An IDE is a regulatory submission that permits clinical investigation of devices to determine safety and effectiveness. An FDA-approved Investigational Device Exemption Application (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 (21 CFR 812.1).
The definition of the term device in section 513(a)(1) of the FD&C Act is an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent or other similar or related article or component part or accessory which:
- is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease.
- is intended to affect the structure or any function of the body.
- does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.
Section 520(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) [21 U.S.C. § 360j(g)] establishes a framework for FDA to a grant a device for investigational use an exemption from certain requirements, such as performance standards or premarket approval, for the purpose of conducting investigations of that device. This exemption is known as an Investigational Device Exemption (IDE). The sponsor makes the initial assessment and justification for risk. If the sponsor determines a device study as significant risk, the sponsor should send an IDE application to the FDA prior to gaining IRB approval. If the sponsor determines the device study to be nonsignificant risk, the protocol should be sent to the IRB for final determination during a full board IRB review. If there is a disagreement between the sponsor and IRB that cannot be resolved, the FDA is the final arbiter in deciding whether a device study poses a significant or nonsignificant risk and whether an IDE is required.
Sponsors must obtain FDA and IRB approval of an IDE application prior to beginning clinical investigations of a significant risk device.
The FDA has two primary objectives in reviewing an IDE according to 21 CFR 812.30(b)(4):
- To assure safety and appropriate patient protections for device trials.
- To assure that the risks to the subjects are outweighed by the anticipated benefits to the subjects and the importance of the knowledge to be gained.
IDEs fall into four categories:
Early Feasibility Study: An early feasibility study is a limited clinical investigation of a device 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). It may be used to evaluate the device design concept with respect to initial clinical safety and device functionality in a small number of subjects (generally fewer than 10 initial subjects) when this information cannot practically be provided through additional nonclinical assessments or appropriate nonclinical tests are unavailable. Information obtained from an early feasibility study may guide device modifications. An early feasibility study does not necessarily involve the first clinical use of a device. Early Feasibility/FIH Clinical Considerations.
First in Human (FIH) study: A first in human (FIH) study is a type of study in which a device for a specific indication is evaluated for the first time in human subjects. This document only discusses FIH studies that meet the definition of an early feasibility study.
Traditional Feasibility Study: A traditional feasibility study is a clinical investigation that is commonly used to capture preliminary safety and effectiveness information on a near-final or final device design to adequately plan an appropriate pivotal study. Because the study of a near-final or final device design takes place later in development than an early feasibility study, FDA would expect to see more nonclinical (or prior clinical) data in a traditional feasibility study IDE application. A traditional feasibility study does not necessarily need to be preceded by an early feasibility study.
Pivotal Study: A pivotal study is a clinical investigation designed 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. It may or may not be preceded by an early and/or a traditional feasibility study. Pivotal Study Clinical Considerations.
Non-Traditional Medical Devices
In thinking about medical devices, some obvious examples may come to mind, like a pacemaker, an MRI, or a blood pressure cuff. However, there are some other "less traditional" devices that also require FDA oversight as a medical device. They are described below.
In vitro diagnostics (IVDs)
In vitro diagnostic products are those reagents, instruments, and systems intended for use in diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body (e.g., blood, spinal fluid, tissue samples, serum, urine).
IVDs are devices as defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act, and may also be biological products subject to section 351 of the Public Health Service Act. Like other medical devices, IVDs are subject to premarket and post market controls. IVDs are generally also subject to categorization under the Clinical Laboratory Improvement Amendments of 1988. The FDA considers the IVD to be the entire process from specimen collection, transport, preparation, examination/analysis, to the method of calculating and reporting results.
Clinical studies, particularly drug studies, often contain objectives with the purpose of determining whether biomarkers correlate with disease state, treatment response, or risk of disease. Depending on study design, this analysis can be considered the early development of an IVD that is subject to 21 CFR 812.
Some things to consider when deciding if IVD regulations may apply are whether the targets for the analysis are specific and well-defined, how much is previously known about the biomarkers, and/or how the disease correlating signature is used.
Software Functions and Mobile Medical Applications
FDA has regulatory oversight of software functions that meet the definition of a device in section 201(h) of the Federal Food, Drug, and Cosmetic Act, and these software functions are referred to as "device software functions." Device software functions may include "Software as a Medical Device (SaMD)" and "Software in a Medical Device (SiMD)."
Software as a Medical Device is defined by the International Medical Device Regulators Forum (IMDRF) as "software intended to be used for one or more medical purposes that perform these purposes without being part of a hardware medical device." Software as a Medical Device ranges from software that allows a smartphone to view images obtained from a magnetic resonance imaging (MRI) medical device for diagnostic purposes to Computer-Aided Detection (CAD) software that performs image post-processing to help detect breast cancer. A Mobile Medical Application (MMA) ". . .is a mobile app that incorporates device software functionality that meets the definition of device in section 201(h) of the FD&C Act; and either is intended:
- to be used as an accessory to a regulated medical device; or
- to transform a mobile platform into a regulated medical device."
Device software functions may be used on a mobile platform (e.g., mobile medical apps), other general-purpose computing platform, or in the function or control of a hardware device. Generally, if a software function is intended to perform a medical device function (i.e., to diagnose disease or other conditions, or cure, mitigate, treat, or prevent disease), it is regulated as a medical device, regardless of the platform on which it is run.
FDA intends to focus its regulatory oversight only to those device software functions that could pose a risk to a patient's safety if they fail to function as intended:
- "Software functions that are an extension of one or more medical devices by connecting to such device(s) for purposes of controlling the device(s) or analyzing medical device data." For example, software that provides the ability to control inflation and deflation of a blood pressure cuff through a mobile platform.
- "Software functions (typically, mobile apps) that transform the mobile platform into a regulated medical device by using attachments, display screens, or sensors or by including functionalities similar to those of currently regulated medical devices." For example, a software function that uses the built-in accelerometer on a mobile platform to collect motion information for monitoring sleep apnea.
- "Software functions that become a regulated medical device by performing patient-specific analysis and providing patient-specific diagnosis, or treatment recommendations." For example, software functions that use patient-specific parameters and calculate dosage or create a dosage plan for radiation therapy.
For software functions that fall under FDA regulatory oversight, the IDE regulations are enforced and apply when the objective of the clinical investigation is to assess the safety and/or effectiveness of the software function. FDA intends to exercise enforcement discretion (meaning it does not intend to enforce requirements under the FD&C Act) for software functions that:
- Help patients (i.e., users) self-manage their disease or conditions without providing specific treatment or treatment suggestions; or
- Automate simple tasks for health care providers."
Please note, for software functions that fall under FDA enforcement discretion, the IDE regulations are not currently being enforced. Additional information on software and mobile medical apps, and more examples of software that fall into the various regulatory oversight categories, can be found in the FDA Guidance for Industry and FDA Staff - Policy for Device Software Functions and Mobile Medical Applications.
IDE Regulations are found in Title 21 of the Code of Federal Regulations (CFR), Part 812 Regulations that apply to IDEs are found in 21 CFR as follows:
21CFR Part 812 - Investigational Device Exemptions
21CFR Part 814 - Premarket Approval of Medical Devices
21CFR Part 860 - Medical Device Classification Procedures
21CFR Part 58 - Good Laboratory Practice for Nonclinical Laboratory (Animal) Studies
21CFR Part 50 - Protection of Human Subjects
21CFR Part 56 - Institutional Review Boards
21CFR Part 201 - Drug Labelling
21CFR Part 54 - Financial Disclosure by Clinical Investigators