1 

Welcome to today’s 

FDA/CDRH Webinar

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participants.

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Conference Number:PW9776650 
REGULATORY OVERVIEW FOR INVESTIGATORS 

AND SPONSORS OF NEUROLOGICAL DEVICES AND 

A PATH TO INITIATING HUMAN STUDIES

Wednesday, September 14, 2016

10:00AM-11:30AM
3 

Webinar Goal

• Introduction to the FDA’s Review of Neurological 

Devices, Nonclinical Testing

• Early Feasibility Studies

• FDA Engagement and the Q-Sub Process

• Points of Contact

In Support of the White House BRAIN Initiative
4 

Introduction

Carlos Peña, PhD, MS

Director

Division of Neurological and Physical Medicine Devices

Office of Device Evaluation

Center for Devices and Radiological Health 
5 

CDRH 

Vision

• Patients in the U.S. have access to highquality, safe, and effective medical devices 

of public health importance first in the 

world. 

• The U.S. is the world’s leader in regulatory science, 

medical device innovation and manufacturing, and 

radiation-emitting product safety. 

• U.S. post-market surveillance quickly identifies poorly 

performing devices, accurately characterizes real-world 

performance, and facilitates device approval or 

clearance. 

• Devices are legally marketed in the U.S. and remain safe, 

effective, and of high-quality. 

• Consumers, patients, their caregivers, and providers 

have access to understandable science-based 

information about medical devices and use this 

information to make health care decisions. 
6 

Medical Device Definition

• Definition of a medical device is specified in section 201(h) of the Federal 

Food, Drug and Cosmetic Act (21 U.S.C. 321) *

• Section 201(h) states in part:

– The term “device”...means an instrument, apparatus, implement, machine, 

contrivance, implant, in vitro reagent, or other similar or related article, including 

any component, part, or accessory, which is...”

– “...intended for use in the diagnosis of disease or other conditions, or in the cure, 

mitigation, treatment, or prevention of disease, in man...” or

– “...intended to affect the structure or any function of the body of man and which 

does not achieve any of its primary intended purposes through chemical 

action....”
7 

Experience in Moving 

Neurological Medical Devices 

From Bench to Market

Clot Retriever for

Ischemic Stroke

Cefaly Medical Device

DEKA Prosthetic Arm For Migraine

Microcatheters for the 

Epilepsy DBS neurovasculature

ADHD 

Neurodiagnostics
8 

A Risk Based Approach for Medical Devices 

since 1976

Class I

 General Controls 

Class II

 General controls

 Special controls 

Class III

 General controls

 Premarket approval (PMA)

Increasing Risk

Classification determines extent of regulatory control (Risk Based)

General Controls

 Electronic Establishment Registration 

 Electronic Device Listing

 Quality Systems 

 Labeling

 Medical Device Reporting (MDR)

 Premarket Notification [510(k)] (unless exempt)

Special Controls (addressing Risk)

 Guidelines (e.g., Glove Manual)

 Mandatory Performance Standard

 Performance testing, such as biocompatibility, 

engineering, animal, etc. 

 Special Labeling
9 

Classifications & Regulatory Pathways

• Class III: generally PMA (Premarket Approval)

• Class II: 510(k) (or premarket notification), if the 

intended use and technology are similar to something 

already classified

• De Novo: devices that aren’t comparable enough to 

something on the market. This generates a new device 

classification regulation, and will typically (but not 

always) be Class II
10

When is Clinical Data Needed?

• PMA: typically needed

• De novo: typically needed, but not always

• 510(k): typically not needed

You can request feedback on any protocols 

through a Q-sub, preferably before starting the 

study
11

Increasing Regulatory Transparency

NEW Targeted Guidance for Sponsors

(and Developers & Innovators)

• Presubmission Guidance

• IDEs for Early Feasibility Clinical Studies Guidance Document

• Design Considerations for Pivotal Clinical Investigations

• Expedited Access for Premarket Approval Medical Devices 

Intended for Unmet Medical Need for Life Threatening or 

Irreversibly Debilitating Diseases or Conditions

NEW Draft Guidance-March, 2016-Not for Implementation

• Clinical Considerations for IDEs for Neurological Devices 

Targeting Disease Progression and Clinical Outcomes
12

Investigational Device Exemption (IDE)

