medical regulation.pdf

tTitle
15:00-15:30 Paving the path for FDA approval of AI based medical devices Gadi Ginot, CEO Physio-Logic
15:30-16:30 Open Q&A session (via Zoom) with the FDA’s Digital Health Center of Excellence. Bakul Patel, Director, Digital
Health Center of Excellence, US FDA
16:30-17:00 How to marry the product, Artificial Intelligence and FDA regulations. Ophir Zamir, Director Product
Development, R&D, Medtronic GI Operation Unit
17:00-17:15 Coffee break.
17:15-17:45 Best Pre-Sub practices Yoav Galil, Head, Digital Health Practice, Physio-Logic
17:45-18:15 Update and tips on the 510(k) program Dr. Tamar Katzav, VP Medical Device Practice, Physio-Logic
18:15-18:30 Q&A and summary
AGENDA
1

tTitle
Gadi Ginot (M.Sc., M.B.A)
CEO & Founder
Paving the Path for FDA’s AI Based Medical
Devices Approval
This presentation is the sole property of Physio-logic Ltd and is protected by Copyright ©. Any use of this presentation without the prior written
approval of Physio-Logic Ltd is prohibited. This presentation does not constitute regulatory advice and should not be regarded as replacing
professional consultation. We recommend that you receive specific professional advice in relation to any regulatory matter
Copyright © 2021 Physio-logic All rights reserved. 2

tTitle
Gadi Ginot (M.Sc., M.B.A), CEO & Founder
Digital Health Regulation
aMoon
This presentation is the sole property of Physio-logic Ltd and is protected by Copyright ©. Any use of this presentation without the prior written
approval of Physio-Logic Ltd is prohibited. This presentation does not constitute regulatory advice and should not be regarded as replacing
professional consultation. We recommend that you receive specific professional advice in relation to any regulatory matter
3

tTitle
Agenda
• Background
• The statutory approval threshold
• Pre-market regulatory considerations
➢ Regulatory
➢ Clinical
➢ Quality
• Summary

5
The US FDA Statutory Approval Threshold
• Dependent on the type of pre-market pathway, for example:
✓ “Substantial equivalence”
✓ “Reasonable assurance of safety and effectiveness, and the probable
benefits of the device outweigh the probable risks”
✓ “Probable benefit outweighs the risk of injury”
• Technology agnostic

6
2021 Physio-Logic Ltd.
Proprietary and Confidential
The End Game
✓ Assure safety & effectiveness
✓ Assure quality
The benefit must outweigh the risks considering the state
of the art!

7
Challenges Associated with regulating Sw
• Indirect risk
• Indirect benefit (CDS)
• New intended uses
• May not necessarily have
independent benefit or claims
• Soft medical benefits
• Multiple functions
• New user
• Use environment
• Platform
• Modifications

• Training, testing and validating
AI model is a process prone for
bias
• Difficult to explain and convey
device limitations
• Unexplainable
• The utilization of big-data from
the “real-world” challenges data
quality and relevancy
• Statistical competency
• Algorithm change over time
(adaptive) – performance
degradation/ improvement
8

9
Sw safety
• Software risks are fundamentally different, predominantly indirect and
require enhanced risk management framework
• Connectivity; Inter-operability; Compatibility; Usability; Privacy & Security
• FDA’s additional risk dimensions: intended user, use environment, use
case and workflow, explainability.

