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
Version 2.0
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
Page
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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
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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.
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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.
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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
Version 2.0
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.
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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
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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 ICTR_Navigators@jhmi.edu 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.
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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]
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ICTR DDRS: IDE Application Guidance & Template for Significant Risk Devices
Enclosure:
Attachment:
[INSERT: designation for any attachment cited in cover letter]
[INSERT: description for any attachment cited in cover letter]
Page 14 of 78
Version 2.0
ICTR DDRS: IDE Application Guidance & Template for Significant Risk Devices
Version 2.0
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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Version 2.0
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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ICTR DDRS: IDE Application Guidance & Template for Significant Risk Devices
Version 2.0
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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Version 2.0
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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ICTR DDRS: IDE Application Guidance & Template for Significant Risk Devices
Version 2.0
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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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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3.0
Version 2.0
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.]
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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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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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[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)
Version 2.0
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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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.
Version 2.0
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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Version 2.0
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.
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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
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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
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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.]
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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.
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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__.”
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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.
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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 <feasibility or pilot>
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 <PMA, 510k> 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.”)]
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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.
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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
7.1
Name, address, and chairperson of each reviewing IRB
Version 2.0
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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Date_______
ICTR DDRS: IDE Application Guidance & Template for Significant Risk Devices
APPENDIX ______
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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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____________
Date
ICTR DDRS: IDE Application Guidance & Template for Significant Risk Devices
APPENDIX ______
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 ______
Version 2.0
FDA FORM 3500A MEDWATCH FDA MEDICAL PRODUCTS REPORTING
FDA FORM 3500A Forms Link
Instructions for Completing Form FDA 3500A
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