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

I. General Information A. Exceptions to the Requirement for the Submission of an IDE application to

the FDAB. Phases of Device Studies

1. Feasibility studies 2. Pivotal studies

a. 510(k) device studies b. PMA device studies

C. FDA Administrative Actions 1. Effective date of FDA acceptance of an IDE application 2. Notice of disapproval or withdrawal

D. Prohibition of Promotion of Investigational Devices and Other Practices

II. IDE Application: Content and Format A. Sponsor Name and Address B. Overall Clinical Plan C. Report of Prior Investigations of the Device D. Investigational Plan

1. Purpose 2. Clinical protocol

a. Content of clinical protocol – Feasibility study b. Content of clinical protocol – Pivotal studies

3. Risk analysis 4. Description of the device 5. Monitoring procedures 6. Labeling 7. Consent materials 8. IRB information 9. Other institutions 10.Additional records and reports

E. Method, Facilities and Controls Information F. Investigator Agreements G. Certification of Investigator Agreement H. Reviewing IRBs I. Other Involved Institutions J. Device Charges K. Device Labeling

1. Labeling of investigational devices a. Content b. Prohibitions

2. Labeling of In Vitro Diagnostic Devices L. Consent Materials

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M. Other Relevant Information

III. Supplemental IDE Applications A. Changes in the Investigational Plan

1. Changes effected for emergency use 2. Changes effected with subsequent (i.e., within 5 days) FDA notice

a. Developmental changes b. Clinical protocol changes

3. Changes submitted in the annual report B. Additional IRB Approvals

1. IRB approval for new facilities 2. IRB approval of changes addressed in a Supplemental IDE Application

I. General Information

A. Exceptions to the Requirement for the Submission of an IDE application to the FDA1

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:

a. Complies with the Labeling of Investigational Device requirements;

b. 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 21 CFR Sec. 812.22 A significant risk device study means a study of the safety and/or effectiveness of an investigational device that (1) is intended as an implant and presents the potential for serious risk to the health, safety, or welfare of a subject; (2) is purported or represented to be for a use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject; (3) is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or (4) otherwise presents a potential for serious risk to the health, safety, or welfare of a subject (21 CFR Sec. 812.3(m)). Implant means a device that is placed into a surgically or naturally formed cavity of the human body if it is intended to remain there for a period of 30 days or more; or for shorter periods if determined by the FDA in order to protect public health (21 CFR Sec. 812.3(d)).

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c. 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);

d. Complies with the requirements for monitoring of ongoing investigations (see Sponsor Responsibilities: Non-Significant Risk Device Studies);

e. Maintains required Sponsor records and makes required Sponsor reports (see Sponsor Responsibilities: Non-Significant Risk Device Studies);

f. Ensures that participating Investigators maintain required Investigator records and make required Investigator reports (see Investigator Responsibilities: Non-Significant Risk Device Studies; and

g. Complies with provisions addressing Prohibition of Promotion of Investigational Devices and Other Practices (21 CFR Part 812.7)

2. A device, other than a transitional device3, in commercial distribution immediately before May 28, 1976, when used or investigated in accordance with the respective labeling indications in effect at that time.

3. 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.

4. An in vitro diagnostic device, if the Sponsor complies with Labeling of In Vitro Diagnostic Device requirements and if the testing:

3 Transitional device means a device that the FDA considered to be a new drug or an antibiotic drug before May 28, 1976 (21 CFR Sec. 812.3(r)).

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a. is noninvasive4;

b. Does not require an invasive sampling procedure that presents significant risk;

c. Does not by design or intention introduce energy into a subject; and

d. Is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure.

5. 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.

6. A custom device5, unless the clinical investigation is for the purpose of determining the safety and effectiveness of the custom device for potential commercial distribution.

B. 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 a device 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

4Noninvasive, when applied to a diagnostic device or procedure, means one that does not by design or intention: (1) penetrate or pierce the skin or mucous membranes of the body, the ocular cavity, or the urethra, or (2) enter the ear beyond the external auditory canal, the nose beyond the nares, the mouth beyond the pharynx, the anal canal beyond the rectum, or the vagina beyond the cervical os. When applied to a diagnostic device, blood sampling that involves simple venipuncture is considered noninvasive, and the use of surplus samples of body fluids or tissues that are left over from samples taken for non-investigational purposes is also considered noninvasive (21 CFR 812.3(k)).5 Custom device means a device that: (1) necessarily deviates from devices generally available or from an applicable performance standard or pre-market approval requirement in order to comply with the order of an individual physician or dentist; (2) is not generally available to, or generally used by, other physicians or dentists; (3) is not generally available in finished form for purchase or for dispensing upon prescription; (4) is not offered for commercial distribution through labeling or advertising; and (5) is intended for use by an individual patient named in the order of a physician or dentist, and is to be made in a specific form for that patient, or is intended to meet the special needs of the physician or dentist in the course of professional practice (21 CFR Sec. 812.3(b)).

