Regulation of Medical Devices in US FDA

1. Regulation of Medical Devices
in US
Ankit Geete
1

2. US Medical Device Markets
2
Source: www.chameleon-pharma.com

3. What is Medical Device ?
As per Title 21 of the Code of Federal Regulations (CFR)
“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:
(1) recognized in the official National Formulary, or the United States
Pharmacopeia, or any supplement to them,
(2) intended for use in the diagnosis of disease or other conditions, or in
the cure, mitigation, treatment, or prevention of disease, in man or
other animals, or
(3) intended to affect the structure or any function of the body of man or
other animals, and which does not achieve its primary intended
purposes through chemical action within or on the body of man or
other animals and which is not dependent upon being metabolized
for the achievement of its primary intended purposes.”
3

4. Whom to we reach out ?
• Center for Devices and
Radiological Health (CDRH)
• CBER has responsibility for
devices related to blood and
cellular products
What if our product is a combination product?
Office of Combination Product (OCP)
Let’s Think
4

5. What needs to be followed ?
21 CFR Parts General Topics
1-100 Administrative Issues and Protection of Human Subjects
100s Food (not covered in this chapter except for dietary supplements)
200s Labeling, CGMPs, Controlled Substances
300s Drugs for Human Use
500s Drugs for Animal Use
600s Biologics
700s Cosmetics
800s Medical Devices
1000-1400s Miscellaneous topics
• 21 CFR 807 Establishment Registration and Device Listing,
Premarket Notification
• 21 CFR 812 Investigational Device Exemptions
• 21 CFR 814 Premarket Approval
• 21 CFR 860 Medical Device Classification Procedures
5

6. Steps to market Medical Devices in US
Complete Establishment Registration and Device Listing
DFUF FURLS
Send Your Premarket Submission to the FDA and Interact with FDA Staff during Review
User Fees eCopy Administrative Filing Review Interactive Review Substantive Interaction
Prepare the Appropriate Information for the Premarket Submission
Design Controls Nonclinical Testing Clinical Evidence Labelling
Select the appropriate Premarket Submission type
PMA 510(k) De Novo HDE IDE
Classify the Device
Class I Class II Class III
6

7. Medical Devices Classification
Class Risk Examples
Safety / Effectiveness
Controls
Regulatory Pathway
I
Low
Tongue
depressor,
hospital
beds
General Controls
- With Exemption
- Without Exemption
Self Registration
Or
510(k)
II Medium
Absorbable
suture,
blood
pressure
cuffs
General controls
- With Exemption
- Without Exemption
Special controls
- With Exemption
- Without Exemption
• Most class II devices are approved
under a 510(k) pre-market
notification submission.
• Few devices of class II are approve
under PMA
• 10-15% devices require clinical
trial
III Highest
Implantable
pacemaker,
coronary
stent
General controls
Special controls
Pre-market authorization
Pre-market approval (PMA)
Almost all require clinical Data
Product Classification Database - Link
7

8. Can I Reclassify the Devices?
as per 21 CFR 860
Extensive scientific data requirement
Ensuring the agreement with originator who
clears the device via PMA
Threat of new entrants
In 2009, FDA initiated the “515 Program
Initiative” to facilitate reclassification for
pre amendment devices
8
Why we need to reclassified?

 Often, reduced information requirements
 Reduced variation/post approval activities
Let’s Think

9. Clarity about the class of medical device….?
513(g) Request for Designation
Cover Letter
A letter with a description of the device
User fee payment
Standard - $3,387 and Small Business - $1,694
Labeling
Timeline: 60 Days
9

10. What is Product Code?
• Three letter code
• Used by FDA to identify and track similar medical Devices
• Used by 510(k) submitters to search for a predicate
device(s)
10

11. What is General Control ?
• Quality Systems - QSR for manufacturing and
recordkeeping
• Requirements for issuing notices about repair
• Appropriate, truthful and non-misleading labeling,
advertising and promotional materials
• Adulteration / Misbranding
• Electronic Establishment Registration
• Electronic Device Listing
• Medical Device Reporting (MDR)
This needs to be followed for all medical device regardless
of classification of medical device
11

