IDE Application for an Investigational Device: Investigational Device Exemption Application Guidance and Template for Significant Risk Devices

ICTR Navigators March 20, 2013 Version 2.0

ACKNOWLEDGEMENT: We are grateful to the Office for Investigator-Sponsored IND and IDE Support at the University of Pittsburgh for the use of selected materials which have been modified and incorporated into this document for use by the Johns Hopkins research community.

ICTR DDRS: IDE Application Guidance & Template for Significant Risk Devices

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1.0 Table of Contents Section 1.0 Table of Contents 2.0 Abbreviations 3.0 FDA Websites 3.1 Definitions 4.0 Introduction 5.0 Guidance and Instructions 5.1 Template Comments 5.2 Regulations and Guidance Documents 5.3 Number of Copies to be Submitted 5.4 Application Header and Footer 5.5 Binding 5.6 FDA Mailing Addresses 5.7 Website Hyperlinks 5.8 Questions and Additional Information 5.9 Application Template Guidance

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2.0 Abbreviations CFR Code of Federal Regulations FDA U.S. Food and Drug Administration CDER Center for Drug Evaluation and Research CBER Center for Biologics Evaluation and Research CDRH Center for Devices and Radiological Health CMC Chemistry, Manufacturing, and Controls GCP Good Clinical Practices GLP Good Laboratory Practices GMP Good Manufacturing Practices BLA Biologic License Application NDA New Drug Application PMA Pre-Market Application IDE Investigational Device Exemption

3.0 FDA Websites A list of several FDA websites containing useful information for investigators using an investigational device is provided below. It is strongly suggested that these websites be reviewed before submitting an IDE application to the FDA. FDA Forms website: 

http://www.fda.gov/aboutfda/reportsmanualsforms/forms/default.htm

FDA Title 21 Regulations Search Engine (e.g., IDE regulations 21CRF812) website: 

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=812&showFR=1

FDA Device Advice: Comprehensive Regulatory Assistance 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/default.htm

FDA Original IDE Application Administrative Checklist 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/Investig ationalDeviceExemptionIDE/ucm046706.htm Page 2 of 78

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Running Clinical Trials website: 

http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm

FDA – CDRH Investigational Device Exemption (IDE) Application website: 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/Investig ationalDeviceExemptionIDE/ucm046706.htm

FDA – Sponsor-Investigator Responsibilities (IDE) website 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/Investig ationalDeviceExemptionIDE/ucm046702.htm

FDA – CDRH Device Guidance Documents: 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm

FDA- Formal Meetings between the FDA and Sponsors or Applicants (pre-IDE):  http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/Investig ationalDeviceExemptionIDE/ucm046164.htm#pre_ide FDA - CDER PRE-IND Consultation Contacts 

http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm134493.htm

FDA CDRH Overview of Device Regulation 

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/default.htm

FDA CDRH Learn (Educational tool) 

http://www.fda.gov/Training/CDRHLearn/default.htm

3.1 Definitions Term Definition Component means any raw material, substance, piece, part, software, Component firmware, labeling, or assembly which is intended to be included as part of the finished, packaged, and labeled device. Custom device Custom device means a device that: (1)Necessarily deviates from devices generally available or from an applicable performance standard or premarket 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 Design history file (DHF )

Design input

Design output

Design history file (DHF) means a compilation of records which describes the design history of a finished device. Design input means the physical and performance requirements of a device that are used as a basis for device design. Design output means the results of a design effort at each design phase and at the end of the total design effort. The finished design output is the basis for the device master record. The total finished design output consists of the device, its packaging and labeling, and the device master record. Page 3 of 78

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Design Validation

Design review means a documented, comprehensive, systematic examination of a design to evaluate the adequacy of the design requirements, to evaluate the capability of the design to meet these requirements, and to identify problems. Design validation means establishing by objective evidence that device specifications conform with user needs and intended use(s).

Device history record (DHR)

Device history record (DHR) means a compilation of records containing the production history of a finished device.

Device master record (DMR)

Investigational device

Device master record (DMR) means a compilation of records containing the procedures and specifications for a finished device Feasibility studies are preliminary studies done with prototypes of the device that may require additional modification once it is used in a clinical setting. The device in these trials is not in its final state (as it will be marketed) and data from these studies is not sufficient to support a marketing application. Finished device means any device or accessory to any device that is suitable for use or capable of functioning, whether or not it is packaged, labeled, or sterilized. Implant is a device that is placed into a surgically or naturally formed cavity of the human body and is intended to remain there for a period of 30 days or more. In order to protect public health, FDA may determine that devices placed in subjects for shorter periods are also implants. Investigation is a clinical investigation or research involving one or more subjects to determine the safety and/or effectiveness of a device. Investigational device is a device, including a transitional device, which is the object of an investigation.

Investigational device exemption (IDE)

IDE refers to the regulations under 21 CFR 812. An approved IDE means that the IRB (and FDA for significant risk devices) has approved the sponsor‟s study application and all the requirements under 21 CFR 812 are met.

Design review

Feasibility Study

Finished device

Implant

Investigation

Investigator

Lot (or batch)

Noninvasive

Pivotal

Investigator is an individual who actually conducts a clinical investigation, i.e., under whose immediate direction the investigational device is administered, dispensed to, or used involving a subject. In the event of an investigation being conducted by a team of individuals, "investigator" refers to the responsible leader of that team. Lot or batch means one or more components or finished devices that consist of a single type, model, class, size, composition, or software version that are manufactured under essentially the same conditions and that are intended to have uniform characteristics and quality within specified limits Noninvasive, 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. For purposes of this part, 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. Pivotal studies are done with the device as it will be in its final state. The purpose of the pivotal clinical study is to collect the primary evidence of safety and effectiveness to support a marketing submission or application. Page 4 of 78

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Premarket Approval (PMA) Premarket Notification [PMN or 510(k)]

Remanufacturer

Rework

Significant risk device (SR device)

Sponsor

Sponsorinvestigator

Transitional device

Unanticipated adverse device effect

Validation

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A premarket approval means any premarket approval application for a Class III medical device, including all information submitted with or incorporated by reference therein. (21 CFR 814.3) 510(k) refers to the type of submission to FDA described under 21 CFR 807 Subpart E in which the applicant must establish that their device is substantially equivalent to a legally marketed device. This type of submission is used for most Class II devices and some Class I devices. Remanufacturer means any person who processes, conditions, renovates, repackages, restores, or does any other act to a finished device that significantly changes the finished device's performance or safety specifications, or intended use. Rework means action taken on a nonconforming product so that it will fulfill the specified DMR requirements before it is released for distribution. Significant risk device is an investigational device that: (1) is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject; (2) is for use in supporting or sustaining human life and represents 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 a subject. Sponsor is a person or other entity that initiates but does not actually conduct the investigation. An entity other than an individual (e.g., a corporation or an agency) which uses one or more of its own employees to conduct an investigation that it has initiated is considered to be a sponsor, not a sponsorinvestigator, and the employees are considered to be investigators. The sponsor of an IDE must be located in the United States (see 21 CFR 812.18). Sponsor-investigator is an individual who both initiates and actually conducts, alone or with others, a clinical investigation, i.e., under whose immediate direction the investigational device is administered, dispensed, or used. The term does not, for example, include a corporation or agency. The obligations of a sponsor-investigator include those of an investigator and those of a sponsor. Transitional device is a device subject to section 520(l) of the FD&C Act and which FDA previously regulated as a new drug or an antibiotic drug before May 28, 1976. Unanticipated adverse device effect is any serious adverse effect on health or safety, any life-threatening problem or death caused by, or associated with a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the application; or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects. Validation means confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled.

Reference: FDA IDE Definitions and Acronyms webpage

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Introduction

4.1. Introduction: The information provided in this document is intended to provide a general process overview and a template for an Investigational Device Exemption (IDE) application submission for significant risk devices reviewed by the FDA Center for Devices and Radiological Health (CDRH). The document is written from the perspective that the person submitting the IDE application is a SponsorInvestigator. A Sponsor-Investigator is someone who is both 1) responsible for initiating the studies conducted with the investigational device and 2) who conducts the studies. The contents of this document are based on the FDA regulations governing investigational devices, 21CFR812 and FDA guidance documents. However, each device and associated clinical trials may have unique features or circumstances that are not addressed by this document or the reference guidance documents cited herein. In such cases, the Sponsor-Investigator should consult with the ICTR-DDRS. 4.2 IDE Application Submission: The necessity to submit IDE applications depends on the purpose, design, and nature of the clinical investigations involving the use of a FDA-approved or unapproved device. If the research is not being conducted for the purpose of determining the safety and effectiveness of the device for a specific clinical indication and the research use of the device does not place the participants at significant risk, then it is generally exempt from the requirement of submission of an IDE application. The submission of an IDE application is required if the reviewing institutional review board (IRB) determines that the device, or its proposed use in the research study, constitutes a “significant risk” to the research participants. A “significant risk device study” is defined by FDA regulations as “a study of a device that presents a potential for serious risk to the health, safety, or welfare of a subject and (1) is an implant; or (2) is used in supporting or sustaining human life; or (3) is of substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents impairment of human health; or (4) otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.” A “non-significant risk device study” is a study of a device that does not meet the FDA‟s definition for a “significant risk device study.” An FDA Guidance document entitled, “Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors: Significant Risk and Non-significant Risk Medical Device Studies” is available for more information on making this risk determination. The clinical investigation of the safety and/or effectiveness of an unapproved 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. 4.3 Feasibility studies Feasibility (pilot or proof-of-concept) studies of an unapproved 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. Page 6 of 78

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4.4 Pivotal studies The conduct of Pivotal (multi-center) studies of an unapproved 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. 510(k) device studies The primary purpose of Pivotal studies directed at obtaining the FDA‟s approval to market an unapproved 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 unapproved device alone. 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. While there are numerous regulations, guidance documents and other references pertaining to significant risk IDE applications, those provided in this document are those most commonly used and/or most widely applicable. The following references will give the Sponsor-Investigator a general overview of the basic IDE application content and format. [FDA Regulation - 21CRF812 Subpart B--Investigational Device Application (IDE): http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=812&showFR=1&subpa rtNode=21:8.0.1.1.9.2 ]

5.0

Guidance and Instructions

5.1 Template Comments The enclosed template guidance is a suggested format based on federal regulations and guidance documents. Within each section of the application template are references to applicable FDA regulations, web addresses to FDA guidance documents, comments/instructions, web addresses to FDA forms, and suggested formatting and/or language. These instructions outline what should be included or inserted into a particular section and may also address special considerations. As this is a basic template and each significant risk device IDE application is unique, best judgment should be used concerning the information to be included in the submission. The SponsorInvestigator may use this format or adapt it as appropriate for the particular investigational device being evaluated. Each section of the application should begin on new page and index tabs should be used to mark each section of the application. Thus, each section in this document should start on a new page. A blank template with just the cover letter, title page, and suggested section headings and subheadings is available for download at the DDRS website.

5.2 Regulations and Guidance documents Throughout this document are a number references to regulations and guidance documents. These references have been included to provide the Sponsor-Investigator with direction and guidance when completing a significant risk IDE application. The references will not address every situation that may be encountered. If the applicant has questions after reviewing the references provided, they should contact the ICTR Research Navigators for assistance by submitting a Connection Request to the DDRS.