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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.

2. 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.

a. 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.

b. 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.

C. FDA Administrative Actions6

1. Effective date of FDA acceptance of an IDE application . An IDE goes into effect:

a. 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) or upon 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.

b. 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

2. Notice of disapproval or withdrawal .

6 21 CFR Sec. 812.307 21 CFR Sec. 812.20(a)(2)

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

a. 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).

b. 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.

D. Prohibition of Promotion of Investigational Devices and Other Practices8

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;

2. 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;

3. 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.

4. Represent that an investigational device is safe or effective for the purpose for which it is being investigated.

II. IDE Application: Content and Format 9

8 21 C FR Sec. 812.79 21 CFR Sec. 812.20(b)

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An IDE application shall include, in the following order:

A. 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 Device10

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

10 21 CFR Sec. 812.27

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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 (21 CFR Part 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 Plan11

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 used and 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 study13

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

11 21 CFR Sec. 812.2512 Note: While only an accurate summary of bullets 1-5 of the Investigational Plan may be submitted, FDA requires the submission of the complete Investigational Plan if no IRB has prior reviewed it, if the FDA has found or determines that an IRB’s review is inadequate, or if FDA requests the complete Investigational Plan. To avoid delays in the FDA review process, it is recommended that the complete Investigation Plan be incorporated into the initial submission of the IDE application.13 IDE Guidance Memorandum #D89-1, “Review of IDEs for Feasibility Studies, May 17, 1989 (D89-1”, Center for Devices and Radiological Health, DHHS.

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defined; and, where applicable, should address and account for critical safety concerns.

b. Content of clinical protocol - Pivotal studies14

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 fora well-controlled investigation is not reasonably applicable to the device. In the latter situation, the FDA may authorize reliance upon other valid scientific evidence15 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

14 21 CFR Sec. 860.715 Valid scientific evidence may include evidence from well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts, and reports of significant human experience with a marketed device; from which it can fairly and reasonably be concluded by qualified experts that there is reasonable assurance of the safety and effectiveness of device under its conditions of use. The evidence required may vary according to the characteristics of the device, its conditions of use, the existence and adequacy of warnings and other restrictions, and the extent of experience with its use. Isolated case reports, random experience, reports lacking sufficient detail to permit scientific evaluation, and unsubstantiated opinions are not regarded as valid scientific evidence to show safety or effectiveness.

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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).

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(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 Required Records 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.

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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 Investigator Responsibilities 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.

I. Other Involved Institutions

Include a list of the name and address of any institution at which a part of the investigation may be conducted and that has not been identified previously under the section of the IDE application that addresses Reviewing IRBs.

J. Device Charges

If the device is to be sold, the amount to be charged and an explanation as to why charging the investigator or research subject for the device does not involve commercialization.

K. Device Labeling

1. Labeling of investigational devices 16

a. Content: The investigational device or its immediate package shall bear a label with the following information:

16 21 CFR Sec. 812.5

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(i) Name and place of business of the manufacturer, packager, or distributor of the device;

(ii) Quantity of contents, if appropriate;

(iii) The statement, “CAUTION – Investigational device. Limited by Federal (or United States) law to investigational use.”; and

(iv)A description (i.e., on the immediate label or other labeling) of all relevant contraindications, hazards, adverse effects, interfering substances or devices, warnings, and precautions.

b. Prohibitions : The labeling of an investigational device shall not bear any statement that is false or misleading in any particular and shall not represent that the device is safe or effective for the purpose for which it is being investigated.

2. Labeling of In Vitro Diagnostic Devices 17

a. In vitro diagnostic devices that are exempt from the IDE requirements of Part 812 must be labeled “For Investigational Use Only. The performance characteristics of this product have not been established.”

b. In vitro diagnostic devices intended for research use (i.e., research IVDs) are devices in the laboratory phase of development and may not be used for clinical (i.e., human) diagnostic or prognostic applications. Research IVDs must be labeled “For research use only. Not for use in diagnostic procedures.”