12. What is Special Control ?
This regulation is specific to
particular medical device
which is submitted for
approval
• FDA guidance documents
• Special labeling requirements
• Tracking of implantable devices
• Guidelines (e.g., Glove Manual)
• Mandatory Performance Standard
• Special Labeling
• Other actions the agency deems
necessary to assure safety and
effectiveness
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Like conditional approval with obligation
Let’s Think

13. Regulatory Pathways for Approval
• Investigational Device Exemption (IDE)
• Premarketing Approval (PMA)
• Humanitarian Device Exemption(HDE)
• Premarket Notification (PMN) - 510(k)
• De Novo
Have a Thought
 Investigational New Drug (IND)
 New Drug Application (NDA) - 505 (b)(1)
 Orphan drug designation
 Abbreviated New Drug Application (ANDA) - 505 (j)
 New Drug Application (NDA) 505 (b)(2)
13

14. What is IDE?
14
• 21 CFR 812
• IDE is a regulatory submission that permits clinical investigation
of devices
• Practically, FDA checks risk of study - not of device
Device Clinical
Study
Not Exempt
Significant
Risk (SR)
Review and
approved By
FDA
Full IDE
Not Significant
Risk (NSR)
Review and
Approved by
IRB
Abbreviated
IDE
Exempt
What is Q-submission?
What if you are not sure that your device is Exempted or SR or NSR?
Q-submission (Q-Sub)  Study Risk Determination
Let’s Think

15. What is PMA
• For Class III medical device
• Most stringent requirement
• Safety and efficacy data for
intended use
Types of PMA
▫ Traditional PMA
▫ Modular PMA
▫ Streamline PMA
▫ Product Development
Process (PDP)
15
Indication for use vs. Intended use
• Indication for Use = The clinical
condition it is intended to diagnose,
treat.
• Intended Use = a device’s effect on
the human body.
• Example – Laser
Intended use- Cut
Indication for use- Keratoplasty
(corneal sculpting)

16. Types of PMA
Traditional PMA
• 21 CFR 814.20(b)
• PMA filing criteria is a two step process-
acceptance review (15 days) and filing
review (45 days)
• GMP - FDA will inspection the
manufacturing site
• Outcomes - Approvable , Not Approvable,
Denial
• Timeline: 180 Days
Modular PMA
• Same content as traditional PMA
• Submit documents in different modular
stages (In agreement with FDA during pre-IDE
meetings )
• After final module submission, PMA number
is assigned
• Timeline: 90 Days for each module and 180
days after final module
• Advantage-
• Proper resources utilization
• Potentially reduces PMA review time
• Continues FDA and Sponsor communication
• Disadvantage -
• More Costly
• More Approval time
• Needs a prior plan for modular PMA before
reaching to FDA
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17. Types of PMA
Streamline PMA
• Used for well known technology
for well-known disease
processes
• Condition-
• Already 2-3 approved PMA of
similar type
• Study Protocol jointly develop
by FDA
• Timeline: 180 Days
• Note: GMP Inspection deferred
if FDA completed that within the
past two years.
Product Development Process (PDP)
• PDP is combination of IDE and
PMA (FD&C Act Section 515(f))
• Timeline: 120 days after
completion of clinical study
• Note: Currently not popular
17

18. Types of PMA Supplements
180-days supplement
• Introduce a major change in the design of the device or in
manufacturing or QC methods
• In Depth review
180-days panel track supplement
• Add a new indication for use (clinical data required)
Special PMA supplement Changes Being Effected (CBE)
• Used when the change enhances or increases the device’s
safety
• Example - labeling changes that add or strengthen a
contraindication, warning, precaution, or information about
an adverse reaction
18

19. PMA Supplements
30-Day Notice and 135-Day PMA Supplement
• Change the manufacturing procedures or methods
• If no response from FDA within 30 days – Accepted by FDA
• If FDA feels 30 days time is less then they notify the sponsor and convert it
to 135 days PMA supplement
Real-time supplement
• Minor modifications in design, software, sterilization, or labeling
• Prior approval from FDA
Annual (Periodic) Report or 30-Day Supplements
• Minor update
PMA Manufacturing Site Change Supplement
19

