Investigational Device Exemptions 
(IDEs) for Early Feasibility 
Medical Device Clinical Studies, 
Including Certain First in Human 
(FIH) Studies  
 
Guidance for Industry and Food 
and Drug Administration Staff 
(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)Document issued on: (cid:50)(cid:70)(cid:87)(cid:82)(cid:69)(cid:72)(cid:85)(cid:3)(cid:20)(cid:15)(cid:3)(cid:21)(cid:19)(cid:20)(cid:22) 
The draft of this document was issued on November 10, 2011.  
For questions regarding this document, contact CDRHs Andrew Farb, 301-7(cid:28)(cid:25)-6343, 
Andrew.Farb@fda.hhs.gov or Dorothy Abel, 301-796-6366, Dorothy.Abel@fda.hhs.gov, or 
CBERs Office of Communication, Outreach and Development at 1-800-835-4709 or 301-827-
1800.  
 
 
     
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Devices and Radiological Health 
Center for Biologics Evaluation and Research  Contains Nonbinding Recommendations 
Preface 
Public Comment 
You may submit written comments and suggestions at any time for Agency consideration to 
the Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, (HFA-305), Rockville, MD, 20852.  Submit electronic comments to 
http://www.regulations.gov.  Identify all comments with the docket number FDA-2011-D-
0787. Comments may not be acted upon by the Agency until the document is next revised or 
 
updated.
Additional Copies 
Additional copies are available from the Internet.  You may also send an e-mail request to 
dsmica@fda.hhs.gov to receive an electronic copy of the guidance or send a fax request to 301-
827-8149 to receive a hard copy.  Please use the document number 1782 to identify the 
guidance you are requesting. 
Additional copies of this guidance document are also available from the Center for Biologics 
Evaluation and Research (CBER) by written request, Office of Communication, Outreach, 
and Development (HFM-40), 1401 Rockville Pike, Rockville, MD  20852-1448, or by 
telephone, 1-800-835-4709 or 301-827-1800, or by e-mail at ocod@fda.hhs.gov, or from the 
Internet at 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/de
fault.htm.   
  2  Contains Nonbinding Recommendations 
Table of Contents 
1.  Introduction ............................................................................................................................... 4 
2.  Regulatory Background ............................................................................................................. 5 
3.  Definitions and Scope ............................................................................................................... 6 
4.  Overview ................................................................................................................................... 7 
5.  Targeting approval for an Early Feasibility Study IDE Application ......................................... 9 
6.  Report of Prior Investigations ................................................................................................. 10 
6.1  Content of the Report of Prior Investigations for an early feasibility study IDE ................. 11 
6.2  Design concept ..................................................................................................................... 12 
6.3  Device evaluation strategy ................................................................................................... 13 
6.3.1  Device evaluation strategy for an early feasibility study ................................................ 13 
6.3.2  Overall device evaluation plan (at the sponsors discretion) .......................................... 18 
6.4  Bench and laboratory testing and computational modeling ................................................. 18 
6.5  In vivo animal studies ........................................................................................................... 19 
6.6  Prior clinical information ..................................................................................................... 20 
7.  Investigational Plan ................................................................................................................. 20 
7.1  Risk analysis and mitigation ................................................................................................. 20 
7.2  Clinical protocol ................................................................................................................... 21 
7.3  Human subject protection measures ..................................................................................... 22 
7.3.1  Informed consent ............................................................................................................ 22 
7.3.2  Institutional Review Boards ........................................................................................... 23 
7.4  Monitoring ............................................................................................................................ 23 
7.4.1  Monitoring procedures.................................................................................................... 23 
7.4.2  Data monitoring committee (DMC) ............................................................................... 23 
8.  Iterations during early feasibility studies ................................................................................ 24 
8.1  Changes requiring FDA notification (5-day notice) ............................................................. 24 
8.2  Changes requiring FDA approval ......................................................................................... 25 
9.  Design controls ........................................................................................................................ 27 
10.  Next steps in clinical evaluation .............................................................................................. 28 
11.  Conclusion ............................................................................................................................... 28 
Appendix 1: Suggested topics for a Pre-Sub for an early feasibility study IDE .................................. 29 
Appendix 2: Device evaluation strategy example ................................................................................ 30 
Appendix 3: Supplemental guidance for the preparation of an early feasibility study informed consent 
document .............................................................................................................................................. 35 
Appendix 4: Device iteration example ................................................................................................. 38 
  3  Contains Nonbinding Recommendations 
Investigational Device Exemptions (IDEs) for 
Early Feasibility Medical Device Clinical 
Studies, Including Certain First in Human 
(FIH) Studies  
Guidance for Industry and  
Food and Drug Administration Staff 
 
This guidance represents the Food and Drug Administration's (FDA's) current thinking on 
this topic.  It does not create or confer any rights for or on any person and does not operate to 
bind FDA or the public.  You can use an alternative approach if the approach satisfies the 
requirements of the applicable statutes and regulations.  If you want to discuss an alternative 
approach, contact the FDA staff responsible for implementing this guidance.  If you cannot 
identify the appropriate FDA staff, call the appropriate number listed on the title page of this 
guidance.  
1.  Introduction  
This document is intended to provide guidance to FDA staff, clinicians, medical device 
innovators, and industry on the development and review of Investigational Device Exemption 
(IDE) applications for early feasibility studies of significant risk devices.1  Early feasibility 
studies allow for early clinical evaluation of devices to provide proof of principle and initial 
clinical safety data.  These studies may be appropriate early in device development when clinical 
experience is necessary because nonclinical testing methods are not available or adequate to 
provide the information needed to advance the developmental process.  As with all clinical 
studies, initiation of an early feasibility study must be justified by an appropriate benefit-risk 
analysis and adequate human subject protection measures.   
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should 
                                                           
1 Significant risk device is defined at 21 CFR 812.3(m) as 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 purported or represented to be for a use in supporting or sustaining human life and presents a potential for 
serious risk to the health, safety, or welfare of a subject; 
(3) Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise 
preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a 
subject; or 
(4) Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject. 
  4  Contains Nonbinding Recommendations 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited.  The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required.  
2.  Regulatory Background
 
Section 520(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) [21 U.S.C.  360j(g)] 
establishes a framework for FDA to grant devices for investigational use an exemption from 
certain requirements so that experts qualified by scientific training and experience can 
investigate their safety and effectiveness.  This exemption is known as an Investigational Device 
Exemption (IDE).  For significant risk devices, the sponsor must first submit an IDE application 
and obtain FDA approval.2  
The FD&C Act expressly recognizes that information to be included in an IDE application may 
vary depending on the investigation.  Section 520(g)(2)(C) states: 
Procedures and conditions prescribed [for granting investigational device exemptions] may 
appropriately vary depending on: 
  the scope and duration of clinical testing to be conducted under such exemption, 
  the number of human subjects that are to be involved in such testing, 
  the need to permit changes to be made in the device subject to the exemption during 
testing conducted in accordance with a clinical testing plan required under paragraph 
(3)(A) [in section 520(g) of the FD&C Act], and 
  whether the clinical testing of such device is for the purpose of developing data to obtain 
approval for the commercial distribution of the device. 
As with all clinical studies of investigational devices, an early feasibility study must comply with 
21 CFR part 812, including the requirements outlined below:   
  Application (21 CFR 812.20): explains when a sponsor must submit an IDE application 
and the information that the IDE application must contain, including the investigational 
plan and report of prior investigations. 
  Investigational Plan (21 CFR 812.25): explains what information the Investigational Plan 
must contain, including the purpose of the investigation, the protocol,  risk analysis, 
description of the device, monitoring procedures, labeling, consent materials, and 
information about the Institutional Review Boards (IRB) reviewing the investigation.   
  Report of Prior Investigations (21 CFR 812.27): explains what information the Report of 
Prior Investigations must contain, including reports of all prior clinical, animal, and 
laboratory testing of the device. 
  Supplemental applications (21 CFR 812.35): explains when changes to the device and 
Investigational Plan must have prior FDA approval and the appropriate manner to notify 
FDA of changes that do not require prior approval.   
                                                           
2 21 CFR 812.20(a).  
  5  Contains Nonbinding Recommendations 
Adopting the principles set forth in section 520(g)(2)(C) of the FD&C Act, Sections 5-8 of this 
guidance clarify how some of these requirements should be applied to early feasibility study 
IDEs. 
3.  Definitions and Scope 
For the purposes of this guidance, clinical study types are defined as follows:3 
  An early feasibility study is a limited clinical investigation of a device early in 
development, typically before the device design has been finalized, for a specific 
indication (e.g., innovative device for a new or established intended use, marketed device 
for a novel clinical application).  It may be used to evaluate the device design concept 
with respect to initial clinical safety and device functionality in a small number of 
subjects (generally fewer than 10 initial subjects) when this information cannot 
practically be provided through additional nonclinical assessments or appropriate 
nonclinical tests are unavailable.  Information obtained from an early feasibility study 
may guide device modifications.  An early feasibility study does not necessarily involve 
the first clinical use of a device. 
  A first in human (FIH) study is a type of study in which a device for a specific 
indication is evaluated for the first time in human subjects.  This document only discusses 
FIH studies that meet the definition of an early feasibility study. 
  A traditional feasibility study is a clinical investigation that is commonly used to 
capture preliminary safety and effectiveness information on a near-final or final device 
design to adequately plan an appropriate pivotal study.  Because the study of a near-final 
or final device design takes place later in development than an early feasibility study, 
FDA would expect to see more nonclinical (or prior clinical) data in a traditional 
feasibility study IDE application.4  A traditional feasibility study does not necessarily 
need to be preceded by an early feasibility study.  
  A pivotal study is a clinical investigation designed to collect definitive evidence of the 
safety and effectiveness of a device for a specified intended use, typically in a statistically 
justified number of subjects.  It may or may not be preceded by an early and/or a 
traditional feasibility study. 
Early feasibility studies may be conducted for multiple reasons, such as obtaining initial insights 
into: 
  the clinical safety of the device-specific aspects of the procedure;  
  whether the device can be successfully delivered, implanted or used;  
  operator technique challenges with device use; 
  human factors (e.g., difficulties in comprehending procedural steps); 
  the clinical safety of the device (e.g., evaluation of device-related serious adverse events);  
  whether the device performs its intended purpose (e.g., mechanical function, making 
intended measurements); 
                                                           
