Table of Contents
- Regulatory Context
- When is an IDE Needed?
- Types of Studies
- IDEs and Collection of Real-World Data
- Role of Sponsors, Investigators, and IRBs
- The IDE Application
- Summary
- Frequently Asked Questions (FAQs)
Regulatory Context
Exemption for Devices for Investigational Use
“It is the purpose of this subsection to encourage, to the extent consistent with the protection of the public health and safety and with ethical standards, the discovery and development of useful devices intended for human use and to that end to maintain optimum freedom for scientific investigators in their pursuit of that purpose.”
Ref. Section 520(g) of the Federal Food Drug and Cosmetic Act
What is the challenge?
Physicians and patients want access to the latest technologies, especially when there are unmet needs, but all research should include the appropriate human subject protections.
Investigational Device Exemption
FDA approval of an IDE is required for a US human study of a significant risk device which does not have marketing authorization for the indication being studied. An IDE exempts the Sponsor from certain provisions of the Food Drug & Cosmetic Act (e.g., requirement for a marketing application, compliance with full Good Manufacturing Practice (GMP) regulations). The FDA Investigational Device Exemption process specifies requirements for informed consent, labeling, monitoring of the study, records and reporting. The initiation of the study requires approval by an Institutional Review Board (IRB).
The provisions for an IDE are found in 21 CFR 812-Investigational Device Exemptions:
- Describes applicability of the IDE regulations
- Provides administrative information
- Outlines the contents of the IDE application
- Describes FDA actions on IDE applications
- Assigns responsibilities to all participants in clinical investigations
When is a FDA Investigational Device Exemption (IDE) Needed?
Many times, marketing or the R&D team will ask if a FDA IDE is required for any new use of an already approved medical device on a patient within the context of a health care practitioner-patient relationship. So, when is an FDA Investigation Device Exemption needed?
- For any new use of an already approved medical device on a patient within the context of a health care practitioner-patient relationship.
- Only for medical device clinical studies that are meant to support a marketing submission (e.g., PMA, or 510(k)) to the FDA.
- For all medical device clinical studies using an unapproved medical device or a new use of an approved device.
- For significant risk medical device clinical studies using an unapproved medical device or a new use of an approved device.
The correct answer is IDEs are for significant risk medical device studies using an unapproved medical device or a new use of an approved device.
Keep in mind that the Food Drug & Cosmetic Act (FD&C Act) does not interfere with the clinician authority as stated below:
“Practice of Medicine”
“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…” Ref: Section 1006 of the FD&C Act, 21 USC 396
The institution may require IRB review and approval, including an informed consent of which other prohibition still applies. The physician should be well informed about the product and use firm scientific rational and sound medical evidence in this situation. Maintain records on use and effects.
Risk Determination
The Sponsor, who initiates and manages the clinical study, has the primary responsibility for evaluating the potential risks of the study. This includes assessing the risks to human subjects and the potential benefits of the research. The IRB reviews the Sponsor’s determination (21 CFR 812.2(b)(1)(ii)) and the IRB will base their decision on the information provided by the Sponsor. This includes the device description, prior investigations, investigational plan, subject selection, risk assessment, and rationale used in making an SR or NSR determination. If the IRB disagrees with a Sponsor’s NSR assessment, the IRB must inform the clinical investigator, and where appropriate, the Sponsor (21 CFR 812.66).
Requests for Study Risk Determination
The IDE regulation describes three types of device studies: significant risk (SR), nonsignificant risk (NSR), and exempt studies. The FDA guidance: “Significant Risk and Nonsignificant Risk Medical Device Studies – Information Sheet” is helpful if a risk determination cannot be made by the Sponsor and acknowledged by the IRB, then the Sponsor can submit a “Study Risk Determination” Q-Submission to the FDA via FDA guidance: Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program. The submission requires a cover letter, device description and clinical study protocol. The FDA will issue a letter indicating if the study is:
- Significant Risk (not exempt)
- Nonsignificant Risk (not exempt)
- Exempt
In this case, the FDA is the final arbiter, and the IRB does not need to conduct an independent assessment of risk.
Types of Studies
We have discussed clinical studies that are for devices that have not been approved or cleared by the FDA. However, we have not discussed in detail when manufacturers may want to extend an indication for use claim or introduce a new indication for use. The manufacturer may find that clinicians are using the device for purposes other than what the FDA originally approved. This is what is called “off label use.” Clinicians may have observed promising results in their practice that haven’t been formally studied. While this practice is legal and common, it raises questions about safety and efficacy, particularly when there’s limited scientific evidence to support this new use.
