On June 14, 2023, FDA issued a guidance titled Content of Premarket Submissions for Device 
Software Functions.1 This final guidance supersedes the Guidance for the Content of Premarket 
Submissions for Software Contained in Medical Devices, issued on May 11, 2005. The final 
guidance issued on June 14, 2023, provides information regarding the recommended 
documentation sponsors should include in premarket submissions for FDAs evaluation of the 
safety and effectiveness of device software functions. In particular, the final guidance includes 
information to help determine a devices Documentation Level (formerly known as Level of 
Concern). The purpose of the Documentation Level is to help identify the minimum amount of 
information that would support a premarket submission that includes device software functions. 
Within the framework of the superseded guidance, implanted Brain-Computer Interface devices 
were considered a device with a Major Level of Concern. Based on the devices risk in the 
context of the devices intended use, as discussed in the final guidance Content of Premarket 
Submissions for Device Software Functions, implanted Brain-Computer Interface devices 
should generally address the recommendations for an Enhanced Documentation Level. The 
actual Documentation Level for your device may vary based on the specifics of your device. For 
more information about the Documentation Level and recommended documentation for a 
premarket submission, sponsors are encouraged to review the guidance Content of Premarket 
Submissions for Device Software Functions. 
 
1 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/content-premarket-
submissions-device-software-functions. Contains Nonbinding Recommendations 
Implanted Brain-Computer Interface 
(BCI) Devices for Patients with 
Paralysis or Amputation -
Non-clinical Testing and Clinical 
Considerations 
Guidance for Industry and Food and 
Drug Administration Staff 
Document issued on May 20, 2021. 
The draft of this document was issued on February 22, 2019. 
For questions about this document, contact the OHT5: Office of Neurological and Physical 
Medicine Devices/DHT5B: Division of Neuromodulation and Physical Medicine 
Devices/Acute Injury Devices Team at (301) 796-6610. 
U.S. Department of Health and Human Services 
U.S. FOOD & DRUG 
Food and Drug Administration 
ADMINISTRATION 
Center for Devices and Radiological Health  Contains Nonbinding Recommendations 
Preface 
Public Comment 
You may submit electronic comments and suggestions at any time for Agency consideration 
to https://www.regulations.gov. Submit written comments to the Dockets Management Staff, 
Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 
20852. Identify all comments with the docket number FDA-2014-N-1130. 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 
CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance. Please use the document 
number 1500045 and complete title of the guidance in the request.  Contains Nonbinding Recommendations 
Table of Contents 
I.  INTRODUCTION........................................................................................................................1 
II.  SCOPE..........................................................................................................................................2 
III.  PRE-SUBMISSION & IDE RECOMMENDATIONS................................................................3 
A. DEVICE DESCRIPTION ...................................................................................................................3 
B. RISK MANAGEMENT .....................................................................................................................7 
C. SOFTWARE ...................................................................................................................................7 
D. HUMAN FACTORS ........................................................................................................................9 
E. BIOCOMPATIBILITY.....................................................................................................................10 
F.  STERILITY ...................................................................................................................................12 
G. PYROGENICITY............................................................................................................................13 
H. SHELF LIFE AND PACKAGING .....................................................................................................13 
I.  ELECTRICAL SAFETY AND ELECTROMAGNETIC COMPATIBILITY (EMC) ..................................14 
J.  WIRELESS TECHNOLOGY............................................................................................................15 
K. MAGNETIC RESONANCE (MR) COMPATIBILITY .........................................................................16 
L. NON-CLINICAL BENCH TESTING ................................................................................................16 
(1)Electrodes ...................................................................................................................................17 
(2)Leads and Connectors.................................................................................................................18 
(3)Implanted Casing and Electronics ..............................................................................................20 
(4)Output Stimulation Measurements.............................................................................................21 
(5)Output Stimulation Safety..........................................................................................................22 
(6)Programmers/Control Unit.........................................................................................................22 
(7)Radiofrequency (RF) Transmitter and Receiver.........................................................................22 
(8)System Level Testing .................................................................................................................23 
M. REFERENCING MASTER FILES (MAF) AND OTHER FDAPREMARKET SUBMISSIONS ................24 
N. NON-CLINICAL ANIMAL TESTING ..............................................................................................24 
(1)General Considerations for Animal Studies...............................................................................25 
(2)Animal Study Protocols..............................................................................................................26 
O. CLINICAL PERFORMANCE TESTING ............................................................................................28 
(1)Report of Prior Investigations.....................................................................................................28 
(2)Clinical Study Considerations ...................................................................................................29 
APPENDIX A STIMULATION OUTPUT SPECIFICATIONS.........................................................38  Contains Nonbinding Recommendations 
Implanted Brain-Computer Interface (BCI) 
Devices for Patients with Paralysis or 
Amputation  Non-clinical Testing and 
Clinical Considerations 
Guidance for Industry and Food and Drug 
Administration Staff 
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or 
the public. You can use an alternative approach if it satisfies the requirements of the applicable 
statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for 
this guidance as listed on the title page. 
I.  Introduction 
This guidance document provides recommendations for Q-Submissions and Investigational 
Device Exemptions (IDEs) for implanted Brain-Computer Interface (BCI) devices for patients 
with paralysis or amputation. The field of implanted BCI devices is progressing rapidly from 
fundamental neuroscience discoveries to translational applications and market access. Implanted 
BCI devices have the potential to bring benefit to people with severe disabilities by increasing 
their ability to interact with their environment, and consequently, providing new independence in 
daily life. For the purposes of this guidance document, implanted BCI devices are 
neuroprostheses that interface with the central or peripheral nervous system to restore lost motor 
and/or sensory capabilities in patients with paralysis or amputation. 
FDAs Center for Devices and Radiological Health (CDRH) believes it is important to help 
stakeholders (e.g., manufacturers, health-care professionals, patients, patient advocates, 
academia, and other government agencies) navigate the regulatory landscape for medical 
devices. Towards this goal, on November 21, 2014, CDRH held an open public workshop on its 
White Oak, MD campus with the aim of fostering an open discussion on the scientific and 
clinical considerations associated with the development of BCI devices.1 FDA considered the 
input provided during this workshop to develop the recommendations provided in this guidance 
document for implanted BCI devices. 
This guidance document provides non-clinical testing and clinical study design recommendations 
associated with implanted BCI devices. Non-clinical device testing can be used to demonstrate 
1 
http://wayback.archive-
it.org/7993/20170112091055/http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm410261 
.htm 
1  Contains Nonbinding Recommendations 
that potential risks have been mitigated prior to initiating a clinical study. Proper design of 
clinical trials is essential to provide a reasonable assurance of safety and effectiveness necessary 
to support a regulatory submission, and translation of BCI devices from concept to assisting 
device users. 
This guidance is a leapfrog guidance, a type of guidance that serves as a mechanism by which 
the Agency can share initial thoughts regarding emerging technologies that are likely to be of 
public health importance early in product development. This leapfrog guidance represents the 
Agencys initial thinking and our recommendations may change as more information becomes 
available. 
The Agency strongly encourages manufacturers to engage with CDRH through the Q-
Submission process to obtain more detailed feedback for BCI devices. For more information on 
Pre-Submissions, see Requests for Feedback on Medical Device Submissions: The Q-
Submission Program.2 
For the current edition of the FDA-recognized consensus standard(s) referenced in this 
document, see the FDA Recognized Consensus Standards Database.3 For more information 
regarding use of consensus standards in regulatory submissions, refer to the FDA guidance titled 
Appropriate Use of Voluntary Consensus Standards in Premarket Submissions for Medical 
Devices - Guidance for Industry and Food and Drug Administration Staff.4 
The contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract. This document is intended 
only to provide clarity to the public regarding existing requirements under the law. FDA 
guidance documents, including this guidance, should be viewed only as recommendations, unless 
specific regulatory or statutory requirements are cited. The use of the word should in Agency 
guidance means that something is suggested or recommended, but not required. 
II.  Scope 
The scope of this document is limited to implanted BCI devices that interface with the nervous 
system to restore motor and/or sensory capabilities in patients with paralysis or amputation. This 
guidance provides general recommendations for non-clinical testing and study design 
considerations for IDE feasibility and pivotal clinical studies. 
Non-clinical testing methods may not be available or may not sufficiently provide the 
information needed to advance to a final version of an implanted BCI device under development. 
Therefore, if your device is still under development, we recommend that you consider 
2 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-
medical-device-submissions-q-submission-program
3 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm 
4 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/appropriate-use-voluntary-consensus-
standards-premarket-submissions-medical-devices 
2  Contains Nonbinding Recommendations 
performing an early feasibility study through an IDE to collect an early clinical evaluation of 
your device to provide proof of the principle and initial clinical safety data. 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. Refer to FDA guidance document 
Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical 
Studies, Including Certain First in Human (FIH) Studies5 for information on performing a 
device evaluation strategy as part of your risk analysis. 
Non-implanted BCI devices are outside the scope of this guidance, as the regulatory 
considerations for non-implanted BCI devices may differ from those recommended in this 
guidance document, depending on various aspects, such as but not limited to the technical 
characteristics and indications for use/patient population. For feedback on regulatory 
considerations for non-implanted BCI devices, we recommend following the Q-submission 
process. 
If your implanted BCI device incorporates technological characteristics, components, or 
indications for use/patient population that are not described or referenced in this document, we 
also recommend that you submit a pre-submission to seek FDA feedback. 
III.  Pre-Submission & IDE Recommendations 
A. Device Description 
We recommend that you include the device descriptive information listed below. 
1.  A complete description of every module of the device. For example, BCI systems 
typically consist of several modules including but not limited to the following modules: 
a.  Signal acquisition (e.g., leads and recording electrodes); 
b.  Signal processing that includes software for decoding and encoding signals and 
providing stimulation (in some cases) and associated hardware; 
c.  Stimulation delivery (internal/external stimulator and stimulating electrodes); 
d.  Assistive effector component (e.g., a prosthetic limb, wheelchair, functional electrical 
stimulators applied to intact limbs, exoskeletons or robotic systems, or 
communication devices and computers); 
5 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigational-device-exemptions-
ides-early-feasibility-medical-device-clinical-studies-including 
3  Contains Nonbinding Recommendations 
e.  Sensor component for neural feedback (e.g., sensors for restoring touch or reporting 
other information), if applicable; and 
f.  Programming module that consists of an operating protocol to control functions, such 
as turning the device on and off and switching between various outputs and programs. 
2.  A general overview of the BCI device as a whole system including a description of how 
the different modules are configured to comprise the whole system and if applicable, a 
description of the different system configurations (e.g., programming, calibration, or 
testing configurations). 