3 In this guidance, the term feasibility is considered synonymous with pilot. For consistency purposes, 
feasibility is the term that should be used in reference to the types of clinical studies that precede the pivotal study 
phase. 
4 Additional nonclinical testing could be completed concurrent with conducting the early feasibility study if needed 
to support the conduct of a traditional feasibility or pivotal study. 
  6  Contains Nonbinding Recommendations 
  device failures; 
  patient characteristics that may impact device performance (e.g., anatomical limitations); 
and 
  therapeutic parameters (e.g., energy applied, sizing, dose released) associated with device 
use. 
Unlike traditional feasibility studies, which are focused on providing initial clinical safety and 
effectiveness information for a near final or final device design or capturing data to guide the 
development of a pivotal study, early feasibility studies have a broader purpose.  Early clinical 
experience obtained from an early feasibility study increases the efficiency of the device 
development process, as it may be used to: 
  identify appropriate modifications to the procedure or device;  
  optimize operator technique; 
  refine the intended use population; 
  refine nonclinical test plans or methodologies; and   
  develop subsequent clinical study protocols.    
To determine which type of clinical study (early feasibility, traditional feasibility, or pivotal) is 
appropriate to pursue, certain factors, such as the novelty of the device, its intended clinical use, 
the stability of the device design, and the amount of test data available to support the IDE 
application should be considered.  An early feasibility study is appropriate when device changes 
are expected and when, due to the novelty of the device or its intended use, a clinical study is 
expected to provide information that cannot be practically obtained through additional 
nonclinical assessments.  An early feasibility study may be appropriate even if a device or a 
prototype of the device has previously been used clinically for the intended clinical use.  Note 
that not all novel devices or uses warrant an early feasibility study, nor would FDA mandate that 
an early feasibility study be conducted.  A traditional feasibility study or a pivotal study may be 
more appropriate if the device design is near-final or final, respectively, depending on the 
amount of data available to justify the study.  Prior to IDE submission and to avoid preventable 
delays, it is advisable to contact FDA to determine whether the proposed investigation can be 
classified as an early feasibility study. 
The guidance provided herein is specific to early feasibility study IDEs only and is not 
applicable to other types of clinical studies.  As discussed above, excluded from the scope of this 
document are studies involving the first human use of a device that do not otherwise meet the 
definition of an early feasibility study.  For example, the first human use of a non-innovative 
device for a well-understood clinical use could appropriately be evaluated under a traditional 
feasibility or a pivotal study rather than an early feasibility study.     
4.  Overview 
FDA recognizes the value of encouraging medical device innovation to address clinical needs 
and improve patient care, particularly when alternative treatments or assessments are 
unavailable, ineffective, or associated with substantial risks to patient safety.  This guidance has 
been developed to facilitate the early clinical evaluation of medical devices in the United States 
under the IDE regulations, using risk mitigation strategies that appropriately protect human 
subjects in early feasibility studies.   
  7  Contains Nonbinding Recommendations 
An early feasibility study IDE application must comply with section 520(g) of the FD&C Act 
[21 U.S.C.  360j(g)] and 21 CFR part 812; however, the procedures and conditions prescribed 
for IDEs may vary depending on the type of clinical study (see Section 2).  
This guidance outlines new policy regarding the application for and approval of early feasibility 
study IDEs.  The essential elements of this policy are as follows:  
1.  FDA approval of an IDE application for an early feasibility study, including certain first in 
human studies, may be based on less nonclinical data than would be expected for a traditional 
feasibility or a pivotal study (see Section 5).  This is because early feasibility studies are only 
appropriate when additional nonclinical testing would not provide the information needed to 
advance the developmental process.  Identification of the data necessary to support an early 
feasibility study should be based on a thorough device evaluation strategy that describes the 
device procedure, performance, and basic safety-related attributes and addresses the potential 
failure modes (see Section 6.3).  This policy is intended to facilitate initiation of clinical 
studies in the United States earlier in the device development process than has historically 
occurred.5   
2.  This guidance introduces new approaches to facilitate timely device and clinical protocol 
modifications during an early feasibility study (see Section 8), while still requiring 
compliance with the IDE regulations in 21 CFR part 812, as follows: 
  more types of modifications that can be made under a 5-day notification without prior 
FDA approval, as compared with other types of studies; 
  a contingent approval process that permits changes contingent upon acceptable 
nonclinical test results without requiring additional FDA action; and 
  interactive review of IDE supplements and amendments. 
This guidance document highlights and reviews key principles unique to an early feasibility 
study IDE with respect to the Report of Prior Investigations, the clinical protocol, risk mitigation 
strategies, and subject protection measures (see Sections 6 and 7).   
Throughout this early feasibility study guidance, there are recommendations for sponsors to 
interact with FDA, utilizing the Pre-Submission (Pre-Sub) process to optimize the preparation 
and quality of early feasibility study IDE applications.6  Appendix 1 summarizes the key 
elements for an early feasibility study Pre-Sub.7 
                                                           
5 Note that this guidance does not recommend that sponsors prematurely initiate clinical testing when further useful 
and appropriate nonclinical testing can be performed for the particular device the sponsor is developing.  
6 For more information on the Pre-Submission process, see FDAs draft guidance Medical Devices: The Pre-
Submission Program and Meetings with FDA Staff  
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm310375.htm).  
FDAs draft guidance represents FDAs proposed approach on this topic. 
7 In the context of this guidance, the term Pre-Sub means a request for informal FDA feedback on information, 
such as a proposed non-clinical testing plan or a draft clinical study protocol, submitted prior to the formal 
submission of an original IDE (to initiate an early feasibility study) or IDE supplement (to request changes to the 
device or study protocol).  
  8  Contains Nonbinding Recommendations 
This guidance is not intended to address all required elements of IDE applications or to provide a 
comprehensive tutorial on best clinical practices for investigational medical device studies.  
Furthermore, while this document outlines the general principles for preparing and reviewing 
early feasibility study IDE applications, it is not intended to provide guidance on the device-
specific nonclinical information needed to justify initiation of an early feasibility study, or the 
specific data required to progress to other phases of clinical study for a particular device type or 
clinical indication.  It is recommended that discussions regarding justification for study initiation 
take place during the Pre-Sub process. 
5.  Targeting approval for an Early Feasibility Study IDE 
Application   
Because there are differences in the amount and type of information that is needed for an early 
feasibility study as compared to a traditional feasibility or pivotal study, the IDE application 
should clearly state that the proposed study is an early feasibility study and provide justification 
for conducting this type of study.  To improve the likelihood of IDE approval, the following 
questions should be addressed with supporting information in the original early feasibility study 
IDE application:    
1.  What is the clinical condition to be treated or assessed by the device? 
2.  What is the standard of care for the clinical condition and expected clinical outcomes 
associated with the standard of care? 
3.  What are the anticipated benefits associated with use of the study device? 
4.  Is the information included in the Report of Prior Investigations (Section 6) adequate to 
support initiation of the study?   
5.  Does the Investigational Plan include a thorough risk analysis, sufficient risk mitigation 
strategies, adequate human subject protection measures, and an appropriate clinical study 
protocol (see Section 7)? 
6.  Are the potential risks associated with the device use likely to be outweighed by the 
anticipated benefits of the early feasibility study, that is, is initiation of the clinical study 
justified based on the clinical need for the device, Report of Prior Investigations and 
Investigational Plan? 
FDA may approve an investigation as proposed, approve it with conditions, or disapprove it.8  
FDA will generally disapprove an IDE if there is reason to believe that the foreseeable risks to 
the study subjects are not outweighed by the anticipated benefits to the subjects and the 
importance of the knowledge to be gained.9  When addressing benefit/risk for an early feasibility 
study, the concepts discussed in the FDA guidance, Factors to Consider When Making Benefit-
Risk Determinations in Medical Device Premarket Approval and De Novo Classifications 
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm2
67829.htm) should be considered.  For early feasibility studies, in addition to the potential risks 
and anticipated benefits to the study subjects and the knowledge to be gained, relevant 
benefit/risk considerations may include the availability of safe and effective alternative therapies;  
                                                           
8 See 21 CFR 812.30(a). 
9 See 21 CFR 812.30(b)(4).   
  9  Contains Nonbinding Recommendations 
prospective study subjects tolerance for risk; risk mitigation strategies included in the clinical 
protocol; and information indicating that the device should perform as intended and catastrophic 
failure will not likely occur.     
Early feasibility studies are designed to gain initial clinical insights when additional nonclinical 
testing methods are not available or adequate to provide the information needed to advance 
device development.  These studies may be initiated before the design of the device is finalized 
and, in light of the early stage of device development and the small number of subjects, may be 
justified based on less evidence than for other types of clinical studies.  As a result, they may 
carry greater unknown risk than traditional feasibility and pivotal studies.  This makes human 
subject protection measures, such as adequate informed consent and IRB review, all the more 
important in an early feasibility study (see Section 7).10  At the same time, benefits deriving from 
the knowledge to be gained may be substantial during the early phase of device development, 
particularly for innovative devices or intended uses.  Even though early feasibility studies are not 
designed or intended to generate statistically valid results, they should be conducted for specified 
purpose(s), enroll the appropriate subjects, utilize meaningful endpoints, and capture relevant 
information so that the results can be used to further device development.  Importantly, although 
early feasibility studies can begin before the design of the device is finalized, there still should be 
reason to believe that the device will function as intended.  
Compared to a traditional feasibility or pivotal study, less nonclinical data would generally need 
to be included in the Report of Prior Investigations for an early feasibility study IDE application.  
For example, nonclinical testing using small sample sizes or short implant durations for in vivo 
animal studies may be sufficient to justify initiation of an early feasibility study.  Under this 
approach, if additional and longer-term bench and animal testing are needed to support a larger 
clinical study of a near-final or final device design, these tests could be completed concurrently 
with the early feasibility study. 
Some essential elements of a pivotal study, such as a prospective definition of study success and 
a prespecified data analysis plan, are not necessary for early feasibility study IDE applications.  
In addition, an early feasibility study protocol may be subject to fewer constraints as compared to 
a pivotal study protocol.  For example, for early feasibility studies, sequential enrollment 
typically would not be necessary. 
6.  Report of Prior Investigations  
The requirements in 21 CFR 812.27 apply to the Report of Prior Investigations for early 
feasibility study IDE applications.  The information in this section is intended to clarify how 
certain of these requirements apply to early feasibility studies and to provide guidance on the 
content of the Report of Prior Investigations for an early feasibility study IDE.   
The Report of Prior Investigations must include the information needed to justify a clinical 
investigation of a device.11  For early feasibility studies, this information should: 
                                                           
10 See 21 CFR parts 50 and 56.  
11 21 CFR 812.27(a). 
  10  Contains Nonbinding Recommendations 
  support an expectation of acceptable clinical use (e.g., successful device placement using 
a benchtop model that simulates clinical conditions and/or a suitable animal model) and 
that the device will function as intended; 
  address basic device safety, including, but not limited to, sterility, biocompatibility, 
software verification and validation, electromagnetic compatibility, chemical 
compatibility (e.g., with concomitant drugs); and  
  characterize catastrophic failure modes and identify risk mitigation approaches. 
When adequately justified, the information may be generated from tests utilizing non-
standardized methodologies (e.g., using loading conditions that are not specified in a guidance 
document or voluntary standard to evaluate fatigue properties of a device for a new intended use, 
or using less sensitive testing equipment than specified in a standard).  In determining the testing 
needed, the sponsor should consider the clinical significance of potential failures and the ability 
to predict clinical performance based on nonclinical testing.  A sponsor may be able to justify 
deferral of certain testing until later stages of device development.   
6.1  Content of the Report of Prior Investigations for an early feasibility study 
IDE 
The information to be provided in the Report of Prior Investigations for an early feasibility study 
IDE application should be presented in three main sections: (1) Background, (2) Executive 
Summary, and (3) Detailed Reports:12  
(1) The Background section should emphasize the unique aspects of the device design and 
intended patient population that will be considered when FDA evaluates whether the 
information provided justifies the initiation of an early feasibility study.  This section should 
describe: 
  the clinical context for the early feasibility study:  
-  the clinical condition the device is intended to treat or assess;  
-  the standard of care, including the types and severity of risks and the benefits 
associated with current treatment options; 
-  the types and severity of potential risks and the anticipated benefits that may be 
associated with the study device; and 
-  the rationale for exposing the target population to the potential risks (i.e., whether the 
anticipated benefits that may be associated with the use of the study device justify the 
potential risks, recognizing the benefits and risks posed by current treatment or 
assessment options); 
  the design concept; and 
  a summary justification regarding the amount and type of information/data needed to 
support initiation of the early feasibility study in the specified patient population, with 
comment on, or comparison to, what may be expected to support the initiation of a larger 
clinical study. 
 