10
Assure Sw Quality

11
Good Machine Learning Practices (GMLPs)
“A set of AI/ML best practices (e.g., data management, feature extraction,
training, interpretability, evaluation and documentation) that are akin to
good software engineering practices or quality system practices”
“Development and adoption of these
practices is important not only for
guiding the industry and product
development, but also for facilitating
oversight of these complex products,
through manufacturer’s adherence to
well established best practices and/or
standards”

12
The Challenge - Assure Performance
The Three Tier Approach

13
Summary
➢ The regulation of AI-based medical devices does not fit the
traditional medical device mold
➢ There are specific pre and post market regulatory, quality and
clinical considerations that should be considered to assure
smooth TPLC

tTitle
Update and Tips on the 510(k) program
14
Dr. Tamar Katzav
VP Project Management

tTitle
✓ Over 15 years experience leading regulation of medical devices, active
substances and drugs in many different territories.
✓ Leads MDSAP, MDR and ISO 13485:2016 certifications
✓ Certified Lead Auditor for ISO 13485:2016 & 21 CFR 820.
About Me
Dr. Tamar Katzav
VP Project Management
15

tTitle
16
• Learning objectives:
✓ Provide an overview of the 510(k) process
✓ Effective determination of a predicate device (key factors to consider when choosing a
predicate)
✓ 510(k) process flow and how to interact with FDA during the Review
✓ Update and tips on the 510(k) program (Identify what’s new)
AGENDA

tTitle
17
FDA Submission Types
• All classes, to request FDA feedback
PRE-SUBMISSIONS (PRE-SUBS)
• Class II- Substantial Equivalence (SE)
510(K) SUBMISSION
• Class III- Premarket approval
PMA
• Class III → Class II down-classification
DE NOVO

tTitle
18
What is a 510(k)?
• A type of premarket submission
• Demonstrate safety and effectiveness
• Substantial equivalence (SE) to a legally-marketed device
Device Advice: Premarket Notification 510(k))

tTitle
19
When is a 510(k) Required?
• Introducing a device into commercial distribution (marketing) for the first time.
• Proposes a different intended use for a device which you already have in commercial
distribution.
• A change or modification of a legally marketed device and that change could
significantly affect its safety or effectiveness.

tTitle
20
510(k) Submission Methods
• Traditional 510(k) (90 days) - the traditional method is the original complete submission as
provided in 21 CFR 807 - can be used under any circumstance. How to Prepare a Traditional 510(k)
The Abbreviated 510(k) and Special 510(k) methods can only be used if certain criteria are met.
• Special 510(k) (30 days) - use of design controls to assure SE for device modifications. Required
elements (21 CFR 807.87). Device modification to manufacturer’s own legally marketed device
and modification does NOT affect the intended use or fundamental scientific technology. No data
is evaluated by FDA. The Special 510(k) Program

tTitle
21
510(k) Submission Methods
• Abbreviated 510(k) - Conformance with Recognized Standards to
reduce data
• Required elements (21 CFR 807.87).
• Relies on the use of guidance documents, special controls, and
recognized standards.
• Under certain conditions, sponsors may not need to submit test
data in an Abbreviated 510(k).
In September 2019, the guidance was split and an expansion to the
Abbreviated pathway was introduced called the Safety and
Performance Based Pathway
How to Prepare an Abbreviated 510(k)

tTitle
22
Substantial Equivalence
• Device is substantially equivalent if, in comparison to a predicate it:
• has the same intended use as the predicate; and has the same technological
characteristics as the predicate; or
• has the same intended use as the predicate; and has different technological
characteristics and the information submitted to FDA: does not raise new questions of
safety and effectiveness; and demonstrates that the device is at least as safe and
effective as the predicate-legally marketed device
[Intended Use, Design, Material, Performance, Safety, Effectiveness, Biocompatibility, Labeling, Standards, Energy
Used or delivered]

tTitle
23
How to Choose Your Predicate Device
Search Similar
Products
Compare
Technology
Identify
Intened Use
Compare
Preformance

tTitle
24
The 510(k) Review Process: What to
expect; When to expect it
Guidance Scope
• 510(k) Decision Making Process
• 510(k) Review Standard
– Predicate Device
– Intended Use
– Technological Characteristics
– Additional Information Requests
Also check for device-specific guidance & X-
cutting guidance docs
– e.g., Contact Lenses guidance
– e.g., Sterility Guidance, Biocompatibility Guidance