3.  A complete description of key components of the device including its function, relevant 
model numbers, materials, location (implanted or external component) and dimensions or 
sizes that a user would need to know to use the device properly. If previously cleared or 
approved, the premarket submission number (i.e., 510(k), PMA number) with a 
description of modifications to the cleared or approved device(s) should be provided. The 
following information is recommended for specific key components: 
a.  Leads and connection cables: The following descriptive information should be 
provided for leads and connection cables: 
(i)  Number of leads and cables; 
(ii)  Insulation and conductor materials; 
(iii)  Length(s); 
(iv)  Diameter; 
(v)  Impedance; 
(vi)  Connectors; 
(vii)  Number and orientation of the conductors within the lead/cable (e.g., parallel to 
lead body, coiled within lead body); and 
(viii) Method of fixation and strain relief. 
b.  Electrodes: The following descriptive information should be provided for 
electrodes: 
(i)  Material (including any coatings or surface treatments); 
(ii)  Length; 
(iii)  Diameter; 
(iv)  Electrode geometry (e.g., cuff, flat, depth) and the electrode contact surface 
area; 
(v)  Number of electrodes/electrode contacts; 
(vi)  Electrode spacing; 
(vii)  Electrode span (from most proximal edge of proximal electrode to distal edge of 
distal electrode); 
(viii) Implant location (brain region, specific peripheral nerve, muscle group, spinal 
cord, external); and 
(ix)  Sensor and/or stimulation location (intracortical, subdural, cutaneous). 
4  Contains Nonbinding Recommendations 
c.  Connectors: A description of the connectors intended to be used for joining leads to 
the other components such as assistive effector components, signal processing 
hardware or programing modules. The description should include the materials, the 
diameter, the number and type of contacts, and how the connections are secured 
(e.g., male-female connection, clip). 
d.  Processing/Stimulation Hardware: The following descriptive information should be 
provided for the processing/stimulation hardware: 
(i)  Description of whether the hardware is implanted or external; 
(ii) Power source/method (e.g., battery, inductive coupling, radio frequency); 
(iii)Description of the signal filters (processing hardware); 
(iv)Number of output and recording channels; and 
(v) Description of output specifications (see Appendix A for more information on 
output modes). 
e.  Assistive effector and/or sensor component: A description of the assistive effector 
and/or sensor component(s) (e.g., a prosthetic limb, computer, sensors), including 
the following: 
(i)  Model Number; 
(ii) Description of modifications to the cleared or approved device(s) (e.g., addition 
of sensors); 
(iii)Degrees of freedom (i.e., the total number of independent displacements or 
aspects of motion); and 
(iv)Description of how the assistive effector or sensor component(s) is controlled 
(e.g., sequential or simultaneous control of the arm joints). 
f.  Programmers/Control Unit: The following information for both the physician and 
patient system for programming and control (if available) should be provided: 
(i)  Description of device and user interface, including all buttons, switches, etc.; 
(ii)  Description of all outputs that are controlled; 
(iii)  Description of data readout (including, if relevant, details such as number of 
channels, rate of digitization, bit size and duration of recording) and/or 
stimulator output (e.g., frequency, pulse width, intensity, electrodes, polarity); 
(iv)  Description of any special programming features; 
(v)  Description of hardware and software platforms; 
(vi)  Method of communication with other components (e.g., wired, wireless); 
(vii)  Power source; 
(viii) Any additional settings; and 
(ix)  All alerts and circumstances in which they are communicated to the user. 
g.  Algorithms:  We recommend that you provide a description of any algorithms used 
in your device. We recommend the use of flow charts (and/or other visual or 
5  Contains Nonbinding Recommendations 
organizational aids) to highlight the input parameters and their sources and the 
output parameters and their implementation (e.g., control of end-effector, for offline 
data analysis). 
h.  Wireless Function: We recommend that you describe the ability of your wireless 
medical device, as applicable, to function properly in the intended use environments 
where other RF wireless technologies will likely be located. In the design, testing, 
and use of wireless medical devices, the correct, timely, and secure transmission of 
medical data and information is important for the safe and effective use of both 
wired and wireless medical devices and device systems. 
i.  Battery: A complete description of all batteries used in the system by the various 
components should be provided, including chemistry and performance 
characteristics (e.g., usable battery amp-hour capacity, shelf life, and life testing 
under worst-case usage). 
4.  A thorough description (e.g., drawings, flow charts) of interactions between the various 
components, the user and patient, and the environment. 
5.  For a device that must be assembled or can be adjusted prior to use, an exploded view 
of the individual components relative to each other. The various components should be 
clearly labeled. 
6.  For a device that includes software, a brief description of the software, including the 
various functions, prompts, user inputs, etc. 
7.  For a device that incorporates radio frequency (RF) wireless technologies, a complete 
description of the exact wireless technology used, its characteristics, performance, risk 
management, and functions, including alarm conditions. See the FDA guidance 
document, Radio Frequency Wireless Technology in Medical Devices -Guidance for 
Industry and Food and Drug Administration Staff6 for additional recommendations for 
evaluating and documenting wireless technologies in premarket submissions. 
8.  A description of all safety features built into the device. 
9.  For a device that applies electrical current to the muscle or nerves, the output stimulation 
characteristics provided in Appendix A should be provided. 
10.  All devices intended to be used in conjunction with the implanted BCI device (e.g., 
implantation tools, clips or belts for body-worn components), and whether the devices are 
packaged or sold with the implanted BCI device, should be described. We recommend 
that you include a detailed description of all the devices packaged with the implanted BCI 
device, including: 
6 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/radio-frequency-wireless-technology-
medical-devices-guidance-industry-and-fda-staff 
6  Contains Nonbinding Recommendations 
(i)  Model number; 
(ii) Design drawings; 
(iii)Materials; and 
(iv)Similarity to all devices intended to be used in conjunction with the implanted BCI 
device that may have been approved/cleared with other leads or electrodes. 
B. Risk Management 
We recommend that you apply accepted risk management principles, such as those described in 
the currently recognized version of ISO 14971: Medical devices  Application of risk 
management to medical devices, while conducting the risk analysis as part of your design 
controls required in 21 CFR 820 during the development of your device. We recommend you 
submit risk management information that identifies hazardous situations, estimates the risks 
(e.g., risks of device malfunction, adverse tissue reaction, infection, use error, extravasation), and 
describes risk control measures and overall residual risk specific to your device. Certain 
verification and validation testing performed as a result of these activities should be provided (as 
described in Sections D to L below). 
We recommend that the risk analysis detail qualitative examination of the potential hazards (e.g., 
hardware, software, non-clinical-related, and clinical-related hazards) of the device from the 
perspective of the user. We also recommend identification of hazards caused by single-fault 
conditions to ensure that the failure of any single component of the implanted BCI device does 
not cause an unacceptable risk during use. 
The risk analysis should be provided in a tabular format and should analyze all potential 
causes for the identified risks. All mitigating strategies or corrective actions should also be 
identified, with a detailed analysis on how the corrective actions reduce the clinical risk to 
acceptable levels. You should provide a rationale for why the levels are acceptable. 
C. Software 
Significance: Software in implanted BCI devices ensures that various components of the 
implanted BCI system, such as the signal processing modules, controllers, stimulation hardware, 
and assistive device, operate as intended and provide software mitigations when appropriate. 
Adequate software performance testing provides assurance that the device is operating within 
safe parameters. 
Recommendation: Refer to the FDA software guidance Guidance for the Content of Premarket 
Submissions for Software Contained in Medical Devices7 for a discussion of the software 
documentation that you should provide in your submission. The software guidance outlines the 
type of documentation to be provided based on the level of concern associated with the device. 
We generally consider the software for implanted BCI devices to present a major level of 
7 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-content-premarket-
submissions-software-contained-medical-devices 
7  Contains Nonbinding Recommendations 
concern. If you believe that the software in your device presents either a minor or a 
moderate level of concern as defined in the software guidance, you should provide a scientific 
justification that supports your rationale for the level of concern based on the possible 
consequences of software failure. 
We recommend that you provide a full description of the software/firmware (including 
programming languages, hardware platforms, operating system and use of Off-the-Shelf 
software, if applicable) supporting the operation of the subject device following the software 
guidance, commensurate with the appropriate level of concern. This recommendation applies to 
original device/systems as well as to any software/firmware changes made to already-marketed 
devices. Changes to software must be revalidated and reverified in accordance with Design 
Controls, 21 CFR 820.30(g)(i), and documented in the Design History File 21 CFR 820.30(j). 
For early feasibility studies, we recommend that you provide adequate software performance 
testing to provide assurance that the system operates within safe parameters. Overall, the 
documentation related to software should provide sufficient evidence to describe the role of the 
software included in the device, risks associated with the device, and performance testing to 
demonstrate that the software functions as intended. In the case of software that will control 
various assistive effector components (i.e., motorized wheelchairs, computer software, upper 
limb prosthetics), we recommend that you account for any software-related hazards, and 
associated changes due to algorithm updates, in your risk-analysis plan. 
As appropriate, you should also provide information on the Cybersecurity aspects of your device. 
For more information on this topic, see FDAs guidance Content of Premarket Submissions for 
Management of Cybersecurity in Medical Devices.8 
If the device includes off-the-shelf software, you should provide the additional information as 
recommended in the FDA documents titled Off-the-Shelf Software Use in Medical Devices9 
and Cybersecurity for Networked Medical Devices Containing Off-The-Shelf (OTS) 
Software10, which provide additional information regarding medical devices utilizing off-the-
shelf software. 
Overall, the documentation related to the software contained in the medical device should 
provide sufficient evidence to describe the role of the software included in the device, and 
performance testing to demonstrate that the software functions as designed. 
8 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/content-premarket-submissions-
management-cybersecurity-medical-devices-0
9 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/shelf-software-use-medical-devices
10 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cybersecurity-networked-medical-
devices-containing-shelf-ots-software 
8  Contains Nonbinding Recommendations 
D. Human Factors 
Significance: Use-related hazards are hazards resulting from failure modes tied to the use of 
implanted BCI devices by end users (e.g., patients, surgeons, prosthetists, caregivers). They are a 
unique form of hazard in that use-related hazards can exist even if the device operates according 
to specifications. They generally do not involve specific failure modes associated with 
mechanical, electrical, and software components that are previously known or reasonably 
anticipated. These hazards might result from aspects of the user interface design that cause the 
user to fail to adequately or correctly perceive, read, interpret, understand or act on information 
from the device. Use-related hazards may vary in severity of potential harm to the user, ranging 
from hazards that lead to user annoyance to hazards that result in death. Regardless of the 
severity of potential harm from a use-related hazard, it is important to understand and identify 
these hazards to ensure that you have designed a safe and usable device. 
Recommendation: To understand and identify the use-related hazards associated with the use of 
an implanted BCI device, it is important to have an accurate and complete understanding of the 
specific behaviors required of users when using the device, the environment(s) in which the 
device will be used, the intended users of the device, and how environmental conditions and 
intended user characteristics could impact device use. With this information, you should be able 
to incorporate use-related hazards into the early stages of your risk management process to 
ensure user safety and satisfaction are integrated into device design and development. Additional 
recommendations on risk management can be found in Section III.B of this guidance document. 
Many implanted BCI devices are likely to undergo early feasibility studies. Human factors 
validation and evaluation is typically not needed to support feasibility study approvals; however, 
human factors data may be needed to support your future marketing submission to the Agency. If 
your device is still under development and you intend to pursue an early feasibility study through 
an IDE, the early feasibility study could be conducted to obtain initial insights into human factors 
(e.g., difficulties in comprehending procedural steps, insufficient training).11 Prior to 
implementing your early feasibility studies for implanted BCI devices, we recommend following 
Section 6 of FDA guidance, Applying Human Factors and Usability Engineering to Medical 
Devices, 12 to take into account human factors considerations. 