 
                                                           
12 Please consult 21 CFR 812.27 for the elements that must be included in a Report of Prior Investigations. 
  11  Contains Nonbinding Recommendations 
(2) The Executive Summary section should provide a summary of the information provided and 
an explanation as to why this information is adequate to support study initiation.  This section 
should include:  
  a summary description of the nonclinical testing that has been performed and relevant 
clinical information;   
  a device evaluation strategy table, as described below, that references the relevant 
individual test reports for the data and/or information collected to address each device or 
procedure-related attribute; and 
  a table describing the purpose of each test or analysis, test sample description, sample 
size, acceptance criteria (if available), test results, any potential clinical significance of 
the results, and cross reference to the test reports.   
(3) The Detailed Reports section should include the reports for tests conducted and additional 
information available to support the initiation of the early feasibility study.  This section 
should include: 
  individual reports for each bench and laboratory test, computational modeling analysis 
(e.g., finite element analysis), and in vivo animal study:   
o  each test report should include the purpose, test method, sample selection, results, 
discussion of the acceptability of the results, and when appropriate, justification 
and clinical applicability of the acceptance criteria;13  
  a summary of leveraged nonclinical information in appropriate detail, depending on the 
source of the information, such as: 
o  individual test reports not previously submitted to FDA; 
o  references to previously reviewed regulatory submissions;  
o  reports in the published literature   
  a summary of any relevant clinical information, with references, if available.  
The following sections provide further guidance on the purpose and preparation of the key 
elements of a Report of Prior Investigations for an early feasibility study IDE.  
6.2  Design concept 
The Background section of a Report of Prior Investigations for an early feasibility study IDE 
should include information to clearly describe the design concept, such as the:  
  device description (e.g., physical description, figures, materials of construction, software 
documentation), principles of operation, what the device key design features are intended 
to do, and how the key design features accomplish the intended objective; 
  intended clinical use, designated by the medical condition or lesion type to be treated or 
assessed, and any associated anatomical locations and limitations; 
  conditions of use/intended in vivo environment; and 
  minimum design-life of the device (i.e., the minimum duration for which a device has 
been designed to function as intended). 
                                                           
13 Characterization tests (i.e., testing conducted to describe the device) may not have specified acceptance criteria 
and it may not be possible to establish acceptance criteria until clinical data are obtained. 
  12  Contains Nonbinding Recommendations 
The device design concept provides the basis for identifying the appropriate testing and test 
methodologies and guides the device evaluation strategy.  
6.3  Device evaluation strategy  
The device evaluation strategy in the Executive Summary section of a Report of Prior 
Investigations should describe and justify the leveraged information and testing conducted to 
support initiation of an early feasibility study, with cross-references to the Detailed Reports 
section of a Report of Prior Investigations.  The purpose of the device evaluation strategy is to 
facilitate FDA's understanding of the value of the leveraged information and why the information 
included in the Report of Prior Investigations is adequate to support IDE approval.  To maximize 
the efficient use of sponsor and FDA resources, it is desirable for the sponsor to consult with 
FDA and for both parties to reach agreement on the strategy before the sponsor conducts the 
proposed testing. Therefore the device evaluation strategy would optimally be discussed during 
Pre-Sub interactions.  This is particularly important when:  
  the sponsor is providing less nonclinical data as compared to what would be expected for 
a traditional feasibility or pivotal study;  
  there is no FDA guidance or voluntary standard specific to the device and intended use 
proposed to be studied; and/or  
  certain nonclinical tests are more relevant than others in addressing basic safety and 
potential catastrophic failures, or to support basic device functionality.   
Section 6.3.1 describes a systematic method for presenting the device evaluation strategy for an 
early feasibility study.  This method involves identifying the key information necessary to justify 
initiation of the study based on a risk assessment, taking into consideration the anticipated 
benefits that may be associated with the device.   
Even if testing has been done in accordance with a guidance document or voluntary standard, a 
justification should be provided to explain why the testing specified in the guidance or standard 
applies to the device and its intended use.  This may involve a modification of the device 
evaluation strategy process described in Section 6.3.1, focusing on the unique aspects of the 
device or intended use as compared to those specifically addressed by the guidance or standard.   
Section 6.3.2 presents an option for obtaining early FDA feedback on a comprehensive device 
evaluation strategy that extends beyond the early feasibility phase.  
6.3.1  Device evaluation strategy for an early feasibility study 
The device evaluation strategy for an early feasibility study should be based on a risk/benefit 
assessment.14  In general, for an early feasibility study, the evaluation strategy should be focused 
on identifying the information needed to address significant safety concerns and support basic 
device functionality.   
The device evaluation strategy is best outlined in a table, with the following column headings: 
                                                           
14 At the early feasibility stage, a descriptive assessment may be more informative than a formal failure modes and 
effect analysis (FMEA), which provides a quantitative ranking of risks.  
  13  Contains Nonbinding Recommendations 
  Column 1, Device Attribute:  Each procedure-related function, performance-related 
function, and basic safety-related feature required for the device to achieve the desired 
performance (i.e., benefit).   
Note: For the purpose of the device evaluation strategy, a function is defined as the 
ability of the device to accomplish a goal and a feature is defined as an essential property 
of the device. 
  Column 2, Potential Failure Modes:  For each Device Attribute, the types of problems or 
failures that might occur and could result in consequences to the device or study subject 
if the function or feature is not attained.   
  Columns 3 and 4, Potential Device and Clinical Effects of Failure: For each Potential 
Failure Mode, the potential effects of the failure mode on the device and/or study subject 
(i.e., risks).     
  Column 5, Device Design Information: For each Potential Failure Mode, the design 
characteristics intended to provide the function or feature or to address or mitigate the 
potential failure mode.  Relevant anticipated benefits associated with the design 
characteristics may be highlighted in this column. 
  Columns 6 and 7, Leveraged Nonclinical Information and Supportive Clinical 
Information: For each Attribute and/or Potential Failure Mode, the information from 
internal or external sources to supplement the assertions that:  
a) the function or feature will be attained; and/or  
b) the failure mode will not likely occur or will not be catastrophic if it does occur. 
  Column 8, Nonclinical Device Testing: The bench, laboratory, analytical, and/or animal 
testing of the study device (i.e., the device that will be used in the clinical study) to  
complete the evaluation of the attribute and the potential failure mode(s).   
  Column 9, Clinical Study Mitigation Strategies: For each Potential Clinical Effect of 
Failure, the mitigation strategies included in the clinical protocol intended to minimize 
the frequency or severity of the potential clinical effects resulting from a failure to attain 
the attribute. 
Note: Although the Clinical Study Mitigation Strategies are a subset of the risk mitigation 
strategies included in the risk analysis section of the Investigational Plan, they should be 
presented within the device evaluation strategy table to emphasize their applicability to 
specific failure modes and effects of failure.   
Table 1 defines the device evaluation strategy column headings and Table 2 describes the 
information recommended for inclusion in a device evaluation strategy table.   
  14  Contains Nonbinding Recommendations 
Table 1: Column Definitions for a Device Evaluation Strategy Table 
Column 5  Column 6  Column 7 
Column 1  Column 2  Column 3  Column 4  Column 8  Column 9 
Knowledge Base  
Potential Effects of 
Supportive Information 
Failure 
Clinical Study 
Device Attribute  PMootdeensti al Failure  PDoevteicneti al  PColitneincatila l  DInefovircmea Dtieosnign  LNeovnecrlaingiecda l  SCulipnipcoarlt ive  NTeosntcinlign i cal Device  MStirtaigteagtiioens  
Effects of  Effects of 
Information   Information
Failure  Failure 
The design 
characteristics 
intended to provide 
Relevant clinical 
the function or 
experience 
feature or to address 
Each individual  Nonclinical  obtained from 
or mitigate the 
device function or  information  internal or 
potential failure 
feature required  leveraged from  external sources 
mode, and the  Bench, laboratory,  Mitigation 
for the device to  internal or  for a similar 
anticipated benefits  analytical, and/or  strategies 
achieve the  external  device or 
The failures that  of these  animal testing of the  included in the 
overall desired  sources to  indication to 
might occur and  The  characteristics.  study device (i.e., the  clinical protocol 
performance.  The  support the  support the 
could result in  potential  device that will be  intended to 
potential  assertions that:   assertion that: 
consequences  effect(s) of  And, if applicable,  used in the clinical  minimize the 
Note: A function  effect(s) of  a) the function  a) the function or 
(effects) to the  the failure  relevant information  study) to complete the  frequency or 
is the ability of  the failure  or feature will  feature will be 
device or study  mode on  considered in the  evaluation of the  severity of the 
the device to  mode on  be attained;  attained; and/or 
subject if the  the study  design of the device  attribute and the  potential clinical 
accomplish a  the device.  and/or   b) based on an 
function or feature  subject.  (i.e., design input) to  potential failure  effects resulting 
goal and a  b) the failure  evaluation of the 
is not attained.  support the  mode(s), considering  from a failure to 
feature is an  mode will not  clinical effects of 
assertions that:   the information in  attain the 
essential  likely occur or  failure, the failure 
a) the function or  Columns 3-7 and 9.  attribute. 
property of the  will not be  mode will not 
feature will be 
device.  catastrophic if it  likely occur or will 
attained; and/or  
does occur.  not be 
b) the failure mode 
catastrophic if it 
will not likely occur or 
does occur. 
will not be 
catastrophic if it does 
occur. 
  15  Contains Nonbinding Recommendations 
Table 2: Information To Be Included In The Device Evaluation Strategy Table 
Column 5  Column 6  Column 7 
Column 1  Column 2  Column 3  Column 4  Column 8  Column 9 
Knowledge Base 
Potential Effects of 
Supportive Information 
Failure 
Potential  Clinical Study 
Device  Device Design  Nonclinical Device 
Failure  Potential  Potential  Mitigation 
Attribute  Information Leveraged  Supportive  Testing  
Modes  Device  Clinical  Strategies 
Nonclinical  Clinical 
Effects of  Effects of 
Information   Information
Failure  Failure
Identify and 
reference any 
relevant clinical 
List the design 
Identify and  experience 
characteristics 
reference the  obtained from 
intended to: a) provide 
nonclinical  internal or external  List and reference 
the function or feature, 
List each  information  sources for a  the testing and/or 
identifying any 
procedure- leveraged from  similar device or  analyses on the 
anticipated benefits 
related function  internal or external  indication to  study device (i.e., 
that may be 
needed for the  sources to support  support the  the device that will 
associated with the  Identify any 
device to be  the assertions that:   assertion that:  be used in the 
characteristics; or b)  applicable 
used  a) the function or  a) the function or  clinical study) to 
address or mitigate the  mitigation 
successfully.  For each  feature will be  feature will be  evaluate the attribute
For each  For each  potential failure mode.  strategies that will 
failure  attained; and/or   attained; and/or  and the potential 
attribute, list  failure  be utilized during 
List each  mode, list  b) the failure mode  b) based on an  associated failure 
the failure  mode, list  And, if applicable,  the clinical study 
performance- the potential  will not likely occur  evaluation of the  mode(s).   
modes that  the potential  to minimize the 
related function  effects of  or will not be  clinical effects of 
could result  effects of  identify and reference  frequency or 
or feature  the failure  catastrophic if it  failure, the failure  For tests or analyses 
if the  the failure  the relevant  severity of the 
needed for  mode on the  does occur.  mode will not likely  intended to address 
attribute is  mode on  information considered  potential clinical 
acceptable  study  occur or will not be  multiple attributes, 
not attained.  the device.  in the design of the  effects resulting 
device  subject.  Explain and justify  catastrophic if it  identify the specific 
device (i.e., design  from a failure to 
performance.  how the specific  does occur.  aspects of the 
input) to support the  attain the 
aspects of the  testing or analysis 
assertions that:   attribute.
List each  testing or analysis  Explain and justify  relevant to the 
a) the function or 
necessary basic  are relevant to the  how the specific  evaluation of the 
feature will be 
safety-related  evaluation of the  aspects of the  attribute or failure 
attained; and/or  
feature.  attribute or failure  clinical experience  mode under 
b) the failure mode will 
mode under  are relevant to the  consideration.  
not likely occur or will 
consideration.   evaluation of the 
not be catastrophic if it 
attribute or failure 
does occur. 
mode under 
consideration.  
 