Clinical studies can be conducted by either manufacturers (industry-sponsored) or academic institutions. Industry-sponsored studies are often designed and funded by medical device companies, while academic studies are typically designed by researchers at academic institutions and funded by grants or other sources. Industry-sponsored studies are often designed with the goal of demonstrating the efficacy and safety of a specific product, while academic studies may have a broader range of objectives, such as exploring different aspects of a disease or treatment. Both industry and academic clinical studies play a crucial roles in advancing medical knowledge. However, oversight is needed to limit bias in the goals of the clinical study validity and generalizability of research findings, and if used to support future medical device submissions.
An Early Feasibility study (EFS), feasibility, and pivotal studies each have a different purpose. EFS are performed before the larger controlled study and the FDA introduced a guidance titled “IDEs for Early Feasibility Medical Device Studies, including Certain First in Human Studies”, which explains how an early feasibility study can capture preliminary safety and effectiveness data in a small number of subjects. The benefits of this type of study are that it informs device design early in the process and results can inform a traditional design of the pivotal study.
A pivotal clinical study for a medical device is a larger controlled study designed to gather definitive evidence of the device’s safety and effectiveness for a specific intended use, typically in a statistically justified number of subjects. It’s typically a Phase III trial used to support regulatory approval, like a PMA submission to the FDA. The study’s results are crucial for demonstrating that the device’s benefits outweigh its risks and for obtaining regulatory approval to market the device. Pivotal studies are more focused on specific measurable outcomes for regulatory approval.
Figure 1. Decision Flow Chart – When are Studies Considered Exempt from an FDA IDE Submission
Exempt Studies
Exempt studies (Figure 1) are human subjects research deemed minimal risk or “non-significant risk” (NSR) clinical studies. NSR studies are subject to a more streamlined approval process and fewer regulatory controls than “significant risk” (SR) studies. A list of exempt studies that do not require an IDE are listed below:
- Commercial devices used in accordance with labeling
- Certain diagnostic devices
- Testing of consumer preference, of a modification, or of a combination of devices
- Not for the purpose of determining safety or effectiveness and not putting subjects at risk
- Veterinary devices
- Certain Software as a Medical Device (SaMD)
- Research on/with laboratory animals
- Custom devices as defined in 21 CFR 812.3(b)
Figure 2. Decision Flow Chart – When are Clinical Studies Not Exempt from an FDA IDE Submission
Non-Exempt Studies
Non-Significant Risk:
- Abbreviated IDE Requirements:
- Labeling (21 CFR 812.5)
- IRB Approval (21 CFR Part 56)
- Informed Consent (21 CFR Part 50)
- Monitoring (21 CFR 812.46)
- Records and Reports (21 CFR 812.140(b)(4)-(5), 812.150(b)(1)-(3) & (5)-(10))
- Annual and final progress report submission to FDA is not required
- Promotion (21 CFR 812.7)
The Institutional Review Board (IRB) serves as the FDA’s surrogate for review, approval, and continuing review of the NSR devices studies. An NSR device study may start at the institution as soon as the IRB reviews and approves the study. However, based on NAMSA’s experience, if the NSR clinical study data will be used to support a marketing application (e.g., 510(k), De Novo or PMA) then it is recommended that the FDA is given an opportunity to review your study protocol before the study is executed. It’s best practice to ensure that no surprises are discovered during the FDA’s review of your submission from your clinical study.
Not Exempt Studies – IDE Needed
Significant Risk:
- Full IDE requirements apply
- Presents a potential for serious risk to the health, safety, and welfare of a subject and is any of the following:
- An implant
- Used in supporting or sustaining human life
- Of substantial importance in diagnosing, curing, mitigating, or treating disease or preventing impairment of human health
- Otherwise poses potential for serious risk
The Sponsor is required to submit an IDE application to the FDA for review and a decision is rendered within 30 days. After both the FDA and IRB approve the investigation, the clinical study may begin.
Ref: 21 CFR 812.3(m)
IDEs and Collection of Real-World Data
Figure 3. IDEs and Collection of Real-World Data
The FDA recognizes that under the right conditions, data derived from real-world sources can be used to support regulatory decisions. In 2017, the FDA introduced a guidance titled “Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices – Guidance for Industry and Food and Drug Administration Staff” which highlights some of the potential uses of RWD, and describes the factors that the FDA considers when evaluating whether specific RWD is of sufficient quality to inform or support a regulatory decision. It also clarifies when an FDA IDE Submission may be needed to prospectively collect and use RWD for purposes of determining the safety and effectiveness of a device. In 2023, the FDA issued a draft guidance, “Use of Real-World Evidence to Support Regulatory Decision-Making For Medical Devices” which further expands the recommendations from the 2017 guidance, which remain in effect until this draft is finalized.
