Content and Format of an Investigational Device Exemption (IDE) Application

  1. General Information
  2. Exceptions to the Requirement for the Submission of an IDE application to the FDA
  3. Phases of Device Studies
  4. Feasibility studies
  5. Pivotal studies
  6. 510(k) devicestudies
  7. PMA device studies
  8. FDA Administrative Actions
  1. Effective date of FDA acceptance of an IDE application
  2. Notice of disapproval or withdrawal
  3. Prohibition of Promotion of Investigational Devices and Other Practices
  1. IDE Application: Content and Format
  2. Sponsor Name and Address
  3. Overall Clinical Plan
  4. Report of Prior Investigations of the Device
  5. Investigational Plan
  1. Purpose
  2. Clinical protocol
  3. Content of clinical protocol – Feasibility study
  4. Content of clinical protocol – Pivotal studies
  5. Risk analysis
  6. Description of the device
  7. Monitoring procedures
  8. Labeling
  9. Consent materials
  10. IRB information
  11. Other institutions
  12. Additional records and reports
  13. Method, Facilities and Controls Information
  14. Investigator Agreements
  15. Certification of Investigator Agreement
  16. Reviewing IRBs
  17. Other Involved Institutions
  18. Device Charges
  19. DeviceLabeling
  1. Labeling of investigational devices
  2. Content
  3. Prohibitions
  4. Labeling of In Vitro Diagnostic Devices
  5. Consent Materials
  6. Other Relevant Information
  1. Supplemental IDE Applications
  2. Changes in the Investigational Plan
  1. Changes effected for emergency use
  2. Changes effected with subsequent (i.e., within 5 days) FDA notice
  3. Developmental changes
  4. Clinical protocol changes
  5. Changes submitted in the annual report
  6. Additional IRBApprovals
  1. IRB approval for new facilities
  2. IRB approval of changes addressed in a Supplemental IDE Application
  1. General Information
  1. Exceptions to the Requirement for the Submission of an IDE application to the FDA[1]

All clinical investigations directed at determining the safety and effectiveness of devices require the submission and FDA acceptance of an IDE application with the following exceptions:

  1. Non-significant Risk Device Studies: A clinical investigation of the safety and/or effectiveness of a device, which does not meet the criteria for a “significant risk device study”[2], is exempt from the submission of a IDE application; provided that the device is not a banned device and the sponsor:
  1. Complies with theLabeling of Investigational Device requirements;
  1. Obtains IRB approval of the clinical investigation after presenting the reviewing IRB with a brief explanation of why the device and its proposed use in the investigation does not constitute a “significant risk device study”, and maintains IRB approval throughout the investigation;
  1. Ensures that each Investigator participating in the investigation of the device obtains, from each subject under the Investigator’s care, written informed consent approved by the reviewing IRB (i.e., unless the reviewing IRB waives the requirement for a written informed consent form);
  1. Complies with the requirements for monitoring of ongoing investigations (see Sponsor Responsibilities: Non-Significant Risk Device Studies);
  1. Maintains required Sponsor records and makes required Sponsor reports (see Sponsor Responsibilities: Non-Significant Risk Device Studies);
  1. Ensures that participating Investigators maintain required Investigator records and make required Investigator reports (see Investigator Responsibilities: Non-Significant Risk Device Studies; and
  1. Complies with provisions addressing Prohibition of Promotion of Investigational Devices and Other Practices (21 CFR Part 812.7)
  1. A device, other than a transitional device[3], in commercial distribution immediately before May 28, 1976, when used or investigated in accordance with the respective labeling indications in effect at that time.
  1. A device, other than a transitional device, introduced into commercial distribution on or after May 28, 1976 which the FDA has determined to be substantially equivalent to a device in commercial distribution immediately before May 28, 1976, and that is used or investigated in accordance with the indications in the FDA-accepted product labeling.
  1. An in vitro diagnostic device, if the Sponsor complies with Labeling of In Vitro Diagnostic Device requirements and if the testing:
  1. is noninvasive[4];
  1. Does not require an invasive sampling procedure that presents significant risk;
  1. Does not by design or intention introduce energy into a subject; and
  1. Is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure.
  1. A device undergoing consumer preference testing, testing of a modification, or testing of a combination of two or more devices in commercial distribution, if the testing is not for the purpose of determining the safety or effectiveness of the device and does not put subjects at risk.
  1. A custom device[5], unless the clinical investigation is for the purpose of determining the safety and effectiveness of the custom device for potential commercial distribution.
  1. Phases of Device Studies