  16  Contains Nonbinding Recommendations 
The process of constructing the device evaluation strategy table can be divided into four parts: 
1)  Device Deconstruction  identify the attributes needed for the device to achieve the 
design goals (Column 1), the potential failure modes (Column 2), and the effects of 
failure (Columns 3 and 4). 
2)  Knowledge Base and Mitigation Strategies  describe what is known from the device 
design (Column 5), leveraged nonclinical and clinical information from internal or 
external sources (Columns 6 and 7), and the clinical study mitigation strategies (Column 
9) applicable to the attributes and failure modes. 
3)  Evidence Gaps   identify gaps in the existing information indicating that additional 
testing may be needed to justify study initiation, considering the Knowledge Base and 
focusing on the following: 
a.  attributes most important for the intended use; 
b.  potential failure modes most likely to be associated with catastrophic failures; and 
c.  basic safety requirements (e.g., biocompatibility). 
4)  Filling the Gaps  identify in Column 8 the bench, laboratory, analytical, and/or animal 
testing to complete the evaluation of the device attributes and the potential associated 
failure modes, considering the following: 
a.  Evidence Gaps;  
b.  clinical context for the early feasibility study [see Section 6.1(1)];  
c.  potential types, frequency, and severity of the clinical effects of failure that may 
be associated with the device or procedure; and 
d.  Mitigation Strategies. 
Any implications of the unique aspects of the device or the proposed intended use should be 
emphasized in the device evaluation strategy table.  Similarly, the items listed under the 
Evidence Gaps (3a-c), above should be highlighted in the table.   
Submitting the draft device evaluation strategy table in a Pre-Sub will maximize efficiency.  In 
the draft table, the Nonclinical Device Testing (Column 8) may include proposed or completed 
testing, but reaching consensus with FDA on the appropriate testing prior to completion is 
preferable.  Pre-Sub discussions on the device evaluation strategy table may focus on the 
following: 
  whether Columns 1-4 (the Device Deconstruction) are complete,  
  the applicability and usefulness of the information in Columns 5-7 and Column 9 (the 
Knowledge Base and Mitigation Strategies),  
  whether the right information was considered when identifying the Evidence Gaps, and 
  whether the additional proposed (or completed) testing described in Column 8 (Filling the 
Gaps) will likely complete the evaluation of the attribute or failure mode.   
These discussions should continue under the early feasibility IDE, when the device evaluation 
strategy table has been further refined, and should focus on whether the information and data 
provided adequately address the specific attributes or failure modes. 
For the early feasibility IDE, the level of detail to include in each row of the device evaluation 
strategy table should be proportional to the importance of the attribute to the intended use, the 
potential severity of the failure modes, and whether the method of assessing the attribute or 
failure mode is generally understood.  A summary of Knowledge Base and Mitigation Strategies 
  17  Contains Nonbinding Recommendations 
information should be included in the rows of the table for the most critical attributes for 
achieving the intended function of the device and for the potentially catastrophic failure modes.  
Descriptive information should be included for novel methods of assessment.  Conversely, for 
less critical attributes, less clinically relevant failure modes, and standardized methodologies, it 
may be adequate to simply identify the applicable information or tests without providing 
descriptive information in the table.  A comprehensive presentation of all leveraged information 
and completed testing should be included in the Detailed Reports section of the Report of Prior 
Investigations.  Interaction between the sponsor and FDA is encouraged to establish consensus 
on the most important attributes and to determine the appropriate level of detail that should be 
included in the rows of the table.      
It is understood that there may be uncertainty regarding some elements of the device evaluation 
strategy, depending on the novelty of the device or intended use.  The device evaluation strategy 
table should be updated as new information emerges about the potential risks and the appropriate 
assessment of the device.   
Depending on the device and intended use, it may be appropriate and acceptable to defer some 
device testing until after the early feasibility study, if the testing will not provide additional 
meaningful information regarding basic device safety or functionality.  For some devices or 
intended uses, particularly for highly innovative devices, FDA recognizes that appropriate 
nonclinical test methodologies to assess some critical parameters may not be available or are 
impractical to complete, and therefore, these parameters would need to be evaluated clinically.  
An example of a portion of a draft device evaluation strategy table for a hypothetical 
permanently implanted, percutaneously delivered, covered metallic device is presented in 
Appendix 2. 
6.3.2  Overall device evaluation plan (at the sponsors discretion)  
It may be useful to obtain FDA feedback on the overall device evaluation plan.  The plan would 
identify the types of information or levels of testing that may be needed to progress beyond an 
early feasibility study and propose the timing of deferred or additional testing.   
The additional information/data that may be used to support progression to each of the planned 
developmental phases (e.g., traditional feasibility study, pivotal study, marketing application) 
can be listed in Column 8 (Nonclinical Device Testing) of the device evaluation strategy table.  It 
should be noted that not all developmental phases may be necessary for every new device or 
intended use. 
6.4  Bench and laboratory testing and computational modeling 
For early feasibility studies, the full battery of tests that would be expected for evaluation of a 
final device design is not required for IDE approval.  As outlined in Section 6.3 FDA encourages 
sponsors to consider the relationship between a device attribute or failure mode and the 
anticipated clinical consequences to determine the testing needed to support the IDE application.  
This approach may be used when justifying the device evaluation strategy, including the use of 
preliminary results or deferral of certain testing at the early feasibility phase of device 
development.   
  18  Contains Nonbinding Recommendations 
Computational modeling (CM) can be used for a variety of purposes to support the initiation of 
an early feasibility study.  For example: 
  For long-term implants in which the boundary and loading conditions are known, CM 
may be used to predict the long-term durability of the device.     
  For long-term implants in which the boundary and loading conditions are not well-
defined, CM may be useful for iterative design modifications, where simulations can be 
used to optimize the device design or enhance the design of prototypes. 
  For certain test scenarios, which cannot be evaluated using other nonclinical methods or 
clinically, CM may be used.  For example, to aid in assessing MRI safety, CM may be 
used to simulate certain worst-case MRI conditions that cannot be replicated in an animal 
model and cannot be tested ethically in humans. 
Discussions with FDA regarding protocols for complex and novel testing are strongly 
encouraged.   
6.5  In vivo animal studies 
In vivo animal studies provide unique anatomic and clinical pathologic information on the local 
and systemic responses to device use.  An animal study may be conducted to support the 
initiation of an early feasibility study when an animal model is needed to further assess basic 
safety or device functionality beyond the information provided from non-animal testing.    
An animal study should involve the use of a validated animal model, when available, for which 
the results are likely to predict risks in humans.  In cases in which a validated animal model is 
unavailable, a focused animal study to address a limited range of safety issues may be conducted 
to complement the non-animal testing.  A rationale for addressing questions typically answered 
by animal studies with alternative methods or data should be provided in the IDE application.  
Animal studies should not be viewed as an alternative to adequate bench testing, and whenever 
possible, protocols should apply the principles of reduce, replace, and refine.  For example, 
substitutions for the use of live animals, such as in vitro methods (e.g., validated cell culture 
experiments), cadaveric studies, or the use of computer simulation may be considered.  The size 
of the animal study depends on the device and how well the animal model provides anatomic, 
physiologic, and procedural similarities to humans.  Recognizing the inherent variability of 
results, animal studies should be large enough to show consistent results.  Short-term animal 
studies may be adequate for the initiation of an early feasibility study.  However, additional 
animal study data may be needed to support a larger clinical study with a near-final or final 
device design. 
Good Laboratory Practices (GLP) for animal care and study conduct as specified in 21 CFR part 
58 assure the quality and integrity of safety data to support IDE applications.  Non-GLP study 
data may be used to support an early feasibility study IDE application only if the deviations from 
GLP are identified and justified and do not compromise the validity of the study results.15  For 
example, if an independent quality assurance unit is not utilized, a sponsor should describe how 
bias was mitigated and how the study was verified to be authentic and complete.  Both GLP and 
                                                           
15 See 21 CFR 812.27(b)(3). 
  19  Contains Nonbinding Recommendations 
non-GLP studies should include independent monitoring and assessments with full disclosure of 
study findings.   
Discussions with FDA on study protocols, including the evaluation of operator technique, safety 
outcomes, and the effects of the biological system on the device, are encouraged prior to the 
initiation of in vivo animal studies.  
6.6  Prior clinical information 
For all IDEs, a summary of any prior clinical studies of the device used for the proposed 
intended use must be provided in the Report of Prior Investigations.16  For early feasibility 
studies, although clinical data may not be available for the test device for its proposed intended 
use, any relevant background clinical information should also be provided.  Relevant information 
includes data or publications on: 
  similar or related devices utilized for the proposed intended use; or 
  the subject device or similar devices used for a different purpose. 
This information may come from clinical use outside of the United States and may be used to 
support proof of principle and/or to address the likelihood of potential failure modes that may be 
observed during the early feasibility study.  If such information is available, it should be 
summarized in a format appropriate for the type of information (e.g., clinical study reports, 
summaries of publications with copies of the citations, individual experience with the device or 
prototype outside of a clinical study). 
7.  Investigational Plan 
The requirements in 21 CFR 812.25 apply to the Investigational Plan for early feasibility study 
IDE applications.  The information in this section is intended to clarify how certain of these 
requirements apply to early feasibility studies.  In the IDE application, the study should be 
clearly designated as an early feasibility study.  The proposed study should reflect the novelty of 
the device and medical need.  Use of the Pre-Sub process to discuss the Investigational Plan with 
FDA is highly recommended.  
Note that small clinical trials to determine device feasibility are specifically excluded from the 
definition of applicable device clinical trials requiring registration on 
www.ClinicalTrials.gov.17  FDA is interpreting this exception to apply to early feasibility 
studies.  
7.1  Risk analysis and mitigation 
The Investigational Plan must include a thorough risk analysis which describes the type and 
estimated severity of risks to the subjects, how risks will be minimized, and a justification that 
the risks are reasonable in relation to the expected benefits.18  The risk analysis should include 
the anticipated benefits and potential clinical effects of failure identified in the device evaluation 
strategy, as well as risks independent of the device that may be related to the underlying disease, 
                                                           