The FDA regulations 21 CFR 50, 56, and 812 apply to all clinical investigations of devices to determine safety and effectiveness, with limited exceptions.
- If the approved or cleared device is used in the normal course of medical practice, an IDE would likely not be required.
- An IDE may be required when RWD collection is intended to determine safety and effectiveness of a medical device and influences patient treatment decisions.
Roles of Sponsors, Investigators and IRBs
The Sponsor initiates the clinical study but does not actually conduct the investigation. The investigator conducts a clinical investigation under the Sponsor’s direction and the test article is administered, dispensed to, or used for a subject. The Institutional Review Board (IRB) reviews, approves (initially and continuously throughout the study) biomedical research at a given institution.
Sponsor Responsibilities
Responsibilities per 21 CFR 812 Subparts A, C
The Sponsor’s responsibilities encompass ensuring the trial’s ethical conduct, adherence to regulations, and accurate data collection.
Additional responsibilities:
- Obtaining IRB and FDA approval for study initiation and for resumption of terminated studies
- Submitting the IDE application to the FDA and any supplements, annual reports, and progress reports
- Ensuring the IRB, participating investigators, and the FDA are promptly informed of significant new information
- Secure compliance; evaluate and handle unanticipated adverse events effects
The Sponsor is responsible for ensuring the study is properly monitored. This includes selecting qualified personnel, preparing necessary documentation, and reporting any adverse events. Ultimately, the Sponsor remains accountable for the overall integrity and safety of the study, even when delegating certain tasks.
Sponsors are responsible for selecting qualified investigators and providing them with the necessary information and training to conduct the investigation properly. This includes obtaining investigator agreements.
Sponsors are responsible for the proper control of the devices used in a clinical study and this control encompasses multiple aspects, including device accountability, proper storage and handling, and adherence to established protocols and regulations.
Sponsors are required to comply with labeling requirements. The labeling must accurately represent the investigational device, including its intended use, warnings, and precautions. It should not make false or misleading claims about the device’s safety or effectiveness. This includes prohibition of promotion, import, and export requirements (Subpart A).
Responsibilities per 21 CFR 812 Subpart G
Sponsors for clinical studies for medical devices are responsible for maintaining accurate and complete records which include the following:
- All correspondence with investigators, monitors, IRBs and the FDA
- Financial disclosure information (investigator agreements)
- Device dispositions (return and destruction) of the investigational device
- Records concerning anticipated and unanticipated adverse events/device effects and complaints
Sponsors of medical device clinical studies are legally obligated to grant the FDA access to their establishments and records for inspections. This includes both access to and the ability to copy and verify any records and reports related to the clinical investigation. The FDA can inspect these records to ensure the study is conducted in compliance with applicable regulations.
During the duration of the clinical study, the Sponsor is responsible for preparing and submitting reports to the FDA, such as:
- Unanticipated adverse device effects
- Withdrawal of IRB approval
- Current Investigator list
- Progress reports
- Recall and device disposition
- Final report
- Failure to obtain informed consent
- Significant risk device determinations
Investigator Responsibilities
Responsibilities per 21 CFR 812 Subpart E
In medical device clinical studies, investigators bear significant responsibility for ensuring the study’s ethical conduct, participant safety, and data integrity. The investigator conducts the investigation per a signed agreement, investigational plan, the FDA regulations, and conditions of approval. They are responsible for the control of the investigational devices, supervising device use, and ensuring appropriate disposal of the device.
Investigators are responsible for obtaining informed consent from study participants and to ensure all participants understand the study’s purpose, risks, and benefits before agreeing to participate in the study.
Investigators are responsible for protecting the rights, safety, and welfare of subjects under their care, including for any adverse events.
Responsibilities per 21 CFR 812 Subpart G
The investigator is responsible for maintaining accurate and complete records from all aspects of the study, which includes:
- Correspondences
- Subject case history
- Case report forms, consents, medical records
- Device Disposition
- Adverse effects and complaints
- Protocol and amendments
Investigators of medical device clinical studies are legally obligated to grant the FDA access to their establishments and records for inspections.
During the duration of the clinical study, the investigator is responsible for preparing and submitting reports to the Sponsor and IRB, including:
- Unanticipated adverse device effects
- Withdrawal of IRB approval
- Progress reports
- Protocol deviations
- Final report
- Failure to obtain informed consent
Institutional Review Boards (21 CFR 56)
The purpose of the institutional review board is to protect the rights and welfare of human subjects involved in FDA-regulated investigations and investigations that support applications for research (e.g., IDEs) or marketing permits. They review the risk determination, review protocols and informed consent, review changes to protocols, and provide continuous review.