The clinical investigation of the safety and/or effectiveness of a non-approved device is typically divided into two phases, Feasibility Studies and Pivotal Studies. A FDA-mandated, clinical investigation of adevice following its FDA approval is a Post-Marketing Study.

  1. Feasibility Studies. Feasibility (pilot or proof-of-concept) studies of an non-approved device represent the initial human experience with the device and typically involve one Investigator at one site with a limited number of subjects (e.g., 10 or less). Data from the feasibility study will not be considered as pivotal evidence of safety and effectiveness but rather as a basis to finalize and confirm the device design and determine its potential for further development.
  1. Pivotal Studies. The conduct of Pivotal (multi-center) studies of a non-approved device may be for the purpose of obtaining the FDA’s approval to market the device as a 510(k) device or to obtain FDA’s approval of a Pre-Market Application (PMA) for the device.
  1. 510(k) device studies: The primary purpose of Pivotal studies directed at obtaining the FDA’s approval to market a non-approved device as a 510(k) device is to validate that the product performs in an equivalent manner to another legally marketed (i.e., predicate) device. Substantial equivalence between the devices may be demonstrated through side-by-side comparisons of the device or pilot studies with the non-approved device alone.
  1. PMA device studies: The primary purpose of Pivotal studies directed at obtaining the FDA’s approval of a PMA for a device is to demonstrate, based on valid scientific evidence, reasonable assurance of the safety and effectiveness of the device for its proposed labeling indication.
  1. FDA Administrative Actions[6]
  1. Effective date of FDA acceptance of an IDE application. An IDE goes into effect:
  1. Thirty (30) days after the FDA receives the IDE application(i.e., unless the FDA notifies the sponsor that the clinical investigation of the device may not begin) orupon earlier notification from the FDA that it has approved, by order, the IDE for the clinical investigation.
  • The FDA will notify the sponsor in writing of the date it receives the IDE application.
  1. A sponsor shall not begin a clinical investigation of a device for which the FDA’s approval of an IDE application is required until the IDE application goes into effect.[7]
  1. Notice of disapproval or withdrawal.

If FDA disapproves an IDE application or proposes to withdraw its approval of an IDE application, FDA will notify the sponsor in writing.

  1. A disapproval order will contain a complete statement of the reasons for disapproval and a statement that the sponsor has the opportunity to request a hearing (i.e., in accordance with FDA’s proceedings on hearings).
  1. A notice of proposed withdrawal of approval will contain a complete statement of the reasons for withdrawal and a statement that the sponsor has the opportunity to request a hearing (i.e., in accordance with FDA’s proceedings on hearings).
  • FDA will provide the opportunity for a hearing before withdrawal of approval, unless FDA specifies in the notice that continuation of testing under the IDE will result in an unreasonable risk to public health and orders withdrawal of approval before any hearing.
  1. Prohibition of Promotion of Investigational Devices and Other Practices[8]

A sponsor, investigator, or any person acting for or on behalf of a sponsor or investigator shall not:

  1. Promote or test market an investigational device until after the FDA has approved the device for commercial distribution;
  1. Commercialize an investigational device by charging the subjects or investigators for a device at a price larger than that necessary to recover costs of manufacture, research, development, and handling;
  1. Unduly prolong an investigation. If data developed by investigation indicate in the case of a class III device that premarket approval cannot be justified or in the case of a class II device that it will not comply with an applicable performance standard or an amendment to that standard, the sponsor shall promptly terminate the device investigation.
  1. Represent that an investigational device is safe or effective for the purpose for which it is being investigated.
  1. IDE Application: Content and Format[9]

An IDE application shall include, in the following order:

  1. Sponsor Name and Address

B.Overall Clinical Plan

A Clinical Plan (about one page) should be included in the initial IDE application submission and updated as necessary. The Clinical Plan should include a brief description (i.e., not a complete protocol) of each of the clinical studies (e.g., feasibility, pilot, pivotal/comparative) of the device currently planned.

