1

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FDA/CDRH Webinar

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participants.

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REGULATORY OVERVIEW FOR DEVELOPERS 

AND SPONSORS OF NEUROLOGICAL and 

PHYSICAL MEDICINE DEVICES:

An Introduction to the De Novo Pathway

Thursday, August 27, 2020

1:00PM-2:30PM
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What We’ll Discuss Today

• Introduction to the Review of Neurological and 

Physical Medicine Devices under the De Novo 

Pathway

• The De Novo Pathway

• Benefit-Risk Analysis

• Case Study

• Engaging with the FDA through the 

Pre-submission process 

• Closing Remarks
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Introduction

Carlos Peña, PhD, MS

Director

Office of Neurological & Physical Medicine Devices

Office of Product Evaluation and Quality

Center for Devices and Radiological Health
5

Center for Devices and Radiological Health (CDRH) Organization

Pathway for Neurological and Physical Medicine Regulatory Submissions

CDRH

Office of 

Product 

Evaluation and 

Quality

Office of 

Communication

& Education

Office of

Science & 

Engineering

Office of

Center

Director

Surgery, 

Infection

Control

Ophthalmic,

Anesthesia

ENT

In Vitro

Diagnostics,

Rad Health

Ortho

Office of Neurological and Physical Medicine Devices

Cardiovascular

Gastrorenal

OB/GYN

General Hosp.

Investing in Review

Office of

Mgmt

Office of

Policy

Strategic 

Partnerships &

Innovation
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CDRH 

Vision

• Patients in the U.S. have access to 

high-quality, 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. 
7

Medical Device Definition

Section 201(h) of the Federal Food, Drug and Cosmetic Act 

(21 U.S.C. 321) states, in part: 

• “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....”
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Experience in Moving 

Neurological Medical Devices 

From Bench to Market

Clot Retriever for

Ischemic Stroke

Medical Device

Prosthetic Arm For Migraine

Microcatheters for the 

Ablation Therapy neurovasculature Cognitive Function

following concussion
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Regulatory Pathways for Medical 

Devices

Stamp 

Legally 

Marketed

in the

United

States

PreMarket Approval (PMA) Submission

De Novo Submission

Premarket Notification 510(k)

NonClinical & Clinical Study Phase

May occur over multiple years of development

FDA Decision Points

Sponsors may submit a presubmission to the FDA 

to start early 

regulatory discussions

and develop a path forward

Sponsors Apply to FDA to Market Device

Humanitarian Device

Exemption

180* Days

150* Days

90* Days

75* Days

*Number of days noted is days the submission is under review by the FDA, not the total time that it may take to get the device technology to 

market or through the review process. In some cases, the review process may take longer depending upon the particular device, technology, 

indication for use, user, and risk of the device.
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Classifications & Regulatory 

Pathways

• Class III: generally PMA (Premarket Approval)

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

intended use and technology are similar to 

something already classified

• Class I: Low risk, general controls are typically 

sufficient; generally exempt from 510(k)
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The De Novo Pathway

Sergio M. de del Castillo, RAC

De Novo Program Lead

Office of Regulatory Programs

Office of Product Evaluation and Quality

Center for Devices and Radiological Health
What Is a De Novo Classification Request?

12
De Novo Classification

• New device type

– Intended for devices that are automatically classified into 

Class III

• Risk-based classification

– Request to FDA to classify new device into Class I or Class II

13
De Novo Classification

• Granted De Novo request

– Creates new classification regulation

– Regulates new device type through 510(k) pathway, when 

De Novo granted as a Class II device 

– Authorizes marketing in U.S.A.

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Is Your Product a New Device Type?

• Must be a medical device (Section 201(h) of 

FD&C Act)

• Must not fit into any existing classification 

regulation

– No predicate device

– Doesn’t fit into existing Class III classification 

regulation

• No approved PMA(s) for same device type

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De Novo Classification Goals

1. Determine if the probable benefits outweigh the 

probable risks to health

2. Identify probable risks to health

3. Determine level of control needed to mitigate risks:

 general controls only = Class I

 general controls + special controls = Class II 16
De Novo Classification Elements

Benefit-Risk Assessment

Risk/Mitigation Table Special Controls (Class II)

New Classification Regulation

17
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Benefit-Risk Assessment

• Based on totality of evidence (primarily clinical)

• Assessment of probable benefits and probable risks

• Assessment of additional factors, for example:

– Uncertainty

– Patient perspectives

– Addressing unmet medical need

See “Factors to Consider When Making Benefit-Risk Determinations in 

Medical Device Premarket Approval and De Novo Classifications”
Preparing a De Novo Request

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Suggested Resources

• CDRH Device Advice – De Novo Classification Request

• De Novo Classification Process (Evaluation of 

Automatic Class III Designation)

• Acceptance Review for De Novo Classification 

Requests

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De Novo Review Process

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Overall Process and Timeline

Goal → Final decision by FDA Day 150

• Typically two separate review cycles (75 days each)

– 1st cycle: issue request for Additional Information, when 

necessary

– 2nd cycle: render final decision (grant or decline)

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23

De Novo Review Process

Step 2.