• Pertains to devices that have not been approved or cleared 

for marketing OR that are being tested for a new indication 

• IDE allows an investigational device to be used in a clinical 

study in order to collect safety and/or effectiveness data 

necessary to support a marketing application (e.g., 510(k), 

PMA, or HDE)

• Sponsors/investigators may submit a Q-sub to obtain 

preliminary feedback from the FDA (e.g., risk 

determination, feedback on proposed study design, etc.)
13

Reducing FDA Review Timelines

* Values calculated on 10/31/13 and 10/31/14 respectively

FY15 

Goal

30

Met
14

Center for Devices and Radiological Health (CDRH) Organization

Pathway for Neurological and Physical Medicine Regulatory Submissions

CDRH

ODE

Device

Evaluation

OIR

In Vitro &

Rad Health

OC

Compliance

OCE

Communication

& Education

OSEL

Science & 

Engineering

OCD

Center

Director

OSB

Surveillance 

& Biometrics

DOD DSD DOED DCD

Division of Neurological and Physical Medicine Devices

DAGRID DRGUD

Investing in Review-A New Division at FDA
15

Division of Neurological and 

Physical Medicine Devices

Coming Soon-New Branch Organization

Neurodiagnostic and 

Neurosurgical Devices

•Cranial Materials & 

Other Sealants

•EEG & Non-EEG 

Diagnostic Devices

•Neurocognitive 

Diagnostic Devices

•Surgical Instruments & 

Tools for the 

Neurovasculature

•Stereotactic Systems 

for the 

Neurovasculature

Neurointerventional 

Devices

•Embolization Coils

•Flow Diverters

•Guidewires & 

Catheters for the 

Neurovasculature

•Neurothrombectomy 

Devices

•Neurovascular & 

Cerebral Interventional 

Devices

•Cerebrospinal Fluid 

Shunts

Neurostimulation 

Devices Neurology 

Branch 

•Stimulation Devices for 

Movement Disorders, 

Epilepsy, Alzheimer’s 

Disease, Headache, and 

Traumatic Brain Injury

•Devices may include 

cortical stimulation 

devices and deep brain 

stimulation devices

Neurostimulation 

Devices Psychiatry 

Branch

•Stimulation Devices 

for Major Depression, 

Obsessive Compulsive 

Disorder, and Post 

Traumatic Stress 

Disorder

•Devices may include 

cranial electrical 

stimulation devices, 

electroconvulsive 

therapy, and 

transcranial magnetic 

stimulation devices

Physical Medicine & 

Rehabilitation Devices

•Brain Computer 

Interfaces

•Diathermy

•Functional Electrical 

Stimulators

•Iontophoresis Devices

•Massagers/Vibrators

•Orthoses, Exoskeletons

•Powered Muscle 

Stimulators

•Rehabilitation 

Equipment

•Wheelchairs, Walkers
16

Nonclinical Testing

Biocompatibility Evaluation

Chandramallika (Molly) Ghosh, PhD, DABT

Division of Neurological and Physical Medicine Devices

Office of Device Evaluation

Center for Devices and Radiological Health
17

Presentation Outline

• Safety assessment of medical devices

– Biocompatibility

– ISO 10993 series of standards

– FDA guidance 

• Considerations for safety assessment of neurological devices

– Special consideration for neurological devices

• Direct contact with brain and CSF

• Limitations of chemical characterization approach for neurotoxicity 

assessment of devices in direct contact with neural tissue

– Biocompatibility assessment of brain implants
18

Nonclinical Review Considerations

• Performance Characteristics

– Does the device provide appropriate performance 

characteristics over the device use life?

• Biocompatibility

– Is the final product biocompatible?
19

What is Biocompatibility?

Biocompatibility of a medical device refers to the 

ability of the device to elicit the desired biological 

response without causing adverse effects in the 

body. Biocompatibility depends on the body’s 

responses to the device as well as the device’s 

responses to the physiological environment inside 

the human body. 
20

Why do we ask for biocompatibility 

assessment?