The Clinical Plan should summarize, for each planned clinical study, the:

1.Descriptive title

2.Student design, including whether concurrent or non-current controls will be used

3.Sample size

4.Primary outcome measures

5.Principal results (achieved or expected)

C.Report of Prior Investigations of the Device[10]

The Report of Prior Investigations shall include reports of all prior clinical, animal, and laboratory testing of the device and shall be comprehensive and adequate to justify the proposed clinical investigation of the device.

Specific contents of the report must include:

1.A bibliography of all publications, whether adverse or supportive, that are relevant to an evaluation of the safety or effectiveness of the device;

2.Copies of all published and unpublished adverse information;

3.Copies of other significant publications if requested by the FDA or the responsible IRB;

4.A summary of all other unpublished information (whether adverse or supportive) in the possession of, or reasonably obtainable by, the sponsor that is relevant to an evaluation of the safety or effectiveness of the device; and

5. If nonclinical laboratory data are provided, a statement that such studies have been conducted in compliance with applicable provisions of the FDA’s Good Laboratory Practice (GLP) regulations (21CFRPart 58), or if any such study was not conducted in compliance with the GLP regulations, a brief statement of the reason for the noncompliance.

  • Note: Failure or inability to comply with the GLP regulations in the conduct of a relevant nonclinical study of a device does not obviate the requirement to provide, in the IDE application, information obtained from the respective study.

D.Investigational Plan[11]

To include, in the following order[12]:

1.Purpose. The name and intended use of the device and the objectives and duration of the investigation.

2.Clinical protocol. A written protocol describing the methodology to be usedand an analysis of the protocol demonstrating that the clinical investigation is scientifically sound. A blank copy of the corresponding Case Report Form (CRF) should also be included under this section of the IDE submission.

a.Content of clinical protocol - Feasibility study[13]

The clinical protocol for a limited Feasibility (or pilot) study of a device is, in general, less ambitious than the clinical protocol(s) for Pivotal studies; the latter being directed at demonstrating reasonable assurance of safety and effectiveness the device. (E.g., the protocol for a Feasibility study may not include comparison of the use of the device with a control, as is required for Pivotal studies of the device.) The clinical protocol for a Feasibility study should, however, have an objective and be reasonably defined; and, where applicable, should address and account for critical safety concerns.

b.Content of clinical protocol - Pivotal studies[14]

The FDA relies upon only valid scientific evidence to determine whether there is reasonable assurance that the device is safe and effective for its proposed labeling indication. Valid scientific evidence used to determine the effectiveness of a device shall consist of one or more well-controlled investigation(s) of the device unless the FDA has determined that the requirement for

a well-controlled investigation is not reasonably applicable to the device. In the latter situation, the FDA may authorize reliance upon other valid scientific evidence[15] which the FDA has determined is sufficient evidence from which to determine the effectiveness of the device (i.e., in the absence of well-controlled investigation). The clinical protocol for, and the report of the results of, a well-controlled investigation shall include the following:

(i)A clear statement of the objectives of the study.

(ii)A method of selection of the subjects that:

  • Provides adequate assurance that the subjects are suitable for the purpose of the study;
  • Provides diagnostic criteria of the condition to be treated or diagnosed and, where appropriate, confirmatory laboratory tests;
  • Provides (i.e., in the case of a device intended to prevent a disease or condition) evidence of susceptibility and exposure to the condition against which prophylaxis is desired;
  • Assigns the subjects to test groups, if used , in such as way as to minimize any potential bias; and
  • Assures comparability between test groups and any control groups of pertinent variables such as sex, severity or duration of the disease, and use of therapy other than the test device.