We recommend identifying a plan in your investigational protocol to capture usability 
information during the course of the early feasibility study. This information can be used to 
modify the procedures or device as necessary. In order to address and mitigate use-related 
hazards in final device designs, we recommend conducting usability evaluations (e.g., cognitive-
walk throughs, simulated-use testing, satisfaction surveys) early in the device design process and 
iteratively throughout the device development and evaluation process. 
11 
See FDA guidance, Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical 
Studies, Including Certain First in Human (FIH) Studies, available at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/investigational-device-exemptions-ides-early-feasibility-medical-
device-clinical-studies-including.
12 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/applying-human-factors-and-
usability-engineering-medical-devices 
9  Contains Nonbinding Recommendations 
E. Biocompatibility 
Significance: Implanted BCI devices contain patient-contacting materials, which, when used for 
their intended purpose (i.e., contact type and duration), may induce a harmful biological 
response. 
Recommendation: You should determine the biocompatibility of all patient-contacting materials 
present in your device. If the components of your BCI device are identical in composition and 
processing methods to components with a history of successful use in the same or similar 
anatomical locations, you may reference previous testing experience or literature. For some 
device materials, it may be appropriate to provide a reference to either a recognized consensus 
standard, or to a Letter of Authorization (LOA) for a device Master File (MAF). You should 
refer to Section M of this guidance document and the following FDA webpage for additional 
information on using device MAFs: https://www.fda.gov/medical-devices/premarket-approval-
pma/master-files. 
If you are unable to identify a legally marketed predicate device with similar location/duration of 
contact and intended use that uses the same materials as used in your device, we recommend you 
conduct and provide a biocompatibility risk assessment. The assessment should explain the 
relationship between the identified biocompatibility risks, the information available to mitigate 
the identified risks, and any knowledge gaps that remain. You should then identify any 
biocompatibility testing or other evaluations that were conducted to mitigate any remaining risks. 
We recommend that you follow FDAs guidance Use of International Standard ISO-10993-1, 
'Biological evaluation of medical devices -Part 1: Evaluation and testing within a risk 
management process13, which identifies the types of biocompatibility assessments that should 
be considered and recommendations regarding how to conduct related tests. 
The type of tests that are applicable to your device may depend on whether the electrodes 
interface with the central or peripheral nervous system. Additionally, devices intended to be used 
in conjunction with the implanted BCI device (e.g., components, surgical tools) may contact the 
patient in different ways and durations. Using ISO 10993-1: Biological evaluation of medical 
devices  Part 1: Evaluation and testing within a risk management process and Attachment A of 
FDAs guidance on ISO-10993-1, the following biocompatibility categories may be applicable to 
your implanted BCI device system: 
Category 1: Implant in permanent contact (>30 days) with neural tissue/bone, 
cerebrospinal fluid (CSF), and blood (indirect contact with blood through CSF as CSF is 
reabsorbed into the venous system) 
13 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-international-standard-iso-
10993-1-biological-evaluation-medical-devices-part-1-evaluation-and 
10  Contains Nonbinding Recommendations 
Intracortical electrodes (i.e., electrodes implanted in the cortex of the brain) or other subdural 
electrodes are examples of an implanted BCI device component in this category. The following 
endpoints should be addressed in your biocompatibility evaluation: 
   cytotoxicity 
   sensitization 
   irritation or intracutaneous reactivity 
   acute systemic toxicity 
   material-mediated pyrogenicity 
   subacute/subchronic toxicity 
   genotoxicity 
   implantation 
   neurotoxicity 
   hemocompatibility (extract hemolysis test) 
   chronic toxicity 
   carcinogenicity testing 
Category 2: Implant in permanent contact (> 30 days) with neural and non-neural 
tissue/bone (i.e., muscle, not intended directly or indirectly to contact CSF or blood) 
Electrodes implanted in peripheral nerve or muscle tissue or percutaneous connectors on the 
skull (i.e., pedestals) are examples of an implanted BCI device component in this category. The 
following endpoints should be addressed in your biocompatibility evaluation: 
   cytotoxicity 
   sensitization 
   irritation or intracutaneous reactivity 
   acute systemic toxicity 
   material-mediated pyrogenicity 
   subacute/subchronic toxicity 
   genotoxicity 
   implantation 
   neurotoxicity 
   chronic toxicity 
   carcinogenicity testing 
Category 3: External communicating device with limited ( 24 hours) tissue/bone contact  
A tunneling tool used to create a pathway in the body for leads is an example of an implanted 
BCI device tool in this category. The following endpoints should be addressed in your 
biocompatibility evaluation: 
   Cytotoxicity 
   Sensitization 
   Irritation or Intracutaneous Reactivity 
11  Contains Nonbinding Recommendations 
   Acute Systemic Toxicity 
   Material Mediated Pyrogenicity 
Category 4: Surface device with limited ( 24 hours) / prolonged (> 24 hours   30 days) / 
permanent (> 30 days) contact with intact skin 
External transmitters used as programmers/control units and assistive effector component (i.e., 
prosthetic limbs) are examples of implanted BCI device system components in this category. The 
following endpoints should be addressed in your biocompatibility evaluation: 
   Cytotoxicity 
   Sensitization 
   Irritation or Intracutaneous Reactivity 
F. Sterility 
Significance: Implanted BCI devices should be adequately sterilized to minimize infections and 
related complications. 
Recommendation: For implanted BCI components and surgical tools labeled as sterile, we 
recommend that you provide the information outlined below. 
1.  For the sterilization method, the sponsor should provide the following: 
a.  a comprehensive description of the sterilization method/process; 
b.  a description of the sterilization chamber if not rigid, fixed (e.g., flexible bag); 
c.  the sterilization site; 
d.  in the case of radiation sterilization, the radiation dose; 
e.  for chemical sterilants (e.g., Ethylene Oxide (EO), H O ), the maximum levels of 
2 2
sterilant residuals that remain on the device, and an explanation of why those levels are 
acceptable for the device type and the expected duration of patient contact. 
In the case of EO sterilization, CDRH has accepted EO residuals information based on 
the currently recognized version of the standard, ANSI/AAMI/ISO 10993-7: Biological 
Evaluation of Medical Devices  Part 7: Ethylene Oxide Sterilization Residuals. 
2.  For the sterilization method, you should provide a description of the method used to validate 
the sterilization cycle (e.g., the half-cycle method) as well as the sterilization validation data. 
The submission should also identify all relevant consensus standards used and identify any 
aspects of the standards that were not met. In the absence of a recognized standard, a 
comprehensive description of the process and the complete validation protocol should be 
submitted and reviewed. 
3.  You should state the sterility assurance level (SAL) of 10-6 for devices labeled as sterile 
unless the device is intended only for contact with intact skin. FDA recommends a SAL of 
10-3 for devices intended only for contact with intact skin. 
12  Contains Nonbinding Recommendations 
We recommend that you describe the sterilization process validated for each sterile 
configuration. If you are only planning to sterilize a limited number of devices using EO for the 
purposes of an IDE, you may want to consider a single lot sterilization process. For 
specifications on the single lot sterilization process, see Annex E: Single Lot Release in ISO-
11135: 2014: Sterilization of health care products  Ethylene oxide  Requirements for 
development, validation and routine control of a sterilization process for medical devices. 
G.Pyrogenicity 
Significance: Pyrogenicity testing is used to help protect patients from the risk of febrile reaction 
due to gram-negative bacterial endotoxins and/or chemicals that can leach from a medical device 
(e.g., material-mediated pyrogens). 
Recommendation: To address the risks associated with the presence of bacterial endotoxins, 
implanted BCI devices should meet pyrogen limit specifications. You should also follow the 
recommendations in Pyrogen and Endotoxins Testing: Questions and Answers.14 To address 
the risks associated with material-mediated endotoxins, follow the recommendations in FDAs 
guidance Use of International Standard ISO-10993-1, 'Biological evaluation of medical devices 
-Part 1: Evaluation and testing within a risk management process.15 
Additionally, we recommend providing your routine batch release Limulus Amebocyte Lysate 
(LAL) monitoring procedures. For guidance, refer to FDAs Guidance for Industry Pyrogen and 
Endotoxins Testing: Questions and Answers and the USP Endotoxin Reference Standard (USP 
Chapter <161> Medical Devices  Bacterial Endotoxin and Pyrogen Tests). You may also refer 
to ANSI AAMI ST72: Bacterial endotoxins  Test methodologies, routine monitoring, and 
alternatives to batch testing for endotoxin testing on your device. 
For devices intended to be labeled as non-pyrogenic, we recommend that both bacterial 
endotoxins and material-mediated pyrogens be addressed. 
H.Shelf Life and Packaging 
Significance: Shelf life testing is conducted to support the proposed expiration date through 
evaluation of the package integrity for maintaining device sterility and/or evaluation of any 
changes to device performance or functionality. 
Recommendation: With respect to package integrity for maintaining device sterility, you should 
provide a description of the packaging, including how it will maintain the devices sterility, the 
protocol(s) used for your package integrity testing, the results of the testing, and the conclusions 
drawn from your results. We recommend that a package validation study include simulated 
14 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pyrogen-and-endotoxins-testing-
questions-and-answers
15 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-international-standard-iso-
10993-1-biological-evaluation-medical-devices-part-1-evaluation-and 
13  Contains Nonbinding Recommendations 
distribution and associated package integrity testing, as well as an aging process (accelerated 
and/or real-time) and associated seal strength testing, to validate package integrity and shelf life 
claims. We recommend you follow the methods described in the current edition of the FDA-
recognized consensus standards ANSI/AAMI/ISO 11607-1: Packaging for terminally sterilized 
medical devices  Part 1: Requirements for materials, sterile barrier systems and packaging 
systems and ANSI/AAMI/ISO 11607-2: Packaging for terminally sterilized medical devices  
Part 2: Validation requirements for forming, sealing and assembly processes. 
With respect to evaluating the effects of aging on device performance or functionality, shelf life 
studies should evaluate the critical device properties to ensure it will perform adequately and 
consistently during the entire proposed shelf life. To evaluate device functionality, we 
recommend that you assess each of the bench tests described in Sections L(1)(a), L(1)(b), L(2)(a-
g), L(3)(a-d) and repeat all tests that evaluate design components or characteristics that are 
potentially affected by aging using aged devices. 
We recommend that you provide the protocol(s) used for your shelf life testing, the results of the 
testing, and the conclusions drawn from your results. If you intend to extend the shelf-life of the 
implanted BCI device after initial approval of your IDE study, we recommend that you provide 
the protocol(s) and results to support the extension in an IDE supplement. We recommend all test 
samples undergo real-time aging to determine definitively the effects of aging on the 
maintenance of sterility and device performance. If you use devices subjected to accelerated 
aging, we recommend that you specify the way in which the device was aged and provide a 
rationale to explain how the results of shelf life testing based on accelerated aging are 
representative of the results if the device were aged in real time. We recommend that you age 
your devices as per the currently FDA-recognized version of ASTM F1980: Standard Guide for 
Accelerated Aging of Sterile Barrier Systems for Medical Devices and specify the environmental 
parameters established to attain the expiration date. We recommend that the accelerated aging 
shelf life testing protocol include a concurrent real-time aging study protocol to confirm the 
results obtained from the shelf life studies on aged samples. 