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5.3 Number of Copies to be submitted Three signed copies of the IDE application are required. One original copy and two photocopies of the IDE application must be sent with the initial submission. Of note: Once the FDA receives the application and begins the review process, they may ask for additional desk copies. 5.4 Application Header and Footer The following is the suggested format of document headers and footers to be used with the initial IDE submission. Note: Headers and footers are not included in the template and must be inserted manually and may be modified as appropriate. Header: [Left Hand Side] IDE Application Date: [INSERT DATE] [INSERT Device Name] Footer: [Left Hand Side] John Hopkins University [INSERT: Sponsor-Investigator Name] Confidential and Proprietary

[Right Hand Side] IDE Number: pending

[Right Hand Side] Page [##]

5.5 Binding for Paper Submissions If a project manager has been assigned to the IDE application being prepared for submission or if contact information is available for a project manager within the Office/Division that will review the application, it is suggested that the Sponsor-Investigator contact the project manager to review how the IDE materials should be bound. If a project manager has not yet been assigned to the IDE, general guidelines for binding a paper IDE application are provided below. Neither CDER nor CDRH specify a color of binders for IDE submissions under their purview, but they do request uniformity in the manner in which the information is bound. CDRH does however provide recommendations concerning the format for paper submissions, which are listed below in under number 3. The following binding guidance information presented is from CBER and may be found at the FDA‟s website in a document entitled “SOPP 8007: DCC Binding Procedures for Regulatory Documents” located at following web address: 

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Procedures SOPPs/ucm109596.htm

IDE submissions that are received loose or which are inadequately bound may be returned to the Sponsor-Investigator for rebinding and resubmission which can significantly delay the FDA review process. 1. FDA Binding Recommendations: NOTE: While the following binders have a 3” capacity, CDRH prefers that each binder not exceed 2”. Neither CBER nor CDER have expressed this preference. a. Archive - ACCO Gray Stock Number 25974 or Smead Stock Number 81552 or Oxford Stock Number ESS-129005 or similar type b. Duplicate (or First Review Copy) - ACCO Executive Red Stock Number 25079 or Smead Red Stock Number 81752 or similar type Page 8 of 78

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c. Second and additional review copies - Any color pressboard report binder except Gray or Red. 2. Information about Binders/Folders: Note: The vendor information listed below is provided as an example of where these items may be purchased and is not intended as an endorsement of the vendor or a mandatory vendor to be used for purchase. a. Archive (original copy)- Gray (ACCO Gray Stock Number 25974 or Smead Stock Number 81552 or Oxford Stock Number ESS-129005 or similar type) i. Example Vendor 1. GovGroup.com: http://www.govgroup.com/pressguard-binder-cover-smd81552-2183502prd1.htm

b. Duplicate (or First Review Copy) – Red (ACCO Executive Red Stock Number 25079 or Smead Red Stock Number 81752 or similar type) i. Example Vendor 1. Office Depot: http://www.officedepot.com/a/products/934380/ACCO-60percent-RecycledPressboard-Binder-With/

c. Second and additional review copies - Any color pressboard report binder except Gray or Red. i. Example Vendor 1. Office Depot: http://www.officedepot.com/a/products/193664/ACCO-Presstex-60percentRecycled-Binder-Side/

3. In order to facilitate FDA's handling of IDE applications, the following recommendations are offered: a. b. c. d.

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 e. 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.) f. All copies of each submission must be identical g. Do not combine IDEs, PMAs and 510(k)s together; each is a separate submission h. 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 i. 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 the submission. j. The outside wrapper of each submission should identify the contents, for example, "IDE Application," "Supplemental IDE," "Waiver," etc.

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4. Identification of binders: Required on front folder in a clear, sharp, permanent-type print in BLACK ink - Permanent adhesive labels may be used in a clear, sharp print - Printing must withstand a "Scotch Tape Test" which consists of pressing a strip of "Scotch" tape firmly on the printed area and removing - There should be NO transfer of the printed area on the tape. NOTE: This is suggested based upon CDER guidance for IND applications. a. All binders being submitted are to identified with the following labels: APPLICATION FOR INVESTIGATIONAL DEVICE EXEMPTION ORIGINAL SUBMISSION IDE NO._____ (For the initial submission of the new application leave blank) NAME OF DEVICE SPONSOR NAME This submission: VOL.___OF___VOLS.

5.6 FDA Mailing Addresses Sponsors of a significant risk device investigation must submit a signed "Application for Investigational Device Exemption" in triplicate. 1) For devices regulated by the Center for Devices and Radiological Health, send to: Food and Drug Administration Center for Devices and Radiological Health Document Mail Center - WO66-G609 10903 New Hampshire Avenue Silver Spring, Maryland 20993-0002 2) For devices regulated by the Center for Biologics Evaluation and Research (CBER), send to: Food and Drug Administration Center for Biologics Evaluation and Research Document Control Center (HFM-99), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448 3) For devices regulated by the Center for Drug Evaluation and Research (CDER), send to: Food and Drug Administration Center for Drug Evaluation and Research Central Document Control Room, 5901-B Ammendale Rd., Beltsville, MD 20705-1266. You must state on the outside wrapper what the submission is (e.g. "original IDE application"). [See: 21 CFR Sec. 812.19 Address for IDE correspondence] [See FDA Device Advice: IDE Application-Address for IDE Applications]

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5.7 Website Address Hyperlinks All hyperlinks to websites included in this document are operational as of the date of this version. If any non-functional hyperlinks are identified in this document, please contact the ICTR Research Navigators via the contact information below so that the links may be updated. 5.8 Questions and Additional Information Contact For questions regarding any of the information presented or use of the template, please contact the ICTR Research Navigators at [email protected] or via telephone at 410-955-8120 or 410-614-5383.

5.9

Application Template Guidance

Application Section Cover Letter Cover Page Form FDA 3415 (optional) Table of Contents Section 1: Sponsor-Investigator Information Section 2: Brief Overview of Clinical Plan Section 3: Report of Prior Investigations Section 4: Investigational Plan Section 5: Methods, Facilities and Controls Information Section 6: Example of Investigator Agreements, Certification of Investigators and Financial Interest Section 7: Reviewing Institutional Review Boards Section 8: Other Involved Institutions Section 9: Device Charges Section 10: Labeling Section 11: Consent Materials Section 12: Other Relevant Information Section 13: Reference List Section 14: Appendices

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Cover Letter [INSTRUCTIONS: The suggested format for the cover letter that accompanies the IDE application may be found below.] [INSERT: Sponsor-Investigator letterhead or address] [INSERT: Date of letter] Food and Drug Administration Center for Devices and Radiological Health Document Mail Center - WO66-G609 10903 New Hampshire Avenue Silver Spring, Maryland 20993-0002 OR Food and Drug Administration Center for Biologics Evaluation and Research Document Control Center (HFM-99) 1401 Rockville Pike, Suite 200N Rockville, MD 20852-1448 OR Food and Drug Administration Center for Drug Evaluation and Research Central Document Control Room 5901-B Ammendale Rd. Beltsville, MD 20705-1266 Re:

Original IDE Application for [INSERT: Name of Device], [If applicable, reference the IDE number or Pre-IDE number here]

Dear Madam/Sir: Pursuant to 21 CFR 812, I am submitting an original, Sponsor-Investigator IDE application for [INSERT: Name of Device]. Enclosed are one original [INSERT: color of original copy binder here (e.g. (Grey)] and two [INSERT: binder color of copies here (e.g. (Blue)] copies for your review. Device Information: Device name: Specify the name of the device under investigation here. Intended use of device: Specify the intended use of the investigational device; i.e., as per the objective(s) of the planned clinical investigation. Page 12 of 78

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Sponsor-Investigator Contact Information: Sponsor-investigator name and degree(s) Academic department or division affiliation Full campus address Telephone number FAX number Manufacturer Information: Name of device manufacturer Full address Contact person Telephone number FAX number Additional Information: Pre-IDE/Pre-IDE meetings: [INSTRUCTIONS: Describe any discussions with the FDA reviewing division regarding this device. If a Pre-IDE document was submitted, indicate the Pre-IDE number assigned and the name of the 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. If there was no Pre-IDE document submitted or Pre-IDE meeting, indicate such here.] Waiver requests: [INSTRUCTIONS: Identify any requests for waivers and include a justification for the waiver. If no waivers are being requested, indicate such here.] Referenced files: [INSTRUCTIONS: Identify any files that are referenced in the IDE application, such as an existing Premarket Approval, Premarket Notification 510(k), IDE, or device master file. If such files were not submitted by the sponsor-investigator, include a letter (e.g. Letter of Authorization or Letter of Cross Reference) from the owner of the files that grants FDA permission to reference the file in its review of this IDE application. If there are no referenced files, indicate such here.] If you have any questions about the material included in this IDE, please do not hesitate to contact me as per above. [COMMENT: If there is another person designated to interact with the FDA on behalf of the Sponsor-Investigator, then state “[INSERT: name] is authorized to interact with the FDA on my behalf and [INSERT: name‟s] contact information is [INSERT: phone, email, and fax].” Thank you in advance for your consideration. Sincerely,

[INSERT: Sponsor-Investigator Name] [INSERT: Title] [INSERT: Affiliation] Page 13 of 78

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Enclosure: Attachment:

[INSERT: designation for any attachment cited in cover letter] [INSERT: description for any attachment cited in cover letter]

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Cover Page [COMMENT: A suggested format for the cover page of the IDE application is provided below.]

Original Investigational Device Exemption Application

[INSERT: DATE]

IDE Application Title:

[Insert title]

Device Name:

[Insert name]

IDE Number:

[Insert “Pending” if not yet assigned]

Sponsor-Investigator:

[Insert typed name and contact information]

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Form FDA 3415 [REGULATORY REFERENCE: Agency Information Collection Activities; Submission for OMB Review; Comment Request; Premarket Notification 510(k) Submissions (FDA; HHS)] “FDA form 3514 was developed to assist respondents in organizing 510(k) data for submission to FDA. This form also assists respondents in organizing and submitting data for other FDA medical device programs such as premarket approval applications, investigational device exemptions, and humanitarian device exemptions.” [INSTRUCTIONS: Completion and inclusion of Form FDA 3415 is optional, however, it is strongly encouraged for device trials under the review of CBER as per the guidance below.] [REGULATORY REFERENCE: CBER Standard Operating Procedures and Policies: Submission of Paper Regulatory Applications to CBER [SOPP 8110 Version #2 April 5, 2010] “CDRH Submission Cover Sheet (Form FDA-3514) is a form used voluntarily by those making submissions to CDRH. Use of this form for device submissions being made to CBER is strongly encouraged since it will facilitate timely processing of submissions by DCC (Document Control Center).‟

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Table Of Contents [SECTION INTRODUCTION: Any requirements for this section of the IDE application will be provided below. Some of the information included may not be applicable to all IDE applications.] [INSTRUCTIONS: An IDE Table of Contents is strongly recommended, but is not specifically required by the regulations. Changes may be made to the Table of Contents provided below based on the needs of individual IDE applications.]

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Table of Contents Volume 1 Section Title 1.0 Sponsor-Investigator Information 2.0 Brief Overview of Clinical Plan 3.0 Report of Prior Investigations 4.0 Investigational Plan 4.1 4.2 4.2.1 4.2.2 4.2.3 4.2.4 4.2.5 4.2.6 4.3 4.4 4.5 4.6

Page

Purpose of the Investigation Clinical Protocol Title of clinical protocol Study design Subject selection Study procedures Study outcome evaluations Sample Case Report Form Risk Analysis Description of investigational device Monitoring procedures Additional Records and Reports

Volume 2 Section Title 5.0 Methods, Facilities and Control Information 6.0 Example and Certification of Investigator Agreements and Financial Interest 7.0 Reviewing Institutional Review Boards 8.0 Other Involved Institutions 9.0 Device Charges 10.0 Labeling 11.0 Consent materials 12.0 Other Relevant Information 13.0 Reference List 14.0 Appendices

Page

LIST OF TABLES Volume 1 Section

Volume 2 Section

Title Table 1 Table 2

Page

Title Table 3 Table 4 Table 5

Page

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LIST OF FIGURES Volume 1 Section

Title

Page

Title

Page

Title

Page

Title

Page

Figure 1 Figure 2 Volume 2 Section Figure 3 Figure 4

LIST OF ATTACHMENTS Volume 1 Section Attachment 1 Attachment 2 Volume 2 Section Attachment 3 Attachment 4

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Section 1.0: Sponsor-Investigator Information [SECTION INTRODUCTION: The requirements for this section of the IDE application are provided below. Some of the information included may not be applicable to all IDE applications. General instructions and comments on the format and content of this section of the IDE application, along with a list of guidance documents and additional regulatory references, are provided. Within each subheading of this section are additional instructions, comments, suggested text, web addresses for forms, web addresses for specific guidance documents, and/or regulations.] [REGULATORY REFERENCE: 21CFR812.20(b)(1)] An IDE application shall include: (1) The name and address of the sponsor. [REGULATORY REFERENCE: 21CFR812.20(a)(3)] (a)(3) A sponsor shall submit three copies of a signed "Application for an Investigational Device Exemption" (IDE application), together with accompanying materials, by registered mail or by hand to the address in 812.19.

1.0

Name, Address and Signature of Sponsor Investigator

[INSTRUCTIONS: Specify the name, address, and contact information of the Sponsor-Investigator of the IDE application here.] Name and degree(s) Title

[INSERT: Full title and academic department here.]

Address

[INSERT: Full campus address here.]