16 See 21 CFR 812.27. 
17 42 U.S.C. 282(j)(1)(A)(ii). 
18 See 21 CFR 812.25 and 812.30(b)(4). 
  20  Contains Nonbinding Recommendations 
comorbidities, or inherent to the procedure, and benefits unique to the device concept.  For 
example, a risk analysis may include the risks associated with use of anesthetic and contrast 
agents and the benefits of a less invasive intervention.  
For an early feasibility study, the methods to minimize risks may include the use of standard 
approaches, with additional mitigation strategies to protect individual study subjects and future 
study participants during the ongoing early feasibility study.  Examples of both standard and 
additional risk mitigation strategies include: 
  use of study sites that have sufficient expertise and resources to manage adverse events 
and provide appropriate alternative therapies if needed;  
  identification of qualified investigators with adequate training to conduct the early 
feasibility study;  
  a plan to capture human factors information during the course of the study to modify the 
procedures or device as necessary based on the information obtained; 
  specifying appropriate study inclusion and exclusion criteria; 
  limiting the sample size to a reasonable number for an early feasibility study (e.g., 5-10 
initial subjects); 
  follow-up assessments at regular intervals to monitor subject safety and device 
effectiveness (i.e., potentially more frequent than for a traditional feasibility or pivotal 
study); 
  timely reporting of serious adverse events (e.g., after each occurrence rather than only in 
a periodic progress report); 
  timely reporting of device performance parameters, which help determine whether the 
device functions as intended (e.g., measurements of deliverability, stability, handling, 
visualization, patency, integrity);  
  non-sequential enrollment, that is, initial device use in subjects with more favorable 
anatomical characteristics as compared to the population otherwise eligible for the early 
feasibility study (e.g., selecting subjects that meet study eligibility requirements but do 
not have anatomic features that may increase the difficulty of device use); and 
  a pre-specified plan for periodic patient outcome assessments and reporting prior to 
enrollment of additional patients (e.g., as frequently as after each use of the device). 
7.2  Clinical protocol 
The Investigational Plan for an early feasibility study must present objectives that reflect the 
purpose of the clinical study.19  The study protocol should include study endpoints, endpoint 
assessment methods, and adverse event definitions as appropriate for an early feasibility study.  
The study protocol must also clearly describe the methodology to be used in the investigation.20  
This should include a comprehensive description of the subjects to be enrolled in the study.  
When identifying the appropriate study population, subject risk tolerance (based on the severity 
of the underlying condition and limitations of alternative treatment options) and the ability to 
utilize the standard of care if the study device does not function as intended should be 
considered.  The subjects may have different clinical characteristics as compared to the 
population to be included in a future pivotal study (e.g., the early feasibility cohort may have 
more comorbidities, or a more advanced stage of disease).  However, to ensure that the study 
                                                           
19 21 CFR 812.25(a). 
20 21 CFR 812.25(b). 
  21  Contains Nonbinding Recommendations 
will provide information useful for the device development process, and to avoid exposing 
subjects to risks in the absence of any anticipated benefit, the study should avoid enrolling 
subjects for whom success is unlikely due to general health issues.    
To allow for appropriate flexibility with respect to patient selection and data interpretation, the 
early feasibility study protocol generally does not need to include the same level of detail as a 
pivotal study protocol (see Section 5), but it needs to ensure adequate capture of adverse clinical 
events and device performance information.   
7.3  Human subject protection measures  
Any early feasibility study involving human subjects must comply with FDA human subject 
protection requirements, including obtaining informed consent and Institutional Review Board 
(IRB) (or ethics committee) oversight.21  These measures should be tailored to the subject 
population and the risk profile of the device under investigation. 
7.3.1  Informed consent 
Sponsors, investigators, and IRBs should pay particular attention to the adequacy of informed 
consent in early feasibility studies.  The informed consent process for early feasibility studies, as 
for all clinical investigations, must adhere to the requirements described in 21 CFR part 50 
subpart B  Informed Consent of Human Subjects.  An informed consent form for early 
feasibility studies must comply with the requirements in 21 CFR 50.25 and should address the 
distinctive aspects of an early feasibility study.  For example, subjects must be told that the study 
involves research and must be provided an explanation of the purposes of the research,22 
including that the proposed investigation is an early feasibility study (e.g., a small study of an 
innovative device or innovative clinical use of a device for which there may be less nonclinical 
data than would be required for a larger study).  The novelty of the device or procedure must also 
be described in language understandable to the subject.23   
As discussed above, an early feasibility study may carry greater unknown risk as compared to 
traditional feasibility and pivotal studies.  Subjects must be made aware during the informed 
consent process that there may be unforeseeable risks associated with participation in the study 
due to limitations in available data and experience with the device.24  A description of any 
benefits to the subject or to others which may reasonably be expected from the research must be 
provided during the informed consent process in accordance with 21 CFR 50.25(a)(3).  For 
example, the form should note that even if there is limited or no expected personal benefit to the 
study subject, future patients with the disease or condition may benefit from the information 
obtained during the early feasibility study.  The consent form should not include language that 
could lead subjects to overestimate the chance of personal benefit. 
Additional guidance on the information to include in an informed consent form for an early 
feasibility study can be found in Appendix 3. 
                                                           
21 See 21 CFR parts 50 and 56. 
22 21 CFR 50.25(a)(1). For more information on Informed Consent see, A Guide to Informed Consent - Information 
Sheet, at http://www.fda.gov/RegulatoryInformation/Guidances/ucm126431.htm. 
23 21 CFR 50.20. 
24 See 21 CFR 50.25(b)(1). 
  22  Contains Nonbinding Recommendations 
7.3.2   Institutional Review Boards 
As with all clinical investigations, early feasibility studies must adhere to the requirements for 
study oversight by an IRB, as described under 21 CFR part 56.  For example, IRBs must 
determine if the risks to the subjects are minimized to the extent possible, and consider whether 
the risks to the subjects are reasonable in relation to anticipated benefits and the importance of 
the knowledge that may be obtained.25  
IRBs must conduct continuing review of research at intervals appropriate to the degree of risk, 
but not less than once per year, as required by 21 CFR 56.109(f).  It is likely that more frequent 
oversight by the IRB to assure human subject protection may be appropriate for early feasibility 
studies.  This may include, for example, continuing review on a more frequent basis than 
annually, continuing review after a small target number of subjects have been studied, and/or 
graduated enrollment based upon a safety analysis of the preceding subjects.   
7.4  Monitoring  
7.4.1  Monitoring procedures 
Detailed monitoring procedures, appropriate for an early feasibility study, must be included in 
the Investigational Plan, as required by 21 CFR 812.25(e).  For more information on standard 
monitoring procedures, see FDAs draft guidance, Oversight of Clinical Investigations  A 
Risk-Based Approach to Monitoring 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM269919.pdf).  FDA's draft guidance represents FDA's proposed approach on this topic.  
Due to the limited number of study sites and subjects, and the expected close oversight of each 
study subject, the monitoring procedures for early feasibility studies may deviate from standard 
procedures and should be tailored to the particular study being conducted.  
7.4.2  Data monitoring committee (DMC) 
FDAs guidance, Establishment and Operation of Clinical Trial Data Monitoring Committees, 
(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf) notes that:  
[E]arly studies are often exploratory in nature; they are frequently not randomized or 
controlled and therefore accumulating results are known to the investigators and sponsor.  
Issues regarding statistical interpretation of interim data, or confidentiality of interim 
data, are therefore generally less relevant in this setting.  Nevertheless, for difficult 
situations in which the potential scientific gain from continuing a study must be evaluated 
in the context of ethical considerations for ensuring subjects rights and welfare, 
particularly in settings such as those described above, DMCs may be helpful to 
investigators, sponsors, and IRBs by providing independent, objective expert counsel. 
For certain early feasibility studies, a DMC composed of clinicians, scientific experts, and 
individuals with ethical expertise may be helpful in evaluating data relatively early in the course 
of the study and would provide an additional layer of human subject protection.  Use of a DMC 
                                                           
25 21 CFR 56.111(a)(1) and (2). 
  23  Contains Nonbinding Recommendations 
could be proposed by a sponsor as a risk mitigation strategy element, particularly for studies 
where additional independent oversight would be of value.   
8.  Iterations during early feasibility studies 
Because modifications to the Investigational Plan are expected during early feasibility studies, 
discussions with FDA to facilitate timely implementation of changes are particularly important 
throughout the Pre-Sub and IDE processes.  The requirements outlined in 21 CFR 812.35 and 
explained in, Changes or Modifications During the Conduct of a Clinical Investigation; 
Final Guidance for Industry and CDRH Staff (http://www.fda.gov/MedicalDevices/DeviceRegu
lationandGuidance/GuidanceDocuments/ucm082145.htm), regarding changes to a device or 
clinical protocol apply to all types of investigational studies.  However, this guidance describes 
new policy, interpreting the requirements differently for early feasibility studies. 
To facilitate timely device and/or clinical protocol modifications during an early feasibility 
study, this guidance introduces the following approaches: 
1.  Permitting a broader array of modifications to the device and the clinical protocol under 
5-day notification without prior FDA approval during an early feasibility study as 
compared to other types of studies; 
2.  For anticipated changes that would require prior FDA approval, allowing a sponsor to  
seek contingent approval beforehand, which would permit changes contingent upon 
acceptable nonclinical test results without requiring additional FDA action;  
3.  For early feasibility study IDE supplements and amendments, utilizing a new interactive 
review process that encourages communication with FDA during the 30-day review 
cycle.  
Note that annual progress reports to the FDA are required by 21 CFR 812.150(b)(5) for studies 
of significant risk devices.  Some minor changes to the purpose of the study, risk analysis, 
monitoring procedures, labeling, informed consent materials, and IRB information are not 
required to be submitted in supplemental applications but must be identified in these annual 
progress reports. 26   
8.1  Changes requiring FDA notification (5-day notice) 
For all IDEs, a sponsor may make certain changes to an investigational device or clinical 
protocol during the study without prior FDA approval of a supplemental application by 
submitting a notice to FDA within 5 working days of making the change.27  A sponsor may make 
changes with 5-day notice if: (i) the changes to the device are made in response to information 
gathered during the course of the investigation, and the changes do not constitute a significant 
modification in design or basic principles of operation; or (ii) the changes to the clinical protocol 
do not affect: (a) the validity of the data or information, or the relationship of likely patient risk 
to benefit relied upon to approve the protocol, (b) the scientific soundness of the plan, or (c) the 
                                                           
26 See 21 CFR 812.35(a)(4). 
27 21 CFR 812.35(a)(3). 
  24  Contains Nonbinding Recommendations 
rights, safety, or welfare of the human subjects involved in the investigation.28  The information 
to be included in such a notice is described in 21 CFR 812.35(a)(3)(iv).   
Device developmental changes that do not constitute a significant change in design or basic 
principles of operation are generally appropriate for 5-day notices.  For early feasibility studies, 
FDA would consider a broader range of changes not to be significant as compared to other types 
of studies.  This is in part because the evaluation of an early feasibility study does not depend on 
statistical analyses of data collected or the pooling of data among study subjects, which would 
require the use of a consistent device design.  However, the changes should be expected not to 
adversely affect device performance or pose additional risk to the study subjects.   
For changes to an early feasibility study clinical protocol, the most relevant requirements for 
application of the 5-day notification option are that the changes: (1) not alter the relationship of 
likely subject benefit and risk relied upon to approve the protocol, and (2) not affect the rights, 
safety or welfare of study subjects.29  Since, as discussed above, early feasibility studies are 
expected to have enhanced risk mitigation strategies and patient protection measures directed 
toward each study subject, sponsors should explain how these instruments provide additional 
support when considering changes appropriate for implementation under a 5-day notice.  The 
other criteria, specifically that changes to the clinical protocol not affect the validity of the data 
or the scientific soundness of the investigational plan,30 should generally be much easier to meet 
for early feasibility studies than for other studies, because these studies are not intended to obtain 
statistically valid data or test statistical hypotheses.   
The types of changes that may be considered for 5-day notices may be discussed during Pre-Sub 
interactions and prospectively identified within the IDE application to facilitate timely 
implementation of device and clinical protocol modifications.  For changes that are appropriate 
for implementation under a 5-day notice, the contingent approval process (described below), in 
which the information needed to justify a change is identified, may be used as an alternative 
approach.  
Appendix 4 includes examples of the types of changes that may be appropriate for 5-day 
notification during an early feasibility study.    
8.2  Changes requiring FDA approval 
The first step in obtaining FDA approval of changes during the early feasibility study should be 
informal discussion with FDA, using the Pre-Sub process when appropriate, to identify the 
proposed modifications, the reasons for the modifications (e.g., adverse events observed during 
the clinical study), the purpose of the modifications, and the evaluations needed to support use of 
a modified device and/or changes to the clinical protocol.   
Following the informal discussion, there are two new approaches for obtaining timely FDA 
approval of changes to early feasibility studies: 1) contingent approval and 2) interactive review.   
                                                           