I.  Electrical Safety and Electromagnetic Compatibility (EMC) 
Significance: Implanted BCI devices are medical electrical equipment and therefore may expose 
the operator and patient to hazards associated with the use of electrical energy or may fail to 
operate properly in the presence of electromagnetic disturbance. 
Recommendation: Implanted BCI devices should be tested to demonstrate that they perform as 
anticipated in their intended use environment. We recommend that this testing be performed as 
described in the currently FDA recognized versions of the following standards for medical 
electrical equipment safety and electromagnetic compatibility: 
   ANSI/AAMI ES60601-1: Medical electrical equipment -Part 1: General requirements 
for basic safety and essential performance. 
14  Contains Nonbinding Recommendations 
   ANSI/AAMI/IEC 60601-1-2: Medical electrical equipment -Part 1-2: General 
requirements for basic safety and essential performance -Collateral standard: 
Electromagnetic disturbances -Requirements and tests. 
   ISO 14708-1: Implants for surgery  Active implantable medical devices  Part 1: 
General requirements for safety, marking and for information to be provided by the 
manufacturer 
ISO 14708-3: Implants for surgery  Active implantable medical devices - Part 3: 
Implantable neurostimulators. 
For additional information on providing electromagnetic compatibility information in a 
premarket submission, see FDAs guidance, Information to Support a Claim of Electromagnetic 
Compatibility (EMC) of Electrically-Powered Medical Devices.16 
J. Wireless Technology 
Significance: In the design, testing, and use of wireless medical devices, the correct, timely, and 
secure transmission of medical data and information is essential for the safe and effective use of 
medical devices and systems. BCI systems may utilize wireless connections to transfer neural 
signals, to control assistive technologies or to drive electrical stimulation. 
Recommendation: If your implanted BCI device incorporates radiofrequency wireless 
technology such as Bluetooth, IEEE 802.11 (Wi-FiTM), RFID (radio frequency identification) 
technology, or other wireless functionalities needed to perform the clinical function of your 
device, we recommended assessing the risk as described in the FDA-recognized version of 
AAMI TIR69: Technical Information Report Risk management of radio-frequency wireless 
coexistence for medical devices and systems. 
The selection of RF wireless operating frequency and modulation should take into account other 
RF wireless technologies and users that might be expected to be in the vicinity of the wireless 
medical device system. These other wireless systems can pose risks that could result in medical 
device signal loss or delay that should be considered in the risk management process. If the risk 
management evaluation of the wireless function is found to be critical to the clinical function of 
the device, FDA recommends that you address your devices environmental specifications and 
needs as outlined in the current FDA-recognized version of ANSI/IEEE C63.27: American 
National Standard for Evaluation of Wireless Coexistence. 
For additional recommendations for home use devices with wireless technology, refer to FDAs 
guidance Design Considerations for Devices Intended for Home Use.17 
16 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/information-support-claim-
electromagnetic-compatibility-emc-electrically-powered-medical-devices
17 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/design-considerations-devices-
intended-home-use 
15  Contains Nonbinding Recommendations 
We recommend that you consult FDAs guidance, Radio Frequency Wireless Technology in 
Medical Devices18 for additional recommendations on this topic. 
K.Magnetic Resonance (MR) Compatibility 
Significance: MR imaging of patients with implanted BCI device poses the following potential 
hazards: 
   Heating of the tissue adjacent to the implanted device produced by gradient and RF 
fields; 
   Tissue damage caused by vibration of the device produced by gradient fields; 
   Tissue damage caused by movement of the device from displacement force from the 
static magnetic fields; 
   Tissue damage due to torque of the device produced by static magnetic fields; 
   Unintended stimulation and tissue damage due to extrinsic electric potential produced 
by gradient field-induced lead voltage; 
   Tissue damage due to rectification produced by RF field-induced lead voltage; and/or 
   Device malfunction specific to MR-environment induced by B , RF, and gradient 
0
fields. 
Recommendation: We recommend that you address the issues affecting safety and compatibility 
of your implanted BCI device in the MR environment as described in the FDA guidance, 
Testing and Labeling Medical Devices for Safety in the Magnetic Resonance (MR) 
Environment.19 
L. Non-Clinical Bench Testing 
We recommend that the non-clinical bench testing outlined below be addressed in your IDE. In 
general, the typical duration of implantation should be considered when determining appropriate 
test methods for characterizing durability (e.g., mechanical and electrical) of the components. 
Testing should ensure that the device meets appropriate specifications that represent a clinically 
relevant, worst-case in vivo conditions during device implantation and the expected life of the 
device. When appropriate, we recommend that the testing simulate the effect of any body fluids 
on the device components that come in contact with such fluids (e.g., after soaking in saline and 
before drying). We also recommend that you specify clinically-justified acceptance criteria for 
testing. 
We recommend that you include relevant information on the non-clinical bench testing provided 
in the form of test report summaries, test protocols and complete test reports, as described in the 
18 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/radio-frequency-wireless-
technology-medical-devices-guidance-industry-and-fda-staff
19 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/establishing-safety-and-
compatibility-passive-implants-magnetic-resonance-mr-environment 
16  Contains Nonbinding Recommendations 
guidance document Recommended Content and Format of Non-clinical Bench Performance 
Testing Information in Premarket Submissions."20 
(1)  Electrodes 
Electrodes can be used to measure physiological signals or provide stimulation to the brain, 
spinal cord, and/or peripheral nerves or muscles for eliciting movement and/or sensation. If 
the implanted BCI device includes electrodes, we recommend testing the following 
characteristics: 
a.  Dimensional verification and visual inspection 
Significance: Accurate dimensions are important to ensure that the electrodes meet the 
specifications that are relevant to the intended use of your device with justification. 
Additionally, if your device is intended to provide stimulation, the dimensions of your 
electrode can influence charge and current density, which can affect the safety and 
effectiveness of your stimulation parameters. 
Recommendation: We recommend that you provide dimensional specifications and 
tolerances for your electrode as manufactured. We recommend that the specified 
tolerances should be based on your risk analysis and intended use of the electrodes (i.e., 
stimulation or recording). In order to provide accurate and consistent measurements, we 
recommend the use of a calibrated tool. 
b.  Impedance 
Significance: Impedance measurements are important to ensure that the electrode has 
conductive properties appropriate for the intended use of the device. 
Recommendation: We recommend that you record and provide the impedance 
specifications and tolerances for your electrode as manufactured. We recommend that 
the specified tolerances be based on your risk analysis and intended use of the 
electrodes (e.g., stimulation for restoring sensory or motor function or recording 
physiological signals). 
c.  Accelerated Lifetime Testing 
Significance: To ensure long-term performance of the device, electrode materials 
should be stable and resist physical and chemical breakdown in the intended implant 
location for the expected duration. 
Recommendation: We recommend that you assess the device functionality (e.g., 
impedance spectroscopy, cyclic voltammetry, voltage transients) or image the device 
integrity (e.g., scanning electron microscopy) following exposure to aging protocols, 
20 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recommended-content-and-format-
non-clinical-bench-performance-testing-information-premarket 
17  Contains Nonbinding Recommendations 
both in the context of recording and stimulating, in a simulated physiological 
environment and over a range of environmental conditions. 
(2)  Leads and Connectors 
Leads are used to connect electrodes to multiple components in an implanted BCI system, 
such as but not limited to processing hardware and power modules. It is important that they 
function appropriately in the implanted BCI device system. We recommend testing to 
characterize the following attributes: 
a.  Dimensional verification and visual inspection 
Significance: Accurate device dimensions are important to ensure that the leads and 
connectors meet the specifications. 
Recommendation: We recommend that you provide dimensional specifications and 
tolerances for your leads and connectors as manufactured. Visual inspection and 
electrical evaluation should be conducted after non-clinical testing. We recommend that 
the specified tolerances should be based on your risk analysis and intended use of the 
lead connection (i.e., stimulation or recording). In order to provide accurate and 
consistent measurements, we recommend the use of a calibrated tool. 
b.  Leakage Current 
Significance: Leakage current from the enclosures of the various implanted BCI device 
components during use of the implanted BCI device system may result in unintended 
electrical shock and potential tissue damage or the loss of recorded neural signal. 
Recommendation: We recommend that the leakage current be measured after soaking 
and before drying to simulate the effect of any body fluids on the lead body. We also 
recommend that you measure the leakage current during full operation (i.e. voltage 
application) and when the device is energized and in stand-by condition. The leakage 
current during voltage application should be within acceptable range (see ISO 14708-
3:2017 Implants for neurosurgery  Active implantable medical devices  Part 3: 
Implantable Neurostimulators, clause 16). 
c.  Lead Body and Connector Flex Fatigue Testing 
Significance: Failures in the lead due to flexural fatigue can result in unintended 
electrical shock and potential tissue damage or the loss of recorded neural signal. 
Recommendation: We recommend flex fatigue testing of the lead body and connector. 
We also recommend that the fatigue test protocol include subjecting different areas of 
the lead to different stresses (e.g., near or at connector joints and lead anchor points) 
during fatigue testing. 
d.  Tensile Strength of Lead 
Significance: Failures in the lead due to tensile forces can result in unintended electrical 
shock and potential tissue damage or the loss of recorded neural signal. 
18  Contains Nonbinding Recommendations 
Recommendation: We recommend that you conduct tensile testing that simulates the 
worst-case forces that the lead or extension could experience during the implantation 
procedure as well as after implantation. 
e.  Connector Insertion and Withdrawal Forces 
Significance: Lead connectors should have a proper fit into the device header cavity to 
form the necessary electrical contacts and to ensure that the seals are in the correct 
location and function as designed. Connectors should be able to tolerate the forces 
associated with insertion and withdrawal. 
Recommendation: We recommend that you ensure that lead and extension connectors 
meet appropriate specifications representing physiologic conditions experienced by the 
device, including the appropriate minimum and maximum withdrawal forces. During 
testing, you should evaluate that leads or extensions are fully inserted, electrical 
connections are made, and that seals between the generator and lead/extension are 
intact after repeated insertions and withdrawals. If repeated connection and 
disconnection is expected to occur, we recommend that you evaluate whether seals 
between the generator and lead/extension are intact after repeated insertions and 
withdrawals. 
f.  Particulate Matter Hazards 
Significance: The release of particulate matter from any part of an implanted system 
that is intended to be in contact with body fluids during normal use is hazardous. 
Recommendation: We recommend that you use test methods described in ISO 14708-3: 
Implants for neurosurgery  Active implantable medical devices  Part 3: Implantable 
Neurostimulators. 
g.  Corrosion Resistance 
Significance: Lead materials should be stable and resist physical and chemical 
breakdown to demonstrate that the lead can withstand the environment of the human 
body and ensure long-term performance. 
