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 following information must be included in an IDE application for a significant risk device investigation. A sponsor cannot begin a significant risk device investigation until FDA and IRB approval are granted. Three copies of a signed IDE application are required and the application must include the following in the order provided (§ 812.20):

1. Name and address of sponsor;

 

2. Report of prior investigations (§ 812.27);


A report of prior investigations must include reports of all prior clinical, animal, and laboratory testing of the device. It should be comprehensive and adequate to justify the proposed investigation.

Specific contents of the report must include:

• a bibliography of all publications, whether adverse or supportive, that are relevant to an evaluation of the safety and effectiveness of the device;
• copies of all published and unpublished adverse information;
• copies of other significant publications if requested by an IRB or FDA;
• a summary of all other unpublished information (whether adverse or supportive) that is relevant to an evaluation of the safety and effectiveness of the device; and
• if nonclinical laboratory data are provided, a statement that such studies have been conducted in compliance with the Good Laboratory Practice (GLP) regulation in 21 CFR Part 58. If the study was not conducted in compliance with the GLP regulation, include a brief statement of the reason for noncompliance.



3. Investigational plan (§812.25)

   The investigational plan shall include the following items in the following order:

   • purpose (the name and intended use of the device and the objectives and duration of the investigation);
   • protocol (a written protocol describing the methodology to be used and an analysis of the protocol demonstrating its scientific soundness);
   • risk analysis (a description and analysis of all increased risks to the research subjects and how these risks will be minimized; a justification for the investigation; and a description of the patient population including the number, age, sex, and condition);
   • description of this device (a description of each important component, ingredient, property, and principle of operation of the device and any anticipated changes in the device during the investigation);
   • monitoring procedures (the sponsor's written procedures for monitoring the investigation and the name and address of each monitor; see "Guideline for the Monitoring of Clinical Investigations" for a more detailed discussion); and
   • additional records and reports (a description of any records or reports of the investigation other than those required in Subpart G of the IDE regulation).

4. A description of the methods, facilities, and controls used for the manufacture, processing, packing, storage, and installation of the device;

5. An example of the agreement to be signed by the investigators and a list of the names and addresses of all investigators. Information that must be included in the written agreement are found in § 812.43;

6. 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.

7. 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 (when available);

8. The name and address of any institution (other than those above) where a part of the investigation may be conducted;

9. The amount, if any, charged for the device and an explanation of why sale does not constitute commercialization;

10. Please note that an environmental assessment as required under 21 CFR 25.40 or a claim for categorical exclusion under 21 CFR 25.30 or 25.34 is no longer required. [§25.34(g)];

11. Copies of all labeling for the device;

12. Copies of all informed consent forms and all related information materials to be provided to subjects as required by 21 CFR 50, Protection of Human Subjects; and

13. Any other relevant information that FDA requests for review of the IDE application.
    Information previously submitted to FDA in accordance with Part 812 may be incorporated by reference.

It is recommended that the cover letter include the following information in the order provided to assist in the administrative processing of the application.

1. Statement that the information provided is an original IDE submission.

 
2. Device Information:
   
   
   • Device Name
   • Intended Use
   
   
3. Sponsor contact information:
   
   
   • Name
   • Address
   • Contact Person
   • Telephone Number
   • Fax
   
   Please note that the sponsor MUST be located in United States [21 CFR 812.18(a)].
   


4. Manufacturer Information:
   
   
   • Name
   • Address
   • Contact Person
   • Telephone Number
   • Fax
   
   
5. Applicant Information:
   
   If the organization submitting the application is not the sponsor, such as a consultant or a lawyer, include contact information for the applicant organization or individual.



6. Provide the following information, if applicable:

   Pre-IDE/Pre-IDE meetings.

   Describe any discussions with the FDA reviewing division regarding this device. If a Pre-IDE was submitted, state the Pre-IDE number and the name of FDA reviewer, if known. If a Pre-IDE meeting occurred, provide the name of the FDA contact person and a copy of the meeting minutes.