tTitle
25
Common across all 510(k) formats
Consider all relevant guidance documents, special controls, and voluntary consensus standards that
apply to the device type or to a scientific topic area (e.g., biocompatibility or electromagnetic
compatibility).
• Even if not FDA recognized standard, still use applicable ones. It takes time for FDA to recognize
new editions (e.g. ISO 14971:2012 and not 2019).
• Refuse to Accept Policy for 510(k)s https://www.fda.gov/media/83888/download
• Evaluating Substantial Equivalence in 510(k)s https://www.fda.gov/media/82395/download

tTitle
26
Performance Testing – Bench
• FDA recommends that your non-clinical bench performance testing include the relevant information described
in the FDA guidance document “https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/recommended-content-and-format-non-clinical-bench-performance-testing-information-premarket
• https://www.fda.gov/medical-devices/premarket-notification-510k/how-prepare-traditional-510k#content

tTitle
27
510(k) Process Overview
FDA receives your
510(k) submission.
1. Submission Receipt 3. Substantive
Review
LR reviews the
submission in detail
5. Final Review
& Decision
Completion of review;
Final decision
by FDA Day 90.
2. RTA Review
Administrative
review by FDA
Day 15.
4. SI Decision
By FDA Day 60, LR
decides whether
Additional information
is needed.
“FDA and Industry Actions on Premarket Notification (510k(k)) Submissions: Effect on FDA Review Clock and Goals”
Guidance For Industry and FDA Staff

tTitle
Interacting with FDA during the 510(k) Review:
28
RTA Review Overview
RTA Review
RTA Accepted
• FDA review clock continues
• Substantive Review Begins
• LR may request information
interactively
RTA Not
Accepted
• FDA review clock stops
• Submitter receives completed
checklist
• Submitter responds w/ missing
info w/in
calendar 180d
• RTA review conducted again

tTitle
29
Tips for Responding to RTA
• Include the reviewer’s checklist &
include page/section numbers where
response can be found
• Provide a rationale for why a missing
item is not relevant
• Resubmit all prior information
• Make changes to the device or
indications

tTitle
30
Tips for Responding to RTA
What it is
• Early notification of “observations” made
during initial RTA review
• An opportunity to address issues likely to
arise during substantive review
What it is not
• Substantive review of submission
• Does not replace an additional information hold
• An official request for additional information
• A delay in RTA review or decision
What Is An Observation?
Issue noted during administrative review that doesn’t determine acceptability of
submission, but would result in a deficiency during substantive review
(Examples: Missing a necessary performance test, or results from a performance test appear deficient)

tTitle
31
Substantive Review Overview
SI Decision
PI: Proceed
Interactively
• FDA review clock continues
• LR may request information
interactively
AI Hold:
Request for
Additional
Information
• FDA review pauses
• Industry clock begins (180d)
• Must respond to all deficiencies
• provide requested info
• provide alternative with
rational

tTitle
32
Day -10 Call
What it is
• Teleconference (The call is not expected to exceed 30 minutes)
• Confirmation that submitter understands deficiencies in the letter
• Can be used to determine whether a Submission Issue Request is
needed.
What it is not
• Review of additional information provided by submitter
• Discussion of issues unrelated to deficiencies in the AI
letter
What Is it?
You can request a call with FDA that occurs within ten (10) days after issuance
of an AI letter. The purpose of the call is to address clarification questions pertaining to
the deficiencies in the letter.