Phone number

[INSERT: Full office telephone number here.]

FAX number

[INSERT: Fax number here.]

Email Address

[INSERT: Email address here.]

Signature of Sponsor-Investigator:___________________ Date: ____________

[IMPORTANT: All three copies of the IDE application (the original and the two copies) submitted to the FDA MUST BE SIGNED AND DATED BY THE SPONSOR-INVESTIGATOR.]

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Section 2.0: Brief Overview of Clinical Plan(s) [SECTION INTRODUCTION: There is no regulatory requirement for this section of the IDE application, however, it is suggested that the applicant provide the following in an attempt to make the job of the FDA reviewer easier. General instructions and comments on the format and content of this section of the IDE application are provided.]

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2.0 Brief Overview of Clinical Plan(s) [ INSTRUCTIONS: Incorporate a very 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. This section should briefly summarize (no more than a paragraph), for each planned clinical study, the title, design, sample size, primary outcome measures and expected principal results.] 2.1

Descriptive title A.

Study design

B.

Sample size

C.

Primary outcome measures

D.

Principal results (expected)

[INSTRUCTIONS: Delete 2.2 if no additional studies are proposed or add 2.3, etc. as required.] 2.2

Descriptive title A.

Study design

B.

Sample size

C.

Primary outcome measures

D.

Principal results (expected)

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ICTR DDRS: IDE Application Guidance & Template for Significant Risk Devices

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Section 3.0: Report of Prior Investigations [SECTION INTRODUCTION: The requirements for this section of the IDE application are provided below. Some of the information included may not be applicable to all IDE applications. General instructions and comments on the format and content of this section of the IDE application, along with a list of guidance documents and additional regulation references, are provided. Within each subheading of this section are additional instructions, comments, suggested text, web addresses for forms, web addresses for specific guidance documents, and/or regulations.] [REGULATORY REFERENCE: 21CFR812.20(b)(2)] (2) A complete report of prior investigations of the device [REGULATORY REFERENCE: Sec. 812.27 Report of prior investigations] Sec. 812.27 Report of prior investigations. (a)General: 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 investigation. (b)Specific contents: The report also shall 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, copies of all published and unpublished adverse information, and, if requested by an IRB or FDA, copies of other significant publications. (2) 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. (3) If information on nonclinical laboratory studies is provided, a statement that all such studies have been conducted in compliance with applicable requirements in the good laboratory practice regulations in part 58, or if any such study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance. Failure or inability to comply with this requirement does not justify failure to provide information on a relevant nonclinical test study. [45 FR 3751, Jan. 18, 1980, as amended at 50 FR 7518, Feb. 22, 1985] [REGULATORY REFERENCE: GUIDANCE ON THE REVIEW OF INVESTIGATIONAL DEVICE EXEMPTIONS (IDE) APPLICATIONS FOR FEASIBILITY STUDIES (May 17, 1989)] Per this guidance, it is the Sponsor-Investigator‟s “responsibility to define and conduct adequate tests to establish the lack of unreasonable risk and the expected performance of a device prior to clinical use. A limited trial may represent the initial introduction of a device into a human population; therefore, FDA must be assured that sufficient batteries of tests have been completed. It is the prerogative of the Sponsor-Investigator to indicate whether some preclinical tests (e.g., chronic toxicity) are not essential to early clinical studies and will be initiated only if the device will undergo further clinical study.”] [COMMENT: The report of prior investigations of the device must include reports of all prior clinical, animal testing, and laboratory testing of the investigational device. The report must be suitably comprehensive and inclusive of adequate data and information so as to justify that the proposed clinical investigation of the device possesses an appropriate benefit-to-risk ratio.]

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ICTR DDRS: IDE Application Guidance & Template for Significant Risk Devices

3.0

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Report of Prior Investigations

[INSTRUCTIONS: Insert the following language and delete Sections 3.1 through 3.3 ONLY if the device(s) under study is/are already cleared or approved by the FDA for commercial distribution. Modify as appropriate: “Please refer to Appendix X for permission from the manufacturer authorizing FDA to access the manufacturer‟s [Insert: PMA, 510K application, or Device Master Record]. No additional 21 CFR 58 compliant studies have been conducted by the Sponsor-investigator in support of this application.”] 3.1

Prior Non-Clinical Investigations of the Device A. Non-clinical investigations conducted under the direction or request of the sponsor-investigator a. Laboratory studies i.

Unpublished laboratory studies: [INSTRUCTIONS: List, by name or purpose of the study, each previously conducted, unpublished laboratory study of the device that is relevant (i.e., whether adverse or supportive) to the proposed clinical evaluation of the safety and/or effectiveness of the device. For each of these listed laboratory studies, provide a summary of the study that includes an adequate 1) description of the study methods; 2) outcome data; and 3) relevant (i.e., safety and/or effectiveness) conclusion(s) of the study. If there are no unpublished laboratory studies that are relevant to the proposed clinical evaluation of the safety and/or effectiveness of the device, specify “None”. Incorporate under this section (or by reference to an Appendix) copies of any adverse information derived from unpublished laboratory studies of the device (if applicable). If the unpublished laboratory studies did not reveal any adverse information, specify this.]

ii.

Published laboratory studies: [INSTRUCTIONS: Provide a bibliography of all published laboratory studies of the device that are relevant (i.e., whether adverse or supportive) to the proposed clinical evaluation of the safety and/or effectiveness of the device. For each of the listed publications, provide a brief summary of the relevant (i.e., safety and/or effectiveness) information or conclusion(s) of the respective study (studies). If there are no published laboratory studies that are relevant to the proposed clinical evaluation of the safety and/or effectiveness of the device, specify “None”. If applicable, incorporate under this section (or a referenced an Appendix) copies of all respective publications that contain adverse information regarding the device. If the published laboratory studies did not reveal any adverse information, specify this.] Page 24 of 78

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b. Animal studies i.

Unpublished animal studies [INSTRUCTIONS: List, by name or nature of the study, each unpublished animal study of the device that is relevant (i.e., whether adverse or supportive) to the proposed clinical evaluation of the safety and/or effectiveness of the device. For each of these listed animal studies, provide a summary of the study that includes an adequate 1) rationale for animal selection; 2) statistical justification for the number of animals studied; 3) description of the study methods; 4) outcome data; and 5) relevant (i.e., safety and/or effectiveness) conclusion(s) of the study. If there are no unpublished animal studies that are relevant to the proposed clinical evaluation of the safety and/or effectiveness of the device, specify “None”. If applicable, incorporate under this section (or by reference to an Appendix) copies of any adverse information derived from unpublished animal studies of the device. If the unpublished animal studies did not reveal any adverse information, specify this.]

ii.

Published animal studies [INSTRUCTIONS: Provide a bibliography of all published animal studies of the device that are relevant (i.e., whether adverse or supportive) to the proposed clinical evaluation of the safety and/or effectiveness of the device. For each of the listed publications, provide a brief summary of the relevant (i.e., safety and/or effectiveness) information or conclusion(s) of the respective study (studies). If there are no published animal studies that are relevant to the proposed clinical evaluation of the safety and/or effectiveness of the device, specify “None”. Incorporate under this section (or by reference to an Appendix) copies of all respective publications that contain adverse information regarding the device (if applicable). If the published animal studies did not reveal any adverse information, specify this.]

c. Compliance with Good Laboratory Practice for Nonclinical Laboratory Studies regulations (21 CFR Part 58) [INSTRUCTIONS: Specify whether or not the unpublished and/or published laboratory and animal studies of the device, described above, were conducted in a laboratory or facility that is certified as operating in full compliance with the FDA‟s GLP regulations. If the studies were not conducted in compliance with the FDA‟s GLP regulations, provide a brief statement of the reason for noncompliance.] B. Relevant non-clinical investigations conducted by other investigators a. Laboratory studies

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ICTR DDRS: IDE Application Guidance & Template for Significant Risk Devices

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[INSTRUCTIONS: Provide a bibliography of all published laboratory studies of the device conducted by other investigators that are relevant (i.e., whether adverse or supportive) to the proposed clinical evaluation of the safety and/or effectiveness of the device. For each of the listed publications, provide a brief summary of the relevant (i.e., safety and/or effectiveness) information or conclusion(s) of the respective study (studies). If there are no other published laboratory studies that are relevant to the proposed clinical evaluation of the safety and/or effectiveness of the device, specify “None”. Incorporate under this section (or by reference to an Appendix) copies of all respective publications that contain adverse information regarding the device (if applicable). If the published laboratory studies did not reveal any adverse information, specify this.] b. Animal studies [INSTRUCTIONS: Provide a bibliography of all published animal studies of the device conducted by other investigators that are relevant (i.e., whether adverse or supportive) to the proposed clinical evaluation of the safety and/or effectiveness of the device. For each of the listed publications, provide a brief summary of the relevant (i.e., safety and/or effectiveness) information or conclusion(s) of the respective study (studies). If there are no other published animal studies that are relevant to the proposed clinical evaluation of the safety and/or effectiveness of the device, specify “None”. Incorporate under this section (or by reference to an Appendix) copies of all respective publications that contain adverse information regarding the device (if applicable). If the published animal studies did not reveal any adverse information, specify this.] 3.2

Prior Clinical Investigations of the Device A.

Prior clinical investigations conducted by the sponsor-investigator a. Unpublished clinical investigations [INSTRUCTIONS: List, by name or nature of the investigation, each prior clinical investigation of the device that is relevant (i.e. whether adverse or supportive) to the proposed clinical evaluation of the safety and/or effectiveness of the device For each of these listed clinical investigations, provide a summary of the investigation that includes an adequate 1) rationale for subject selection; 2) statistical justification for the number of subjects studied; 3) description of the study methods; 4) outcome data; and 5) relevant (i.e., safety and/or effectiveness) conclusion(s) of the investigation. If there are no unpublished, prior clinical investigations that are relevant to the proposed clinical evaluation of the safety and/or effectiveness of the device, specify “None”. Incorporate under this section (or by reference to an Appendix) copies of any adverse information derived from prior, unpublished clinical investigations of the device (if applicable). If the prior, unpublished clinical investigations of the device did not reveal any adverse information, specify this.]

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b. Published clinical investigations [INSTRUCTIONS: Provide a bibliography of all publications regarding prior clinical investigations of the device that are relevant (i.e., whether adverse or supportive) to the proposed clinical evaluation of the safety and/or effectiveness of the device. For each of the listed publications, provide a brief summary of the relevant (i.e., safety and/or effectiveness) information or conclusion(s) of the respective clinical study (studies). If there are no publications of prior clinical investigations that are relevant to the proposed clinical evaluation of the safety and/or effectiveness of the device, specify “None”. Incorporate under this section (or by reference to an Appendix) copies of all respective publications that contain adverse information regarding the device (if applicable). If the publications of prior clinical investigations did not reveal any adverse information, specify this.] c. Authorization to access other IDE applications under which prior clinical investigations of the device were conducted [INSTRUCTIONS: As applicable, incorporate into this section (or a reference Appendix) a letter, signed by the Sponsor-Investigator, that authorizes the FDA to access (each of) the prior IDE application(s) under which the above-cited, prior clinical investigations of the device were conducted.] B.

Other published clinical investigations [INSTRUCTIONS: Provide a bibliography of all publications of prior clinical investigations of the device conducted by other investigators that are relevant (i.e., whether adverse or supportive) to the proposed clinical evaluation of the safety and/or effectiveness of the device. For each of the listed publications, provide a brief summary of the relevant (i.e., safety and/or effectiveness) information or conclusion(s) of the respective clinical study (studies). If there are no other publications of prior clinical investigations that are relevant to the proposed clinical evaluation of the safety and/or effectiveness of the device, specify “None”. Incorporate under this section (or a referenced an Appendix) copies of all respective publications that contain adverse information regarding the device (if applicable). If the publications of prior clinical investigations did not reveal any adverse information, specify this.]

3.3

Clinical, Animal and Laboratory Studies Supporting Prior FDA-Approval to Market the Device [INSTRUCTIONS: Incorporate this section only if the device being evaluated is already approved by the FDA for marketing; (i.e., for an indication that is different than that being evaluated in the proposed clinical investigation.) If the device is marketed commercially, incorporate under this section (or by reference to an Appendix) written correspondence from the device manufacturer that permits the FDA to access the manufacturer‟s Pre-Market Approval (PMA) or 510k application for the device.]