Recommendation: We recommend that the corrosion resistance be evaluated on the 
finished leads and connectors. Appropriate signal and stimulation parameters (e.g., 
signal to noise ratio, pulse rate, amplitude, and pulse width) should be chosen to 
evaluate the functionality of the leads and device system following exposure to 
corrosive environments that simulate the physiological environment of the device. This 
should include testing the lead in saline, using the smallest electrode surface area. 
h.  Compliance with 21 CFR 898.12 
Significance: Accessible connectors from percutaneous leads or other cables in contact 
with the patients may be connected to the incorrect components or mains power in 
error, resulting in unintended electrical shock and harm to the patient. 
19  Contains Nonbinding Recommendations 
Requirement: Percutaneous leads or other cables having a conductive connection to a 
patient must comply with the performance standard in 21 CFR 898.12, which states that 
any connector in a cable or electrode lead wire having a conductive connection to a 
patient shall be constructed in such a manner as to comply with subclause 56.3(c) of the 
following standard: International Electrotechnical Commission (IEC) 601-1: Medical 
Electrical Equipment Part 1  General requirements for safety (1988, amendment No.1, 
1991, amendment No. 2, 1995). However, FDA believes conformance to applicable 
subclauses in the currently FDA-recognized version of the IEC 60601-1: Medical 
Electrical Equipment Part 1  General requirements for basic safety and essential 
performance (2005, MOD) standard would provide the same level of or improved 
protection of the public health and safety from unintended electrical shock as the FDA 
performance standard in 21 CFR 898.12, and that conformity to this currently FDA-
recognized standard would be sufficient to meet the performance standard in 21 CFR 
898.12. Therefore, firms may submit a declaration of conformity to this currently FDA-
recognized standard.21 
(3)  Implanted Casing and Electronics 
Electronics are often implanted, covered in a can or similar casing, which serve to process 
signals received from the leads and/or to provide electrical stimulation signals to the leads. 
We recommend you provide the following testing: 
a.  Hermeticity Testing 
Significance: A high level of moisture enclosed inside a hermetic casing can lead to 
device failure. 
Recommendation: We recommend conducting hermeticity testing for integrity of all 
joints, bonds, etc., to verify that the implanted casing is leak-proof. 
b.  Environmental Testing 
Significance: The implanted casing and electronics should be subjected to a sequence 
of mechanical and environmental tests to ensure that the device will meet its 
specifications after being subjected to conditions that adequately capture stress that the 
device would encounter during worst case handling, shipping, storage, surgery and 
clinical use conditions. 
Recommendation: We recommend tests evaluating the following be conducted: 
a.  Temperature changes (including temperature cycling); 
b.  Atmospheric pressure changes; and 
c.  Mechanical forces. 
We recommend that you use methods described in ISO 14708-3: Implants for surgery  
Active implantable medical devices  Part 3: Implantable neurostimulators or 
equivalent methods. 
21 
See Section 514(c) of Federal Food, Drug and Cosmetic Act. 
20  Contains Nonbinding Recommendations 
c.  Header Adhesion Testing 
Significance: If a header is attached to the casing for the purposes of connecting leads 
to the casing, header adhesion testing should be performed to ensure that the header 
does not separate from the casing and ensure the continuity of the current path for 
stimulation, recording, or powering. 
Recommendation: The header cavity should have a proper fit with the lead and 
extension connectors to form the necessary electrical contacts, and to ensure that the 
seals are in the correct location and function as designed. We recommend that the lead 
ports and header connection be tested to ensure that the lead can withstand suitable 
force without being pulled out of the connector block. 
d.  Battery 
Significance: If a battery is a part of the implanted casing and electronics, testing to 
evaluate the suitability and performance of the battery for use in the implanted device 
should be performed to ensure it operates as intended and risks (e.g., overheating) 
associated with battery failures (e.g., short circuiting) are appropriately mitigated to 
minimize harm to the patient. 
Recommendation: The tests should assess the characteristics and general reliability of 
the battery when subjected to stresses anticipated under normal usage and clinically 
relevant worst-case conditions. Testing should also demonstrate how the batteries are 
protected from over discharge and overcharge and measure the battery and devices 
surface temperatures in the event of a battery short circuit. 
See the following voluntary consensus standards for additional battery-related safety 
information: 
   UL 2054: Household and Commercial Batteries; 
   UL 1642: Lithium Batteries; 
   IEC 60086-4: Primary batteries  Part 4: Safety of lithium batteries; and 
   IEC 60086-5: Primary batteries  Part 5: Safety of batteries with aqueous 
electrolyte. 
(4)  Output Stimulation Measurements 
Significance: For devices that deliver electrical stimulation, it is important that the output 
stimulation delivered by the device and stimulation output limitations are appropriately 
characterized. 
Recommendation: We recommend using methods described in ISO 14708-3: Implants for 
surgery -Active implantable medical devices -Part 3: Implantable neurostimulators. For 
each output mode, we recommend that you provide an oscilloscope trace describing the 
electrical output waveform of the individual pulse output waveform under physiologic loads 
that may be encountered. Additionally, one tracing should be provided showing a series of 
21  Contains Nonbinding Recommendations 
pulses under a 500   load. We recommend that you provide the following information with 
each trace: 
   Name of the output mode; 
   Clearly labeled amplitude and time axes; 
   Identification of the amplitude baseline; and 
   Listing of all output parameter settings (e.g., amplitude, pulse width, frequency). 
Traces should demonstrate ability to achieve maximum stimulation settings in each trace and 
remain within specification. Results can be recorded in the format recommended in 
Appendix A. 
(5)  Output Stimulation Safety 
Significance: For devices that deliver electrical stimulation to the nervous system and 
muscles, it is important that the output stimulation delivered to the tissue be safe for the 
intended use and stimulation duration. Excessive stimulation can produce tissue damage that 
could result in serious injury or death, depending on the stimulation location. 
Recommendation: We recommend that you provide a scientific rationale (e.g., from 
literature and/or animal studies as outlined in Sections III(N)(1) and III(N)(2) to support the 
safety of the stimulation output parameters (e.g., maximum current, charge density, current 
density, charge per phase, frequency, and duration). An analysis of the safety of the output 
stimulation parameters provides assurance that the risk of tissue damage is minimized 
during use of the device. 
(6)  Programmers/Control Unit 
Significance: Hardware used to program stimulation parameters or select different device 
modes are often called programmers/control units and may present risks to the patients if 
they do not operate as intended. 
Recommendation: We recommend that programmers/control units be subjected to 
verification testing to assess electrical safety, functional, environmental, EMC, software, and 
reliability performance. This testing should be designed to ensure that the system level 
operation is verified in accordance with specifications. The testing should also verify that the 
system performance is maintained under specified, expected environmental conditions, as 
well as in storage, shipping and handling. For programmers/control units that communicate 
with implanted electronics, testing demonstrating that the programmer/control unit is capable 
of communicating with and programming the implanted electronics should be provided. If 
applicable, the transmitting and receiving antennae, transmitting distance, reed switch, and 
magnet should be tested to ensure that they function as intended. 
(7)  Radiofrequency (RF) Transmitter and Receiver 
Significance: Radiofrequency (RF) communication through a transmitter and receiver (e.g., 
inductive coupling) is sometimes used for programming/controlling implanted components 
or recharging implanted batteries. RF transmitters and receivers may present risks to the 
patients if they do not operate as intended. For example, inductive coupling may lead to 
tissue heating or tissue damage. 
22  Contains Nonbinding Recommendations 
Recommendation: Testing for the RF transmitter should include information outlined for the 
programmer/control unit as described in Section L(6) above. In addition, we recommend that 
you provide the following testing for the RF transmitter: 
1.  Mechanical testing; 
2.  Electrical testing; and 
3.  Transmission distance and orientation between the external emitting antenna and the 
antenna inside the receiver. 
Testing for the transmitter and receiver should consider the testing recommendations for 
wireless technology outlined in Section J above. To adequately demonstrate protection from 
heating and ionizing radiation during the RF energy transfer, we recommend referring to the 
currently recognized version of ISO 14708-3: Implants for surgery -Active implantable 
medical devices -Part 3: Implantable neurostimulators. 
(8)  System Level Testing 
Many BCI device technologies have multiple components that may be interchangeable to 
achieve different and configurable clinical uses (i.e., a modular approach). For example, a 
system may include an implanted electrode that acquires neural signals. These signals are 
then sent to another system component where they are processed (i.e., decoded and encoded) 
and used to control an assistive effector component. Additionally, a separate programmer 
may be used to control functions such as turning the device on and off and switching between 
various outputs and programs. 
Given the variability of individual patient needs, manufacturers may choose to develop BCI 
systems with individual components manufactured by different manufacturers, which allows 
mix and match compatibility across several manufacturers. Such individual components 
can be produced by different manufacturers and subsequently combined to make a complete 
system. For example, a cortical electrode may be developed and manufactured by Company 
A and used to record neural signals to be acquired, processed, and transferred by an 
acquisition system and software developed by Company B. The data transferred from 
Company Bs acquisition system is then used to control an assistive technology developed by 
Company C. 
Significance: A thorough understanding of how various components interact with one 
another, with the user and patient, and with the environment is essential to demonstrate the 
safety and effectiveness of implanted BCI systems. While each component of the system has 
characteristics that can introduce risk individually, new risks can arise when the components 
interact to perform as a system. 
Recommendation: To verify all system components operate together as set forth by the 
system specifications, FDA intends to evaluate the entire system and associated performance 
testing of the system. Electrical safety, EMC, and wireless coexistence testing should be 
performed on the full complete system for the proposed intended use. In addition, you should 
identify specific criteria that demonstrate compatibility of the component with other device 
components and provide scientific or clinical justification for the criteria. However, if 
23  Contains Nonbinding Recommendations 
system-level testing is not feasible, a rationale for the exclusion of system-level testing and 
description of how risks will be mitigated should be provided. In this event, we also 
recommend that you provide a rationale for how malfunctions in system operation can be 
traced back to the modular component in which the malfunction occurred and how the 
malfunction was resolved and mitigated. All devices intended to be used in conjunction with 
the implanted BCI device (e.g., implantation tools, clips or belts for body-worn components, 
components from another marketed medical device) should be compatible. Incompatibility 
can result in device damage or other clinical adverse events. Therefore, we recommend that 
you identify and provide specifications needed to ensure compatibility between all modular 
components of the system in the protocol and any labeling provided to the 
operators/investigator. 
M. Referencing Master Files (MAF) and other FDA Premarket 
Submissions 
Often a sponsor submitting an IDE needs to use another party's product (e.g., material, 
subassembly, or component) from another marketed medical device (i.e., modular component, 
see Section III(L)(8) or use another partys facility in the manufacture of the device. In this 
circumstance where a sponsor chooses to leverage information related to the other party's 
product, facility, or manufacturing procedures in their submission, a device master file (MAF) 
may be referenced as part of the submission to FDA with a Letter of Authorization (LOA). You 
should refer to the following FDA webpage for additional information on using device MAFs: 
https://www.fda.gov/medical-devices/premarket-approval-pma/master-files. 
N. Non-Clinical Animal Testing 
Significance: Non-clinical animal testing is generally recommended to evaluate the in vivo safety 
of implanted BCI devices, particularly for new designs, significant device modifications, and 
new indications. 