tTitle
33
Least Burdensome (LB) Flag
What it is
• Opportunity to address LB discrepancies in an AI letter
• Opportunity for submitters to address situations when they feel
they are being held to a different standard
What it is not
• An Appeal Meeting
• Change to 180 Response deadline
Description: You feel that deficiency(s) do not adhere to the least burdensome principles and
request a discussion and review with a manager.
The Least Burdensome Provisions: Concept and Principles Guidance for Industry and FDA (February 2019)

tTitle
Yoav Galil, Head of Digital Health Practice
Best Pre-sub Practices

Agenda
• Introduction to the Pre-sub program
➢ Definition
➢ Objective
➢ Scope
➢ Schedule
• Our tips
• Q&A

title
Objectives
37
• Solicit feedback (meeting, TCC, email) from the FDA prior to premarket
submission
• Help guide product development, develop protocols, prepare
premarket applications
Copyright © 2021 Physio-logic All rights reserved.

title
Definition
• A procedure/a process
• A formal written request for feedback from the FDA
• Response in written form or meeting (physicalTeleconference)
38

title
Definition
• Voluntary
• No user fee
• Q-Sub (2019) interactions with the FDA
• Pre-Submission
• Study Risk Determinations
• Informational Meetings
• Submission Issue Requests
• Early Collaboration Meetings
• PMA Day 100 Meetings
39

title
Q-Submission Admin
40
• All Q-Submissions follow the same general processes regarding:
➢ Formal submissions to the Document Control Center (DCC)
➢ eCopy (electronic copy) requirements
➢ Tracking with original Q-Submissions, supplements, & amendments
➢ Meeting formats and submission of meeting minutes
FDA guidance: Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission
Program. May 2019

title
41
Pre-sub Review Schedule
Performance Goal
Meeting
Scheduled Due
Meeting
Scheduled
RTA
• Meeting Set
Date
• Written
Feedback Date
5 Days before
meeting or Day 70
– whichever is
sooner
By Day 30
By Day 15
Pre-Submission
Meeting
• Written
Feedback Date
Day 70
N/A
By Day 15
Pre-Submission
Written Feedback
• MDUFA IV commitments for review time

title
Pre-Sub Package
• Guidance emphasizes the need for specific question (examples)
• No “one size fits all”
• Recommended TOC:
➢ Table of Contents
➢ Detailed Device Description
➢ Proposed Intended Use/Indications for Use
➢ Summary of Previous Discussions or Submissions Regarding the Same Device
➢ Overview of Product Development
➢ Specific Questions for FDA Feedback
➢ Preferred method for FDA Feedback
43

title
FDA’s Feedback
“FDA intends that feedback the Agency provides in a Pre-Submission will not change,
provided the information submitted in a future IDE or marketing application is
consistent with that provided in the Pre-Submission and documented in the Pre-
Submission, and that the data and other information in the future submission do not
raise any important new issues materially affecting safety or effectiveness. The minutes
described above will serve as the record of the Agency’s Pre-Submission feedback.
Modifications to FDA’s feedback will be limited to situations in which FDA concludes
that the feedback does not adequately address important new issues materially
relevant to a determination of safety and/or effectiveness or substantial equivalence.
Such a determination will be supported by the appropriate management concurrence
consistent with applicable guidance and SOP”
44

title
Our Experience
• An effective Pre-sub:
➢ Early but not too early
➢ The right questions are asked
➢ The questions are answered
➢ Improve predictability
➢ Increase confidence
45

title
Our Experience
• Ineffective Pre-Sub:
➢ Results in over regulation
➢ Irrelevant for the modified device
➢ More questions than answers
➢ Results in confusion
➢ Invalidates assumptions and turns off investors
➢ Rate limiting
46

title
Lessons Learned
47
Successful
Pre-Sub
Timing
Content
Questions
Meeting
Match
Expectatio
n

2019 Physio-Logic Ltd. Proprietary and Confidential 48
Take Home Messages
• AI based medical device are different
• Particular regulatory requirements
• Impact on GMP compliance
• Impact on the content of pre-market submissions
Summary

medical regulation.pdf

Recommended

Recommended

More Related Content

Similar to medical regulation.pdf

Similar to medical regulation.pdf (20)

Recently uploaded

Recently uploaded (20)

medical regulation.pdf