7. Waiver Requests.

Identify any requests for waivers and include a justification for the waiver.

8. 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.

In order to facilitate FDA's handling of IDE applications, the following recommendations are offered:

• Use paper with nominal dimensions of 8 1/2" by 11".
• Use at least a 1 1/2" wide left margin to allow for binding into jackets.
• Use 3-hole punched paper to allow for binding into jackets.
• If the submission exceeds 2" in thickness, separate into volumes and identify volume number.
• Clearly and prominently identify submission as original IDE application or, for additional submissions to an IDE application, clearly identify the FDA assigned document number (e.g., G960000) and the reason for the submission (e.g., amendment or supplement) and the type of submission (e.g., Response to FDA letter; Addition of New Institution, etc.).
• All copies of each submission must be identical.
• Do not combine IDEs, PMAs and 510(k)s together; they must be separate submissions.
• Unless the IDE sponsor has provided authorization in writing for another person to submit information on the sponsor's behalf, only the IDE sponsor may amend, supplement, or submit reports to the IDE.
• Sequentially number the pages, providing a detailed table of contents, and use tabs to identify each section. This will help to facilitate the review of your submission.

Common Problems With Original IDE Applications

The sponsor should assure that the device, all preclinical testing, and the investigational plan are described and provide adequate justification for the initiation of the clinical trial. Submitters should avoid submitting the IDE application prematurely. There are three common areas that are frequently deficient in IDE applications.

• Inadequate report of prior investigations
• Inadequate investigational plan
• Inadequate/incomplete design and manufacture

A report of prior investigations must include reports of all prior clinical, animal, and laboratory testing of the device. It should be comprehensive and adequate to justify the proposed investigation.

1. Laboratory Studies
   
   
   • inadequate description of methods
   • inadequate or no summary or conclusion
   • conclusions not supported by data
   
   
2. Reports of Animal Studies
   
   
   • no rationale for animal selection
   • no statistical justification for the number of animals selected
   • inappropriate duration or follow-up
   • failure to address compliance with Good Laboratory Practices for Nonclinical Studies, 21 CFR 58
   
   
3. Reports of Prior Publications
   
   
   • incomplete searches
   • copies of relevant publications not included
   • omission of adverse information
   • failure to identify relevant parts or information and to summarize
    

Common deficiencies with investigational plan

• questionable scientific soundness
• failure to clearly develop or define study objectives
• inadequate description of the protocol
• failure to identify all risks
• failure to develop proper monitoring procedures

Design

Inadequate characterization or description of the device and its operation due to inadequate or omitted:

• Design/engineering drawing of device
• Rationale for device design
• Device and performance specifications
• Description of materials (including biocompatibility information)
• Description of function - how does device and/or components/subsystems work together to achieve desired function
• Validation testing for subsystems and main system

Manufacture

Inadequate or missing description of the controls used to ensure that the devices are produced consistently and as designed.

Following is a suggested checklist that submitters may use to ensure that their original IDE application is administratively complete. The first section is a screening to determine whether an IDE application is required to be submitted to FDA. The next section is the information suggested to be included in the cover letter or cover page of the IDE application. Inclusion of this information should help speed FDA's administrative processing of the application. The last section is a checklist to ensure that all the information required by regulation is addressed in the application.

Screening Information - Is an IDE application to FDA necessary?

Checklist for an IDE Application

Address for IDE Applications

Changes in investigational plan that require prior approval (§ 812.35)

A sponsor must obtain approval of a supplemental application and IRB approval (when appropriate under conditions described in §56.110 and §56.111 prior to implementing a change to an investigational plan except in situations described below. If a sponsor intends to conduct an investigation that involves an exception to informed consent under §50.24 (see Informed Consent), the sponsor must submit a separate investigational device exemption (IDE) application [§812.20(a)].