28 21 CFR 812.35(a)(3)(i) and (ii).  These changes must be supported by credible information as defined at 21 CFR 
812.35(a)(3)(iii).  21 CFR 812.35(a)(3). 
29 See 21 CFR 812.35(a)(3)(ii). 
30 21 CFR 812.35(a)(3)(ii)(A) and (B). 
  25  Contains Nonbinding Recommendations 
1)  Contingent approval.  When device iterations or changes to the clinical protocols are 
anticipated, identified, and explained prospectively, the contingent approval process may 
be used. This process may be informally discussed during Pre-Sub interactions and 
formally proposed during the original early feasibility study IDE application or in IDE 
supplements.   
In order to obtain contingent approval, during the 30 day review cycle the sponsor and 
FDA should reach final concurrence on the nonclinical test plan and associated 
acceptance criteria to evaluate the anticipated changes.  Once these are agreed upon, FDA 
may approve the anticipated changes contingent on the sponsors successful completion 
of the test plan and the reporting of the test data to FDA within 10 calendar days of 
implementing the change.   
  If the sponsor deviates from the conditions of FDAs approval, the contingent approval 
would no longer be valid, and the sponsor would need to renegotiate the test plan with 
FDA and obtain a new contingent approval.  Alternatively the sponsor could seek 
approval through the submission of a 30-day IDE supplement. 
  If the sponsor is able to anticipate multiple changes to the clinical protocol or potential 
device iterations, a proposal that covers these changes may be provided in the original 
early feasibility IDE application or in a single supplement.  For device modifications, the 
sponsor would need to prospectively identify the appropriate testing plan and acceptance 
criteria for each type of change to allow for contingent approval of all of the proposed 
changes.  For example, if a sponsor anticipates iterations of the materials of construction 
based on clinical data generated during the early feasibility study, they may present their 
strategy in a single IDE supplement and receive approval for the iterative plan, contingent 
on successful completion of the test plan for each material type.  Within 10 days of 
implementing each change, an IDE supplement should be submitted to provide the data 
and to report to FDA the current device iteration being used in the study.   
  For the clinical protocol, the sponsor could propose changing several clinical parameters 
during the early feasibility study to determine the most relevant parameters for future 
evaluation of the device.  If the sponsor can adequately justify the use of each parameter 
within the initial IDE submission or in an IDE supplement, the approval of the changes 
would be contingent only on reporting to FDA, within 10 days of implementing each 
change, that the changes were made.  This report should include a copy of the clinical 
protocol currently being used.  For other changes to the clinical protocol, it may be 
necessary to collect additional information (e.g., outcomes for the initial patients treated) 
to support the changes.  In this case, FDA concurrence with the information to be 
collected and the results needed to support the change would need to be obtained prior to 
FDA granting contingent approval.  The approval would be contingent on reporting the 
information, in addition to providing a copy of the protocol currently being used.   
  Appendix 4 includes examples of the types of changes that may be appropriate for 
contingent approval during an early feasibility study.   
  26  Contains Nonbinding Recommendations 
2)  Interactive review.  Interactive review involves the continuation of informal discussions 
with FDA during the 30-day IDE supplement review cycle.  This process may be used in 
situations where the sponsor has completed nonclinical testing to evaluate device 
modifications, or where changes to the clinical protocol do not meet the criteria for a 5-
day notice, and FDA decides that the additional information needed to address 
outstanding questions can be provided and reviewed within the 30-day review cycle.   
  For this process, the sponsor should submit an IDE supplement that requests the 
modifications and addresses any prior FDA feedback.  During the interactive review, 
FDA may request, and the sponsor may provide, additional information to enable the 
approval of the supplement within 30 days.  The success of the interactive review process 
depends on the availability of FDA and sponsor resources to provide timely and high 
quality feedback, as well as the acceptability of the test results. 
9.   Design controls 
The current good manufacturing practice requirements of the quality system regulation (21 CFR 
part 820) govern the methods used in, and the facilities and controls used for, the design, 
manufacture, packaging, labeling, storage, installation, and servicing of all finished devices 
intended for human use.  An approved IDE exempts a device from the good manufacturing 
practice requirements under section 520(f) of the FD&C Act except for the requirements found 
in 21 CFR 820.30 (design controls).31   
When complying with the requirements of 21 CFR 820.30 under an IDE, a device manufacturer 
shall establish and maintain a plan that describes or references the design and development 
activities specific to the medical device being designed or manufactured.  This plan does not 
need to be submitted in the IDE application.  The design plan shall describe or reference the 
following design and development activities in accordance with 21 CFR 820.30.   
-  Definition of responsibility for the implementation of the design and developmental 
activities; 
-  Identification and  description of the interfaces with different groups or activities that 
provide or result in input to the design development process;  
-  Verification that the design outputs that are essential for the proper functioning of the 
device were identified; 
-  Formulation of a plan to conduct design reviews to assess the progress of the design, 
and confirm the design is ready to move to the next phase of development; 
-  Assurance that the design outputs met the design input requirements as part of the 
design verification; 
-  Completion of a design validation to show that the approved design met the 
predetermined user needs and intended uses; 
                                                           
31 See section 520(g)(2)(A) of the FD&C Act; 21 CFR 812. 1.  See also 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDevic
eExemptionIDE/ucm051602.htm. 
  27  Contains Nonbinding Recommendations 
-  Performance of a risk analysis and consideration of risk throughout the design 
process; 
-  Documentation and control of design changes occurring during pre-production and 
post-production of the device; and 
-  Documentation of the design transfer into production specifications.  
Appropriate documentation and establishment of the aforementioned elements of the device 
design plan will facilitate meeting the design control requirements in 21 CFR 820.30 as the 
device design evolves.   
10. Next steps in clinical evaluation 
After obtaining clinical information from an early feasibility study, the type of subsequent 
clinical evaluation will depend on whether changes in the device design are expected, the 
availability of adequate data to justify the next study, and the purpose of the clinical study.  Early 
feasibility studies involve the investigation of devices that may be in a rapid phase of device 
iteration.  If clinical information is needed after device modification and further device iterations 
are expected, a sponsor may submit an IDE supplement including a request for expansion of the 
early feasibility study.  Once approved, the sponsor may enroll additional subjects in the early 
feasibility study.  If the device design is near-final or final, and the results of the early feasibility 
study support the initial safety of the device and proof of principle, it may be more appropriate 
for the sponsor to pursue either a traditional feasibility study or a pivotal study.  Progression to a 
traditional feasibility or pivotal study should be requested under an IDE supplement and should 
include the information needed to justify initiation of the larger study.  The approval of any IDE 
supplement will ultimately depend on the availability of nonclinical and clinical data to justify 
initiation of the specific type of study requested.   
Informal communications with FDA are important to help determine the most appropriate next 
step in the clinical evaluation of a device. 
11. Conclusion 
Early feasibility studies may be used to provide proof of principle and initial clinical safety data.  
Data from an early feasibility study may lead to device modifications and be used to refine the 
bench, analytical, and in vivo animal studies and future clinical study protocols.   
Conducting an early feasibility study under an IDE provides a unique opportunity to obtain 
clinical experience with a new or modified device or new clinical use, while utilizing appropriate 
subject protection measures and good clinical study practices.  Vital clinical information can be 
captured and used to optimize the device design, design evaluation, and clinical investigation 
plans.   
Initiation of an early feasibility study and progression toward a pivotal study benefit from a 
flexible process that relies on sound nonclinical assessments and appropriate risk-based 
rationales.  A high degree of interaction between FDA and the sponsor and use of the Pre-Sub 
process will be instrumental in the successful implementation of this guidance. 
  28  Contains Nonbinding Recommendations 
Appendix 1: Suggested topics for a Pre-Sub for an early feasibility 
study IDE  
Although use of the Pre-Sub process is not a requirement, interactions between the FDA and 
sponsor are encouraged to enhance the predictability of the early feasibility study IDE review 
process.  Based on the recommendations outlined in the guidance, the following topics may be 
useful to discuss during Pre-Sub interactions prior to the submission of the original IDE 
application:  
1.  Design concept 
2.  Clinical context 
a.  Clinical condition the device is intended to treat or assess 
b.  The standard of care, including the types and severity of risks and the benefits associated with 
current treatment options 
c.  The types and severity of potential risks and the anticipated benefits that may be associated 
with the study device 
d.  The rationale for exposing the target population to the potential risks (i.e., whether the 
anticipated benefits that may be associated with the use of the study device justify the potential 
risks, recognizing the benefits and risks posed by current treatment or assessment options) 
3.  Rationale for early feasibility study, considering: 
a.  Novelty of the device or its intended clinical use 
b.  Stability of the device design 
c.  Whether additional nonclinical testing would likely provide the information needed to further 
device development 
4.  Nonclinical testing plan 
a.  Draft device evaluation strategy for the early feasibility study  
b.  Draft device evaluation strategy for device development beyond the early feasibility phase, if 
the sponsor wishes to obtain FDA feedback that may assist with future submissions 
c.  Summary justification regarding the amount and type of information/data needed to support 
initiation of the early feasibility study in the specified patient population, with comment on, or 
comparison to, what may be expected to support the initiation of a larger clinical study 
d.  Protocols for complex and novel nonclinical (e.g., bench, animal and computational modeling) 
testing or analyses, when available  
5.  Investigational plan 
a.  Clinical study protocol summary 
b.  Summary of risk analysis and mitigation strategies 
c.  Informed consent language regarding the early feasibility nature of the study 
6.  Anticipated design iterations and clinical protocol changes and proposals for using the strategies 
outlined in the guidance 
7.  Projected device development timeline (e.g., significant regulatory and testing milestones) 
 