Acceptance 

Review 

Step 1.

Submission 

Receipt 

Step 3.

Substantive 

Review 

Step 4.

Final Review & 

Decision

START DE

NOVO 

REVIEW

END DE

NOVO 

REVIEW
Submission Receipt

• De Novo sent to Document Control Center 

(DCC)

• DCC verifies following criteria are met:

– Applicable user fee is paid

– Valid electronic copy (eCopy) is provided

• If above criteria are met, De Novo is assigned 

to lead reviewer

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Acceptance Review

• Determine if De Novo is administratively complete

• Intend to complete review within 15 calendar days of 

receiving original De Novo

• Once accepted, proceed to substantive review

See “Acceptance Review for De Novo Classification Requests”

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Substantive Review

• Classification summary – verify device is eligible

• If eligible:

– review all information/data in the De Novo

• Includes benefit-risk assessment

– identify any questions (deficiencies)

– interactive review (where feasible)

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Substantive Review

• When appropriate, FDA will send request for 

Additional Information (AI), which stops review clock

• Submitter has 180 days to provide complete 

responses to AI letter

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Final Review & Decision

• Submitter provides responses to AI letter

• If FDA determines complete responses provided, the 

review clock resumes

• FDA reviews responses, including any new data

– Includes updated benefit-risk assessment

• FDA renders final decision: grant or decline

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Decline Decision

• Typical reasons for a decline decision:

– Benefits do not outweigh risks

– Cannot develop/determine if special controls mitigate risks

– Ineligible (1st review cycle)

• Decline order will be issued to requester

• Decline order will identify all outstanding deficiencies

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Granting Decision

 Determine probable benefits outweigh probable risks 

 Identify probable risks to health

 Determine level of control needed to mitigate risks to 

health

– General controls only = Class I

– General controls + special controls = Class II

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After a De Novo Is Granted

• FDA sends granting order

• De Novo device may be legally marketed

– Subject to applicable requirements, including 

special controls

• New classification regulation is established

• De Novo device may be used as a predicate 

device

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After A De Novo Is Granted

• FDA updates De Novo Database

– Granting order

– Decision Summary

• FDA publishes notice in Federal Register

– Mechanism for updating Code of Federal 

Regulations

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Summary

• De Novo pathway is intended for new device types.

• A granted De Novo creates a new classification 

regulation.

• Classification is determined by benefit-risk 

assessment and controls needed to mitigate risk.

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34

http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-meddevgen/documents/document/ucm517504.pdf
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Benefit-Risk Determinations

• Balance considerations of probable 

benefits and probable risks as part of 

determination of a reasonable assurance

of safety and effectiveness for the device 

for its intended use

• Both clinical and non-clinical data can play a 

role in benefit-risk determinations

• Probable risks and probable benefits 

supported by valid scientific evidence
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• A reasonable assurance of safety occurs when “it can be 

determined, based upon valid scientific evidence, that the probable 

benefits ... outweigh any probable risks,” and can be demonstrated 

by establishing “the absence of unreasonable risk of illness or injury 

associated with the use of the device for its intended uses and 

conditions of use.” (21 CFR 860.7(d)(1)). 

Benefit-Risk Determinations
37

Benefit-Risk Determinations

• A reasonable assurance of effectiveness of a device shall consist 

principally of well-controlled investigations, as defined in [21 

CFR 860.7(f)], unless the Commissioner authorizes reliance upon 

other valid scientific evidence which the Commissioner has 

determined is sufficient evidence from which to determine the 

effectiveness of a device, even in the absence of well-controlled 

investigations. The Commissioner may make such a 

determination where the requirement of well-controlled 

investigations in [21 CFR 860.7(f)] is not reasonably applicable to 

the device. 21 CFR 860.7(e)(2). 
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Benefit-Risk: Factors 

the FDA Considers

Benefits Risks

Extent of the probable benefit(s):

• Type of benefit(s)

• Magnitude of the benefit(s)

• Probability of the patient 

experiencing one or more benefit(s)

• Duration of effect(s)

• Degree of Uncertainty 

Extent of the probable risk(s)/harm(s):

• Severity, types, number and rates of 

harmful events associated with the 

use of the device

- Device related serious adverse 

events

- Device related non-serious 

adverse events

- Procedure related complications

• Probability of a harmful event

• Duration of harmful events

• Risk from false-positive or falsenegative results for diagnostics

• Degree of Uncertainty
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Benefit Considerations

Factors Questions to Consider?

Type of 

benefit

• What benefit was evaluated? 

