common amendment reasons include Response to Disapproval and Response to Approval with Conditions. Supplements are generally submitted by a sponsor to request something that requires an FDA decision. Common supplement reasons include New Study and Change in Protocol. Finally, reports are used to track all IDE reports and may not be combined with any other submission. Common report reasons include the annual report and 6 month investigator list.