- Significant Risk Device
- Nonsignificant Risk Device
- IDE Exempt Investigations
- Who Must Apply for an IDE
- When to Apply
- Pre-Submission Process
- FDA Action on IDE Applications
Investigations covered under the IDE regulation are subject to differing levels of regulatory control depending upon the level of risk. The IDE regulation distinguishes between significant and nonsignificant risk device studies and the procedures for obtaining approval to begin the study differ accordingly. Also, some types of studies are exempt from the IDE regulations.
A significant risk device presents a potential for serious risk to the health, safety, or welfare of a subject. Significant risk devices may include implants, devices that support or sustain human life, and devices that are substantially important in diagnosing, curing, mitigating or treating disease or in preventing impairment to human health. Examples include sutures, cardiac pacemakers, hydrocephalus shunts, and orthopedic implants. Guidance on distinguishing between significant risk and nonsignificant risks studies are outlined in the document 'Significant Risk and Nonsignificant Risk Medical Device Studies'.
Studies of devices that pose a significant risk require both FDA and an Institutional Review Board (IRB) approval prior to initiation of a clinical study. FDA approval is obtained by submitting an IDE application to FDA (§812.20).
In order to conduct a significant risk device study, a sponsor must:
- submit a complete IDE application (§812.20) to FDA for review and obtain FDA approval of the IDE;
- select qualified investigators, provide them with all necessary information on the investigational plan and report of prior investigations, and obtain signed investigator agreements from them.
Upon receipt of an IDE application, sponsors are notified via email of the date that FDA received the original application and the IDE number assigned. An IDE application is considered approved 30 days after it has been received by the FDA, unless the FDA otherwise informs the sponsor via email prior to 30 calendar days from the date of receipt, that the IDE is approved, approved with conditions, or disapproved. In cases of disapproval, a sponsor has the opportunity to respond to the deficiencies and/or to request a regulatory hearing under 21 CFR Part 16.
Once an IDE application is approved, the following requirements must be met in order to conduct the investigation in compliance with the IDE regulations:
- Labeling - The device must be labeled in accordance with the labeling provisions of the IDE regulations (§812.5) and must bear the statement "CAUTION - Investigational Device. Limited by Federal (or United States) law to investigational use."
- Distribution - Investigational devices can only be distributed to qualified investigators §812.43(b).
- Informed Consent - Each subject must be provided with and sign an informed consent form before being enrolled in the study. 21 CFR 50, Protection of Human Subjects, contains the requirements for obtaining informed consent.
- Monitoring - All investigations must be properly monitored to protect the human subjects and assure compliance with approved protocols under §812.46.
- Prohibitions - Commercialization, promotion, and misrepresentation of an investigational device and prolongation of the study are prohibited (§812.7).
- Records and Reports - Sponsors and investigators are required to maintain specified records and make reports to investigators, IRBs, and FDA (§812.140 and §812.150).
Nonsignificant risk devices are devices that do not pose a significant risk to the human subjects. Examples include most daily-wear contact lenses and lens solutions, ultrasonic dental scalers, and Foley catheters.
A nonsignificant risk device study requires only IRB approval prior to initiation of a clinical study. Sponsors of studies involving nonsignificant risk devices are not required to submit an IDE application to the FDA for approval. Submissions for nonsignificant device investigations are made directly to the IRB of each participating institution. Sponsors should present to the reviewing IRB an explanation why the device does not pose a significant risk. If the IRB disagrees and determines that the device poses a significant risk, the sponsor must report this finding to the FDA within five working days [§812.150(b)(9)]. The FDA considers an investigation of a nonsignificant risk device to have an approved IDE when the IRB concurs with the nonsignificant risk determination and approves the study.
