CitiusTech delivered a poster presentation on the FDA compliance landscape (PMA, De Novo, 510k and Pre Cert) and its implication on AI in Healthcare, at the Mayo Clinic AI Symposium earlier this year.

1. FDA Compliance Landscape (PMA, De Novo, 510k and Pre Cert) & What it Means to Your AI Aspirations
Fernando Schwartz, Vice President - Data Science & Consulting, CitiusTech
The FDA categorizes medical devices into one of three classes – Class I, II, or III – based on their risks and the
regulatory controls necessary to provide a reasonable assuranceof safety and effectiveness.
 Class I and II devices generally pose the lowest risk to the patient and/or user can undergo 510(k) premarket
notification process
 Class III devicespose the highest risk subject to Premarket Approval (PMA) process
Premarket Approval (PMA)
Most stringent regulatory
category for medical devices
Applies to Class III devices. Dueto
the level of risk associated with
Class III devices, they require a
Premarket Approval (PMA)
application under section 515 of
the FD&C Act in order to obtain
marketing clearance.
De Novo Compliance
Less stringent compared to PMA
pathway, specially targeted for
devices which do not have a valid
predicate
Applies to Class I or Class II
devices for which general
controls or general and special
controls provide a reasonable
assuranceof safety and
effectiveness.
510(k) premarket notification process
Most common regulatory path to market
for medical devices
To market a Class I, II, and III device
intended for human use, for which a PMA
is not required, must submit a 510(k).)
Precertification (Pre-Cert)
Most stringent regulatory category for medical devices
The Software Precertification (Pre-Cert) Program is envisioned as a voluntary pathway that embodies a regulatory
model more tailored than the current regulatory paradigm to assess the safety and effectiveness of software
technologies without inhibiting patient access to these technologies. It aims to evaluate necessary information at
different points in the product’s lifecycle, to establish a reasonable assurance of safety and effectivenessfor the
product.
Premarket Approval (PMA) Overview and Types
A Premarket Approval (PMA) application is a scientific, regulatory documentation to FDA containing below
information in addition to administrative elements -
 Technical Sections: The technical sections containing data and information should allow FDA to determine
whether to approve or disapprove the application
 Non-clinical Laboratory Studies Section: Non-clinical laboratory studies section includes information on
microbiology, toxicology, immunology, biocompatibility, stress, wear, shelf life, and other laboratory or animal
tests. Non-clinical studies for safety evaluation must be conducted in compliance with 21CFR Part 58
 Clinical Investigations Section: Clinical investigations section includes study protocols, safety and
effectiveness data, adverse reactions and complications, device failuresand replacements, patient information,
patient complaints, tabulations of data from all individual subjects, results of statistical analyses, and any other
information from the clinical investigations
Tradi�onal PMA Modular PMA
Streamline PMA Product Development Process (PDP)
 21 CFR 814.20(b)
 PMA filing criteria is a 2 step process:
Acceptancereview (15days) and filing
review (45 days)
 GMP: FDA will inspect the site
 Timeline: 180 days
 Submit documents in different modular
stages
 Need prior plan for modular PMA before
reaching to FDA
 Timeline: 90 days for each module and 180
days after final module
 Use for known technologies with known
disease processes
 Already 2-3 approved PMA for similar
types must be present
 GMP: Inspection is deferred if FDA has
completed inspection within past 2 years
 Timeline: 180 days
 PDP is a combination of IDE and PMA
(FD&C Act Section 515F)
 Not very popular
 Timeline: 120 days after completion of
clinical study
Types of PMA
De Novo Compliance Process
Step 1: Pre-Submission: Available for sponsors and manufacturers to obtain regulatory feedback
 Topics that may be addressed using the Pre-Sub process include, but are not limited to -
o Specific preclinical performance testing required to support pre-market clearanceor approval application.
o The appropriate regulatory path for a novel device, such as the 510(k) route or a de novo application.
o The formal designation of a device clinical study as either "significant risk" (SR) or "non-significant risk" (NSR).
 Request a Pre-Sub meeting with FDA -
o Cover Letter
o Thorough description of medical device
o Mechanism of action on the body
o Technical characteristics of device -AI/ML, etc.
o Planned testing strategy
o Queries to be asked to FDA
Step 2: Submission of De Novo
 Submission of FDA 513(g) if no clear predicate can be established -
o “Request for Information” - outline the characteristicsof your device and include rationale on why it falls into a
specific class. In 60 days FDA will issue classification with suitable regulation number and product code.
 New Devices De Novo -
o New devices will automatically fall into Class III. However, not all devices are high risk. Submit a De Novo request and
in 120 days FDA will determine Class I or II for device and may issue an entirely new product code and regulation
number.
Step 3: Granting of De Novo
 The specific device and device type is classified as Class I or Class II. The device may then be marketed immediately and
served as a predicate device.
FDA 510k Decision Making Process for Approval
510(k) Compliance Overview and Types
 510(k) compliance is necessary to market a Class I, ClassII, and III device(s) in US -
o Intended for human use
o Premarket Approval(PMA) is not required
 A 510(k) is a premarket submission made to FDA to demonstrate that the device to be marketed is at least as safe and
effective (substantially equivalent) to a legally marketed device (21 CFR 807.92(a)(3)) that is not subject to PMA
 Submitters must compare their device to one or more similar legally marketed devices and make, support their
substantial equivalenceclaims
Workflow: Types of 510k Compliances
Tradi�onal 510k Abbreviated 510k
 21 CFR 807
 Used for any original 510k or for
a modification to a previously
created device under 510k
 Submitted when a guidance document
exists
 A special control has been established
or FDA has recognized a relevant
consensus standard
Special 510k
 Maybe submitted for a modification to a device which does not
affect intended use or does not alter fundamental scientific
technology
 Device modification is mostly around design control
 No data is evaluated by FDA (Declaration of Conformity –
Conformance Assurance
Pre-Cert – How it’s different from Traditional Pathway
Pre-Certification Process
Which Compliance to Use
PMA De Novo 510k
When To assure the safety and
effectiveness of Class III
devices.