 
  29  Contains Nonbinding Recommendations 
Appendix 2: Device evaluation strategy example 
The following hypothetical example illustrates the concepts described in Section 6.3. 
A sponsor approaches FDA with an early feasibility study proposal to evaluate an innovative, 
covered, metallic implant to treat a disease common in the elderly.  The device is unique in that 
delivery of the treatment will be through a catheter, rather than by open surgery (the standard of 
care).  The expected benefits of this approach include less bleeding, fewer major adverse events, 
less pain, shorter hospital stay, and faster recovery as compared to the open surgery.  There are 
aspects of the new device that are similar to a device approved for a different indication. 
In a Pre-Sub, the sponsor describes the design concept and provides a draft device evaluation 
strategy table as described in Tables 1 and 2 of Section 6.3.  Portions of the table are presented in 
Tables 3-5 for a procedure-related function, a performance-related function, and a basic safety-
related feature.   
The procedure-related functions for this device include the ability to:  
  access the target site;  
  deploy the implantable portion of the device; and  
  withdraw the delivery system.   
For the the ability to access the target site attribute, the potential failure modes are: 
  the inability to safely advance the system to the target site; and 
  implant dislodgement from the delivery system. 
Table 3 outlines the information for the attribute the ability to access the target site and the 
potential failure mode of the inability to safely advance the system to the target site.   
Some of the performance-related functions and features include: 
  implant integrity; 
  fixation effectiveness; and 
  patency. 
For the implant integrity attribute, the potential failure modes are: 
  corrosion; and 
  structural failure of the implant. 
Table 4 outlines the information for the attribute implant integrity and the potential failure 
mode of corrosion.   
The basic safety-related features include: 
  biocompatibility; 
  sterility; and 
  MR compatibility. 
For the biocompatibility attribute, the potential failure mode is non-biocompatibility.  Table 5 
outlines the information for the attribute biocompatibility and the potential failure mode of 
non-biocompatibility.   
  30  Contains Nonbinding Recommendations 
Table 3: Device Evaluation Strategy Table, Procedure-Related Function  Ability to Access  
Column 1  Column 2  Column 3  Column 4  Column 5  Column 6  Column 7  Column 8  Column 9 
Potential Effects of 
Supportive Information 
Failure 
Device-
Potential Failure  Potential  Potential  Device Design  Nonclinical Device  Clinical Study Mitigation 
Related  Leveraged  Supportive 
Modes  Device  Clinical  Information Testing   Strategies 
Attribute  Nonclinical  Clinical 
Effects of  Effects of 
Information   Information
Failure  Failure 
Device  The failures that  The  The  Relevant design  Nonclinical  Relevant clinical  Proposed testing of  Mitigation strategies included in 
function or  might occur and  potential  potential  characteristics intended  information  experience  the study device  the clinical protocol intended to 
feature  could result in  effect(s) of  effect(s) of  to provide the function  leveraged from  obtained from  (i.e., the device that  minimize the frequency or 
required for  consequences  the failure  the failure  or feature or to address  internal or  internal or  will be used in the  severity of the potential clinical 
the device to  (effects) to the  mode on  mode on  or mitigate the potential  external sources    external sources  clinical study) to  effects resulting from a failure to 
achieve the  device or study  the device  the study  failure mode, and other  for a similar  complete the  attain the attribute 
overall desired  subject, if the  subject  information considered  device or  evaluation of the 
performance  function or feature  in the design of the  indication  attribute and the 
is not attained  device     potential failure 
mode(s), considering 
the information in 
Columns 3-7 
Ability to  Inability to safely  -  Delivery  - Embolism  Design characteristics:  - Volume 2,  - Volume 2,  The following tests  For all events 
access the  advance the  system  - Procedural  -  Unique tip to  Section 1 of  Section 2 of  will be conducted on  -  Timely detection, treatment, 
implantation  system to the  damage  failure  minimize tissue  the Pre-Sub  the Pre-Sub  the study device:  and reporting of adverse 
site  target site  -  Implant  - Tissue  trauma  describes  describes the  -  Acute and 30-day  events 
damage  damage at  -  Enhanced flexibility  nonclinical  clinical use of  animal study (see 
access  to accommodate  testing  our similar  study protocol in  For Embolism 
site  tortuous anatomy  conducted on  device   Volume 3,  - Clinical evaluations and 
-  Safety features to  our similar  Section 1)  imaging post-procedure for 
prevent completion  device   Reference to this  -  Simulated use  early detection of distal organ 
of deployment steps  information is  testing (see  damage to allow for early 
out of sequence  Reference to this  appropriate  protocol in  treatment and to identify the 
information is  because the new  Volume 3,  need to change the procedure 
Relevant information  appropriate  intended use  Section 2)  or device 
considered in the  because the  does not involve  -  Tensile bond  - Embolic protection device use 
design of the device:  study device has  targeting a new  strength  
-  Use of same  the same  anatomical  -  Torsional bond  For Procedural failure 
delivery mechanism  delivery  implantation site  strength  -  Pre-operative imaging to 
as our similar  mechanism as  and therefore  confirm appropriate anatomy 
device with a   the approved,  would not likely  - Plan to treat subjects with the 
known clinical  similar device.  negatively affect  current standard of care if the 
performance  the ability of the  delivery system cannot be 
(without  study device to  advanced  
catastrophic  access the 
failures), approved  implantation site.   For Tissue damage at access 
to treat a different  site 
disease process in  -  Pre-operative imaging to 
the same anatomic  confirm appropriate anatomy 
location 
  31  Contains Nonbinding Recommendations 
Table 4: Device Evaluation Strategy Table, Performance-Related Function  Implant Integrity 
Column 
Column 2  Column 3  Column 4  Column 5  Column 6  Column 7  Column 8  Column 9 
1 
Potential Effects of Failure  Supportive Information 
DRAteetvlraiibcteued-te   PFMaooitdleuenrseti  al  PDEfoefvteeiccntesti  aolf   PColitneicnatila El ffects  DInefovircmea Dtieosnign  LInefvoermraagteiodn N  onclinical  SCulipnipcoarlt ive  NDTeoesvnticicnleign  ical  CStlrinaitceagli eSst udy Mitigation 
of Failure  Information
Failure 
                 
Implant  Corrosion   -  Component  - Foreign body  Design  - Volume 2, Section 3 of the  - Volume 2,  No device- For all events 
integrity  separation  embolization  characteristics:  Pre-Sub describes  Section 4 of the  specific  -  Timely detection, treatment, 
  -  Fracture  - Loss of  -  Electropolished  nonclinical testing  Pre-Sub  testing  and reporting of adverse 
-  Movement  biocompatibility  metallic  conducted on our similar  describes the  needed prior  events 
from  - Effectiveness  components to  device with known  clinical use of  to initiation of   
intended  failure (specify)  improve corrosion  corrosion resistance   our approved  the early  For Foreign body embolization, 
implant  due to  resistance   device   feasibility  trauma to adjacent structures and 
location  component    Reference to this    study  all other clinical effects of failure 
separation  Relevant information  information is appropriate  Reference to this  -  No additional mitigation 
  - Effectiveness  considered in the  because the risk of  information is    strategies beyond timely 
failure (specify)  design of the device:  corrosion is similar to the  appropriate  detection, treatment, and 
due to implant  -  Use of same  previously approved device.   because the new  reporting of adverse events 
movement  metallic  The study device will be  device will be   
- Trauma to  components and  exposed to an in vivo  exposed to the  - For Loss of biocompatibility 
adjacent  surface finishing  environment that has the  same in vivo  -  Assess inflammatory 
structures  as our similar,  same relevant  environment.   biomarkers post-procedure 
approved device  characteristics (e.g., body  -  Monitoring of subjects for 
with acceptable  fluid contact, externally  signs and symptoms of 
corrosion  applied forces), has a  allergic reactions to allow for 
resistance   similar design and is  early treatment
constructed with the same   
metal, using the same  For Effectiveness failure (specify) 
manufacturing methods.  due to implant movement or 
component separation 
  -  Imaging studies at regular 
intervals to evaluate device 
position  
-  Plan to implant additional 
devices if the original device 
moves from the targeted 
implant site 
 
  32  Contains Nonbinding Recommendations 
Table 5: Device Evaluation Strategy Table, Basic Safety-Related Feature  Biocompatibility 
Column 1  Column 2  Column 3  Column 4  Column 5  Column 6  Column 7  Column 8  Column 9 
Potential Effects of 
Supportive Information 
Failure 
Device-Related 
Potential  Potential  Potential  Device Design  Clinical Study 
Attribute  Leveraged  Supportive  Nonclinical Device Testing  
Failure Modes  Device  Clinical  Information Mitigation Strategies 
Nonclinical  Clinical 
Effects of  Effects of 
Information   Information
Failure  Failure 
                  
Biocompatibility  Non- No device  Adverse  Relevant  No leveraged  No leveraged  The following tests will be  For all events 
biocompatibility  effects  biological  information  nonclinical  clinical  conducted to support the  -  Timely detection, 
  response  considered in  information  information  initiation of the early feasibility  treatment, and 
the design of  study:  reporting of adverse 
the device:  Although the  -  Testing in accordance with  events 
-  Use of  metallic  Part 1 of ISO 10993 (see 
materials with  component is  Volume 3, Section 3)  - For Adverse biological 
histories of  identical to one  -  Acute and 30-day animal  response or loss of 
clinical use  of our approved  study (see study protocol in  biocompatibility
devices, there  Volume 3, Section 4)  -  Assess 
are additional    inflammatory 
materials used  The specific aspects of  biomarkers post-
in the  biocompatibility that will be  procedure 
construction of  assessed in the animal study  -  Monitoring of 
the device, and  are acute systemic and  subjects for signs 
therefore,  subchronic toxicity, in vivo  and symptoms of 
biocompatibility  thrombogenicity, hemolysis and  allergic reactions to 
testing on the  local irritation.  These will be  allow for early 
study device is  assessed through complete  treatment 
needed.  necropsy and target tissue 
gross and histologic evaluation. 
 