The sponsor also must comply with the abbreviated IDE requirements under §812.2 (b):
- Labeling - The device must be labeled in accordance with the labeling provisions of the IDE regulations (§812.5) and must bear the statement "CAUTION - Investigational Device. Limited by Federal (or United States) law to investigational use.";
- IRB Approval – The sponsor must obtain and maintain Investigational Review Board (IRB) approval throughout the investigation as a nonsignificant risk device study;
- Informed Consent – The sponsor must assure that investigators obtain and document informed consent from each subject according to 21 CFR 50, Protection of Human Subjects, unless documentation is waived by an IRB in accordance with §56.109(c);
- Monitoring - All investigations must be properly monitored to protect the human subjects and assure compliance with approved protocols (§812.46). Guidance on monitoring investigations can be found in Guideline for the Monitoring of Clinical Investigations.
- Records and Reports - Sponsors are required to maintain specific records and make certain reports as required by the IDE regulations.
- Investigator Records and Reports – The sponsor must assure that participating investigators maintain records and make reports as required (see Responsibilities of Investigators); and
- Prohibitions –Commercialization, promotion, test marketing, misrepresentation of an investigational device, and prolongation of the study are prohibited (§812.7).
All clinical investigations of devices must have an approved IDE or be exempt from the IDE regulations. Investigations that are exempted from 21 CFR 812 are described in §812.2(c) of the IDE regulations. Studies exempt from the IDE regulations include:
- a legally marketed device when used in accordance with its labeling
- a diagnostic device if it complies with the labeling requirements in §809.10(c) and if the testing:
- is noninvasive;
- does not require an invasive sampling procedure that presents significant risk;
- does not by design or intention introduce energy into a subject; and
- is not used as a diagnostic procedure without confirmation by another medically established diagnostic product or procedure;
Additional guidance for an in vitro diagnostic device studies can be found in "Regulating In Vitro Diagnostic Device (IVD) Studies."
- consumer preference testing, testing of a modification, or testing of a combination of devices if the device(s) are legally marketed device(s) [that is, the devices have an approved PMA, cleared Premarket Notification 510(k), or are exempt from 510(k)] AND if the testing is not for the purpose of determining safety or effectiveness and does not put subjects at risk;
- a device intended solely for veterinary use;
- a device shipped solely for research with laboratory animals and contains the labeling "CAUTION – Device for investigational use in laboratory animals or other tests that do not involve human subjects."
Depending upon the nature of the investigation, those studies which are exempt from the requirements of the IDE regulations may or may not be exempt from the requirements for IRB review and approval under Part 56 and the requirements for obtaining informed consent under Part 50. For guidance regarding the applicability of these regulations with respect to investigations being conducted under the provisions of §812.2(c), contact the reviewing IRB and/or the CDRH IDE Staff at (301) 796-5640 or CBER’s Office of Communication, Outreach and Development (OCOD) at 301-827-1800.
The sponsor of the clinical trial is responsible for submitting the IDE application to the FDA (§812.40) and obtaining Institutional Review Board (IRB) approval before the study can begin. Foreign companies wanting to conduct a clinical study in the U.S. MUST have a U.S. sponsor (§812.18). Under certain circumstances, the clinical investigator may wish to submit an IDE and would, therefore, also act as the sponsor of the study.
Study approval must be obtained PRIOR to enrolling patients at the study site. Each site must have approval from the reviewing IRB for that site prior to beginning the study. For significant risk device studies, in addition to IRB approvals, the sponsor must also have an approved IDE from FDA prior to beginning the study at any site. The review of applications by the FDA and the IRBs are independent and, therefore, may be submitted simultaneously.
Sponsors are encouraged to contact the FDA to obtain further guidance prior to the submission of an IDE application. This is especially beneficial to new sponsors who have not previously had contact with the Agency and for sponsors proposing to study new technologies or new uses for existing technologies. Early interaction with the Agency will help increase the sponsor's understanding of the FDA requirements, regulations, and guidance documents, and will allow FDA personnel to better understand the new technologies. Increased interaction between the FDA and sponsors will speed the regulatory process and minimize delays in the development of useful devices intended for human use.
Please refer to the final guidance “Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff.”