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ICTR DDRS: IDE Application Guidance & Template for Significant Risk Devices

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Section 4.0: Investigational Plan [SECTION INTRODUCTION: The requirements for this section of the IDE application are provided below. Some of the information included may not be applicable to all IDE applications. General instructions and comments on the format and content of this section of the IDE application, along with a list of guidance documents and additional regulation references, are provided. Within each subheading of this section are additional instructions, comments, suggested text, web addresses for forms, web addresses for specific guidance documents, and/or regulations.] [REGULATORY REFERENCE: 21CFR812.25] Sec. 812.25 Investigational plan. The investigational plan shall include, in the following order: (a)Purpose. The name and intended use of the device and the objectives and duration of the investigation. (b)Protocol. A written protocol describing the methodology to be used and an analysis of the protocol demonstrating that the investigation is scientifically sound. (c)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 investigation; and a description of the patient population, including the number, age, sex, and condition. (d)Description of 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. (e)Monitoring procedures. The sponsor's written procedures for monitoring the investigation and the name and address of any monitor. (f)Labeling. Copies of all labeling for the device. (g)Consent materials. Copies of all forms and informational materials to be provided to subjects to obtain informed consent. *(h)IRB information A list of the names, locations, and chairpersons of all IRB's that have been or will be asked to review the investigation, and a certification of any action taken by any of those IRB's with respect to the investigation. *(i)Other institutions The name and address of each institution at which a part of the investigation may be conducted that has not been identified in paragraph (h) of this section. (j)Additional records and reports. A description of records and reports that will be maintained on the investigation in addition to those prescribed in subpart G. *[NOTE: Items (h) and (i) are addressed in Sections 7.0 and 8.0]

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ICTR DDRS: IDE Application Guidance & Template for Significant Risk Devices

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[NOTE: 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.] [REGULATORY REFERENCE: GUIDANCE ON THE REVIEW OF INVESTIGATIONAL DEVICE EXEMPTIONS (IDE) APPLICATIONS FOR FEASIBILITY STUDIES (May 17, 1989)] With regard to feasibility studies, per this guidance, the Sponsor-Investigator must “include a thorough risk analysis which describes the risks to the subject, how they will be minimized and a justification that they are reasonable in relation to the expected benefits. The scope and duration of limited studies will vary, but in general, are less ambitious than full clinical studies which provide the pivotal evidence of safety and effectiveness. The investigational plan should have a valid scientific objective and reasonable study protocol.” Per this guidance, “disapprovals” are “limited to situations where there are critical safety-related concerns.” Additionally per the guidance, “deficiencies (other than critical safety-related concerns) can be corrected or clarified under a conditional approval decision.”] 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 wellcontrolled 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 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 wellcontrolled investigation shall include the following: (i)

A clear statement of the objectives of the study.

(ii)

A method of selection of the subjects that:     

(iii)

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 a 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.

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.

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(iv)

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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 patientsubject. 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).

[GUIDANCE DOCUMENTS FOR STATISTICAL CONSIDERATIONS OF DEVICE TRIALS: 

Guidance for the Use of Bayesian Statistics in Medical Device Clinical Trials http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/uc m071072.htm



Statistical Guidance: How many subjects and sites do I have to include in the study? http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevic e/InvestigationalDeviceExemptionIDE/ucm051480.htm#statistics



Statistical Guidance for Clinical Trials of Non Diagnostic Medical Devices http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/uc m106757.htm



Perspectives on Clinical Studies for Medical Device Submissions (Statistical) http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo cuments/UCM106755.pdf

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ICTR DDRS: IDE Application Guidance & Template for Significant Risk Devices

4.0

Investigational Plan

4.1

Purpose of the Investigation A.

Version 2.0

Name of investigational device [INSTRUCTIONS: Specify the name of the investigational device.]

B.

Intended use of the investigational device [INSTRUCTIONS: Summarize the intended use of the investigational device.]

C.

Objectives of the clinical investigation a. Primary objective(s) [INSTRUCTIONS: Describe the primary objective(s) of the proposed clinical investigation of the device. Additionally, indicate that the proposed clinical investigation constitutes a: Feasibility study directed at or involving a(n): o o o o o

Initial evaluation of the device in humans or a certain clinical population Evaluation of potential safety issues associated with the use of the device Evaluation of device design; Assessing certain human factors (e.g., patient or operator) associated with the use of the device; or Other specified device characteristic or device application consideration.

Pilot study to obtain preliminary data upon which to base a subsequent pivotal study of the device OR Pivotal clinical study to collect the primary evidence of safety and effectiveness to support a marketing submission or application]

b. Secondary objective(s) [INSTRUCTIONS: If a feasibility study, describe any secondary objective(s) of the proposed clinical investigation of the device. If a pivotal study, provide a best estimate of the number of months or years it will take to complete (1) the clinical study addressed under section 2.0, Clinical Protocol; and (2) the overall clinical investigation of the device to determine safety and efficacy.]

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D.

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Anticipated duration of the clinical investigation: [INSTRUCTIONS: Provide a best estimate of the number of months or years it will take to complete the proposed study of the device.]

4.2

Clinical Protocol The full clinical protocol is included for FDA review in Appendix___. [INSERT: Provide full version of the clinical protocol in the referenced appendix.]

A.

Title of clinical protocol [INSTRUCTIONS: Specify the title of the clinical study.] a. Protocol Number [INSTRUCTIONS: Incorporate only if applicable.] b. Version number and date [INSTRUCTIONS: Number supplemental applications consecutively and include the date of the current application.]

B.

Study design a. General study design [INSTRUCTIONS: If a feasibility trial, describe the type/design (e.g., open-label, observational) of the proposed clinical study. Note that for Pivotal Studies of investigational devices, the results of treatment or diagnosis with the investigational device must be compared with a control in such a fashion as to permit a quantitative evaluation. The precise nature of the comparison (control) group must be specified in the general description of the study design; i.e.: No treatment control, Placebo control, active treatment control, or historical control.] i.

Minimization of potential bias. [INSTRUCTIONS: If a feasibility trial, delete. For pivotal trials only, describe the specific measures (e.g., randomization, blinding) that will be taken to minimize/avoid bias on the part of the subjects, investigators, and analysts.]

b. Study design schematic [INSTRUCTIONS: Provide a schematic diagram of the study design, procedures, and stages as applicable.]

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C.

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Detailed description of conduct of the trial and all methodologies to be used [SPECIAL NOTE: Applicant must be certain that the language used in the following section of the IDE application is consistent with language contained in the clinical protocol.] a. General characteristics of the proposed subject population(s) [INSTRUCTIONS: Provide a general description of the characteristics of the proposed subject population(s). Provide a justification for the suitability of this (these) population(s) for the purpose of the investigation.] i.

Women and Minorities [INSTRUCTIONS: Provide a brief description and/or justification of how these populations will be incorporated or excluded into the investigation.]

b. Anticipated number of research subjects [INSTRUCTIONS: Define „enrollment‟. Specify the estimated total number of subjects to be enrolled into the clinical study and the anticipated number of subjects expected to complete the study.] c. Inclusion criteria [INSTRUCTIONS: List the specific criteria for including subjects for participation in the clinical study. Note that these criteria should be inclusive of diagnostic criteria and, where appropriate, confirmatory laboratory tests applicable to the specific disease or condition to be treated or diagnosed by the investigational device. In the case of an investigational device intended to prevent a disease or condition, the criteria for subject inclusion should provide for evidence of susceptibility and exposure to the condition against which prophylaxis is desired]. d. Exclusion criteria [INSTRUCTIONS: List the specific criteria for excluding subjects from participation in the clinical study.] D.

Study procedures [SPECIAL NOTE: Applicant must be certain that the language used in the following section of the IDE application is consistent with language contained in the clinical protocol.] a. Screening procedures [INSTRUCTIONS: Describe or list the procedures that will be performed to verify a subject‟s eligibility for participation in the clinical study.]

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b. Study treatment and/or diagnostic product procedures [INSTRUCTIONS: Describe, in detail, the study treatment or diagnostic products (e.g., the investigational device and, if applicable, comparative devices or products) that will be administered to each study group or arm of the proposed clinical investigation; to include, for each study treatment or diagnostic product, the product name and FDA-approval status, dose or dose range (if applicable), route/mode of administration, dosing or exposure schedule, and treatment or exposure duration. Describe, if applicable, any plans for dose or exposure reductions or increases based on the data accrued with study progression.] i.

Allocation to treatment [INSTRUCTIONS: Incorporate only if the proposed clinical study involves multiple treatment arms. Describe the plan and procedures for allocating subjects to the various treatment or diagnostic arms of the study so as to ensure comparability between test groups and any control groups with regard to pertinent variables such as gender, severity or duration of disease, and use of therapy other than the investigational device.]

ii. Breaking the blind [INSTRUCTIONS: Incorporate only if the proposed clinical study is blinded. Describe the procedures for breaking the blind should a given subject suffer a serious adverse event wherein knowledge of the identity of the study treatment or diagnostic product received by the subject is necessary for effective emergency treatment of the event.] iii. Treatment adherence/Study compliance [INSTRUCTIONS: If applicable, describe the procedures that will be used to assess subject compliance/adherence with the assigned study treatment or diagnostic product regimen. Specify the criteria and procedures for withdrawing subjects from study participation due to non-compliance with the study treatment or diagnostic product regimen, if applicable, and/or the study procedures or investigators instructions. Specify if subjects withdrawn from study participation due to noncompliance will be replaced and, if so, the corresponding procedures for their replacement.] c. Follow-up procedures i.

Procedures to assess efficacy [INSTRUCTIONS: If applicable, specify the parameters (i.e., observations and/or measurements) that will be used to evaluate the efficacy of the study treatment or diagnostic product(s); to include the methods and timing for assessing, recording, and analyzing these parameters. Page 34 of 78

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If the proposed clinical study does not involve evaluation(s) of the efficacy of the investigational device, state this.] ii.

Procedures to assess safety [INSTRUCTIONS: Specify the parameters (i.e., procedures, laboratory tests, or other measures) that will be used to evaluate the safety of the study treatment or diagnostic product(s); to include the methods and timing for assessing, recording, and analyzing these parameters.]

iii.

Supportive care [INSTRUCTIONS: Describe any supportive care (i.e., procedures, laboratory tests, or other measures) that will be administered in the course of trial follow-up.]

d. Schedule of activities (Study Table) [INSTRUCTIONS: Incorporate, as a referenced attachment (i.e., Appendix ___), a table that summarizes the protocol procedures that will be performed at screening, for treatment or diagnosis, and at follow-up (if applicable).] E.

Statistical Considerations and Study outcome evaluations [SPECIAL NOTE: Applicant must be certain that the language used in the following section of the IDE application is consistent with language contained in the clinical protocol.] a. Study endpoints [INSTRUCTIONS: Summarize the primary and, if applicable, secondary endpoints or outcomes that will be evaluated in the clinical study. Primary endpoint(s):

Secondary endpoints:

b. Sample size determination [INSTRUCTIONS: Specify the number of subjects planned to be enrolled into the clinical study (i.e., to complete the clinical study) and the reason(s) for the choice of this sample size. Include, if applicable, calculations of the power of the study or provide an alternate explanation for the proposed sample size. For example, if the purpose of the proposed clinical study is to obtain pilot data upon which to base a subsequent pivotal study of the investigation device, state this and provide a clinical justification for the sample size selected.]

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c. Outcome data and data analysis [INSTRUCTIONS: Use this header for feasibility trials. Delete „Data analysis, efficacy analysis, safety analysis, and interim analysis headers below. Describe the specific observations and/or measurements that will form the basis for evaluating the primary and, if applicable, secondary endpoints or outcomes of the clinical study. Describe how these data will be evaluated in addressing the feasibility objective(s) of the clinical study and/or in making a decision to proceed with further clinical investigation of the investigational device.] Data analysis [INSTRUCTIONS: Use “Data Analysis” header for pivotal trials. Outcome data and data analysis‟ above.]