(iii)An explanation of the methods of observation and recording of results utilized, including the variables measured, quantitation, assessment of any subject’s response, and steps taken to minimize any possible bias of subjects and observers.

(iv)A comparison of the results of treatment or diagnosis with a control in such a fashion as to permit quantitative evaluation. The precise nature of the control must be specified and an explanation provided of the methods employed to minimize any possible bias of the observers and analysts of the data. Level and methods of “blinding”, if appropriate and used, are to be documented. Generally, four types of comparisons are recognized:

  • No treatments. Where objective measurements of effectiveness are available and placebo effect is negligible, comparison of the objective results in comparable groups of treated and untreated patients.
  • Placebo controlled. Where there may be a placebo effect with the use of a device, comparison of the results of the use of the device with an ineffective device used under conditions designed to resemble the conditions of use under investigation as far as possible.
  • Active treatment control. Where an effective regimen of therapy may be used for comparison; e.g., the condition being treated is such that the use of a placebo or the withholding of treatment would be inappropriate or contrary to the interest of the patient-subject.
  • Historical control. In certain circumstances, such as those involving diseases with high and predictable mortality or signs and symptoms of predictable duration or severity, or in the case of prophylaxis where morbidity is predictable, the results of use of the device may be compared quantitatively with prior experience historically derived from the adequately documented natural history or the disease or condition in comparable patients or populations who received no treatment or who followed an established effective regimen (i.e., therapeutic, diagnostic, prophylactic).

(v)A summary of the methods of analysis and an evaluation of the data derived from the study, including any appropriate statistical methods utilized.

3.Risk analysis. A description and analysis of all increased risks to which subjects will be exposed by the investigation; the manner in which these risks will be minimized; a justification for the clinical investigation; and a description of the patient population, including the number, age, sex, and condition.

4.Description of the device. A description of each important component, ingredient, property, and principle of operation of the device and of each anticipated change in the device during the course of the investigation of the device to determine its safety and effectiveness.

5.Monitoring procedures.The sponsor’s written procedures for monitoring the clinical investigation of the device and the name and address of any monitor to be utilized in this capacity.

6.Labeling. Copies of all labeling for the device (see Device Labeling).

7.Consent materials. Copies of all forms and informational materials to be provided to subjects to obtain their informed consent.

8.IRB information. A list of the names, locations, and chairpersons of all IRBs that have been or will be asked to review the clinical investigation, and a certification of any action taken by those IRBs will respect to the clinical investigation.

9.Other institutions.The name and address of each institution at which a part of the clinical investigation of the device may be conducted and which has not been prior identified under IRB information, above.

10.Additional records and reports. A description of any records and reports that will be maintained on the investigation in addition to the reports required by FDA regulation (see RequiredRecords and Reports).

E.Method, Facilities and Controls Information

To include a description of the methods, facilities and controls used for the manufacture, processing, packing, storage, and, where appropriate, installation of the device; provided in sufficient detail so that a person generally familiar with the FDA’s good manufacturing practice (i.e., Quality System) standards can make a knowledgeable judgment about the quality control used in the manufacture of the device.

F.Investigator Agreements

To include an example (see IDE Template: Investigator Agreement) of the agreement to be entered into by all investigators so as to address compliance with InvestigatorResponsibilities for device investigations, and a list of all investigators who have signed the agreement to date.

G.Certification of Investigator Agreement

To include a certification that (i) all investigators who participate in the investigation have signed an Investigator Agreement; (ii) that the list of investigators provided under E. Investigator Agreements, above, includes all of the investigators participating in the clinical investigation of the device; and (iii) that no investigators will be added to the clinical investigation of the device until they have signed an Investigator Agreement.

H.Reviewing IRBs

Include a list of the name, address, and chairperson of each IRB that has been or will be asked to review the clinical investigation of the device and a certification of the action concerning the device investigation taken by each such IRB.