Formal Guidance Meetings
There are two types of Formal Guidance Meetings:
Determination Meeting - A sponsor or applicant anticipating the submission of a PMA may submit a written request to discuss the type of valid scientific evidence that will be necessary to demonstrate that the device is effective for its intended use. This meeting is to focus on the broad outline of clinical trial design. The request and summary information for a meeting should be submitted as a pre-submission and identified as a determination meeting request. FDA’s determination is provided to the applicant via email within 30 days following the meeting.
Agreement Meeting - A sponsor or applicant may submit a written request for a meeting to reach an agreement with FDA regarding FDA's review of an investigational plan (including a clinical protocol). The request and summary information should be submitted as a pre-submission and identified as an agreement meeting request. This meeting should take place no later than 30 days after receipt of the request. The written request should include a detailed description of the device, a detailed description of the proposed conditions of use of the device, a proposed plan (including a clinical protocol) for determining whether there is a reasonable assurance of effectiveness, and, if available, information regarding the expected performance of the device. If an agreement is reached between FDA and the sponsor or applicant regarding the parameters of an investigational plan (including a clinical protocol), the terms of the agreement are put in writing and made part of the administrative record by FDA.
Additional information regarding Determination and Agreement meetings can be found in the guidance document "Early Collaboration Meetings Under the FDA Modernization Act (FDAMA), Final Guidance for Industry and CDRH Staff"
Approval or Disapproval §812.30
FDA will notify the sponsor via email of the date it receives an IDE application. FDA may approve, approve with modification, or disapprove an IDE application. FDA may request additional information about an investigation. The sponsor may provide the requested information or the sponsor may treat such a request as a disapproval of the application and request a hearing in accordance with 21 CFR 16. The clinical investigation may begin after FDA and the IRB approves an IDE for the investigation. An investigation may begin 30 days after FDA receives the IDE application for the investigation of a device if IRB approval has been obtained unless FDA notifies the sponsor that the investigation may not begin.
Grounds for disapproval or withdrawal
FDA may disapprove or withdraw approval of an IDE application if FDA finds that:
- The sponsor has not complied with applicable requirements of the IDE Regulations, any other applicable regulations or statutes, or any condition of approval imposed by an IRB or the FDA.
- The application or a report contains untrue statements or omits required material information.
- The sponsor fails to respond to a request for additional information within the time prescribed by the FDA.
- There is reason to believe that the risks to the human subjects are not outweighed by the anticipated benefits to the subjects or the importance of the knowledge to be gained.
- The informed consent is inadequate.
- The investigation, as proposed, is scientifically unsound.
- There is reason to believe that the device as used is ineffective.
- It is unreasonable to begin or to continue the investigation due to the way in which the device is used or the inadequacy of:
(i) the report of prior investigations or the investigational plan; (ii) the methods, facilities, and controls used for the manufacturing, processing, packaging, storage, and, where appropriate, installation of the device; or (iii) the monitoring and review of the investigation.
For more information, see the draft guidance “FDA Decisions for Investigational Device Exemption (IDE) Clinical Investigations.” FDA’s draft guidance represents FDA’s current approach to this issue.
Notice of Disapproval or Withdrawal
If FDA disapproves an IDE application or proposes to withdraw approval, FDA will notify the sponsor via email. A disapproval order will contain a complete statement of the reasons for disapproval and will advise the sponsor of the right to request a regulatory hearing under 21 CFR 16. FDA will provide an opportunity for a hearing before withdrawal of approval unless FDA determines that there is an unreasonable risk to the public health if testing continues.
Grounds for Clinical Hold
FDA may prohibit the sponsor of an investigation from conducting the investigation (referred to ‘clinical hold’) if an approved IDE represents an unreasonable risk to the safety of the persons who are the subjects of the clinical investigation, taking into account the qualifications of the clinical investigators, information about the device, the design of the clinical investigation, the condition for which the device is to be investigated, and the health status of the subjects involved.
The sponsor of an IDE that is on clinical hold may request by writing to FDA to remove the clinical hold. Any such request shall include sufficient information to support the removal of such clinical hold.