Delete „c.

i. Efficacy analysis [INSTRUCTIONS: Describe the analysis population(s) and statistical methods that will be employed in the analysis (analyses) of primary and secondary (if any) endpoints related to evaluation(s) of the efficacy of the study treatment or diagnostic product(s). Include the level(s) of significance to be used.] ii. Safety analysis [INSTRUCTIONS: Describe the analysis population(s) and statistical methods that will be employed in the analysis of the safety of the study treatment or diagnostic product(s). Include the level of significance to be used.] iii. Interim analysis [INSTRUCTIONS: Incorporate only if an interim analysis is planned. Describe the timing and nature of the planned interim analysis. Address corresponding procedures; such as who will perform the interim analysis and to whom the results of the analysis will be provided. Describe the procedures for reporting, to the FDA, any deviation(s) from the original statistical plan based on the results of the interim analysis (i.e., any deviation(s) from the original statistical plan should be described and justified in a supplemental IDE application).] d. Data and Safety Monitoring (DSM) Plan/Committee [INSTRUCTIONS: Describe the Data and Safety Monitoring Plan. If a Data Safety Monitoring Committee will provide oversight, describe the composition and operations or include DSM Charter as a referenced attachment (i.e., Appendix ___).]

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[For additional information about DSM plans, see “Guidance for Data and Safety Monitoring Plans: Sponsor-Investigator Initiated Clinical Trials”] e. Early stopping rules [INSTRUCTIONS: Describe the early stopping rules of the trial.] f.

Study Interruption or withdrawal [INSTRUCTIONS: Include here any potential reasons for interruption or discontinuation of the protocol.]

4.3

Risk Analysis [SPECIAL NOTE: Applicant must be certain that the language used in the following section of the IDE application is consistent with language contained in the clinical protocol.]

A.

Anticipated risks [INSTRUCTIONS: Describe all increased risks to which the subjects (patientssubjects and normal controls, if applicable) will be exposed as a result of their participation in the clinical study. Address the steps that will be taken to minimize these risks. Provide an analysis of the benefit-to-risk ratio of study participation (i.e., for each of the study populations, as applicable) and a corresponding justification for conducting the clinical study.]

B.

Adverse event recording/reporting a. Adverse event definitions [INSTRUCTIONS: The following is an EXAMPLE of suggested text used by the University of Pittsburgh. Prior to submission for FDA review, the applicant should confirm that the clinical protocol definitions and definitions used here are consistent.] Adverse effect: Any untoward medical occurrence in a clinical study of an investigational device; regardless of the causal relationship of the problem with the device or, if applicable, other study treatment or diagnostic product(s). Associated with the investigational device or, if applicable, other study treatment or diagnostic product(s): There is a reasonable possibility that the adverse effect may have been caused by the investigational device or, if applicable, the other study treatment or diagnostic product(s). Disability: A substantial disruption of a person‟s ability to conduct normal life functions.

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Life-threatening adverse effect: Any adverse effect that places the subject, in the view of the Sponsor-Investigator, at immediate risk of death from the effect as it occurred (i.e., does not include an adverse effect that had it actually occurred in a more severe form, might have caused death). Serious adverse effect: Any adverse effect that results in any of the following outcomes: death, a life-threatening adverse effect, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Hospitalization: Hospitalization shall include any initial admission (even if less than 24 hours) to a healthcare facility as a result of a precipitating clinical adverse effect; to include transfer within the hospital to an intensive care unit. Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical adverse effect (e.g., for a preexisting condition not associated with a new adverse effect or with a worsening of the preexisting condition; admission for a protocol-specified procedure) is not, in itself, a serious adverse effect. Unexpected adverse effect: Any adverse effect, the frequency, specificity or severity of which is not consistent with the risk information described in the clinical study protocol(s) or elsewhere in the current IDE application, as amended. Unanticipated adverse device effect (UADE): Any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or IDE application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects (21 CFR 812.3(s)).

b. Eliciting adverse effect information [INSTRUCTIONS: The following is an EXAMPLE of suggested text used by the University of Pittsburgh. Prior to submission for FDA review, the applicant should confirm that the clinical protocol description of how adverse effect information will be elicited from subjects and text used here are consistent.] Clinical study participants will be routinely questioned about adverse effects at study visits. c. Recording and assessment of adverse effects [INSTRUCTIONS: The following is an EXAMPLE of suggested text used by the University of Pittsburgh. Prior to submission for FDA review, the applicant should confirm that the clinical protocol description of how adverse effects will be recorded and assessed and the text used here are consistent.] All observed or volunteered adverse effects (serious or non-serious) and abnormal test findings, regardless of treatment group, if applicable, or suspected causal relationship to the investigational device or, if applicable, other study treatment or diagnostic product(s) will be recorded in the subjects‟ case Page 38 of 78

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histories. For all adverse effects, sufficient information will be pursued and/or obtained so as to permit 1) an adequate determination of the outcome of the effect (i.e., whether the effect should be classified as a serious adverse effect) and; 2) an assessment of the casual relationship between the adverse effect and the investigational device or, if applicable, the other study treatment or diagnostic product(s). Adverse effects or abnormal test findings felt to be associated with the investigational device or, if applicable, other study treatment or diagnostic product(s) will be followed until the effect (or its sequelae) or the abnormal test finding resolves or stabilizes at a level acceptable to the Sponsor-Investigator. i.

Abnormal test findings: [INSTRUCTIONS: The following is an EXAMPLE of suggested text used by the University of Pittsburgh. Prior to submission for FDA review, the applicant should confirm that the clinical protocol and text used here regarding abnormal test findings are consistent.] An abnormal test finding will be classified as an adverse effect if one or more of the following criteria are met: • •

• •

The test finding is accompanied by clinical symptoms. The test finding necessitates additional diagnostic evaluation(s) or medical/surgical intervention; including significant additional concomitant drug or other therapy. (Note: simply repeating a test finding, in the absence of any of the other listed criteria, does not constitute an adverse effect.) The test finding leads to a change in study dosing or exposure or discontinuation of subject participation in the clinical study. The test finding is considered an adverse effect by the SponsorInvestigator.

ii.

Causality and severity assessment

iii.

[INSTRUCTIONS: The following is an EXAMPLE of suggested text used by the University of Pittsburgh. Prior to submission for FDA review, the applicant should confirm that the clinical protocol and text used here regarding causality and severity assessment are consistent.] The Sponsor-Investigator will promptly review documented adverse effects and abnormal test findings to determine 1) if the abnormal test finding should be classified as an adverse effect; 2) if there is a reasonable possibility that the adverse effect was caused by the investigational device or, if applicable, other study treatment or diagnostic product(s); and 3) if the adverse effect meets the criteria for a serious adverse effect. If the Sponsor-Investigator‟s final determination of causality is “unknown and of questionable relationship to the investigational device or, if applicable, other study treatment or diagnostic product(s)”, the adverse effect will be classified as associated with the use of the investigational device or study treatment or diagnostic drug product(s) for reporting Page 39 of 78

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purposes. If the Sponsor-Investigator‟s final determination of causality is “unknown but not related to the investigational device or, if applicable, other study treatment or diagnostic product(s)”, this determination and the rationale for the determination will be documented in the respective subject‟s case history. d. Reporting of adverse effects to the FDA [INSTRUCTIONS: The following is an EXAMPLE of suggested text used by the University of Pittsburgh. Prior to submission for FDA review, the applicant should confirm that the clinical protocol description of adverse effect reporting to FDA and the text used here are consistent. NOTE: An example Form FDA 3500A has been included in the Appendices for the applicant‟s reference only. Instructions for form completion are also provided. Neither the example form nor the instructions for completion should be included in the IDE submission for FDA review. NOTE: In the case of Sponsor-Investigator, the reports should be reported to FDA and the IRB at the same time.]

The Sponsor-Investigator will submit a completed FDA Form 3500A to the FDA‟s Center for Devices and Radiological Health for any observed or volunteered adverse effect that is determined to be an unanticipated adverse device effect. A copy of this completed form will be provided to all participating sub-investigators. The completed FDA Form 3500A will be submitted to the FDA as soon as possible and, in no event, later than 10 working days after the SponsorInvestigator first receives notice of the adverse effect. If the results of the Sponsor-Investigator‟s follow-up evaluation show that an adverse effect that was initially determined to not constitute an unanticipated adverse device effect does, in fact, meet the requirements for reporting; the Sponsor-Investigator will submit a completed FDA Form 3500A as soon as possible, but in no event later than 10 working days, after the determination was made. For each submitted FDA Form 3500A, the Sponsor-Investigator will identify all previously submitted reports that that addressed a similar adverse effect experience and will provide an analysis of the significance of newly reported adverse effect in light of the previous, similar report(s). Subsequent to the initial submission of a completed FDA Form 3500A, the Sponsor-Investigator will submit additional information concerning the reported adverse effect as requested by the FDA. e. Reporting of adverse effects to the responsible IRB [INSERT: Suggested text is provided below. If used, the applicant should confirm that the clinical protocol description of adverse effect reporting to the IRB and the text used here are consistent prior to submission for FDA review.] Page 40 of 78

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As per the Johns Hopkins Medicine Institutional Review Board Guideline entitled „Research Using FDA Test Articles (August 2010),” the IDE SponsorInvestigator will submit to all reviewing IRBs and participating investigators any evaluation of an unanticipated device effect within ten (10) working days of first receiving notice of the effect (21 CFR 812.150 (b)(1)). Follow-up information to reported adverse effects will be submitted to the IRB as soon as the relevant information is available. If the results of the SponsorInvestigator‟s follow-up investigation show that an adverse effect that was initially determined to not require reporting to the IRB does, in fact, meet the requirements for reporting; the Sponsor-Investigator will report the adverse effect to the IRB as soon as possible, but in no event later than 10 calendar days, after the determination was made. C.

Withdrawal of subjects due to adverse effects [INSTRUCTIONS: Specify the criteria and procedures for withdrawing subjects from continued exposure to the investigational device or, if applicable, other study treatment or diagnostic product(s) due to an observed or volunteered adverse effect; to include the type and timing of data to be collected from withdrawn subjects. Specify if subjects withdrawn from study participation due to an adverse effect will be replaced and, if so, the corresponding procedures for their replacement.]

4.4

Description of the Investigational Device [INSTRUCTIONS: Provide a description of each important component, ingredient or element, property, and principle of operation of the investigational device. Describe any anticipated change(s) in the investigational device during the course of the clinical study, if applicable. If no changes to the device are anticipated, state this.]

4.5

Monitoring Procedures [INSERT: Incorporate the text provided below as written, then add the information addressed in the „instructions‟ below.] Johns Hopkins University policy requires a monitoring process for receipt, dispensing, and record keeping concerning all devices that are studied using an IDE granted by FDA. The monitoring process shall be performed by the Compliance Monitoring Specialists of the Johns Hopkins Office of Human Subjects Research (OHSR). The address of the Johns Hopkins Office of Human Subjects Research is: Johns Hopkins Office of Human Subjects Research 1620 Mc Elderry Street Reed Hall - B130 Baltimore, MD 21205-1911 Researchers who serve as a Sponsor-Investigator for an IDE research study are required by the Johns Hopkins University to follow FDA regulations 21 CFR 812 Subpart C applicable to Sponsor responsibilities. Page 41 of 78

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Compliance Monitoring Specialists of the Johns Hopkins OHSR will conduct a monitoring visit for investigators holding an IDE to determine compliance with FDA Sponsor requirements in 21 CFR 812 before initiation of the research. [INSTRUCTIONS: Describe the nature and timing of any quality control/quality assurance reviews (i.e., independent of the previously described monitoring activities) that will be undertaken by the Sponsor-Investigator to ensure appropriate conduct of the clinical study and quality and completeness of the accrued study data. I.e., describe the data and safety monitoring plan for the clinical study as outlined in the IRB application or include DSM plan/charter in the appendices and reference same here. As 21CFR 812.43(d) does not give specific criteria for selection of monitors, as SponsorInvestigator, the applicant is responsible for choosing appropriate monitors based on identified risk. Therefore, if one or both (internal and external) monitors are required they must be identified here. The investigator running the trial is technically responsible for overall „internal monitoring‟, but may delegate this responsible to another project team member. If a Sponsor-Investigator is running trial, then she/he is technically responsible for all trial monitoring, whether internal or external. Include names and contact information for internal and external monitors.] Internal Monitor: Name Title Address Phone number FAX number Email Address External Monitor: Name Title Address Phone number FAX number Email Address

4.6

Additional Records and Reports A.

Data handling and record-keeping [INSTRUCTIONS: Describe the procedures for management and retention of study data including accounting for any missed, unused, and/or spurious data. In appendices, include a copy of Case Report Forms (CRF) and reference “See Appendix__.” Page 42 of 78

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Identify, if applicable, any clinical study data that will be recorded directly on the CRF, whereupon the CRF data is to be considered the Source Data. It is strongly suggested that CRFs NOT be used to collect source data. However, if any CRFs are to be used to collect source data, then there must be an SOP describing the CRFs and the procedures for documenting the source data on the CRFs. Additionally, the CRFs must be signed and dated at the time the data is collected by the person collecting the data. If an electronic system will be used as the sole instrument for the recording and analysis of clinical and laboratory data related to the safety and/or efficacy of the investigational device, address compliance with the FDA‟s electronic records and electronic signatures regulations at 21 CFR Part 11.] B.