The IRB registration process involves electronically submitting information about the IRB, including its members and policies, to the Office for Human Research Protections (OHRP). This registration ensures the IRB is operating in accordance with ethical guidelines and federal regulations for protecting human subjects in research.
An IRB must comply with IRB (Part 56) and IDE (Part 812). The FDA performs periodic inspections of the IRB’s records and procedures to determine compliance with the regulations.
FDA Submissions After Approval
Expect changes to take place after your FDA Investigational Device Exemption has been approved. These changes may be simple modifications, such as clarifying the instructions for use, or they may be significant changes, such as modifications to the study design or the device materials. To help understand more about what changes require FDA interaction through a report or via supplements, refer to Changes or Modifications During the Conduct of a Clinical Investigation; Final Guidance for Industry and CDRH Staff. A list is provided below:
- Reports (21 CFR 812.150)
- Annual progress (also called IDE Annual)
- Unanticipated adverse device effects
- Enrollment and follow-up completion
- Withdrawal of IRB or FDA approval
- Current list of investigators
- Final report
- Supplements (21 CFR 812.35)
- Change in protocol
- Change in device
The IDE Application (21 CFR 812.20)
The Sponsor of a significant risk device study must submit a complete IDE application to the FDA. The following information must be included:
- Name and address of the Sponsor
- Report of prior investigations (21 CFR 812.27) and investigational plan (21 CFR 812.25)
- Manufacturing, processing, packing, and storage of device
- Investigator agreement (example, listing, certification)
- List of the name, address, and chairperson of each IRB
- Participating institutions
- Charge for device
- Environmental assessment
- Labeling
- Subject materials including informed consent
- Additional information requested by FDA
FDA Review of the Application
Once the IDE application is filed with the FDA, they will send an acknowledgement letter via email and assign an IDE # for tracking: GYYxxxx (e.g., G250001). The IDE will be sent to the appropriate review division based on the intended use of the device. The FDA will send a notification of who will be your Lead Reviewer, and, in the background, they will assemble a team of experts to review the application and make decisions/recommendations with management’s concurrence within 30 days. If all goes well, the FDA will issue a decision letter to the Sponsor.
Evaluating Benefits and Risks
All IDE studies involve risk. The FDA may request additional information (AI) or modifications to protect subjects. Prohibiting the investigation may also delay potential benefits of the technology for subjects in the study and future patients (a different kind of risk). The FDA recommends reviewing the guidance Factors to Consider When Making Benefit-Risk Determinations for Medical Device Investigational Device Exemptions – Guidance for Investigational Device Exemption Sponsors, Sponsor-Investigators and Food and Drug Administration Staff. The purpose of this guidance is to provide clarity to FDA staff and Sponsors regarding the principal factors that the FDA considers when assessing the benefits and risks of an IDE application for human clinical studies. Keep in mind, the Sponsor should mitigate risks to a level that allows a study to begin when appropriate.
FDA Decisions and Letters
Decisions:
- Approval
- Approves the trial for specific 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
- Enrollment can begin once IRB approval is obtained
- Disapproval
- Study may not begin
- Deficiencies will be listed
- Sponsor must address deficiencies and obtain FDA approval to start study
Mechanisms for Feedback from the FDA
It’s good practice to interact with the FDA early and throughout the IDE Submission process. The FDA has mechanisms available to Sponsors through the Q-Submission Program. There are multiple Q-submission types to take advantage of:
- Study Risk Determination
- Informational Meeting (no expectation of feedback)
- Submission Issue Request
- Pre-Submission
- Request for feedback from the FDA in the form of a written response or meeting on specific questions
It’s recommended to review relevant guidance and internet resources, specifically Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program.
In Summary
The FDA Investigational Device Exemption statue and regulations encourage discovery and development of medical devices while protecting public health and safety. An approved IDE application is needed to conduct a significant risk study of an unapproved device or new use of an approved device. Submission and review of a significant risk study under an IDE is subject to full IDE regulatory requirements, which are ongoing for the life of the IDE study, until officially closed. There are many opportunities available to receive feedback from and interact with the FDA before, during, and after submission of an IDE application.
Frequently Asked Questions (FAQs)
Are IDE records released to the public?