• What value do patients place on the benefit? 

Magnitude of 

the benefit(s)

• What was the magnitude of each treatment effect? 

• How did the benefit rank on the scale used to measure benefit? 

Probability of 

the patient 

experiencing 

one or more 

benefit(s)

• Was the study able to predict which patients will experience a benefit?

• What is the probability that a patient for whom the device is intended will 

experience a benefit?

• How did the benefits evaluated vary across sub-populations? 

• Was there a variation in public health benefit for different populations?

• Even if the benefit is in a small portion of the population, do those patients who 

would experience the benefit value it?

Duration of 

effect(s)

• Could the duration, if relevant, of each treatment effect be determined? If so, what 

was it?

• Is the duration of the benefit achieved of value to patients?
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Risk Considerations

Factors Questions to Consider?

Severity, types, number

and rates of harmful 

events

• What are the device related serious adverse events?

• What are the device related non-serious adverse events?

• What are other procedure related complications?

Probability of a harmful 

event

• What percent of the intended patient population would expect to 

experience a harmful event?

• What is the incidence of each harmful event in the study population?

• How does the incidence of harmful events vary by sub-population (if 

applicable)?

• Are patients willing to accept the probable risk of the harmful event, given 

the probable benefits of the device?

Duration of harmful 

events

• How long does the harmful event last?

• Is the harmful event reversible?

• What type of intervention is required to address the harmful event?

Risks from false-positive 

or false-negative results 

for diagnostics

• What are consequences of a false-positive, or false-negative?

•Is this the only means of diagnosing the problem, or is it part of an overall 

diagnostic plan?
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Benefit-Risk: Additional Factors

• Uncertainty

• Patient-centric assessments and patient-reported 

outcomes (PROs)

• Characterization of the disease

• Patient perspectives

• Availability of alternative treatments or diagnostics

• Risk mitigation

• Post-market data

• Novel technology addressing unmet medical need
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Hypothetical Case Study

Using the De Novo Process to Classify 

and Bring to Market an Innovative, LowRisk Device
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Step 1 

Define Technology and Intended Use

“B-Stim” Device

Intended Use

Treat acute pain of headache caused by bruxism

Technology

• wearable (forearm), battery-powered device 

• low energy electrical pulses

• controlled by a mobile app 

• 45 minutes per treatment

• turns off automatically
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Step 2

Is the “B-Stim” a medical device?

[201(h) of the FD&C Act (21 U.S.C. 321)]

• “...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....”
45

Step 3

Is this Device eligible for De Novo 

Classification?

• Is there a predicate Class II or Class I 

device?

• Is there a similar Class III PMA device?

FDA website “Classify Your Medical Device”: 

http://www.fda.gov/MedicalDevices/DeviceRegulationandG

uidance/Overview/ClassifyYourDevice/default.htm
46

Is a Non-Invasive Stimulation Device 

an Appropriate Predicate Device?

• Decision 1: Is there a legally marketed similar device? 

• Decision 2: Does the “B-Stim” have the same intended 

use? 

• Decision 3: Does the “B-Stim” have the same 

technological characteristics? 

• Decision 4: Do the different technological characteristics 

raise different questions of safety and effectiveness? 

*

Also see Fig. 1 of FDA Case Study or 510(k) Guidance Document: “The 

510(k) Program: Evaluating Substantial Equivalence in Premarket Notification 

[510(k)]”
47

Is “B-Stim” Similar to

TENS for Pain Relief Devices?

• Same Intended Use? 

No
48

Step 4

Assess the risks and mitigations

Can general controls or general and 

special controls provide reasonable 

assurance of safety and 

effectiveness?
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Step 5

Obtain FDA Feedback?

[Optional and recommended]

• Section 513(g) Request

• Pre-submission (informal feedback on 

specific questions)

Neither of these submissions represent final FDA 

decisions with regard to legally marketing the 

medical device in the United States.
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Step 6

Submit the De Novo to the FDA

The FDA performs 

• classification review

• Benefit-risk review

• substantive review
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Step 7

Benefit-Risk Assessment

• Based on totality of evidence (primarily clinical)

• Assessment of probable benefits and probable risks

• Assessment of additional factors, for example:

– Uncertainty

– Patient perspectives

– Addressing unmet medical need

See “Factors to Consider When Making Benefit-Risk Determinations in 

Medical Device Premarket Approval and De Novo Classifications”
52

PRE-SUBMISSION 

BEST PRACTICES

Patrick Antkowiak, PhD

Team Lead, Neurodiagnostic Devices Team

Office of Neurological & Physical Medicine Devices

Office of Product Evaluation and Quality

Center for Devices and Radiological Health
53

Q-Submission Guidance

• “Requests for Feedback on Medical Device 

Submissions: The Q-Submission Program and 

Meetings with Food and Drug Administration 

Staff”:

https://www.fda.gov/media/114034/download

• The guidance covers multiple types of 

interactions, but this webinar focuses on the 

“Pre-Submission”
54

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 aim to provide 

written feedback 5 days in advance of the 

scheduled date of the meeting

• Feedback is typically provided 70 days after 

receipt of a submission 

• If a meeting is requested, they typically last 

approximately 1 hour and should be planned 

accordingly
55

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

– Particularly useful if there are concerns related to 

novel technology, testing, or the need for a clinical 

study 

• If needed, you can submit a supplement to get 

additional feedback
56

Common Issues: eCopy

• Make sure you comply with the eCopy 

guidance

– https://www.fda.gov/regulatory-information/searchfda-guidance-documents/ecopy-program-medicaldevice-submissions

• Your submission will NOT be officially logged 

in, the review clock will not start until FDA 

receives a valid eCopy

• Questions: cdrh-eCopyinfo@fda.hhs.gov
57

Submission Contents

• Cover Letter 

• Background information, which can include:

– Device description

– Proposed indications for use

– Bench/animal testing protocols

– Clinical study protocols

• Specific Questions

• Submission should NOT contain data
58

• Additional information for Pre-Submissions 

regarding potential future De Novo 

submissions 

– Proposed Class (I or II)

– Discussion of relevant existing classification 

regulations

– Benefit - risk analysis

– Proposed special controls, if relevant

– Prior regulatory history

Submission Contents
59

Common Issue: Not Enough Information 

Provided Upfront

• We recommend you first identify the proposed 

intended use and key aspects of the device 

design before submission

• Lack of Device Description information, 

especially for devices we have not previously 

reviewed, may hinder meaningful discussion
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How This Impacts the Review 

Process

• Without enough information to understand 

the device, CDRH ends up asking a lot of 

clarifying questions. 

• Providing complete responses to such 

questions takes time, and extends the 

overall length of the review process.
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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 rationale 

and provide justification when submitting a 

Pre-Submission, the more we can focus on 

the substance and give you better feedback
62

Best Practices: Background 

Information

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

be more information than we may need

– Make sure information is 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. We don’t 

need: 

– Circuit diagrams

– Lines of software code

– A copy of your entire grant
63

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 non-human primate model. Some other 

model and protocol may be better suited to 

your particular situation
64

Common Issue: “Specific” 

Questions

• Not providing your own proposal for us to 

review:

– “What animal model should we use?” 

– “What should our clinical control group be?”

• Wanting the FDA to review data:

– “Does the FDA have any comments on the 

nonclinical test results?”
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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 to support 

device safety?”

– Good question: “Based on the intended use, is 

the selected control group in our proposed 

clinical trial appropriate?”
66

Best Practices: Specific Questions 

for a De Novo

• “Based on the information provided (device description, 

indications for use, predicate analysis), does FDA agree that 

my device is eligible for a De Novo submission?”

• “Does FDA believe that there are risks, other than the ones 

we have identified, that must be mitigated?”

• “Are there other special controls that should be considered 

to provide a reasonable assurance of safety and 

effectiveness?”
67

It’s About the Patients
68

Questions?

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; Subheading: Neurological Devices

Please complete a short survey about your FDA CDRH webinar 

experience. The survey can be found at www.fda.gov/CDRHWebinar

immediately following the conclusion of the live webinar
69

Resources

Slide 

Number

Cited Resource URL

5 CDRH Device Advice – Classify Your 

Device

https://www.fda.gov/medical-devices/overview-deviceregulation/classify-your-medical-device

12 CDRH Device Advice – De Novo 

Classification Requests

https://www.fda.gov/medical-devices/premarketsubmissions/de-novo-classification-request

12 De Novo Classification Process 

(Evaluation of Automatic Class III 

Designation)

https://www.fda.gov/regulatory-information/search-fdaguidance-documents/de-novo-classification-process-evaluationautomatic-class-iii-designation

12, 19 Acceptance Review for De Novo 

Classification Requests

https://www.fda.gov/regulatory-information/search-fdaguidance-documents/acceptance-review-de-novo-classificationrequests

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70

Resources

Slide 

Number

Cited Resource URL

13 Requests for Feedback and 

Meetings for Medical Device 

Submissions: The Q-Submission 

Program

https://www.fda.gov/regulatory-information/search-fdaguidance-documents/requests-feedback-and-meetings-medicaldevice-submissions-q-submission-program

14 Factors to Consider When Making 

Benefit-Risk Determinations in 

Medical Device Premarket 

Approval and De Novo 

Classifications

https://www.fda.gov/regulatory-information/search-fdaguidance-documents/factors-consider-when-making-benefitrisk-determinations-medical-device-premarket-approval-and-de

25 DEN160062 – Decision Summary https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN160062

.pdf

31 De Novo Database http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/den

ovo.cfm

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