Record maintenance and retention [INSTRUCTIONS: Insert the following text provided, then add information discussed in instructions below. Prior to submission for FDA review, the applicant should confirm that the clinical protocol and provided text used here are consistent.] The Sponsor-Investigator will retain the specified records and reports for up to 2 years after the marketing application is approved for the investigational device; or, if a marketing application is not submitted or approved for the investigational drug, until 2 years after investigations under the IDE have been discontinued and the FDA so notified. [INSTRUCTIONS: Describe how the subject-specific data and Case Report Forms will be coded and how these materials, and the subject identification code list, will be stored so as to protect the subjects‟ confidentiality. Specify that subject names or other directly identifiable information will not appear on any reports, publications, or other disclosures of clinical study outcomes.]

C.

Clinical Trial Registration [COMMENTS: Per Title VIII of the Food and Drug Administration Amendments Act of 2007 or FDAAA (U.S. Public Law 110-85) clinical trial registration and reporting requirements, all applicable trials must be registered at clinicaltrials.gov, and results reported as required. As part of this requirement, the FDA created the Form FDA 3674 to certify compliance with registration of trials. To follow are a number of resources that provide additional guidance and information concerning this requirement. If the Sponsor-Investigator needs additional guidance, please contact the ICTR Research Navigators. Even if the protocol being submitted is not required to be registered at ClinicalTrials.gov, the Sponsor-Investigator must check the appropriate box in section 9 of the form and submit the Form FDA 3674, entitled „Certification of Compliance, under 42 U.S.C § 282(j)(5)(B), with Requirements of ClinicalTrials.gov Data Bank (42 U.S.C § 282(j))‟, with the IND application.]

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[GUIDANCE INFORMATION RESOURCES FOR TRIAL REGISTRATION]  FDA Guidance Document on registering trials on ClinicalTrials.gov  Clinicaltrials.gov Protocol Registration System Information Website  NIH Grantees Clinicaltrials.gov and FDAAA Policy Site  Elaboration of Definitions of Responsible Party and Applicable Clinical Trial  JHM IRB Organizational Policy  JHM IRB Organizational Guideline  Form FDA 3674 website to download PDF fillable form  Form FDA 3674 instructions website [INSTRUCTIONS: An “applicable device” clinical trial is a prospective clinical study of health outcomes comparing an intervention with a device against a control in human subjects (other than a small clinical trial to determine the feasibility of a device, or a clinical trial to test prototype devices where the primary outcome measure relates to feasibility and not to health outcomes). If the applicant‟s clinical trial meets the definition of “applicable device” trial, include the following text and provide a completed FDA Form 3674 in appendices. If it does not meet the definition of applicable trial, state so here.]

Please see the signed and dated Form FDA 3674 in Appendix ____.

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Section 5.0: Methods, Facilities and Controls Information [SECTION INTRODUCTION: The requirements for this section of the IDE application are provided below. Some of the information included may not be applicable to all IDE applications. General instructions and comments on the format and content of this section of the IDE application, along with a list of guidance documents and additional regulation references, are provided. Within each subheading of this section are additional instructions, comments, suggested text, web addresses for forms, web addresses for specific guidance documents, and/or regulations.] [REGULATORY REFERENCE: 21CFR812.20(b)(3)] A description of the methods, facilities, and controls used for the manufacture, processing, packing, storage, and, where appropriate, installation of the device, in sufficient detail so that a person generally familiar with good manufacturing practices can make a knowledgeable judgment about the quality control used in the manufacture of the device. [REGULATORY REFERENCE: 21CFR820.30 Design Controls] (a)General: (1) Each manufacturer of any class III or class II device, and the class I devices listed in paragraph (a)(2) of this section, shall establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met. (2) The following class I devices are subject to design controls: (i) Devices automated with computer software; and (ii) The devices listed in the following chart: Section

Device

868.6810

Catheter, Tracheobronchial Suction.

878.4460

Glove, Surgeon's.

880.6760

Restraint, Protective.

892.5650

System, Applicator, Radionuclide, Manual

892.5740

Source, Radionuclide Teletherapy

(b)Design and development planning; Each manufacturer shall establish and maintain plans that describe or reference the design and development activities and define responsibility for implementation. The plans shall identify and describe the interfaces with different groups or activities that provide, or result in, input to the design and development process. The plans shall be reviewed, updated, and approved as design and development evolves. (c)Design input: Each manufacturer shall establish and maintain procedures to ensure that the design requirements relating to a device are appropriate and address the intended use of the device, including the needs of the user and patient. The procedures shall include a mechanism for addressing incomplete, ambiguous, or conflicting requirements. The design input requirements shall be documented and shall be reviewed and approved by a designated individual(s). The approval, including the date and signature of the individual(s) approving the requirements, shall be documented. Page 45 of 78

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(d)Design output: Each manufacturer shall establish and maintain procedures for defining and documenting design output in terms that allow an adequate evaluation of conformance to design input requirements. Design output procedures shall contain or make reference to acceptance criteria and shall ensure that those design outputs that are essential for the proper functioning of the device are identified. Design output shall be documented, reviewed, and approved before release. The approval, including the date and signature of the individual(s) approving the output, shall be documented. (e)Design review: Each manufacturer shall establish and maintain procedures to ensure that formal documented reviews of the design results are planned and conducted at appropriate stages of the device's design development. The procedures shall ensure that participants at each design review include representatives of all functions concerned with the design stage being reviewed and an individual(s) who does not have direct responsibility for the design stage being reviewed, as well as any specialists needed. The results of a design review, including identification of the design, the date, and the individual(s) performing the review, shall be documented in the design history file (the DHF). (f)Design verification: Each manufacturer shall establish and maintain procedures for verifying the device design. Design verification shall confirm that the design output meets the design input requirements. The results of the design verification, including identification of the design, method(s), the date, and the individual(s) performing the verification, shall be documented in the DHF. (g)Design validation: Each manufacturer shall establish and maintain procedures for validating the device design. Design validation shall be performed under defined operating conditions on initial production units, lots, or batches, or their equivalents. Design validation shall ensure that devices conform to defined user needs and intended uses and shall include testing of production units under actual or simulated use conditions. Design validation shall include software validation and risk analysis, where appropriate. The results of the design validation, including identification of the design, method(s), the date, and the individual(s) performing the validation, shall be documented in the DHF. (h)Design transfer: Each manufacturer shall establish and maintain procedures to ensure that the device design is correctly translated into production specifications. (i)Design changes: Each manufacturer shall establish and maintain procedures for the identification, documentation, validation or where appropriate verification, review, and approval of design changes before their implementation. (j)Design history file: Each manufacturer shall establish and maintain a DHF for each type of device. The DHF shall contain or reference the records necessary to demonstrate that the design was developed in accordance with the approved design plan and the requirements of this part.

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Methods, Facilities and Control Information [COMMENT: This section of the IDE application should incorporate or reference a description of the methods, facilities, and controls used for the manufacturing, processing, packaging, and (if applicable) installation of the device.]

5.1

Device Manufacturer A.

Manufacturer name, address, and contact information [INSTRUCTIONS: Incorporate the following information.] Name of device manufacturer: Address: Contact person: Telephone number: FAX number:

B.

Manufacturer compliance with Subpart C, Design Controls (section 820.30), of the Quality System Regulations (21 CFR Part 820): [INSTRUCTIONS: Specify whether or not the manufacturer of the device is a commercial or contract manufacturer with a history of operating in full compliance with the FDA‟s Quality System Regulations; in particular the Design Controls section (i.e., Section 820.30) of these regulations. If the manufacturer of the device does not operate, or does not have a history of operating, in full compliance with these regulations, provide a reason for such non-compliance (e.g., INSERT: “The manufacturer of the device does not have a history of operating in full compliance with 21 CFR 820 because Johns Hopkins University is an academic institution and the proposed clinical investigation of the device is limited to a study.”) If the device being evaluated in the proposed clinical investigation is currently a commercially marketed device (i.e., labeled for a different clinical indication), specify this and incorporate under this section (or in a referenced Appendix), a letter or other written notification from the commercial manufacturer authorizing the FDA to access the manufacturer‟s respective PMA or 510K application or, if applicable, the manufacturer‟s Device Master Record. (E.g. INSERT: “The device under study is commercially available and is under investigation for a new indication. A Letter of Authorization to the manufacturer‟s is included in this application as Appendix X.”) If the device being evaluated in the proposed clinical investigation is currently being evaluated (e.g., for a different clinical indication) under a separate industrysponsored IDE, specify this and incorporate under this section (or in a referenced Appendix), a letter or other written notification from the manufacturer authorizing the FDA to access the manufacturer‟s respective IDE or Device Master Record (i.e., the compilation of records containing the procedures and specifications for a finished device). (E.g. INSERT: “The device under study is currently being evaluated for a different clinical indication under an industry sponsored IDE. A Letter of Authorization to the manufacturer‟s Device Master Record is included in this application as Appendix X.”)] Page 47 of 78

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Device Design and Manufacturing Information [INSTRUCTIONS: Incorporate these sections if the device (or other components of the device system) is/are being manufactured by or under the direction of the Sponsor-Investigator for the specific purpose of its evaluation under this IDE application. If this is not the case, so state here and delete Section C.a through and including Section E.] Note: The extent of the manufacturing information to be provided under this section must be adequate so as to permit a judgment that the manufacturing, processing and quality control testing procedures will result routinely in a device that meets the intended specifications. It is recommended that the manufacturing information be presented in the following format and address, at a minimum, the following information: a. Device design: [INSTRUCTIONS: Provide an adequate characterization or description of the device and its operation to include the (a): • Design/engineering drawing of the device • Rationale for the device design • Device and device performance specifications • Description of the device materials (including biocompatibility information) • Description of device function (e.g., how does the device and/or other components/subsystems work together to achieve the desired function) • Validation testing for the subsystems and main system Note: the manufacture of devices for evaluation under Sponsor-Investigator IDE applications is subject to compliance with the Design Controls section (Section 820.30) of the FDA‟s Quality System Regulations (21 CFR Part 820). While it is not necessary to address compliance with each of the Design Control requirements in the IDE application, the Sponsor-Investigator and/or manufacturer should be able to provide certain documentation that the following activities have occurred and/or that applicable processes and procedures are in place: i.

Design input [INSTRUCTIONS: Design input refers to the process for ensuring that design requirements relating to a device are appropriate and address the intended use of the device, including the needs of the user and patient. Design input establishes the desired physical and performance requirements of device that are used as a basis for device design. The design input discussions and requirements should be documented and should be reviewed and approved by the Sponsor-Investigator. The approval, including the date and signature of the Sponsor-Investigator, should also be documented.

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Design output [INSTRUCTIONS: Design output refers to the process for defining and documenting that the output of the device will be in conformance with the design input requirements. Design output procedures shall contain or make reference to acceptance criteria and shall ensure that those design outputs that are essential for the proper functioning of the device are identified. Design output discussions (i.e., which are anticipated to occur at each design phase and at the end of the total design effort) should be documented, reviewed, and approved by the Sponsor-Investigator before the next design phase or release of the device. The approval, including the date and signature of the Sponsor-Investigator, should be documented. Note that the design output process forms the basis for the acceptance criteria of the final device that appear in a Device Master Record; i.e., the compilation of the records containing the procedures and specifications for a finished device.]

iii.

Design verification [INSTRUCTIONS: Design verification involves confirmation by examination/testing and the provision of objective evidence that the design output meets the design input requirements. The results of the design verification, including identification of the design stage, method(s), the date, and the individual(s) performing the verification should be documented in a Design History File; i.e., the compilation of records which describes the design history of a finished device.]

iv.

Design review [INSTRUCTIONS: Design review refers to formal, systematic (i.e., conducted at planned intervals) reviews of the design verification results conducted at appropriate stages of the device‟s design development for the purpose of evaluating the adequacy of the design requirements, evaluating the capability of the design to meet these requirements, and identifying problems. The outcome of the design reviews, including identification of the design stage, the date, and the individuals involved in the review should be documented in the Design History File.]

v.