• Don’t always know everything in a final product 

• CDRH regulates medical devices, not materials

– CDRH doesn’t clear/approve materials (vs. CDER - e.g., drugs, 

excipients) 

• CDRH recommends biocompatibility assessment on final, 

sterilized (if applicable) product unless otherwise justified 

• Toxicological activity of a medical device

– Leachable chemicals / manufacturing residuals

– Response to surface geometry/chemistry

– Potential degradation products

– Interactions
21

Safety Evaluation of a Medical Device

• Effects of leachable chemicals from the device 

(classical toxicological testing);

• Biological response to surface properties (e.g., bound 

chemicals, surface properties, and/or device 

micro/macro geometric features) (testing specific for 

devices – not applicable for drugs/biologics); plus

• Consideration of how biological response affects 

device performance (testing specific for devices – not 

applicable for drugs/biologics).
22

ISO 10993 Series

Biological Evaluation of Medical Devices

• International Standards Organization (ISO) 10993 

series – Biological evaluation of medical devices

• ISO 10993 has different parts

• Some parts are specific in testing methods, while 

others are very general

• ISO 10993-1 provides guidance on biocompatibility 

assessment strategy

– Device categorization

– Recommends assessment of biocompatibility endpoints 

based on the category of the device

22
23

FDA Guidance and ISO 10993 Standards

• FDA Guidance: Use of International Standard ISO 10993-1, 

“Biological evaluation of medical devices – Part 1 : Evaluation 

and testing within a risk management process” 

http://www.fda.gov/downloads/medicaldevices/deviceregulatio

nandguidance/guidancedocuments/ucm348890.pdf

– Final guidance issued on June 16, 2016

– Guidance implemented on September 14, 2016

• CDRH Standards Program

– Guidance on the recognition and use of consensus standards

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance

/GuidanceDocuments/ucm077295.pdf

23
24

Device Categorization (ISO 10993-1)

Selection of Biocompatibility Endpoints for Assessment

• Device categorization is based on

– Nature of Tissue contact

• Surface contacting device

• External communicating device

• Implant device

– Duration of Tissue contact

• A: Limited (≤ 24 hours)

• B: Prolonged (> 24 hours to 30 days)

• C: Permanent (> 30 days)

• Assessment is based on the category of the device

24
25

Biocompatibility Assessment

• Biocompatibility Endpoints

• Chemical characterization / risk assessment approach to evaluate some 

biocompatibility endpoints (subchronic/chronic tox, carcinogenicity etc.)

Biocompatibility Endpoints – Cytotoxicity – Sensitization – Irritation/Intracutaneous reactivity – Acute Systemic Toxicity – Pyrogenicity – Subchronic & Chronic Toxicity – Hemocompatibility – Genotoxicity – Neurotoxicity – Implantation – Carcinogenicity – Reproductive/Developmental Toxicity – Immunotoxicity – Biodegradation
26

Some Examples of Neurological Devices 

• Deep Brain Stimulator (DBS) leads (polyurethane, 

PT/IR, epoxy) 

• Dura Substitutes (biological & synthetic substitutes) 

• Cortical Electrodes (PT/IR, polymer coatings, epoxy) 

• Intracranial Stents (Nitinol)

• Ventricular Catheters (silicone elastomer, polymer 

coatings)
27

A Few Considerations for 

Neurological Devices

• Neurological implants in direct contact with neural 

tissue and CSF bypass the protective function of BBB

• Need for animal implant testing in relevant neural 

tissue to assess neurotoxic effects

• We recommend devices in contact with neural tissue 

and CSF be non-pyrogenic with confirmatory LAL 

endotoxin testing (2.15 EU/device limit) and materialmediated pyrogenicity testing
28

Challenges for Using Chemical 

Characterization/Risk Assessment Approach for 

Neurotoxicity Assessment

• Chemical characterization/risk assessment approach may not be 

relevant for assessing local tissue response

• Chemical characterization/risk assessment approach may only 

be used to assess the potential neurotoxicity of chemicals from 

neural implants if toxicological data on the chemicals are 

available from clinically relevant route of exposure studies (for 

example, intracerebroventricular) 

28
29

One Example of a Biocompatibility 

Assessment of a Brain Implant

Permanent implant with neural tissue, CSF, and 

blood (indirect contact through CSF) contact:

• Biocompatibility assessment per ISO 10993-1/ 

FDA Biocompatibility Guidance, June 16, 2016 (Cytotoxicity, Sensitization, Irritation or intracutaneous reactivity, Acute systemic toxicity, Material-mediated pyrogenicity, Subchronic toxicity, Genotoxicity, Implantation, Hemolysis, Chronic toxicity, and Carcinogenicity) 