Recommendation: Animal testing of implanted BCI devices should address factors that cannot be 
evaluated through bench tests or in a clinical study. The study design and endpoints should be 
based upon the mechanism of action of the device and mitigation of risk. 
FDA supports the principles of the 3Rs, to reduce, refine, and replace animal use in testing 
when feasible. You should consider the best practices for the development, conduct and 
presentation of these animal studies while incorporating modern animal care and use strategies. 
In addition, we encourage you to consult with FDA if you wish to use a non-animal testing 
method that you believe is suitable, adequate, validated, and feasible. We will consider if such an 
alternative method could be assessed for equivalency to an animal test method. For details on the 
24  Contains Nonbinding Recommendations 
Q-Submission Program, refer to the guidance Requests for Feedback on Medical Device 
Submissions: The Q-Submission Program.22 
We encourage manufacturers to take advantage of the Q-Submission Program to ensure that the 
animal study protocol addresses safety concerns and contains the appropriate elements (e.g., the 
study should be performed under Good Laboratory Practice (GLP) regulations as stated in 21 
CFR 58 at an animal study facility with appropriate licensure and accreditations). 
In most cases, we recommend that you conduct animal testing on a final, finished device to 
support the assessment that the risks to the subjects do not outweigh the anticipated benefits to 
the subjects and the importance of the knowledge to be gained, in a human clinical trial. For 
devices evaluated in early feasibility studies, an animal study using a final, finished device may 
not be needed if an adequate rationale is provided. See FDA guidance, Investigational Device 
Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Including Certain First 
in Human (FIH) Studies23 for more details on the device evaluation strategy and how leveraged 
information may support your rationale. 
(1)  General Considerations for Animal Studies 
Implanted BCI devices encompass a variety of device designs, neural targets, and 
mechanisms of action. For example, they can include recording or stimulation actions, 
penetrating or surface electrodes, or components from another marketed medical device (i.e., 
modular design, see Section III(L)(8)), and central or peripheral nervous system targets. They 
also offer a variety of therapeutic and restorative benefits to patients. Each of these variables 
may affect the types of risks and benefits posed to the patient, and consequently, the non-
clinical information needed to support use in human subjects. Therefore, you may need to 
customize your animal protocols to establish the data needed to support a future clinical 
study. Prior to initiating your animal study, we strongly recommend that you submit a Pre-
Submission to obtain FDA feedback on your animal model and study design. General factors 
to consider for animal study protocols are provided below. 
1.  Purpose of the animal study The main purpose for conducting an animal study is to 
provide evidence of device safety. Animal studies may also provide evidence of 
device performance that cannot be adequately obtained from bench testing, including 
in vivo reliability over time. However, alternative methods may be needed in 
situations in which animal studies may be inappropriate, such as cognitive 
assessments. 
2.  Study protocol and reported results  When designing the study protocol, specific 
determinations of study variables (such as the number of animals studied, the study 
duration, the type of animal model, the choice of controls) depend on both the risks of 
the device and the currently available scientific information that can be leveraged to 
mitigate expected risks. An understanding of device risks includes device attributes 
and mechanisms of action, anatomical target, and surgical implementation. Examples 
22 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-
medical-device-submissions-q-submission-program
23 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigational-device-exemptions-
ides-early-feasibility-medical-device-clinical-studies-including 
25  Contains Nonbinding Recommendations 
include the way in which the device interfaces with the target tissue (such as 
penetrating vs non-penetrating), the device location and the corresponding biological 
and mechanical stress inflicted on the device, the robustness of the device 
mechanisms of action (e.g., neural stimulation may be more robust to tissue responses 
than neural recording), and the expected device lifetime. Existing scientific 
information with sufficient rationale may be leveraged to lower the burden associated 
with conducting animal studies (e.g., smaller number of animals, short duration of 
animal study) or justify why additional animal studies may not be needed. Such 
scientific information includes the use of the device or device components in clinical 
studies, prior studies in animals using the device or device prototypes, bench testing 
of device performance, and published literature with direct relevance to the device 
attributes. 
Many BCI devices involve implanted, multi-component systems designed for long-
term use in human patients. For these devices, animal studies that address chronic in 
vivo evaluation of the final device system provide a greater degree of understanding 
of device safety than acute studies or chronic investigations of partial systems. A full 
evaluation of device risks and available scientific evidence will allow for the 
determination of the appropriate protocol for a given BCI system. 
When describing the results of conducted animal studies, we recommend that you 
include a discussion of how the findings support preliminary safety of the device for 
your proposed clinical study. 
3.  Good Laboratory Practices  Good Laboratory Practices (GLP) for animal care and study 
conduct as specified in 21 CFR Part 58 ensure the quality and integrity of animal data to 
support IDE applications. Non-GLP study data may be used to support an IDE 
application only if the deviations from GLP are identified and justified24 and do not 
compromise the validity of the study results. See FDA guidance, Investigational Device 
Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Including 
Certain First in Human (FIH) Studies25, for more information on when non-GLP animal 
study data may be used to support an IDE study. 
(2)  Animal Study Protocols 
We recommend that animal study evaluations include macroscopic and microscopic effects 
on tissue and evaluation of the explanted device components. The animal study test protocols 
should include, but are not limited to, the following items: 
   Study objective; 
   Study design including the species, strain (if applicable to the proposed animal model) 
and number of animals used, study duration, as well as the rationale for the design; 
   Details regarding the device to be tested and a rationale for any difference between the 
study device and the device intended for clinical use; recording and/or stimulation 
24 See 21 CFR 812.27(b)(3). 
25 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigational-device-exemptions-
ides-early-feasibility-medical-device-clinical-studies-including 
26  Contains Nonbinding Recommendations 
location; and stimulation intensities, including stimulation type (voltage or current), 
amplitude, pulse mode (monophasic, biphasic), duration, frequency, charge density, 
charge per phase, electrode surface area and material (if applicable); 
   Stimulation evoked response testing (if applicable); 
   Recording signal quality at both acute and chronic timepoints (if applicable); and 
   Histopathology of the surrounding tissues. 
Some recommendations for an animal study design evaluating BCI devices include: 
1.  Choice of animal models: The choice of animal models depends on the BCI device 
and may vary based on device type, indication, and implant site. We believe that the 
animal and its related environmental and physiologic attributes should provide a test 
system that offers a best attempt at simulating the clinical setting. Animal models that 
can accommodate human-sized devices may be preferable, although the use of scaled 
devices might be acceptable in some circumstances if appropriate scientific 
justification is provided. 
2.  Number of animals: We recommend inclusion of a sufficient number of animals with 
justification. 
3.  Controls: Appropriate controls should be identified in the study protocol. In some 
studies, non-implanted contralateral tissue is an appropriate control. For evaluation of 
stimulation safety only, implanted but non-stimulated contralateral tissue may be 
used. 
4.  Study duration: Study duration is dependent upon the profile of expected device risks. 
We recommend that you provide a justification of the length of your animal study. 
5.  Safety tests: We recommend histopathological or histomorphological evaluation of 
implanted tissue, including both structural analysis and evaluation of injury markers 
that are relevant for the neural tissue. Such markers might include necrotic neurons, 
neural processes, astrocytes and microglia/macrophages in central nervous system 
tissue, or an analysis of axons, Schwann cells and myelin in peripheral nervous 
system. We recommend that you justify the use of specific histological markers and 
provide evidence that the histological protocol is adequate to capture major adverse 
reactions. Histopathological results should be quantified (e.g., the volume of necrotic 
tissue) by an independent veterinary pathologist who is blinded to study groups. In 
order to better predict clinical adverse effects, behavioral and functional assays are 
recommended. 
For devices involving a stimulation component, we also recommend that you provide 
experiments to establish the safety of stimulation. The exact stimulation protocol 
varies depending on the application of the device. If the device is designed for 
continuous activation, both acute and long-term tests are recommended. If the device 
is intermittently active, long-term testing should be performed. See below for acute 
and long-term stimulation testing recommendations. 
27  Contains Nonbinding Recommendations 
6.  Reliability test: For devices designed for chronic implantation, long-term device 
performance should be established in a biological environment, unless scientific 
evidence for device performance in vivo has already been collected (e.g. prior animal 
studies and/or published literature using the same or similar electrode configuration). 
For devices involving recording components, periodic recording should be performed 
over the lifetime of device implantation and evaluated with a quantitative metric, such 
as signal to noise ratio and spike amplitudes. In vivo impedance of electrodes may be 
acquired to demonstrate the functionality of the device. For devices involving 
stimulation components, impedance measurements should be performed to 
characterize the functionality of the device, although care should be taken to assure 
that measurement protocol does not affect interpretation of data from control animals. 
Microscopic evaluation of explanted devices should be used to identify physical 
damage or other failure modes to device components (i.e., electrode conductor or 
insulation, leads and connectors). 
7.  Acute stimulation test: To test stimulation safety, electrode stimulation at the 
maximal limits should be applied for durations of up to 24 hours. The animal may be 
sedated during the stimulation protocol. After testing, histological evaluation of tissue 
responses should be performed. 
8.  Long-term stimulation test: Periodic stimulation at maximal limits, or the highest 
stimulation intensity that is acceptable for the welfare of the animal, should be 
applied for a period that is reflective of your clinical protocol, with justification. After 
explantation, tissue around the implant should be examined to identify any 
histological or pathological response. We also recommend that you evaluate the 
explanted device at a magnification sufficient to detect any failure mechanisms such 
as corrosion or insulation degradation. A detailed comparison of animal study and 
clinical IDE study stimulation parameters should be included. If the stimulation 
charge delivered in animal studies is less than the maximal proposed limit for human 
studies, we recommend providing a scientific justification discussing why this is an 
accurate representation of the safety risk posed to patients. 
9.  Surgical Approach A detailed description of the implantation approach should be 
provided along with its translatability to human implantation. Included in this section 
should be a rationale for the anatomical device target, with justifications for any 
differences from the intended human implantation site. Whenever possible, the 
surgical tools designed for human implantation should be used for animal surgery. If 
the clinical plan involves explantation of the device, incorporate surgical device 
removal strategies into the surgical approach of the animal study. 
O.Clinical Performance Testing 
(1)Report of Prior Investigations 
For an Investigational Device Exemption (IDE), a summary of any prior clinical studies of 
the device used for the proposed intended use must be provided in the report of prior 
28  Contains Nonbinding Recommendations 
investigations.26 For early feasibility studies, although clinical data may not be available with 
the subject 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 use. 
This information may come from clinical use outside of the United States (OUS) and may be 
used to support proof of principle and/or to address the likelihood of potential failure modes 
that may be observed during an IDE 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). 
A narrative description of the other clinical study or studies should be provided in this 
section. The narrative should be brief, and should include the following information for each 
study: 
   the purpose of the study (e.g. proof of concept, patient perspective study) 
   whether the study was a pivotal, supporting, or feasibility study 
   the design of the study, including any randomization, blinding, and the control(s) 
used 
   the number of patients enrolled 
   the number of investigational sites both inside the United States (US) and OUS 
   the primary study endpoint(s) 
   the amount of available follow-up 
   a summary of results/conclusions 
(2)  Clinical Study Considerations 
The recommendations for some aspects of a clinical study for implanted BCI devices may 
vary with device development stage and the type of IDE study (e.g., Early Feasibility, 
Traditional Feasibility, Pivotal) being performed. If an Early Feasibility Study is submitted, the 
study type should be clearly stated as such in the IDE. The following FDA guidance 
documents describes the Agencys current thinking on clinical study design for early 
feasibility studies and Pivotal IDE studies: 
   Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device 
Clinical Studies, Including Certain First in Human (FIH) Studies27 
26 
See 21 CFR 812.27. 