Design validation [INSTRUCTIONS: Design validation refers to the process and procedures for confirming, by the collection of objective evidence, that the device specifications conform to the user‟s needs and intended use(s). Design validation should be performed under defined operating conditions on initial production units, lots, or batches, or their equivalents. Design validation should include testing of production units under actual or simulated use conditions; and should, where appropriate, include software validation and risk analysis. The results of the design validation evaluation(s), including identification of the design, method(s), the date, and the individual(s) performing the validation should be documented in the Device History File.]

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Design transfer [INSTRUCTIONS: There should be an established (i.e., written) process and corresponding procedures for ensuring that the acceptance criteria associated with the final device design acceptance are correctly translated into production specifications.]

vii.

Design changes [INSTRUCTIONS: There should be an established (i.e., written) process and corresponding procedures for the identification, documentation, validation or where appropriate verification, review, and approval of design changes before their implementation.]

D.

Manufacturing controls [INSTRUCTIONS: Provide a description of the process validation and the manufacturing controls (i.e., quality control testing) that will be used to ensure that the device(s) is (are) produced in accordance with the device design and performance specifications. Note that process validation refers to objective evidence that a process consistently produces a product that meets its predetermined specifications. Appropriate process validation is particularly important if the manufacturing process results in the production of multiple units of the device wherein only a sample of the total batch or lot will actually undergo defined quality control testing to ensure that the devices meet or exceed defined specifications prior to their release for human use. Emphasis on appropriate process validation may be lessened if the manufacturing process is directed at producing a lot or batch comprised of only one or a very limited number of devices and the quality control testing is performed on each device in the lot or batch prior to its release for human use. It is thus important to specify under this section if the manufacturing process will be directed at producing only one or a limited number of devices per given lot or batch.]

E.

Processing, Packaging, Storage and Installation [INSTRUCTIONS: Provide a description of any processing, package, storage and/or installation of the device (as applicable.)]

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Section 6.0: Example of Investigator Agreements, Certification of Investigators and Financial Interest [SECTION INTRODUCTION: The requirements for this section of the IDE application are provided below. Some of the information included may not be applicable to all IDE applications. General instructions and comments on the format and content of this section of the IDE application, along with a list of guidance documents and additional regulation references, are provided. Within each subheading of this section are additional instructions, comments, suggested text, web addresses for forms, web addresses for specific guidance documents, and/or regulations.] [REGULATORY REFERENCE: 21CFR812.20(b)(4&5)] (b)Contents: An IDE application shall include: (4) An example of the agreements to be entered into by all investigators to comply with investigator obligations under this part, and a list of the names and addresses of all investigators who have signed the agreement. (5) A certification that all investigators who will participate in the investigation have signed the agreement, that the list of investigators includes all the investigators participating in the investigation, and that no investigators will be added to the investigation until they have signed the agreement. [REGULATORY REFERENCE: 21 CFR 54 Financial Disclosures By Clinical Investigators 21 CFR 54.4 Certification and disclosure requirements For purposes of this part, an applicant must submit a list of all clinical investigators who conducted covered clinical studies to determine whether the applicant's product meets FDA's marketing requirements, identifying those clinical investigators who are full-time or part-time employees of the sponsor of each covered study. The applicant must also completely and accurately disclose or certify information concerning the financial interests of a clinical investigator who is not a full-time or part-time employee of the sponsor for each covered clinical study. Clinical investigators subject to investigational new drug or investigational device exemption regulations must provide the sponsor of the study with sufficient accurate information needed to allow subsequent disclosure or certification. The applicant is required to submit for each clinical investigator who participates in a covered study, either a certification that none of the financial arrangements described in 54.2 exist, or disclose the nature of those arrangements to the agency. Where the applicant acts with due diligence to obtain the information required in this section but is unable to do so, the applicant shall certify that despite the applicant's due diligence in attempting to obtain the information, the applicant was unable to obtain the information and shall include the reason. (a) The applicant (of an application submitted under sections 505, 506, 510(k), 513, or 515 of the Federal Food, Drug, and Cosmetic Act, or section 351 of the Public Health Service Act) that relies in whole or in part on clinical studies shall submit, for each clinical investigator who participated in a covered clinical study, either a certification described in paragraph (a)(1) of this section or a disclosure statement described in paragraph (a)(3) of this section. (1) Certification: The applicant covered by this section shall submit for all clinical investigators (as defined in 54.2(d)), to whom the certification applies, a completed Form FDA 3454 attesting to the absence of financial interests and arrangements described in paragraph (a)(3) of this section. The form shall be dated and signed by the chief financial officer or other responsible corporate official or representative. Page 51 of 78

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(2) If the certification covers less than all covered clinical data in the application, the applicant shall include in the certification a list of the studies covered by this certification. (3) Disclosure Statement: For any clinical investigator defined in 54.2(d) for whom the applicant does not submit the certification described in paragraph (a)(1) of this section, the applicant shall submit a completed Form FDA 3455 disclosing completely and accurately the following: (i) Any financial arrangement entered into between the sponsor of the covered study and the clinical investigator involved in the conduct of a covered clinical trial, whereby the value of the compensation to the clinical investigator for conducting the study could be influenced by the outcome of the study; (ii) Any significant payments of other sorts from the sponsor of the covered study, such as a grant to fund ongoing research, compensation in the form of equipment, retainer for ongoing consultation, or honoraria; (iii) Any proprietary interest in the tested product held by any clinical investigator involved in a study; (iv) Any significant equity interest in the sponsor of the covered study held by any clinical investigator involved in any clinical study; and (v) Any steps taken to minimize the potential for bias resulting from any of the disclosed arrangements, interests, or payments. (b) The clinical investigator shall provide to the sponsor of the covered study sufficient accurate financial information to allow the sponsor to submit complete and accurate certification or disclosure statements as required in paragraph (a) of this section. The investigator shall promptly update this information if any relevant changes occur in the course of the investigation or for 1 year following completion of the study. (c) Refusal to file application. FDA may refuse to file any marketing application described in paragraph (a) of this section that does not contain the information required by this section or a certification by the applicant that the applicant has acted with due diligence to obtain the information but was unable to do so and stating the reason.

[NOTE: Examples of an Investigator Agreement, Form FDA 3454 (Financial Interest Certification) and Form FDA 3455 (Financial Interest Disclosure) are provided in the Appendices for applicant reference]

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Example of Investigator Agreements, Certification of Investigators and Financial Interest

6.1

Investigator‟s Agreement A.

As an example of the investigator‟s agreement used in this study, the document as completed by supply name of Sponsor Investigator, the Principal Investigator of this study, is shown in Appendix_____ [INSERT: Include correct Appendix number]

B.

The investigator's curriculum vitae is provided in Appendix_____ [INSERT: Include correct Appendix number]

C.

A statement of the investigator's relevant experience (including the dates, location, extent and type of experience) is provided in Appendix_____ [INSERT: Include correct Appendix number]

D.

An explanation of the circumstances that led to the termination of any investigation or research endeavor in which the investigator was involved has been provided in Appendix_____ [INSERT: Include correct Appendix number]

E.

A statement of the investigator's commitment to: conduct the investigation in accordance with the agreement, the investigational plan, Part 812 and other applicable FDA regulations, and conditions of approval imposed by the reviewing IRB and FDA; supervise all testing of the device involving human subjects; and ensure that the requirements for obtaining informed consent are met is provided in Appendix ____ [INSERT: Include correct Appendix number]

F.

A statement of the investigator‟s commitment to provide sufficient and accurate financial disclosure information and update information if any relevant changes occur during the investigation and for one year following the completion of the study is provided in Appendix _____ [INSERT: Include correct Appendix number]

G.

Certification that all participating investigators have signed the agreement and that no investigator will be added until the agreement is signed is provided in Appendix _____ [INSERT: Include correct Appendix number]

H.

Name and address of investigators who have signed the agreement. The list containing the names and respective address of investigators who have signed the investigator‟s agreement for this study is shown in Appendix _____ [INSERT: Include correct Appendix number]

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Section 7.0: Reviewing Institutional Review Boards [SECTION INTRODUCTION: The requirements for this section of the IDE application are provided below. Some of the information included may not be applicable to all IDE applications. General instructions and comments on the format and content of this section of the IDE application, along with a list of guidance documents and additional regulation references, are provided. Within each subheading of this section are additional instructions, comments, suggested text, web addresses for forms, web addresses for specific guidance documents, and/or regulations.] [REGULATORY REFERENCE: 21CFR812.20(b)(6)] (b)Contents: An IDE application shall include: A list of the name, address, and chairperson of each IRB that has been or will be asked to review the investigation and a certification of the action concerning the investigation taken by each such IRB should be included here. If the IRB application has not yet been submitted and no designation has been made as to which JHM IRB will be reviewing the application, list all JHM IRB chairpersons here.]

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Reviewing Institutional Review Boards

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Name, address, and chairperson of each reviewing IRB

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A. This study will be reviewed by a single IRB [INSTRUCTIONS: Include if applicable, otherwise delete this statement] Name: Address: Chairperson(s):

B. Certification of action taken by IRB [INSTRUCTIONS: Complete and include the applicable statement. applicable statement.]

Delete non-

a. This investigation has already been approved by the following IRB‟s (The respective approval letters are shown in Appendix number(s) (Supply correct designation(s): [INSERT: List all applicable IRB‟s] b. This investigation is currently awaiting or is under review by the following IRB‟s: [INSERT: List all applicable IRB‟s]

C. Names and addresses of additional institutions, not previously identified, where a part of the investigation may be conducted [INSERT: List all applicable IRB‟s. If none, indicate so here.]

Name: Address: Chairperson(s):

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Section 8.0: Other Involved Institutions [SECTION INTRODUCTION: The requirements for this section of the IDE application are provided below. Some of the information included may not be applicable to all IDE applications. General instructions and comments on the format and content of this section of the IDE application, along with a list of guidance documents and additional regulation references, are provided. Within each subheading of this section are additional instructions, comments, suggested text, web addresses for forms, web addresses for specific guidance documents, and/or regulations.] [REGULATORY REFERENCE: 21CFR812.20(b)(7)] (b)Contents: An IDE application shall include: (7) The name and address of any institution at which a part of the investigation may be conducted that has not been identified in accordance with paragraph (b)(6) of this section.

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Other Involved Institutions

[INSTRUCTIONS: If applicable, list the name(s) and address(es) of any institution(s) at which a part of the clinical investigation of the device may be conducted and that has (have) not already been identified under the previous section (Reviewing Institutional Review Boards). If no institutions, other than those already listed above will be involved in conducting part of the clinical investigation, specify “None”.] Name: Address: Chairperson(s):

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Section 9.0: Device Charges [SECTION INTRODUCTION: The requirements for this section of the IDE application are provided below. Some of the information included may not be applicable to all IDE applications. General instructions and comments on the format and content of this section of the IDE application, along with a list of guidance documents and additional regulation references, are provided. Within each subheading of this section are additional instructions, comments, suggested text, web addresses for forms, web addresses for specific guidance documents, and/or regulations.] [REGULATORY REFERENCE: 21CFR812.20(b)(8)] (b)Contents: An IDE application shall include: (8) If the device is to be sold, the amount to be charged and an explanation of why sale does not constitute commercialization of the device. [REGULATORY REFERENCE: 21CFR812.7] Promotion of Investigational Devices Under §812.7, a sponsor, investigator, or any person acting for or on behalf of a sponsor or investigator cannot:  Promote or test market an investigational device, until after FDA has approved the device for commercial distribution.  Commercialize an investigational device by charging the subjects or investigators a higher price than that necessary to recover costs of manufacture, research, development, and handling.  Unduly prolong an investigation. If data developed by the investigation indicate that premarket approval (PMA) cannot be justified, the sponsor must promptly terminate the investigation.  Represent that an investigational device is safe or effective. However, the sponsor may advertise for research subjects to solicit their participation in a study. Appropriate advertising methods include but are not necessarily limited to: newspaper, radio, TV, bulletin boards, posters, and flyers that are intended for prospective subjects. Advertisements should be reviewed and approved by the IRB to assure that it is not unduly coercive and does not promise a certainty of cure beyond what is outlined in the consent and the protocol. No claims should be made, either explicitly or implicitly, that the device is safe or effective for the purposes under investigation, or that the test article is known to be equivalent or superior to any other device. FDA considers direct advertising for study subjects to be the start of the informed consent and subject selection process. Additional guidance is available in the following guidance documents: "Information Sheets: Guidance for Institutional Review Boards and Clinical Investigators, 1998 Recruiting for Study Subjects Preparing Notices of Availability of Investigational Medical Devices and for Recruiting Study Subjects

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Device Charges

[INSTRUCTIONS: Specify whether or not any of the investigators or the research subjects or their insurance providers will be charged for the device. If there will be a charge for the device, indicate the amount that will be charged and provide an explanation as to why charging this amount does not involve commercialization of the device (i.e., justify that the amount charged for the device represents only the actual costs associated with research and development, manufacture and distribution of the device.)]