20. What is HDE
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Humanitarian Use Device (HUD) - Title 21 CFR 814.3(n)
• For treatment and diagnosis of disease or condition
that affects less than 4000/year
• Evaluate by Office of Orphan Products
Development (OOPD)
• No other comparable device available
Humanitarian Device Exemption (HDE) - Title 21 CFR 814.2
• Content is same as PMA, however exempted from effectiveness requirement
• FDA approval of HDE application - does not pose unreasonable risk and benefit
outweighs risk
• HDE label states - The device is a Humanitarian Use Device (Special Control)
• Checklist provided by FDA
• IRB Review: Initial Review and continuing Review (Renewal 1 Year)
• Timeline: Original and supplement/Amendment: 75 days (including 30 days for HUD)

21. HUD/HDE in Summary
21
• Title 21 CFR
814.3(n)
• Submit by Sponsor
• No other
comparable device
available
HUD Designation
Request
• Office of Orphan
Products Development
(OOPD)
• Timeline: 30 days
HUD Designation
Granted
• Title 21 CFR 814.2
• The HDE allows marketing
distribution for the HUD
• Timeline: 75 days
(including 30 days for HUD)
• HDE Checklist by FDA
HDE Application
and Approval
• Local IRB is oversee the
clinical introduction and
use of the device
• Initial Review and
continuing Review
(Renewal 1 Year)
IRB role after
FDA Approval
FDA HDE Database: Link
How much Market Exclusivity is given to
orphan Medical device?
Let’s Think
Unlike orphan drug, for medical device
used for orphan disease, have NO
market exclusivity

22. PMA vs. HDE
22
HDE PMA
Safety and benefit outweighs risk Safety and effectiveness
Rare (<4000 patients/year) General
Require HUD designation from
OOPD
Does not require HUD designation
from OOPD
Clinical data not absolutely required Yes
IRB approval required after approval
from FDA
(Initial and continuing Review)
No
Timeline: 75 Days Timeline: 180 days
No User Fee
User Fee:
Standard:$2,50,895
Small Business:$62,724
Some Profit limit
Annual Distribution Number (ADN)
No Profit limit as per market trend

23. What is 510(k)
23
• To demonstrate that a new or modified
device is SE “substantially equivalent”
in intended use, safety and
effectiveness as a “predicate device”
• SE = “Just as Safe and Just as Effective”
• Sponsor uses a recently cleared device
under 510(k) as a predicate device
• Multiple Predicate
• Split Predicate
Marketing Clearance Process for Class I
products, “most Class II” products and a small
number of Class III
What is Predicate, pre-
amendment and post-
amendment Devices
Let’s Think
Predicate Device -A device recently cleared
device under 510(k) mainly
May 28,
1976
Pre-
Amendment
Device
Post-
Amendment
Device
Devices which are approved

24. 510(k) – General information
24
Who must submit 510(k)
• Manufacturers
• Specifications Developers
• Repackagers who change device or its
labelling
• Relabelers who change the labelling- e.g.,
instructions for use
• Anyone who both manufactures &
distributes
Who is Not Required to Submit a 510(k)?
• Private Label Distributor
• Repackager who does not alter labeling
• Distributor or Importer who furthers
marketing of the legally marketed device
and does not alter labeling or change
device
When to submit the 510(k)
• Introducing a device to the market
for the first time
• Changing the indications for use of
a previously cleared device
• Making significant modification(s)
to a previously cleared device
Licensing of 510(k)s
A firm may not BOTH manufacture
and distribute a device without
their own 510(k)

25. Types of 510(k)
25
• 21 CFR 807
• Used for any original 510(k) or for a modification to a previously cleared
device under 510(k)
• May be used under any circumstance
Traditional
510(k)
• Device manufacturers may choose to submit an Abbreviated 510(k)
when:
• a guidance document exists,
• a special control has been established, or
• FDA has recognized a relevant consensus standard
Abbreviated
510(k)
• Use of Design Controls or Quality System Regulation to assure SE for
device modifications
• May be submitted for a modification to a device [no affect on intended
use or alter the fundamental scientific technology]
• Special 510(k): Device Modification - Basis for approval - Design
Control
• No data is evaluated by FDA (Declaration of Conformity –
Conformance Assurance)
• Example – Change in environmental specifications, performance
specifications, ergonomics of the patient-user interface, dimensional
specifications, software or firmware
Special
510(k)