FDA believes that the following types of protocol changes would require an approved IDE supplement because they are likely to have a significant effect on the scientific soundness of the trial design and/ or validity of the data resulting from the trial:

• change in indication,
• change in type or nature of study control,
• change in primary endpoint,
• change in method of statistical evaluation, and
• early termination of the study (except for reasons related to patient safety).

In addition, FDA believes that expanding the study by increasing either the number of investigational sites or the number of study subjects participating in a clinical investigation affects the rights, safety, and welfare of the subjects. Therefore, the study may not be expanded without submission and approval of an IDE supplement.

The IDE supplement should be identified with the IDE number on the cover sheet and submitted in triplicate. The outside wrapper of the submission should identify the contents as "Supplemental IDE."

Changes that do not require prior FDA approval.

The sponsor of an IDE may modify the device and/or clinical protocol without approval of a new application or supplemental applications if the modifications meet certain criteria. The notice must be provided to FDA within 5 working days of making the change.

1. Emergency Use.

   FDA approval of a supplement does not apply in the case of a deviation from the investigational plan to protect the life or physical well-being of a subject in an emergency. However, such deviation must be reported to FDA within 5-working days after the sponsor learns of it [§812.150(a)(4)].   Additional information can be found in "Guidance on IDE Policies and Procedures"

http://www.fda.gov/cdrh/ode/idepolcy.html
http://www.fda.gov/cdrh/ode/idepolcy.pdf

2. Certain Developmental Changes.

   Criteria

   An FDA approved supplement is not required for developmental changes in the device (including manufacturing changes) that do not constitute a significant change in design or basic principles of operation and that are made in response to information gathered during the course of an investigation. This determination is made by the sponsor and must be based on credible information. Credible information to support developmental changes in the device (including manufacturing changes) includes data generated under the design control procedures of §820.30 (See Design Controls), preclinical/animal testing, peer reviewed published literature, or other reliable information such as clinical information gathered during a trial or marketing. The sponsor must provide notice to FDA within 5-working days of making these changes.

   Generic types of device and manufacturing changes include changes to the control mechanism, principle of operation, energy type, environmental specifications, performance specifications, ergonomics of patient-user interface, dimensional specifications, software or firmware, packaging or expiration dating, sterilization, and the manufacturing process (including the manufacturing site). Sponsors may refer to ``Deciding When to Submit a 510(k) for a Change to an Existing Device'' for assistance in identifying the types of changes which may qualify for implementation under this provision. Any specific change within a particular type may or may not be appropriate under the 5-day notice provision because changes in each of these categories could range from minor to significant depending upon the particular device, the type of modification, and the extent of the modification. The impact of the change would still need to be determined by information generated by design controls or other appropriate means to assess the significance of the change to the device design or manufacturing process and the appropriateness of a 5-day notice submission.

   Please note that all developmental changes need to be reported to the IRB in the sponsor’s annual report. In addition, the changes may be subject to IRB review procedures under 21 CFR 56.110.

   All changes to the basic principles of operation of a device are considered to be significant changes that should be submitted in an IDE supplement.

   5-day Notice

   The sponsor must submit a notice of the change to the IDE no later than 5-working days after making the change. Changes to devices are deemed to occur on the date the device, manufactured incorporating the design or manufacturing change, is distributed to the investigator(s). These notices must be identified as a ``notice of IDE change.''

   For a developmental or manufacturing change to the device, the notice must include a summary of the relevant information gathered during the course of the investigation upon which the change was based; a description of the change to the device or manufacturing process (cross-referenced to the appropriate sections of the original device description or manufacturing process); and, if design controls were used to assess the change, a statement that no new risks were identified by appropriate risk analysis and that the verification and validation testing, as appropriate, demonstrated that the design outputs met the design input requirements. If another method of assessment was used, the notice must include a summary of the information which served as the credible information supporting the change. FDA will only notify the sponsor if questions arise or additional information is needed.

