The Investigational Device Exemption (IDE)

Purpose (+) Scope

An Investigational Device Exemption (IDE) is a regulatory submission allowing, if approved, the use of a device (called in this context a investigational device) to be used in clinical investigation (clinical study/clinical trial) in order to collect safety and effectiveness data.

As per 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”.

In essence, you ask the FDA to allow your device to be used in clinical investigation as you want to collect substantial clinical evidences to support a future FDA submission for in fine placing the device in the U.S. market.

Introduction

An investigational device exemption (IDE) allows the investigational device to be used in a clinical study in order to collect safety and effectiveness data. Clinical studies are most often conducted to support a PMA. Only a small percentage of 510(k)s require clinical data to support the application. Investigational use also includes clinical evaluation of certain modifications or new intended uses of legally marketed devices. All clinical evaluations of investigational devices, unless exempt, must have an approved IDE before the study is initiated. – The U.S. Food & Drug Administration (FDA).

The Code of Federal Regulations Title 21 Part 812 (21 CFR 812) contains the procedures and requirements governing the IDE and the conduct of clinical research of devices.

A Pre-Sub meeting may be held prior to the submission of an IDE in order to seek FDA input on the IDE components. As a reminder, a Pre-Sub meeting provides the opportunity for a submitter to obtain FDA feedback prior to an intended premarket submission (i.e., IDE, PMA, HDE, De Novo request, 510(k), Dual, BLA, IND). The Pre-Sub is a type of Q-Submission. If a manufacturer has had a Pre-Sub meeting, the advantage is that it can now tailor the information to what FDA has indicated it expects for the particular device.

IDE Application

A sponsor of a significant risk device study must submit a complete IDE application to FDA. There are no preprinted forms for an IDE application; however, an IDE application must include certain required information. The sponsor must demonstrate in the application that there is reason to believe that the risks to human subjects from the proposed investigation are outweighed by the anticipated benefits to subjects and the importance of the knowledge to be gained, that the investigation is scientifically sound, and that there is reason to believe that the device as proposed for use will be effective – The U.S. Food & Drug Administration (FDA).

Several required elements must be included in an IDE application such as:

A report of prior investigations – containing at least a bibliography of all publication, copies of all published and unpublished adverse information, copies of other significant publications if requested by an Institutional Review Board (IRB) or FDA, a summary of all other unpublished information, if nonclinical laboratory data are provided, a statement that such studies have been conducted in compliance with the Good Laboratory Practice (GLP) regulations or a rational if not.
An investigational plan (21 CFR 812.25) – including at least the purpose of the investigation, a protocol, a risk analysis, a justification for the investigation; a description of the patient population, a description of the device, the monitoring procedures and additional records and reports. The investigational plan must be approved by each participating study site’s IRB.
A description of the methods, facilities, and controls used for the manufacture, processing, packing, storage, and installation of the device.
An example of the agreement to be signed by the investigators and a list of the names and addresses of all investigator.
Certification that all investigators have signed the agreement, that the list of investigators includes all investigators participating in the study, and that 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.
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.
Any other relevant information that FDA requests for review of the IDE application.

The required content of an IDE is provided in 21 CFR 812.20, including the specific order in which the information should be presented. FDA is, however, somewhat liberal on sequence, as long as all the information is included and presented in a logical fashion.

As a reminder, a clinical study performed in the U.S. must have a U.S. sponsor (A clinical study sponsor is a person, company, institution, group, or organization that oversees or pays for a clinical investigation and collects and analyzes the data). Therefore, a foreign manufacturer must have a U.S. entity submit the IDE.

Format

The signed IDE application is submitted to FDA in triplicate, either with three paper copies, or with two electronic copies (using the eCopy Program) and one paper copy. The submission must be signed by the sponsor’s authorized representattive and delivered via courier to the document mail center of the Center for Devices and Radiological Health (CDRH).

The paper copy volumes must be paginated and bound in volumes must no more than two inches (about 5 cm) thick. FDA requires standard U.S. letter size paper (8.5 x 11 inches) white paper for all submissions. Specific FDA guidance on the Pre-Sub program can be found in the FDA guidance document Requests for Feedback and Meetings for Medical Device Submissions:The Q-Submission Program.

The electronic copy must conform to the requirements in FDA guidance document eCopy Program for Medical Device Submissions, including requirements for cover letter, file type (.pdf), bookmarks, file naming, file size limitations, etc.

Cover Letter

The FDA specifies that a cover letter describing the submission and/or a Form 3514 (Voluntary form used to help provide basic administrative info for all types of premarket notification submissions) is required to be included in the IDE. The cover letter should include:

A statement that the information provided is an original IDE submission.
The device information (Device name, intended use)
The sponsor contact information
The manufacturer information
If the organization submitting the application is not the sponsor, such as a consultant or a lawyer, include contact information for the correspondent organization or individual.
If applicable, a description of Q-Submission/Pre-Submission meetings, any discussion with the FDA reviewing division, the Q-Sub number and a copy of the written feedback, the name of the FDA contact person and the minutes of the meetings.
The identification of any waiver requests and the justification
Referenced Files: Identify any files that are referenced in the IDE application, such as Premarket Approval, Premarket Notification 510(k), IDE, or device master files. If files were not submitted by the sponsor, include a letter from the owner of the files that grants FDA permission to reference the files in its review of the current application.

Devices Studies Types and IDE Study Types

Device studies are categorized into three types according to the regulations of 21 CFR 812:

Exempt studies: These studies are exempt from the requirements of 21 CFR 812. Examples of exempt studies include diagnostic device studies (e.g., in vitro diagnostic studies), consumer preference testing, testing of a device modification, veterinary devices, animal studies, custom devices, etc. (see 21 CFR 812.2 (c).
Significant risk (SR) device studies: These studies require an approved IDE from the FDA and must comply with the complete regulations at 21 CFR 812.
Nonsignificant risk (NSR) device studies: These studies must meet the abbreviated IDE requirements at 21 CFR 812.2(b).

For SR and NSR device studies, the following IDE Study Types are available:

Early Feasibility Study (EFS) – To provide proof of principle and initial clinical safety data with a limited clinical investigation (<15). Study performed usually early in development, typically before the device design has been finalized, for a specific indication (e.g., innovative device for a new or established intended use, marketed device for a novel clinical application).
First in Human (FIH) Study – When a specific indication is evaluated for the first time in human subjects. Note that a FIH can be a EFS, but not all FIH studies would be considered EFSs.
Traditional Feasibility Study – To capture preliminary safety and effectiveness information on a near-final or final device design. To adequately plan an appropriate pivotal study. Does not necessarily need to be preceded by an EFS.
Pivotal Study – To collect definitive evidence of the safety and effectiveness of a device for a specified intended use, typically in a statistically justified number of subjects. May or may not be preceded by an early and/or a traditional feasibility study.