• Neurotoxicity assessment due to brain contact

 Neuroimplantation study (Clinically relevant implant site study per ISO 10993-6)

• LAL Testing (2.15 EU/device) per FDA Guidance issued on January 21, 2016: “Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile”

http://www.fda.gov/downloads/MedicalDevices/.../ucm109897.pdf
30

One Example of a 

Neurotoxicity Assessment of a Brain Implant

• Currently, no standard protocol for brain implantation study (ISO 

10993-6 Annex in development)

• Some Considerations for neurotoxicity assessment of brain implants: 

– Brain implantation study (e.g. rabbit model for passive DBS lead implant)

– Separate test and control (e.g. biomaterial control like HDPE) groups

– Equal number of male and female animals

– Implantation period – Acute and chronic responses 

– Clinical observations

– Neurobehavioral assessment

– Body weight change, food consumption, clinical chemistry, hematological 

parameters

– Gross necropsy

– Histopathology – Neurodegeneration, gliosis, and myelinopathy
31

Neurotoxicity Assessment from a Functional Study: 

Theoretical Case Study

• Large animal study (e.g. pig) with active DBS leads

• Test groups to evaluate different stimulation parameters

• Control groups

– Sham surgical control (passive leads implanted and immediately 

withdrawn to control for the effect of surgical procedure)

– Control group with passive implant 

• Different time points

• Clinical observation and behavioral assessment

• Blood work (CBC, clinical chemistry pre- and post-implant and pretermination), Body weight, food consumption

• Gross necropsy

• Histopathology (H & E, Fluoro-Jade B, Luxol fast blue, GFAP) 
32

Nonclinical Testing

Animal Studies

Dhanya K. Williams, M.S.

Division of Neurological and Physical Medicine Devices

Office of Device Evaluation

Center for Devices and Radiological Health 
33

What is the purpose of conducting an 

Animal Study?

Animal studies are intended to demonstrate that the device 

under study is sufficiently safe for early human experience 

[e.g., to support an investigational device exemption (IDE) 

application] or to demonstrate device safety in support of a 

marketing application, while incorporating modern animal 

care and use strategies. 
34

Good Laboratory Practice Requirements

• Good Laboratory Practice (GLP), as outlined in 21 CFR 

Part 58 (GLP Regulations), applies to nonclinical animal 

studies.

• Non-GLP studies may be acceptable in some submissions, 

however, sponsors should provide adequate justification 

why GLP provisions were not met, how the study 

deviated from GLP, and why these deviations would not 

impact the study outcome.
35

Considerations in Designing 

a Nonclinical Animal Study

• Animal Model

• Study design (study size and duration)

• Study Endpoints
36

Animal Model

Provide scientific justification for the animal model used.

• An animal model should be generally accepted for the 

study of the device type

• Clinical relevance of implant/treatment site

• Address limitations to the selected animal model

• Diversity in animal models used for neurological devices

– Rats, Rabbits, Sheep, Swine, Canine
37

Study Design

Use the minimum number of animals necessary to 

generate valid and meaningful scientific data to 

demonstrate reasonable safety and performance. 

• Include appropriate treatment and control animals to 

evaluate safety and performance

• Include animal cohorts to evaluate tissue responses over 

the course of the study based on expected duration of 

clinical use

• Animal loss
38

Study Endpoints 

• Safety

– Clinical observations

– Histopathology

• Performance 

– Device condition following use

– Device specific functional endpoints

– Labeling claims need to be substantiated

• Consider methods to minimize bias (e.g., blinding, 

multiple evaluators, randomization, etc.)
39

Q-subs

The FDA will review proposed biocompatibility evaluation 

strategies and animal study rationale, design and protocols, 

however please note that data cannot be reviewed in the 

Pre-submission process. 
40

Available Resources 

Biocompatibility Guidance: Use of International Standard ISO 10993-1, "Biological 

evaluation of medical devices - Part 1: Evaluation and testing within a risk management 

process" (June 16, 2016)

http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidance

documents/ucm348890.pdf

21 CFR PART 58 GLP FOR NONCLINICAL LABORATORY STUDIES:

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=58

Recognized Consensus Standards:

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfstandards/Search.cfm

FDA Guidance Documents:

http://www.fda.gov/RegulatoryInformation/Guidances/default.htm
41

Early Feasibility Studies

A Valuable Regulatory Tool for 

Neurological and Physical Medicine Device 

Development

Erin Keegan, MS and Devjani Saha, PhD

Early Feasibility Study Representatives

Division of Neurological and Physical Medicine Devices

Office of Device Evaluation

Center for Devices and Radiological Health
42

Agenda 

• What is an EFS?