L. Consent Materials

Include copies of all forms and informational materials to be provided to subjects to obtain informed consent.

M. Other Relevant Information

Include any other relevant information FDA requests for review of the application.

III. Supplemental IDE Applications 18

17 21 CFR Sec. 809.10(c)(2)(i)18 21 CFR Sec. 812.35

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A. Changes in the Investigational Plan

A sponsor must obtain FDA and, when appropriate, IRB approval prior to implementing any change to a previously accepted Investigational Plan; with the following exceptions:

1. Changes effected for emergency use . Prior approval of the FDA and IRB is not required in the case of a deviation from the investigational plan to protect the life or physical well-being of a subject in an emergency.

a. The sponsor shall report such deviation to the FDA within 5-working days after the sponsor becomes aware of it.

b. The involved investigator shall report such deviation to the reviewing IRB promptly after its occurrence.

2. Changes effected with subsequent (i.e., within 5 days) FDA notice . A sponsor may make the following changes to an Investigational Plan without prior FDA approval; provided that the changes are based on “creditable information” and the sponsor provides notice of the changes to the FDA within 5-working days of making the changes.

a. Developmental changes in the device that do not constitute a significant change in design or basic operation and that are made in response to information gathered during the course of an investigation.

(i) 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).

(ii) Creditable information to support developmental changes in the device (including manufacturing changes) includes data generated under the device control procedures (21 CFR Sec. 820.30), preclinical/animal testing, peer reviewed published literature, and other reliable information such as clinical information gathered during a clinical trial or marketing.

(iii) For a developmental or manufacturing change to a device, the “Notice of IDE Change” shall include (i) a summary of the relevant information gathered during the course of the investigation upon which the change was based; (ii) a description of the change to the device or manufacturing process (i.e., cross-referenced to the appropriate sections of

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the original device description or manufacturing process); and (iii) 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 shall include a summary of the information which served as the creditable information supporting the change.

b. Clinical protocol changes that do not affect (i) the validity of the data or information resulting from the completion of the approved protocol, or the relationship of the 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 human subjects involved in the investigation.

(i) 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 investigator-sponsored studies, when the investigator-sponsor incorporates the change in the protocol.

(ii) Creditable information to support changes to clinical protocols includes the sponsor’s documentation supporting the conclusion that the 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 shall include such as peer reviewed published literature, the recommendation of the clinical investigator(s), and/or data gathered during the clinical trial or marketing.

(iii) For a clinical protocol change, the Notice of IDE Change shall include (i) a description of the change (cross-referenced to the appropriate sections of the original protocol); (ii) an assessment supporting the conclusion that the change does not have a significant impact on the study design or planned statistical analysis; and (iii) a summary of the information that served as the creditable information supporting the sponsor’s determination that the change does not affect the rights, safety, or welfare of the subjects.

(iv)Note: All changes to the clinical protocol are subject to prior IRB approval.

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3. Changes submitted in the annual report . A sponsor may make the following changes to an Investigational Plan without prior FDA approval; provided that the respective changes are reported in the annual progress report for the IDE (see Progress Reports).

a. Minor changes to the purpose of the study, risk analysis, monitoring procedures, labeling, informed consent materials, and IRB information that 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.

b. Note: Changes to the clinical protocol (e.g., purpose of the study, risk analysis), monitoring procedures, informed consent materials, and other IRB information are subject to prior IRB approval.

B. Additional IRB Approvals

1. IRB approval for new facilities . A sponsor shall submit to the FDA a certification of any additional IRB approvals of an investigation or part of an investigation not included in the initial IDE application. If the investigational plan is otherwise unchanged, the supplemental application shall consist of:

a. An updated 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 of the device; and

b. A description of any modifications in the investigational plan required by the additional IRB(s) as a condition of approval.

2. IRB approval of changes addressed in a Supplemental IDE Application. A certification of IRB approval, when applicable, need not be included in the initial submission of a Supplemental IDE Application, and such certification is not a precondition for FDA consideration of the application. Nevertheless, a sponsor may not begin a revised part of an investigation at a facility until the reviewing IRB for that facility has approved the respective revision of the investigation, FDA has received the certification of such IRB approval, and FDA has approved

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the supplemental application relating to that part of the revised investigation.

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