The FDA will not disclose the existence of an IDE unless one of the following is met:
- The FDA determines that the information had been previously disclosed to the public
- The FDA approves a PMA for a device subject to an IDE
- A notice of completion of a Product Development Protocol (PDP) is in effect
If the existence of an IDE file has not been publicly disclosed or acknowledged, no data or information in the file are available for public disclosure except for information on banned devices and a report of an adverse effect to an individual on whom an investigational device has been used. (§812.38)
Data or information contained in the file is not available for public disclosure before approval of an application for PMA or the effective date of a notice of completion of a PDP. Upon approval, the FDA will release a summary of the safety and effectiveness data on which the decision was based. Other disclosable information available after the device has been approved includes any protocol for a test or study, adverse reaction reports, and correspondence after confidential information has been deleted. Information available for public disclosure is outlined in 21 CFR 814 Premarket Approval of Medical Devices section §814.9.
Can I receive advice from the FDA on non-clinical (preclinical) testing and/or on my clinical protocol?
Yes. There are numerous guidance documents available from the FDA that provide recommendations on the non-clinical and clinical testing of specific device types. Additionally, the FDA accepts Pre-Submissions, in which you can submit information to them and receive advice on topics such as a non-clinical testing plan and/or a draft clinical protocol. Additional information on Pre-Submissions may be found in the FDA guidance “Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program.” The FDA’s guidance represents approach to this topic.
Additionally, there are two types of early collaboration meetings available that are discussed in the FDA guidance “Early Collaboration Meetings Under the FDA Modernization Act (FDAMA)“. These formal interactions (Determination Meetings and Agreement Meetings) are specific to clinical investigations and do not address non-clinical testing or protocols.
Can a foreign company submit an IDE or is a U.S. Sponsor required?
A foreign company cannot Sponsor an IDE; the company must have a U.S. agent who acts as the Sponsor (see 21 CFR 812.18(a)). The U.S. agent must fulfill all the responsibilities of a sponsor identified in the IDE regulations.
Do clinical studies have to be conducted in the U.S. or will foreign studies be accepted?
The FDA continues to promote global harmonization in many aspects of medical device development and regulation, including a commitment to recognize the value of and accept, where appropriate, data from multiple sources and countries.
For more information regarding the FDA’s acceptance of clinical data refer to the FDA guidance titled “FDA Acceptance of Clinical Data to Support Medical Device Applications and Submissions Frequently Asked Questions.”
Do the IDE regulations apply to in vitro diagnostic devices?
Many in vitro diagnostic (IVD) devices are exempt from the IDE regulations. Under section §812.2(c) of the IDE regulations, studies exempt from the IDE regulations include diagnostic devices if the testing meets the following requirements:
- Is noninvasive
- Does not require an invasive sampling procedure that presents significant risk
- Does not by design or intention introduce energy into a subject
- Is not used as a diagnostic procedure without confirmation by another medically established diagnostic product or procedure
IVD devices that are under study, including IVD devices that are exempt from the IDE regulations, must comply with labeling requirements under 21 CFR 809.10(c)(2). One of two statements is required, as applicable for each case: “For Research Use Only. Not for use in diagnostic procedures”, or “For Investigational Use Only. The performance characteristics of this product have not been established.”
Studies which are exempt from the requirements of the IDE regulations are not exempt from the requirements for IRB review and approval under Part 56 and the requirements for obtaining informed consent under Part 50. In addition, IDE exempt studies are not exempt from §812.119, Disqualification of a clinical investigator.
Additional guidance for in vitro diagnostic device studies can be found in the guidance “In Vitro Diagnostic (IVD) Device Studies – Frequently Asked Questions.”
Will insurance cover treatment with an investigational device?
For patients with Medicare, the Centers for Medicare and Medicaid Services (CMS) determines whether costs associated with routine care and the investigational devices are covered. To support this determination, the FDA categorizes IDE-approved devices based on whether available data demonstrates that initial questions of safety and effectiveness have been resolved. IDE-approved devices are assigned to one of two categories:
- Category A – Experimental
- Category B – Non-Experimental/Investigational
The FDA communicates the assigned category in a formal letter sent to the study Sponsor. The Sponsor submits the letter to CMS, which considers the FDA-assigned category and other factors to determine whether or not a device meets the requirements for Medicare coverage. The background and criteria associated with the FDA’s categorization process is described in the guidance document titled, “FDA Categorization of IDE Devices to Assist CMS with Coverage Decisions.”
For an IDE-approved device assigned to Category A, CMS may cover only routine care items and services, but not the cost of the device itself. For an IDE-approved device assigned to Category B, CMS may cover routine care items and services as well as the cost of the investigational device if specific criteria are met. If the criteria are not met for a Category B device, neither the device nor other elements of the study are covered by Medicare. To review the criteria and process for requesting coverage for an IDE, the IDE Sponsor may refer to their website (Medicare Coverage Related to Investigational Device Exemption (IDE) Studies).