• How can an EFS benefit you? 

• Stages of an EFS Pathway to IDE

• Key EFS Principals and DNPMD Examples

• Tips

• Initiating your EFS
43

What is an EFS?

IDE - Investigational Device Exemption

• An IDE submission allows an investigational device to be used in a 

clinical study in order to collect safety and effectiveness data

EFS IDE - A standard IDE except... 

• Small number of subjects (< 10) in the clinical investigation

• Device is generally early in development 

• Device iterations are expected

• Limited non-clinical data may be available 

• Enhanced clinical mitigations may be required

EFS is an informal designation
44

How can an EFS benefit you?

Permits A More Efficient Pathway to US Commercialization

• FDA feedback early in product development may help you improve 

your development strategy and reduce unnecessary testing 

• Data collection in the US patient population may be easier to 

leverage to support later studies or marketing applications

Enables collection of high quality clinical data for:

• Optimizing device design or operator technique

• Refining the intended use population

• Refining nonclinical test plans

• Developing subsequent clinical study protocols
45

Stages of an EFS Pathway to IDE

• Stage 1: Informal discussion with EFS representatives

• Stage 2 (optional): Informational meeting pre-submission

• Stage 3: Initial pre-submission as outlined in the EFS guidance

• Stage 4: Additional pre-submissions as needed (e.g., if test 

requirements are uncertain/discussion of clinical protocol)

• Stage 5: IDE submission
46

Key Principles of EFS 

and DNPMD Examples 
47

Just-In-Time Testing (JITT) 

Concern: Comprehensive testing during early phases of device development 

may add cost without significant return

EFS Approach: 

• Doing the right testing at the right time

• EFS should not take the place of informative nonclinical testing 

DNPMD Examples: 

• Long term durability testing may be deferred given criticality of short 

term benefit (e.g. glioblastoma, SCI, severe psychiatric disorders)

• Limiting use of a device to the hospital instead of a patient’s home may 

change testing strategy (e.g. EMC for electronic based assistive devices) 

• Small number of devices may rely on single lot Ethylene Oxide (EO) 

sterilization versus full EO sterility validation (e.g. novel leads for spinal 

cord stimulation)
48

Enhanced Risk Mitigation Strategies

Concern: An EFS may carry greater unknown risks as compared to traditional 

feasibility and pivotal studies

EFS Approach: 

• Enhanced clinical monitoring specified in the protocol

• More frequent/detailed reporting to the FDA

• Informed consent should highlight greater unforeseeable risk

DNPMD Examples: 

Risks Mitigations

Stimulation related 

adverse events

• Titrating therapy

• Turn device off and revert to standard of care

Novel endovascular 

stroke intervention 

• Surgery performed at select sites with expert surgical 

and clinical team 

Infection caused by lead 

implantation

• Ongoing monitoring of implantation sites and body 

temperature 
49

Leveraging Existing Data

Concern: Applicable data may already exist in non-traditional formats (e.g., 

testing or literature from marketed products or earlier prototypes) 

EFS Approach: 

• Leveraged data can be used to provide information without unnecessary 

burden

• You should provide a leveraging rationale and a detailed discussion of 

differences (e.g., material, design, manufacturing) between the 

leveraged data and the proposed device 

DNPMD Examples: 

• Some biocompatibility endpoints could be leveraged from an animal 

study 

• Data from published literature could support device safety (e.g. 

approved SCS parameters for novel PNS)
50

Timely Device & Clinical Protocol Changes

Concern: Devices studied under EFS are expected to change throughout the 

study and require timely device iterations.