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Section 10.0: Device Labeling [SECTION INTRODUCTION: The requirements for this section of the IDE application are provided below. Some of the information included may not be applicable to all IDE applications. General instructions and comments on the format and content of this section of the IDE application, along with a list of guidance documents and additional regulation references, are provided. Within each subheading of this section are additional instructions, comments, suggested text, web addresses for forms, web addresses for specific guidance documents, and/or regulations.] [REGULATORY REFERENCE: 21CFR812.20(b)(10)] (b)Contents: An IDE application shall include: (10) Copies of all labeling for the device [REGULATORY REFERENCE: 21CFR812.5] Sec. 812.5 Labeling of investigational devices. (a)Contents. An investigational device or its immediate package shall bear a label with the following information: the name and place of business of the manufacturer, packer, or distributor (in accordance with 801.1), the quantity of contents, if appropriate, and the following statement: "CAUTION--Investigational device. Limited by Federal (or United States) law to investigational use." The label or other labeling shall describe 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 purposes for which it is being investigated. (c)Animal research. An investigational device shipped solely for research on or with laboratory animals shall bear on its label the following statement: "CAUTION--Device for investigational use in laboratory animals or other tests that do not involve human subjects." (d) The appropriate FDA Center Director, according to the procedures set forth in 801.128 or 809.11 of this chapter, may grant an exception or alternative to the provisions in paragraphs (a) and (c) of this section, to the extent that these provisions are not explicitly required by statute, for specified lots, batches, or other units of a device that are or will be included in the Strategic National Stockpile.

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Device Labeling [INSTRUCTIONS: Incorporate under this section (or by reference to an Appendix) a copy of the label that will be attached to the device or its immediate package and any other product labeling that will be provided to investigators. Note that the FDA‟s investigational device regulations (21 CFR Sec. 809.10(c)(2)(i)) specify that the investigational device or its immediate package shall bear a label with the following information: •

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

•

Quantity of contents, if appropriate;

•

The statement, “CAUTION – Investigational device. Limited by Federal law to investigational use”

•

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

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Section 11.0: Consent Materials [SECTION INTRODUCTION: The requirements for this section of the IDE application are provided below. Some of the information included may not be applicable to all IDE applications. General instructions and comments on the format and content of this section of the IDE application, along with a list of guidance documents and additional regulation references, are provided. Within each subheading of this section are additional instructions, comments, suggested text, web addresses for forms, web addresses for specific guidance documents, and/or regulations.] [REGULATORY REFERENCE: 21CFR812.20(b)(11)] (b)Contents: An IDE application shall include: (11) Copies of all forms and informational materials to be provided to subjects to obtain informed consent.

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Consent Materials [INSTRUCTIONS: Incorporate under this section (or by reference to an Appendix) the proposed informed consent form(s) that will be used for the clinical investigation(s) of the device included as part of this IDE application. If applicable, incorporate under this section (or by reference to an Appendix) any other informational materials that will be provided to potential research subjects in obtaining their informed consent for study participation.]

11.1

Patient Consent Forms A.

A copy of the proposed Informed Consent document for this trial is provided in Appendix____. [INSERT: Provide correct appendix number.]

B.

A copy of _________________ [INSERT: Include other patient educational or informational documents that are to be presented to the subject which are being provided for FDA review] materials have been provided in Appendix ______. [INSERT: Provide correct appendix number.]

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Section 12.0: Other Relevant Information [SECTION INTRODUCTION: The requirements for this section of the IDE application are provided below. Some of the information included may not be applicable to all IDE applications. General instructions and comments on the format and content of this section of the IDE application, along with a list of guidance documents and additional regulation references, are provided. Within each subheading of this section are additional instructions, comments, suggested text, web addresses for forms, web addresses for specific guidance documents, and/or regulations.] [REGULATORY REFERENCE: 21CFR812.20(b)(12)] (b)Contents: An IDE application shall include: (12) Any other relevant information FDA requests for review of the application.

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Other Relevant Information

[INSTRUCTIONS: Incorporate under this section, any other relevant information that the FDA has requested for review of the application; e.g., information requested subsequent to a pre-IDE discussion of the proposed application.]

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Section 13.0: Reference List [SECTION INTRODUCTION: Provide a list of references cited in the IDE application here. NOTE: The bibliographical information may instead be provided after each of the IDE application sections. If the Sponsor-Investigator chooses to do this, delete this section here and from the table of contents.]

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13. Reference List [INSTRUCTIONS: Insert bibliographical information/literature cited.]

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Section 14.0: Appendices [SECTION INTRODUCTION: Provide a list of the appendices in order of appearance in the sections of the IDE application. Before each new appendix, include a cover page describing the document(s) that will be found in that appendix. [ADDITIONAL INSTRUCTIONS: Copies of selected papers referenced in the IDE application: While not required, it is strongly suggested that the Sponsor-Investigator provide copies of key papers that are referenced in the body of the IDE application. Providing copies of any significant papers will make it easier for the FDA reviewers should they want additional information. As with the other appendices, include a cover page with this appendix, listing in order of appearance the citations for the papers being submitted with the IDE application.]

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Appendices [INSTRUCTIONS: Insert and number appendix cover pages and materials in the order of appearance within the IDE ]

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(EXAMPLE) APPENDIX ______

INVESTIGATOR AGREEMENT FOR CLINICAL INVESTIGATION OF THE ___________________________ (Specify Investigational Device(s))

I, __________________________, agree to participate as the Principal Investigator in the clinical investigation of the ______________________________ [INSERT: Specify investigational device.] I have reviewed the following Food and Drug Administration (FDA) regulations: 21 CFR Part 812, Investigational Device Exemptions; 21 CFR Part 50, Protection of Human Subjects; and 21 CFR Part 54, Financial Disclosure by Clinical Investigators. I agree and/or certify that: 1. I will conduct the clinical investigation in accordance with this agreement, all requirements of the investigational plan, IDE regulations, other applicable regulations of the FDA, and any conditions of approval imposed by my reviewing Institutional Review Board (IRB) or FDA. I agree to abide by all of the responsibilities of Investigators addressed under 21 CFR Part 812, Subpart E and Subpart G, including but not limited to the following: a. I will obtain written approval from the authorized IRB for the institution at which this investigation will be conducted. If I am not also the sponsor-investigator of the corresponding IDE application, I will submit the certification of IRB approval and any conditions of this approval to the Sponsor (Sponsor-Investigator). b. I will ensure that Informed Consent is obtained from each subject participating in this clinical investigation in accordance with the informed consent regulation found in 21 CFR Part 50, and that a signed copy of the informed consent is available to the Sponsor (Sponsor-Investigator) and the Sponsor‟s (Sponsor-Investigator‟s) designated monitor. c. I will supervise all testing of the [INSERT: Specify investigational device] on human subjects and will allow only those physician co-investigators listed on the last page of this agreement to administer this devices and/or perform follow-up medical evaluations on the device. d. I will be responsible for accountability of the [INSERT: Specify investigational device] at the study site and, if I am not also the Sponsor-Investigator of the corresponding IDE application, I will return all unused [INSERT: Specify investigational device] to the Sponsor (SponsorInvestigator) or otherwise follow the instructions of the Sponsor (Sponsor-Investigator) for disposal of the unused devices. e. I will ensure the accurate completion of protocol case report forms and, if I am not also the Sponsor-Investigator of the corresponding IDE application, I will submit completed protocol case report forms, progress reports, and a final report to the Sponsor (Sponsor-Investigator) at the time frames specified in the Protocol and/or FDA regulations. f.

I will direct the retention of required records and documents related to the investigation.

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2. I have the appropriate, relevant qualifications to conduct and to oversee the conduct of the clinical investigation as documented by the following: [Check applicable statement] ____

My relevant qualifications, including dates, location, extent, and type of experience, are listed in my most recent curriculum vitae (CV), which is attached to this Agreement and which will be maintained by the sponsor (sponsor-investigator) of the corresponding IDE application.

____

My curriculum vitae (CV) does not reflect my relevant qualifications, therefore attached to this Agreement is a statement of my relevant experience (including dates, location(s), extent, and type of experience) which will be maintained by the sponsor (sponsorinvestigator) of the corresponding IDE application.

3. There are no reasons to question my ability to oversee the appropriate conduct of this clinical investigation. [Check applicable statement] ____ I have never participated in an investigation or other research activity which was terminated (disqualified) by FDA, the IRB (or equivalent), or sponsor of a study due to a noncompliance issue. ____ I have participated in an investigation or other research activity which was terminated (disqualified) by FDA, the IRB (or equivalent), or sponsor of a study due to a noncompliance issue. The specific circumstances leading to this termination and my role in the respective problems or issues and the resolution of these problems or issues are summarized in an attachment to this Agreement.

5. As required by 21 CFR Part 54, Financial Disclosure by Clinical Investigators, I will disclose sufficient and accurate financial information to the sponsor (sponsor-investigator) by completing the Certification of Financial Interest form (attached) and if applicable, the Disclosure of Financial Interest form (attached). I will also notify the sponsor (sponsor-investigator) if my disclosed financial information changes at any time during the clinical investigation or up to one year following the closure of the study.

Investigator‟s Signature___________________________________

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CERTIFICATION OF ALL PARTICIPATING INVESTIGATORS

PRINCIPAL INVESTIGATOR ____________________________________________ Name of Principal Investigator (please print or type) ____________________________________________ Office (Mailing Address) ____________________________________________ ______________________________ ______________________________ City/State/Zip E-mail ______________________________ ______________________________ Telephone FAX ____________________________________________ __________________ Signature of Principal Investigator Date

PHYSICIAN CO-INVESTIGATORS [INSTRUCTIONS: A current CV or statement of relevant experience and a completed Certification of Financial Interest statement and, if applicable, Financial Interest Disclosure statement is required to be submitted to the Sponsor (Sponsor-Investigator) for each physician co-investigator listed below.] As a physician co-investigator for this investigation, I have read the foregoing and agree to be bound by its terms. ____________________________________________ Name of Physician Co-Investigator (please print or type) ____________________________________________ Signature

____________ Date

____________________________________________ Name of Physician Co-Investigator (please print or type) ____________________________________________ Signature

____________ Date

____________________________________________ Name of Physician Co-Investigator (please print or type) ____________________________________________ Signature

____________ Date

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NON-PHYSICIAN CO-INVESTIGATORS [INSTRUCTIONS: A current CV or statement of relevant experience and a completed Form FDA 3454 (Certification of Financial Interest) and, if applicable, a completed Form FDA 3455 (Financial Interest Disclosure) is required to be submitted to the Sponsor (Sponsor-Investigator) for each nonphysician co-investigator listed below.] As a non-physician co-investigator for this investigation, I have read the foregoing and agree to be bound by its applicable terms.

_____________________________________________ Name of Co-Investigator (please print or type) _____________________________________________ Signature

____________ Date

_____________________________________________ Name of Co-Investigator (please print or type) _____________________________________________ Signature

____________ Date

_____________________________________________ Name of Co-Investigator (please print or type) _____________________________________________ Signature

____________ Date

_____________________________________________ Name of Co-Investigator (please print or type) _____________________________________________ Signature

____________ Date

_____________________________________________ Name of Co-Investigator (please print or type) _____________________________________________ Signature

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CVs OF ALL PARTICIPATING INVESTIGATORS

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APPENDIX ______ CERTIFICATION: FINANCIAL INTERESTS AND ARRANGEMENTS OF CLINICAL INVESTIGATORS Form FDA -3454

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APPENDIX ______

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DISCLOSURE: FINANCIAL INTERESTS AND ARRANGEMENTS OF CLINICAL INVESTIGATORS

Form FDA 3455

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APPENDIX ______

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FDA FORM 3500A MEDWATCH FDA MEDICAL PRODUCTS REPORTING

FDA FORM 3500A Forms Link Instructions for Completing Form FDA 3500A

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