3. Certain changes to the clinical protocol.

   Criteria

   An FDA approved supplement is not required for changes to clinical protocols that do not affect:

   • The validity of the data or information in the approved protocol, or the patient risk to benefit relationship relied upon to approve the protocol;
   • The scientific soundness of the investigational plan; or
   • The rights, safety, or welfare of the human subjects involved in the investigation.

   This determination is made by the sponsor and must be based on credible information. Credible information to support changes to clinical protocols is defined as the sponsor's documentation supporting the conclusion that a change does not have a significant impact on the study design or planned statistical analysis, and that the change does not affect the rights, safety, or welfare of the subjects. Documentation must include information such as peer reviewed published literature, the recommendation of the clinical investigator(s), and/or the data gathered during the clinical trial or marketing. The sponsor must provide notice to FDA within 5-working days of making these changes.

   Examples of these types of changes may include the following changes:

   
   
   • Modification of inclusion/exclusion criteria to better define the target patient population
   • Increasing the frequency at which data or information is gathered
   • Inclusion of additional patient observations or measurements
   • Modifying the secondary endpoints (Secondary endpoints usually support a secondary labeling claim that the sponsor wants to make for the device and are not used to determine the safety or effectiveness of the device.)

   5-day Notice

   The sponsor must submit a notice of the change to the IDE no later than 5-working days after making the change. Changes to a clinical protocol are deemed to occur when a clinical investigator is notified by the sponsor that the change should be implemented in the protocol or, for sponsor-investigator studies, when a sponsor-investigator incorporates the change in the protocol. These notices must be identified as a ``notice of IDE change.''

   For a protocol change, the notice must include a description of the change (cross-referenced to the appropriate sections of the original protocol); an assessment supporting the conclusion that the change does not have a significant impact on the study design or planned statistical analysis; and a summary of the information that served as the credible information supporting the sponsor's determination that the change does not affect the rights, safety, or welfare of the subjects. FDA will only notify the sponsor if questions arise or additional information is needed.

Changes to be submitted in the annual report.

Minor changes in the following areas:

• the purpose of the study,
• risk analysis,
• monitoring procedures,
• labeling,
• informed consent materials, and
• IRB information

may be reported in the annual progress report for the IDE if the changes do not affect: (i) The validity of the data or information resulting from the completion of the approved protocol, or the relationship of likely patient risk to benefit relied upon to approve the protocol; (ii) The scientific soundness of the investigational plan; or (iii) The rights, safety, or welfare of the human subjects involved in the investigation [812.150(b)(5)].  If the changes do affect the above criteria, then prior approval must be obtained.

IDE supplements for new facilities

FDA will review initial IDE applications that do not contain a certification of IRB approval for each site. FDA may approve the investigational sites without IRB approval. The sponsor is required to submit the certification in an IDE supplement when he obtains IRB approval. If the site is already approved and the supplement is just the certification of IRB approval, FDA usually does not provide a written response to the certification since the site has previously been approved by FDA.

If the sponsor has determined the number of investigational sites for the study but not yet identified all the sites at the time the IDE is submitted, FDA may grant a waiver to the sponsor. The waiver would allow the sponsor to enroll the sites, obtain IRB approvals, and then submit all the certifications of IRB approval to FDA at one time (or at 6 month intervals if it takes that long to enroll the sites) instead of requesting each site as it is identified.

Once the IDE is approved, the sponsor may submit an IDE supplement to request approval of additional clinical study sites. FDA will respond in writing to the supplement approving or denying the request. The sponsor is required to submit;

• Identification of the investigational site,
• certification of IRB approval,
• information updating the initial IDE application (if the investigation is changed), and
• a description of any modifications required by the IRB as conditions of approval.

Certification of IRB approval for a new sites does not need to be included in the request but the sponsor will need to submit it to us once he has IRB approval.

The sponsor may not begin any part of the investigation at an institution until:

• IRB approval is obtained;
• FDA receives certification of IRB approval; and
• FDA approves the supplemental application.

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