EFS Approach: 

• Contingent approval: device changes that are anticipated during the study 

may be executed without additional FDA action if the proposed change, 

supporting test plans, and acceptance criteria were agreed upon in an IDE 

or IDE Supplement

• Broader implementation of 5-day notice IDE supplements

DNPMD Examples: 

• 5-Day notice: device changes that do not constitute significant changes to 

the design or principal of operation (e.g. ergonomic modifications) 

• Contingent Approval: adjust stimulation parameters, interchange 

prosthetic devices/components
51

Tips

If you are making design modifications:

• record device modifications with rationale

• record testing completed with each device iteration 

• keep samples of previous generation to help for leveraging in 

future submissions (e.g. biocompatibility)

If you would like to use test results that were not obtained per standard 

FDA recommendations: 

• provide an explanation for why the data is sufficient 

e.g. if your animal study deviates from 21 CFR 58 (GLP) tabulate 

each part of the regulations, list how the study deviates and how 

you will ensure data integrity and minimize bias
52

Tips

If you would like to use short-term animal studies to support EFS 

initiation of a device intended for long-term use, please note the 

following:

• providing supporting evidence that short-term results are 

predictive of long-term safety

• applying additional clinical mitigation strategies (e.g., longer-term 

follow-ups)

• conducting additional nonclinical testing (e.g., mechanical integrity 

testing under exaggerated conditions, computational modeling) 

Please also note that additional long-term animal study data may be 

needed to support a larger clinical study
53

When are you ready for an EFS? 

You can: 

• describe why additional nonclinical testing will not be informative 

and therefore a human clinical study is needed; 

• justify how any leveraged information supports your clinical trial; 

and

• identify potential risks and how they will be adequately mitigated

The Device Evaluation Strategy as described in the EFS guidance is a 

useful regulatory tool to support initiation of your study 

• See Appendix 2 in the EFS Guidance available online:

http://www.fda.gov/downloads/medicaldevices/deviceregulationa

ndguidance/guidancedocuments/ucm279103.pdf
54

When is a good time to talk to the FDA 

about an EFS?

After...

• You have established your general device design, intended use, 

and what information you would like to gather from the EFS

Before...

• Expensive and time consuming non-clinical testing has been 

started

We recommend that you reach out to DNPMD EFS representatives 

informally to discuss submission strategy 
55

PRE-SUBMISSION BEST PRACTICES

Tim Marjenin

Branch Chief

Neurostimulation Devices Neurology Branch

Division of Neurological and Physical Medicine Devices

Office of Device Evaluation

Center for Devices and Radiological Health
56

Q-Sub Guidance 

• “Requests for Feedback on Medical Device 

Submissions: The Pre-Submission Program and 

Meetings with Food and Drug Administration 

Staff”: 

http://www.fda.gov/downloads/medicaldevices/de

viceregulationandguidance/guidancedocuments/uc

m311176.pdf 

• While the guidance covers multiple types of 

interactions, today we will focus on the “Pre- Submission”
57

Timeframe for Review

• Per the guidance, the FDA strives to hold a meeting (if 

requested) within 75-90 days of acknowledged receipt

– If you request a meeting, we will provide written feedback 

about 3 days in advance of the scheduled date of the 

meeting 

• You should generally plan to meet with us or receive 

written feedback 75-90 days after receipt, due to 

workload considerations of review staff

• Make sure you budget your time accordingly
58

Why Engage As Early As You Can? 

• Pre-submission interactions allow potential 

issues to be identified earlier, and we can work 

through them with you as appropriate

– This is particularly useful if there are concerns 

related to novel technology or testing

• If needed, you can submit a supplement to get 

additional feedback
59

Common Issue: eCopy

• Make sure you comply with the eCopy guidance

– http://www.fda.gov/ucm/groups/fdagovpublic/@fdagov-meddevgen/documents/document/ucm313794.pdf

• Your submission will NOT be officially logged in, the 

review clock will not start, and nothing else will 

happen until we receive a valid eCopy

• Questions: cdrh-eCopyinfo@fda.hhs.gov 
60

Submission Contents

• Cover Letter 

• Background information, which can include:

– Device description

– Bench/animal testing protocols

– Clinical study protocols

• Specific Questions
61

Common Issue: Not Enough Information 

Provided Upfront

• An analysis of a number of Investigational Device 

Exemption (IDE) letters showed that the area 

generating the most questions was “Device 

Description”:

– What the device is and does

– Instructions for use

– Hazard Analysis 

• We encounter similar issues across other 

submission types
62

How This Impacts the Review Process

Without enough information to understand the 

device, CDRH ends up asking a lot of questions. 