Novel devices of low to
moderate risk (Class I and II).
Class I, II, and III device intendedfor
human use, for which a Premarket
Approval (PMA) is not required.
Device Class 3 Class 1 and 2 Class 1, 2 and 3
Why Due to the level of risk
associated with Class III
devices, FDA has
determinedthat general
and special controls
alone are insufficientto
assure the safety and
effectiveness of Class III
devices.
Therefore, these devices
requirea premarket
approval (PMA)
application under section
515 of the FD&C Act in
order to obtain
marketing clearance.
Do not have a valid
predicate device.
To demonstrate that the device to
be marketed is at least as safe and
effective (substantiallyequivalent)to
a legally marketed device that is not
subject to PMA.
Submitters must compare their
device to one or more similar legally
marketed devices (predicates) and
make and support their substantial
equivalencyclaims.
Risk Factor The manufacturer must
prove that the risk factor
presentedwith this
device is a medium risk.
The manufacturer must
prove that the risk factor
presentedwith this device is
a medium risk.
The manufacturer must merely
prove that the risk presented by the
device is no greater than its
substantial equivalence device.
Complexity Most Stringent Moderate Least Stringent
Timeline 180 days 120 days 90 days
Submission
Cost
Std Fee - $322,147
Small Business Fee -
$80,537
Std Fee - $96,644
Small Business Fee -
$24,161
Std Fee - $10,953
Small Business Fee - $2,738
Example GuardianConnect
System
Contact (Viz.ai) Icobrain
FDA
Compliance
Landscape
Pre-Submission
(OPTIONAL)
Submission of De Novo
Request
No existing active submission for
same device, information provided to
determine whether a potential
predicate device exists, and proposed
special controls provided (if proposed
as class II device)
FDA Classification Review
Decline De Novo
Request : PMA
Required
OR
Discuss
Reclassification
under 513(e) or
513(f)(3)
Likely predicate, class III
regulation or approved
PMA for same device type
exists?
Decline De Novo
Request : Submit
510(k) (unless
510(k) exempt)
FDA Substantive Review
Additional information
(AI) needed to complete
the substantive review?
De Novo Request
placed on hold,
request AI
Requirements for
class I or class II
met?
Grant De Novo Request;
device may be legally
marketed
De Novo Request
placed on hold
submitter notified of
issue(s) to be resolved
Yes, class III
regulation or
approved PMA Yes, likely predicate
No
Yes
Yes
No
Decline De Novo
Request : PMA or
New De Novo
Request Required
No
No
Yes
<= 120 FDA
calendar days to
Grant/ Decline
Identify the new device
and predicate device
Decision 1:
Is the predicate
device ally
marketed?
Decision 2:
Do the devices
have the same
intended use?
Decision 3:
Do the devices
have the same
technological
characteristics?
Review design, materials,
energy source and other
features of the devices.
Review all labelling and assure
that it’s consistent with IFU
statements
No
No
No
Yes
Yes
Yes
Yes
SE
NSE
NSE
NSE
Determine the questions of
safety and effectiveness the
different technological
characteristics may raise
Decision 4:
Do the different
technological
characteristics of the
devices raise different
questions of safety and
effectiveness?
Decision 5a :
Are the methods
acceptable?
Review the proposed scientific
methods for evaluating new /
different characteristics’ effect
on safety and effectiveness
Decision 5b :
Does the data
demonstrate substantial
equivalence?
Evaluate performance data
No
SE
Yes
No
NSE
NSE
NSE
Yes
Traditional Approach
Pre-submission
Document
Administrative
Review
Clinical
Evaluation
FDA Review
Feedback for
Safety
Go-To-Market
Expected Timeline – 90-180 Days, as review, interaction, feedback starts after pre-submission of
document with product information and intended usage
90-180 days
Pre-submission Document Interac�ve Review Period
Go-To-Market and Post-Market
Surveillance (RWD)
Pre-Cert Program Approach
Expected Timeline – 20-25 days, as review, interac�on, feedback starts before pre-submission of
document with product informa�on, intended usage, clinical evalua�on result, organiza�onal
appraisal process, and feedback review and comments
20-25 Days
Excellence Determination
(Mandatory Step)
Real World Performance
(Mandatory Step)
Review Determination
(Mandatory Step)
 Develop premarket review framework
based on risk of the product
 Pre-submission document covers
information of each element of SaMD
 KPI and metrics designed across five principles to
gauge quality – Product Quality, Patient Safety,
Clinical Responsibility, Cybersecurity and Proactive
Culture
 Collect post launch data from diverse sources
 During stage 1, all organizations are supposed
to showcase capability for RWP (post
surveillance)
 Run three major analytics – real world health
analytics, user experience analytics, and
product performance analytics
Pre-9102margorPtoliPnoitacifitreC
1
Streamlined Premarket Review
(Mandatory Step for High Risk Device)
 FDA conducts this review based on previous
feedback
 Identify requirements for premarket review
 Analyze safety and effectiveness of product to
assure it further
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