27 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigational-device-exemptions-
ides-early-feasibility-medical-device-clinical-studies-including 
29  Contains Nonbinding Recommendations 
   Design Considerations for Pivotal Clinical Investigations for Medical Devices28 
Generally, we believe implanted BCI devices addressed by this guidance document are 
significant risk (SR) devices subject to all requirements of the IDE regulation, 21 CFR Part 
812. For studies that are not exempt from the IDE regulation, sponsors are responsible for 
making the initial risk determination (SR or nonsignificant risk (NSR)) and presenting it to 
the Institutional Review Board (IRB). For more information, see the Information Sheet 
Guidance for Institutional Review Boards (IRBs), Clinical Investigators, and Sponsors, 
Significant Risk and Nonsignificant Risk Medical Device Studies.29 In addition to the 
requirements of 21 CFR 812, sponsors of such trials must comply with the regulations 
governing institutional review boards (21 CFR 56) and informed consent (21 CFR 50). 
Certain components of the clinical study design are especially important, when designing a 
clinical study intended to evaluate the performance of a BCI system. For each clinical study 
design component, scientifically supported and justified descriptions are essential to provide 
clarity and facilitate understanding. In addition, adaptive trial designs, when properly 
implemented, can reduce resource requirements and/or increase the chance of study 
success.30 The following design components should be considered and supported with a 
justification in your IDE submission when developing the clinical study protocol: 
a.  Patient Populations 
A variety of patient populations may benefit from BCI devices whose function is to 
augment their ability to interact with their environment and improve communication. 
Such populations include patients with limb amputations or diseases and conditions 
such as spinal cord injury (SCI), stroke, paralysis, and neuromuscular disorders. For an 
IDE approval, the potential benefit to the patient for any device should outweigh the 
potential risks.31 Patients with different medical conditions may have different needs 
and different risk tolerance for a BCI system; therefore, sponsors should consider a 
subject population with needs that are appropriately addressed by the device, so that the 
potential benefits and risks are appropriately considered. 
b.  Home Use 
It is important to study BCI devices in realistic, home use environments since lab 
conditions may not adequately reflect the possible risks and/or benefits that the patients 
will experience during actual use in the environments in which the patient will be using 
28 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/design-considerations-pivotal-
clinical-investigations-medical-devices
29 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/significant-risk-and-nonsignificant-
risk-medical-device-studies 
30 
See FDA Guidance Adaptive Designs for Medical Device Clinical Studies, available at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/adaptive-designs-medical-device-
clinical-studies. 
31 
See FDA Guidance Factors to Consider When Making Benefit-Risk Determinations for Medical Device 
Investigational Device Exemptions, available at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/factors-consider-when-making-benefit-risk-determinations-medical-device-investigational-device. 
30  Contains Nonbinding Recommendations 
the device. Additionally, for home use, it may be necessary to have a caretaker who is 
willing, able, and available to perform essential tasks related to the BCI system such as: 
   manage startup and maintenance of the BCI: attach electrodes, start the system; 
   monitor patient progress, if applicable; and 
   can contact the physician when necessary. 
Therefore, it is important to incorporate assessment of caregiver safety and their ability 
to assist the user (i.e., time, attention and physical ability) in the clinical study metrics. 
To ensure safe use of your device in the home setting, we recommend that you 
specifically describe in your clinical protocol how subjects and caregivers will be 
trained to use the device at home. We also recommend that you describe how you plan 
to assess the effectiveness of your training program. 
Refer to the FDA guidance titled Design Considerations for Devices Intended for 
Home Use32 for recommendations on minimizing the risks associated with home use 
devices. 
c.  Investigational Plan 
The following information is intended to clarify how the investigational plan can be 
developed for IDE studies for implanted BCI devices.33 
i.  Purpose/Objective 
The clinical protocol should begin with clearly defined objective(s) and 
hypothesis(es). There should be an overall statement of the purpose/objective of 
conducting the study (e.g., to evaluate the safety and effectiveness of the BCI 
device in the treatment of a specific condition as compared to a control). In 
addition, the purpose should include a precise, medically accepted definition of 
the condition to be treated and a scientifically sound rationale for the proposed 
clinical study. For pivotal clinical studies, the null and alternative hypotheses for 
the proposed study should be stated in terms of the specific study endpoints, 
outcomes, and parameters used to measure the success/failure of the system. The 
study should then be designed to test these hypotheses. 
ii.  Study Design 
Your study design description should include, but not be limited to, the following 
basic elements: 
   whether it is randomized or non-randomized; 
32 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/design-considerations-devices-
intended-home-use 
33 
See 21 CFR 812.25 
31  Contains Nonbinding Recommendations 
   whether it is controlled or uncontrolled and, if controlled, the type of 
control(s); 
   whether the study results will be compared to a performance goal34 and, if so, 
how the performance goals were derived; 
   a description of the study success criteria (e.g., superiority or non-inferiority 
when compared to the control) and a description of patient-level 
success/failure if a responder analysis is being used; and 
Studies may include more than one treatment group such as SCI, stroke, or other 
conditions with proper justification as to why the different populations can be 
pooled. See FDAs Guidance for Industry, E9 Statistical Principles for Clinical 
Trials35 for more details on how to effectively incorporate and analyze multiple 
subject populations in a single study. 
iii.  Study Duration and Follow-up Schedule 
In order to assess all safety and primary effectiveness outcomes sufficiently, the 
proposed study should include a sufficient amount of safety and an appropriate 
level of effectiveness data. A long-term follow up period of at least 1 year is 
recommended due to the current lack of data regarding the long-term 
effectiveness of implanted electrodes and to identify any long-term safety signals. 
Long-term clinical durability and reliability are important factors to long-term 
efficacy of the implanted BCI device; for example, over time, implanted 
electrodes can lose their ability to detect signals from physical or biological 
processes. Although some information on electrode durability and reliability can 
be obtained from animal studies (see Animal Study Protocols in Section 
III(N)(2)), animal studies may not accurately predict long-term clinical 
performance in humans. 
iv.  Inclusion/Exclusion Criteria 
Adequate inclusion and exclusion criteria are essential to define the appropriate 
patient population for the proposed device, and eventually the intended use 
population for a marketing submission. The criteria for enrollment into any 
clinical study of an implanted BCI system will differ depending on the population 
targeted for the proposed treatment and the type of the disease process (e.g., SCI, 
Amyotrophic Lateral Sclerosis (ALS), amputations, and stroke). 
Regardless of the indication being investigated for any implanted BCI system, the 
following general inclusion criteria should be considered: 
34 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-real-world-evidence-support-
regulatory-decision-making-medical-devices
35 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e9-statistical-principles-clinical-
trials 
32  Contains Nonbinding Recommendations 
   Range of patient ages (skeletally mature, if applicable) 
   Spinal injury levels involved (e.g., C2-C7, L2-S1, if applicable) 
   Type of clinical condition (i.e., diagnosis) and level of paralysis/impaired 
function (measurement depending on the type of neurologic condition) 
   Clinical conditions for patient entry (e.g., preoperative function score, 
preoperative neurological score) 
   Description with suggested time frame of any prior, unsuccessful, non-
operative or conservative treatment (e.g., physical therapy, medication 
trials) 
   Ability of patient to understand and sign the informed consent 
   Ability of patient to communicate verbally or via typing on a computer 
   Ability of patient to meet the proposed follow-up schedule 
   Ability of patient to follow the postoperative management program 
   Willingness and ability of caregiver to monitor for surgical site 
complications and behavioral changes of the patient on a daily basis 
Regardless of the indication being investigated for any BCI system, the following 
patients should be considered for exclusion from the clinical study: 
   History of seizure 
   Intellectual impairment 
   Presence of clinically relevant memory problems 
   Psychotic illness or chronic psychiatric disorder, including major 
depression if untreated (diagnosis of Axis I or Axis II) 
   Active wound healing or skin breakdown issues 
   History of poorly controlled autonomic dysreflexia 
   Medical contraindications for general anesthesia, craniotomy, or surgery 
   Diagnosis of acute myocardial infarction or cardiac arrest within the last 6 
months 
   Any type of destruction and/or damage to the primary motor cortex region 
as determined by magnetic resonance imaging (MRI) 
   Other active implantable devices such as cardiac defibrillator, pacemaker, 
vagal nerve stimulator, spinal cord stimulator, etc. 
   Reliance on ventilatory support 
   Co-morbid conditions that would interfere with study activities or 
response to treatment, which may include: 
Severe chronic pulmonary disease 
o 
Local or systemic acute or chronic infectious illness 
o 
Life threatening cardiac arrhythmias 
o 
Severe collagen vascular disorder 
o 
Kidney failure or other major organ systems failures 
o 
   History of a neurological ablation procedure 
33  Contains Nonbinding Recommendations 
   Labeled contraindication for MRI 
   History of hemorrhagic stroke 
   History of HIV infection or ongoing chronic infection 
   Pregnant or of child-bearing potential and not using contraception 
   Concurrent participation in another device or drug trial 
If you believe any of the above inclusion/exclusion criteria does not apply to your 
proposed clinical study or intend to propose new or alternative 
inclusion/exclusion criteria, we recommend providing a clinical justification. 
v.  Patient Demographics 
Characteristics of the planned patient population that could affect the results of 
the study should be described, including: 
   Characteristics such as age, race, gender, disease;36,37 and 
   If performing a study that includes non-US study sites OUS, any 
differences between US and non-US populations that may be expected, 
based on specific population characteristics, disease progression or 
treatment paradigms. 
Your description should also explain how expected differences (if any) will be 
accounted for in the clinical study design or analysis of the results. 
vi.  Treatment Parameters/Protocol (including post-operative 
regimen) 
The clinical study protocol should include sufficient information regarding the 
implantation procedure, the post-surgical recovery period and regimen, the 
treatment duration, any other surgical procedures anticipated such as device 
removal. 
vii.  Endpoints and Other Outcomes 
1.  Primary safety endpoint(s): The study safety endpoints should include a 
characterization of all adverse events (AEs) for all subjects, including, but not 
limited to, subjects in both the treatment and control groups (if applicable), 
and adverse events related to the implant surgical procedure, the implantable 
device, and the assistive effector component. In addition to identifying safety 
endpoints, we recommend that you include in your protocol a description of 
your plan for addressing adverse events when they occur and safety criteria in 
36 
See FDA guidance Evaluation of Sex-Specific Data in Medical Device Clinical Studies, available at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/evaluation-sex-specific-data-medical-
device-clinical-studies-guidance-industry-and-food-and-drug. 
37 
See FDA guidance, Evaluation and Reporting of Age-, Race-, and Ethnicity-Specific Data in Medical Device 
Clinical Studies, available at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/evaluation-and-reporting-age-race-and-ethnicity-specific-data-medical-device-clinical-studies. 