Providing complete responses to our questions 

takes time, and extends the overall length of the 

review.
63

What You Can Do

• Remember, YOU as the applicant know the 

most about your device technology, not the FDA

• The more you can explain your thought 

processes when you submit a pre-submission, 

the more we can focus on the substance and 

give you better feedback
64

Understand the Existing Landscape

• Search for and review applicable guidance 

documents and standards (if there are any), such 

as:

– Biocompatibility, if you are not using an approved device 

(ISO 10993)

– “Guidance for the Content of Premarket Submissions for 

Software Contained in Medical Devices”

• Explain the relationship of what you’re proposing 

compared to what’s been done in the past
65

Best Practices: Background Information

• It’s ok to err on the side of including what you think may 

be more information than we would need

– Make sure it’s organized and easy to follow

• If you cite literature articles, please provide copies in the 

submission 

• There is such a thing as too much information: 

– Circuit diagrams

– Lines of software code

– A copy of your entire grant
66

Best Practices: Background Information

• Avoid assumptions:

– Unless there is an applicable guidance, standard, or 

other regulatory precedent you can cite, identify the 

most appropriate approach for YOUR needs and justify 

it

– Example: not every animal study needs to use a nonhuman primate model. Some other model and protocol 

may be better suited to your particular situation
67

Common Issue: “Specific” Questions

• Not providing your own proposal for us to 

review:

– “What animal model should we use?” 

– “How large should the sample size be?”

• Wanting the FDA to review data:

– “Does the FDA have any comments on the 

nonclinical test results?”
68

Best Practices: Specific Questions

• The questions should build on the background 

information you have provided

– Good question: “What concerns do you have with 

our proposed animal model?”

– Good question: “Are the proposed sample size 

calculation method and related elements of the 

statistical analysis plan appropriate for the proposed 

clinical study?”
69

SIGNIFICANT RISK, 

NON-SIGNIFICANT RISK, AND 

BASIC PHYSIOLOGICAL RESEARCH 

Risk Determinations 
70

When is an IDE Not Required? 

• Exempt studies per 21 CFR 812.2(c), such as:

– Studies of approved devices used in accordance with their 

labeling

– Certain diagnostic device studies

• Basic physiological research: Not for the purpose of 

evaluating safety/effectiveness of the device

• “Practice of medicine” – care of specific patient with an 

approved device. 

• Non-significant risk studies
71

Closing Remarks
72

It’s About the Patients
73

Other Available Resources and Programs

www.fda.gov/MedicalDevices 

• CDRH Learn

• Device Advice

• CDRHNew
74

Resources 

Nonclinical & Animal Studies

Biocompatibility Guidance: Use of International Standard ISO 10993-1, "Biological 

evaluation of medical devices - Part 1: Evaluation and testing within a risk management 

process" (June 16, 2016)

http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidance

documents/ucm348890.pdf

21 CFR PART 58 GLP FOR NONCLINICAL LABORATORY STUDIES:

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=58

Recognized Consensus Standards:

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfstandards/Search.cfm

FDA Guidance Documents:

http://www.fda.gov/RegulatoryInformation/Guidances/default.htm
75

• Early Feasibility Study Guidance

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/

GuidanceDocuments/UCM279103.pdf2 

• EFS CDRH Learn Modules

http://www.accessdata.fda.gov/cdrh_docs/presentations/EFS/story.html 

• Pre-Submission Guidance 

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/G

uidanceDocuments/UCM311176.pdf 

• IDE Submission Information

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarke

tYourDevice/InvestigationalDeviceExemptionIDE/ucm046706.htm#reqele

• Design Controls Guidance

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDoc

uments/ucm070627.htm

• Electronic Submissions Guidance

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/

GuidanceDocuments/UCM313794.pdf 

Resources 

Early Feasibility Studies
76

Division of Industry and Consumer Education: 

DICE@fda.hhs.gov

Slide Presentation, Transcript, and Webinar Recording 

will be available at:

http://www.fda.gov/training/cdrhlearn Under the 

heading: Specialty Technical Topics; Sub-heading: 

Device-Specific Topics 

QUESTIONS?