26. 510(k) Submission Process
26
What is 510(k) number or
“k-number”
6 digit - “KXXZZZZ”
Let’s Think
Sponsor
prepare
510(k)
Applicati
on
Submit to
CDRH
Document
Control
Centre
(DCC)
Assigned a
unique
number
i.e.
k-number
DCC
checks
User Fee
Valid
eCopy
Hold Letter
Or
Acknowled
gment
Letter
Acceptance
Review
RTA
Substantive
Review
(Substantive
interaction
and
interactive
Review)
• Evaluated by Office of Device
Evaluation (ODE) or Office of In Vitro
Diagnostics and Radiological Health
(OIR)
• Hold Letter issued by FDA within 7
days of submission and given 180
days to resolve the deficiency
otherwise submission will be deleted
and new submission require
Where, K= 510(K)
XX= year of submission
ZZZZ= Sequence Number
Example: K150012

27. 510(k) Submission Process
27
By Day 90
FDA sends final MOUFA Decision on 510(k).
By Day 60
FDA conducts Substantive Review
1. Substantive Interaction (Review clock will not stop)
2.Additional information (Review clock will stop)
By Day 15
FDA conduct Acceptance Review
FDA inform to submitted if application is accepted for substantive review

28. 510(k) Decision
28
510(k)
Documents
510(k)
Decision
Substantive equivalent
(SE) Letter
• Indications for Use Form
• 510(k) Summary or
510(k) Statement
Publically Available on FDA Website
Not Substantive equivalent
(NSE) Letter

29. PMA vs. 510 (k)
29
PMA 510 (k)
Safety and efficacy Substantial equivalent
Medical Device Classes: III Medical Device Classes: I, II, some III
Scientific evidence Comparison with predicate device
Always clinical data require 10-15% Application require clinical data
Detailed lengthy Application Short
Approved Clearance
Timeline: 180 days Timeline: Traditional and Abbreviated: 90 Days
Special 510(k): 30 Days
Pre Approval inspection No pre approval inspection
Post marketing activities (Supplements)
require
No post marketing activity
Not easy to replicate Easy to replicate
Advisory panel review required but not for all
PMA
Rare advisory panel review
User Fee: Standard:$2,50,895
Small Business:$62,724
User Fee: Standard: $5018
Small Business:$2509

30. 510(k) Decision
30
510(k)
Documents
510(k)
Decision
Substantive equivalent
(SE) Letter
Not Substantive equivalent
(NSE) Letter• No predicate device
• Device has a NEW
intended use or used a
different technology
• Device is not as safe
and effective as the
predicate
New 510(k)
Or
PMA
Or
Reclassification
Petition
or
Other submission
pathway???

31. What is De Novo Pathway
31
Problem
New Device definition explained in 513(f)(1)
 Post-amendment devices
 a device not equivalent to a Class I or II device is
classified as Class III
If No Predicate device  PMA
Solution De Novo Submission
• Less risk devices for which predicate device is not available
• This process called as “Evaluation of Automatic Class III Designation”
• Timeline: 120 Days
• After granting de novo application -
• New Device is Legally Marketed
• FDA generates “classification order” and “decision summary” that is publicly
available
• Now this can be used as predicate for future submission
FDA De Novo Database: Link

32. De Novo Process Type
32
Submission identification: 510(k) and DEN Numbers DEN Numbers
What is DEN Number
“DENXXZZZZ”
DEN = de novo
XX= year of submission
ZZZZ= submission increments from 0001
Let’s Think

33. Establishment Registration and Device Listing
Device Facility User
Fee (DFUF)
•Payment Identification
Number (PIN)
•Payment Confirmation
Number (PCN)
FDA’s Unified
Registration and
Listing System
(FURLS)
Establishment
Registration
Device Listing
33

34. Does this fill our bucket…?
34

35. 35

36. What’s Next
36
• GHTF-STED/ Technical file / Design dossier?
• eCopy – Volume based and Non-Volume based
• Document requirement for PMA, 510(k), De Novo,
HDE, IDE pathway
• Design control
• MDUFA III and features
• Medical Device Labelling
• Medical Device Tracking
• Quality System Regulation (QRS)
• Medical Device Reporting
• Regulation of medical device in EU

37. 37
Thank you