  33  Contains Nonbinding Recommendations 
To help support the device evaluation strategy, the sponsor identifies the novel and most 
clinically relevant attributes (i.e., those that support an expectation of acceptable clinical use or 
are associated with basic device safety) and those that could be affected by differences in their 
study device as compared to existing devices.  The sponsor explains why certain potential failure 
modes would not likely be associated with catastrophic failures, discusses the likelihood and 
severity of the potential clinical effects of failure, emphasizes the unique anticipated benefits of 
their novel technology, and details how the mitigation strategies can be used to minimize harm to 
study subjects.  The sponsor also describes their rationale for deferring some nonclinical testing.   
The FDA interacts with the sponsor to reach agreement on the comprehensive list of device-
related attributes and the potential failure modes that could occur if the desired functions or 
features are not achieved.  They then discuss whether the proposed bench, laboratory, analytical, 
and animal testing of the study device should be adequate to complete the evaluation of the 
attributes and the potential failure modes, considering the information provided in Columns 5-7 
of the device evaluation strategy table.   
The sponsor plans to modify the device design based on the information obtained from the early 
feasibility study.  The sponsor elaborates on the planned testing to be completed for the modified 
device, prior to progressing beyond the early feasibility study.  For example, to justify the 
initiation of the early feasibility study, an animal study is planned to evaluate the potential for 
catastrophic failure of the device acutely and in the intermediate-term.  To support initiation of a 
pivotal trial, the sponsor proposes a long-term animal study, which will be carried out concurrently 
with the traditional feasibility study, to demonstrate complete healing at the implant site.  The 
sponsor will update their overall device evaluation strategy table as information is obtained from 
their nonclinical testing and early feasibility study. 
The sponsor continues to interact with the FDA as they complete the nonclinical testing of their 
device.  The Pre-Sub interactions regarding the device evaluation strategy enhance the 
predictability of the review process by increasing the likelihood that the Report of Prior 
Investigations will be adequate to help support IDE approval. 
  34  Contains Nonbinding Recommendations 
Appendix 3: Supplemental guidance for the preparation of an early 
feasibility study informed consent document 
The informed consent process for early feasibility studies, as for all clinical investigations, must 
adhere to the requirements described in 21 CFR part 50 subpart B  Informed Consent of Human 
Subjects.  The outline below presents the general informed consent requirements listed in 21 
CFR 50.25.  The specific recommendations relevant to an early feasibility study are found under 
each applicable general consent requirement.  Some of these recommendations may be 
appropriate for other types of clinical studies, but are particularly relevant for early feasibility 
studies.    
Note that the recommendations below are not presented in plain language.  When drafting an 
informed consent form, appropriate wording should be used to effectively communicate the 
information to the potential study subject. 
Introduction 
General consent requirement: 
      a statement that the study involves research  
Early feasibility consent recommendations: 
  include a statement that this is an early feasibility study and explain the significance of such 
studies 
  describe the consent process and the purpose of the consent process  
Note: It may be appropriate to have a patient advocate present during the consent process 
and/or have an independent individual, other than the investigator, be responsible for 
explaining the study. 
Purpose of the Study 
General consent requirement: 
      an explanation of the purposes of the research 
Early feasibility consent recommendations: 
  Generic early feasibility study information 
  describe an early feasibility study, that is, a study of an innovative device or innovative 
clinical use of a device in a small number of patients  
  explain that the study is designed to gain initial insights into the basic safety and device 
functionality  
  explain that there may be unforeseeable risks associated with participation in an early 
feasibility study due to limitations in available data and experience with the device 
Specific information regarding the proposed investigation 
  name the device and the number of patients to be enrolled 
  provide a brief description of the underlying medical condition, the device (including the 
innovative device features) and what the device is intended to do 
  explain how different the device or procedure is from currently available therapies 
  provide information on whether this study involves the first human use of the device or 
whether there has been previous clinical use of this or a similar device for the same or a 
different intended use 
  35  Contains Nonbinding Recommendations 
Study Procedures  
General consent requirement: 
      a description of the procedures to be followed 
Early feasibility consent recommendation: 
  include a description of all procedures and follow-up requirements 
General consent requirements: 
      identification of any procedures which are experimental 
      the expected duration of the subject's participation 
Early feasibility consent recommendation: 
  indicate how the procedures and follow-up in the study differ from the standard of care  
Risks 
General consent requirement: 
      a description of any reasonably foreseeable risks or discomforts to the subject 
Early feasibility consent recommendations: 
Note: This section should reflect the risk analysis and risk mitigation strategies in the clinical 
protocol. 
  include a statement to indicate that not all risks associated with the use of the study device 
are currently known 
  list reasonably foreseeable risks, but indicate that there may not be information to fully 
predict the frequency and severity of these risks  
  describe risk mitigation strategies (e.g., if the investigational treatment is unsuccessful, the 
patient may still be eligible for treatment with the current standard of care) 
Benefits 
General consent requirement: 
      a description of any anticipated benefits to the subject or others 
Early feasibility consent recommendations: 
  without overestimating the chance of personal benefit, describe any anticipated benefits to 
the subject which may reasonably be expected  
  disclose that there may be little information to support a likelihood of personal benefit 
  indicate that even if there is limited or no personal benefit to the study subject, future patients 
with the disease or condition may benefit from the information obtained during the early 
feasibility study 
Alternative Treatments 
General consent requirement: 
      a disclosure of appropriate alternative procedures or courses of treatment that might be 
advantageous to the subject 
Early feasibility consent recommendation: 
  describe the benefits, risks, and limitations of current treatment options  
Other Information 
General consent requirements: 
      a statement describing the extent to which confidentiality of the subject's records will be maintained 
and that notes that FDA may inspect the records 
      for research involving more than minimal risk, an explanation as to whether any compensation 
and/or medical treatments are available if injury occurs and, if so, what they consist of or sources of 
further information 
  36  Contains Nonbinding Recommendations 
      an explanation of whom to contact for answers to questions about the study and the subject's rights 
and whom to contact in the event of a research-related injury  
     a statement that participation is voluntary and that subjects may refuse to participate or discontinue 
participation at any time without penalty or loss of benefits, and whom to contact if they wish to 
withdraw 
Early feasibility consent recommendation: 
  if applicable, include a statement that an investigator(s) has a proprietary interest in the test 
article and identification of the person the study subject can speak to about potential financial 
conflicts 
 
 Additional elements, when appropriate:   
General consent requirements: 
      a statement that the procedure or treatment may involve unforeseeable risks to subject, or to the 
embryo or fetus should the subject become pregnant 
      anticipated circumstances under which the investigator may terminate the subject's participation 
without regard to the subject's consent 
      any additional costs to subject as a result of participation 
      consequences of a subject's decision to withdraw and procedures for withdrawal 
       a statement that significant new findings developed during the course of research which may relate 
to the subject's willingness to participate will be provided to the subjects  
      the approximate number of subjects involved in the study 
Early feasibility consent recommendations: 
  clearly indicate the consequences of withdrawal if, for example: 
  withdrawal results in termination of therapies, testing, or monitoring; or  
  transfer to an another health care provider is required 
  if early termination of treatment and/or withdrawal from the study might adversely affect the 
subject, describe the specific procedures that are recommended to ensure the subjects 
safety and why these procedures are important to the subjects welfare 
  if continued follow-up is recommended to ensure the subjects safety following withdrawal, 
explicitly inform the subject of the potential adverse effects of premature termination and the 
need for continued follow-up   
  include a statement indicating that information will be provided to the study subject that may 
relate to the subjects willingness to participate  
  37  Contains Nonbinding Recommendations 
Appendix 4: Device iteration example 
The following is a hypothetical scenario that illustrates the concepts described in Section 8 
regarding device iteration during an early feasibility study. 
Using the Pre-Sub process, a sponsor approaches FDA with a proposal to evaluate an innovative 
device in an early feasibility study to treat a disease common in the elderly.  The device is unique 
in that delivery of the treatment will be through a catheter, rather than through the standard 
procedure which involves open surgery.  The sponsor proposes to enroll up to 10 subjects at up 
to 3 investigational sites.  The sponsor will evaluate the device performance and clinical 
outcomes after each subject is treated, and prior to enrolling the next subject.   
In the Pre-Sub, the sponsor describes several potential device changes that may be implemented 
during the early feasibility study.  The sponsor proposes the following specific iterative changes 
for which they will request contingent approval under the original early feasibility IDE, if the 
information obtained during the clinical study suggests that these device modifications are 
needed to optimize the device design: 
  improvements in maneuverability, including: 
o  modifying the shape of the nose cone of the introducer (e.g., increase or reduce 
tapering); and  
o  making the sheath stiffer or more flexible; 
  changing the length of the catheter to allow for the use of alternative access sites; 
  modifying the hemostatic valve by changing material properties or device dimensions to 
improve hemostasis or reduce friction;  
  implementing ergonomic changes in the handle that do not affect the overall function of 
the device (e.g., changing texture of knobs or handle); and 
  modifying the operator interface console. 
During the Pre-Sub discussions, the sponsor and FDA reach agreement on the test plan to 
evaluate the proposed changes, including the acceptance criteria to be included in the original 
IDE application.  Although some of these changes may be appropriate for 5-day notices, 
obtaining prospective, contingent approval under the original IDE will provide the sponsor with 
more predictability in the regulatory process for their device modification plans.    
The sponsor, with help from the principal investigator, identifies other types of changes that may 
be needed for their device and clinical protocol during the conduct of their early feasibility study.  
In the original IDE application, the sponsor seeks FDA concurrence on their proposed 
approaches for implementing these changes, as outlined in Table 6.   
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Table 6: Regulatory process for anticipated modifications  
Changes that may be  Changes that may be appropriate for  Changes that may be 
appropriate for 5-day  contingent approval   appropriate for 30-day 
notification  interactive IDE 
supplement 
Add a previously characterized  If a surface coating is added, modify the  Expand the subject 
surface coating to the catheter if  distribution, thickness or area covered by  selection criteria (e.g., 
lubricity is needed to improve  the coating  inclusion of younger 
access*  subjects than defined in 
the original protocol) 
Adding, moving, or changing the  Improve the catheter resistance to  Change from 
radiopaque bands on the  kinking, with the type of modification and  percutaneous access to 
catheter to improve visibility.   appropriate testing to be identified prior  open surgical access  
to supplement submission 
Changes in the device  Change the device to accommodate a 
preparation for use   broader range of subject anatomies (type 
of modification and therefore type of 
appropriate testing not identified in the 
original IDE) 
Add the use of an approved  Add new types of imaging studies to 
ancillary device  (e.g., use of a  monitor device performance, if the 
longer introducer sheath)  modalities specified in the original 
intended to improve the safety  protocol are found to be inadequate and 
of the procedure*   if the new imaging procedure is 
supported through a risk assessment 
Modify the subject selection 
criteria to limit, rather than 
expand, the criteria*  
Modify procedural imaging 
modalities* 
Reduce follow-up assessments 
if early data support the change 
(i.e., the clinical data indicate 
that the change would not affect 
the safety of the subjects)* 
Change case report forms to 
capture additional information  
* These types of changes would not generally be appropriate for 5-day notification in a pivotal study 
due to their possible effect on the scientific soundness of the investigational plan and/or data validity. 
FDA considers the proposed approaches to be reasonable.   
The developmental device changes proposed for the 5-day notification process are considered 
appropriate in this case because they:  
  are reasonably defined such that appropriate testing and expected outcomes are known; 
  do not constitute significant changes in the basic principles of operation; and 
  are not considered significant because they would not adversely affect the interpretability 
of the results of an early feasibility study, and would not be expected to adversely affect 
device performance or to be associated with additional risk to the study subjects.  
Similarly, the clinical protocol changes would be appropriate for 5-day notification because the 
changes do not affect: 
  subject safety, rights, or welfare;  
  39  Contains Nonbinding Recommendations 
  the validity of the data or information resulting from the completion of the approved 
protocol, because the data or information will not be pooled; or 
  the relationship of likely patient risk to benefit relied upon to approve the protocol. 
The additional subject protection measures included in the early feasibility study protocol 
augment patient safety. 
FDA recognizes that more types of changes are appropriate for 5-day notification during this 
early feasibility study than would normally be acceptable for a study enrolling a larger number of 
subjects or requiring a stable device design and clinical protocol to allow for pooling of the data 
from study subjects.  For example, reducing the follow-up assessments would not likely be 
appropriate under a 5-day notice for a pivotal study; prior clinical studies would have been used 
to identify the appropriate follow-up assessments to ensure that consistent data are captured for 
each study subject.  For this early feasibility study illustration, since the optimal study subject 
follow-up has not been defined, the sponsor plans to require laboratory testing on days 3, 7 and 
14, but may find that, based on the results from the initial 5 subjects, the 7-day assessment is not 
informative and can be safely omitted.  As the safety of subsequent study subjects would not be 
compromised with this change, FDA agrees that such a change during this study could be made 
with a 5-day notification.    
During the course of the early feasibility study, the sponsor makes some of the anticipated 
changes, but also identifies an additional modification that had not been predicted in the original 
IDE submission.  The sponsor proposes contingent approval for a change in a material used in 
the construction of their device based on obtaining acceptable results with the same types of 
nonclinical testing used to evaluate the original device design.  To formally request this change, 
the sponsor submits an IDE supplement that describes the change and evaluation plan, including 
the acceptance criteria for the testing.  FDA and the sponsor reach a consensus regarding the 
proposal during the 30-day review time for the supplement, and FDA grants approval of the 
modification, contingent on the successful completion of the test plan and reporting of the 
change and supporting information to FDA within 10 days of implementing the change.  The 
sponsor evaluates the modified device according to the test plan, obtains acceptable results, 
implements the change and submits their test report to FDA 7 days after making the change.  
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