34  Contains Nonbinding Recommendations 
your study that would require device removal or subject discontinuation in the 
study. 
2.  Primary effectiveness endpoint(s) and second effectiveness endpoints, (if 
applicable): In addition to identifying the primary and secondary effectiveness 
endpoints, you should include how the primary effectiveness endpoint was 
validated (if applicable) for the intended use population/subjects, the minimal 
clinically important difference, and how the timing of the assessments is 
appropriate and clinically meaningful. Although validated endpoints are 
recommended, FDA realizes that feasibility studies may be used to validate 
desired clinical metrics and may not require a priori validated clinical 
endpoints. Likewise, early feasibility studies may use clinical endpoints not 
validated due to the type of data that are often pursued during device 
development. For non-validated endpoints that may be used in early feasibility 
studies and other feasibility studies, similar information (other than validation 
methods), as well as justification for their clinical utility, should be included. 
3.  Patient Input (patient engagement, patient preference information, patient-
reported outcome measures): 
Patient engagement during clinical trial design may positively impact how an 
implanted BCI study is designed and conducted. Patients may provide 
recommendations to improve the patient experience of the trial, and improve 
the relevance, quality, and impact of the study results. 
Patient preference information (PPI) may be an important factor in the design 
and benefit-risk evaluation of a medical device, including implanted BCI 
devices. Ideally, a BCI technology should be comfortable, easy to don and 
doff (i.e., put on and take off, if applicable), user friendly, reliable, and 
aesthetically neutral or appealing, so patients are willing to accept and use the 
device. Factors such as requirements for daily calibration, fatigue with use, 
and inconsistent performance may affect the benefit-risk tradeoff patients are 
willing to make when deciding among treatment options. Additionally, risk 
tolerance may vary depending on the severity of the disability. For example, a 
patient with quadriplegia may be more willing to accept risks associated with 
a brain-implanted device than a person with a single limb amputation. FDA 
recommends early discussion on a potential PPI study to ensure its regulatory 
relevance; note that PPI studies are generally conducted separate from an IDE 
clinical study, although it is possible to integrate them into the overall study 
plan. Refer to the FDA guidance titled Patient Preference Information  
Voluntary Submission, Review in Premarket Approval Applications, 
Humanitarian Device Exemption Applications, and De Novo Requests, and 
35  Contains Nonbinding Recommendations 
Inclusion in Decision Summaries and Device Labeling38 for more 
information on incorporating PPI into a study or submission. 
A patient-reported outcome measure (PROM) can be used when the outcome 
of interest and desired intended use are best measured from the patients 
perspective, (e.g., pain reduction). In such cases, it is important to select a 
scoring assessment that is validated for the appropriate context of use,39 in 
this case: subject population and condition being treated, and desired intended 
use. For this reason, early discussion with FDA during the study design phase 
is important. These measures are often used in conjunction with other clinical 
outcome assessments (COAs) as part of a composite endpoint. When using 
PROMs in multinational trials, sponsors should make sure that the PROMs are 
interpretable, measure the same concept, and valid across cultures and 
languages. See the FDA guidance titled Patient-Reported Outcome 
Measures: Use in Medical Product Development to Support Labeling 
Claims40 for more information on incorporating a PROM into a study or 
submission. 
d.  Informed Consent Document 
The informed consent document (ICD) must include all required elements and be 
worded appropriately.41 We recommend ensuring that the document only contains 
words and terms that the average patient would be able to understand. The ICD 
should not include language that could lead subjects to overestimate the chance of 
personal benefit. 
e.  Statistical Analysis Plan (SAP) Considerations 
The statistical analysis plan (SAP) will vary based on upon the type of clinical 
trial. For example, a feasibility study may have a small number of subjects and the 
clinical study protocol may be designed to lead to an understanding of the new 
therapy. Therefore, the statistical plan may be limited to descriptive statistics. 
For a clinical study designed to demonstrate effectiveness (e.g., pivotal study), the 
study protocol should include a detailed, pre-specified SAP that includes plans to 
evaluate, to the extent possible, key assumptions that were made in the design of 
the study (e.g., pooling analysis across clinical sites or geographic regions, 
assessment of carry-over effects in a crossover study design, or proportionality of 
hazards in a survival analysis). The predefined SAP should be adhered to in 
analyzing the data at the completion of the study to support the usefulness of the 
38 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-preference-information-
voluntary-submission-review-premarket-approval-applications
39 Context of Use: a statement that fully and clearly describes the way the medical product development tool is to be 
used and the medical product development-related purpose of the use. 
(https://www.ncbi.nlm.nih.gov/books/NBK338448/#IX-C) 
40 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-reported-outcome-measures-
use-medical-product-development-support-labeling-claims
41 See 21 CFR 50.25. 
36  Contains Nonbinding Recommendations 
evidence generated by the study.42 Advanced analysis techniques such as 
Bayesian statistics can also be used to accommodate adaptive trial designs, 
analyze complex models, or perform sensitivity analyses.43 
42 See FDA guidance, Design Considerations for Pivotal Clinical Investigations for Medical Devices, available at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/design-considerations-pivotal-clinical-
investigations-medical-devices. 
43 
See FDA guidance entitled, Guidance for the Use of Bayesian Statistics in Medical Device Clinical Trials, 
available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-use-bayesian-
statistics-medical-device-clinical-trials-pdf-version. 
37  Contains Nonbinding Recommendations 
APPENDIX A 
Stimulation Output Specifications 
An output mode is defined (for reporting purposes) as a version of a waveform produced 
by the unit. For example, biphasic symmetrical and biphasic asymmetrical would be 
considered separate output modes. If multiple values are available for a given parameter 
within the output mode, then the manufacturer should provide the range and identify the 
different steps that may be selected in that range if not continuous. The following table 
provides an example of how this information may be organized for each output mode. 
This table is not intended to represent an exhaustive list of parameters; ensure you 
provide all relevant device descriptive characteristics, as outlined in Section III(A) and 
Section III(L) above. 
Output Characteristic  Device Output 
Number of Output Channels1 
- Synchronous, alternating 
- Method of channel isolation 
Waveform2 (e.g., charge balanced biphasic symmetrical, 
biphasic asymmetrical) 
Pulse Shape (e.g., rectangular, sinusoidal) 
Current/voltage regulated? 
Compliance voltage (if current source)? 
Maximum Output Voltage (specify units) (+/-______%) 
[voltage should be reported at 500  and at impedances  
covering the minimum, typical, and maximum range of 
physiologic impedances for the location being stimulated] 
Maximum Output Current (specify units) (+/-______%) 
[current should be reported at 500  and at  impedances 
covering the minimum, typical, and maximum range of 
physiologic impedances for the location being stimulated] 
For multiphasic waveforms2: 
-Symmetrical or Asymmetrical phases? 
-Phase Duration3 (include units) 
(state range, if applicable) 
(both phases, if asymmetrical) 
Pulse Duration2, 4 (specify units) 
Frequency (Hz)5 
Method of Balancing Charge6 
Are charge balancing cycles always completed?7 
Net Charge (C per pulse) @ 500   
Leakage Current8 (nA) @ 500   
38  Contains Nonbinding Recommendations 
Output Characteristic  Device Output 
Net DC Current9 (A) at maximum pulse rate @ 500   
Maximum Phase Charge (C) @ 500   
Maximum Charge Density10 (C/cm2/phase) @ 500   
Maximum Phase Power (W/phase) @ 500   
Maximum Phase Power Density (W/cm2/phase) @ 500   
Pulse Delivery Mode (continuous/bursts (pulse trains)) 
Burst Delivery11: 
a. Pulses per burst; 
b. Bursts per second; 
c. Burst duration (seconds); and 
d. Duty Cycle [Line a X Line b] 
ON Time12 (seconds) 
OFF Time12 (seconds) 
Current Path Options13 (bipolar, unipolar, multipolar) 
Additional Features, if applicable 
Notes: 
Variable Parameters:  For continuously variable parameters, specify the full range; for 
parameters with discrete settings, specify all available selections. 
Density Measurements: Maximum density values should be calculated using the conductive 
surface area of the smallest electrode and worst-case current path option available; sample 
calculations should be provided. The maximum power density should be based on the maximum 
duty cycle and should be averaged over an appropriate timeframe. 
Output Mode: An output mode is defined as a version of a waveform produced by the unit (e.g., 
biphasic symmetrical and biphasic asymmetrical). 
1Output Channels: The number of independently controlled circuits. For example, two leads that 
are independently controlled would be two channels and 8 electrodes that are independently 
controlled would be 8 channels. Synchronous channels both operate on the same on/off cycle. 
Alternating channels alternate between on and off states. Interleaved channels are generated by 
gating the outputs of a single-channel generator. If more than one channel is available, the 
method of channel isolation should be provided. 
39  Contains Nonbinding Recommendations 
2Waveforms: 
phase 
I  I  phase 
I  I 
I  I 
time  time 
I 
:  I 
- -~  -
Pulse  Pulse 
width  width 
Biphasic Asymmetric  Biphasic Symmetric 
3Phase Duration: A phase is the current flow in one direction for a finite period of time. The 
phase duration is the time elapsed from the beginning to the end of one phase of a pulse or cycle. 
4Pulse Width: The time elapsed from the beginning to the end of all phases plus the interphase 
interval within one pulse. Note that for monophasic waveforms pulse and phase are synonymous. 
5Frequency: The number of pulses per second for pulsed current. 
6Charge Balance Method: Charge may be balanced passively through capacitive coupling or 
actively by delivering pulse phases of equal and opposite charge. Both methods may also be 
combined. 
7Completion of Charge Balancing Phases: If charge is balanced only by means of balanced pulse 
phases, pulse cycles may not be completed if a burst is terminated before the delivery of a charge 
balancing phase. With repeated bursts a net charge imbalance can occur. Operating parameters 
that can result in charge imbalance and resulting local pH changes, electrode corrosion, and/or 
tissue damage, should be mitigated through design of the output circuitry or through 
programming ability to prevent these effects. 
8Leakage Current: current that is not functional. 
9Net DC Current: Current due to charge imbalance or incomplete charge recovery when the 
device is delivering pulses. 
10Maximum Charge Density per Phase: Note that the maximum charge density per phase should 
be safe for the site of stimulation.  
11Pulse Delivery Mode: The mode is continuous if there is a continuous repetitive sequence of 
pulses. A burst is a finite series of pulses delivered for an identified duration. 
12ON/OFF Time: ON time is the time during which trains of pulses are delivered. OFF time is 
the time between trains of pulses. 
40  Contains Nonbinding Recommendations 
13Current Path Options: Bipolar involves the activation of one positive (anode) and one negative 
electrode (cathode) in close proximity to one another. Unipolar involves the activation of one or 
more negative electrodes and typically the IPG case as a positive electrode. Multipolar involves 
the activation of more than two electrodes (e.g., two positive and one negative, two positive and 
two negative). If more than one channel is included, a discussion of current flow between leads 
should be provided. Since output characteristics such as current density may be affected by 
different current paths, the worst case available current path should be used in such calculations. 
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