Device World:
The Basics
SR and NSR Determinations
Expanded Access
Susie Hoffman
University of Virginia
Margaret Foster Riley, J.D.
University of Virginia, School of Law, School of
Medicine, Batten School of Leadership and
Public Policy
2
Definition of Device §201(h)
• “an instrument, apparatus, implement, machine,
contrivance, implant, in vitro reagent, or other
similar or related article, including any
component, part or accessory, which is
▫ …(2)intended for use in the diagnosis of disease or
other conditions, or in the cure, mitigation,
treatment or prevention of disease
3
Definition of Device §201(h)
• “(3)intended to affect the structure or 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 animlas and which is not
dependent upon being metabolized to achieve its
primary intended purposes”
4
Medical Devices
• Vast number
▫ Tongue depressor, stethoscope, stents that hold
blood vessels open
• Vary in complexity and risk as well as benefit
• Characterized by “on the spot” innovation
• FDA interprets the statute broadly and claims
authority over many articles that may not seem
to be devices: e.g. reagents for assays, genetic
tests and software (even maybe medical records)
5
Line between device and drug not clear
• Saline
• Contrast imaging agents
▫ Can be either but must treat them consistently
• Combination products
▫ E.g. Clot busting stents
▫ Office of combination products at FDA
Devices are Different
• Not just in “substance” but in regulation
• Different pathways (different statutory roots)
• Devices can be confusing because there are a
number of different types of “risk assessment”—
need to be clear on what question is being asked
Three Classifications based on Risk
▫ I bedpans, crutches,
▫ II blood pressure cuffs, catheters, wheelchairs,
heating pads, and x-ray film processing machines
▫ III defibrillators, heart valves, and implanted
cerebral stimulators
Marketing Pathways for New Devices
• New and novel automatically class III; go through
PMA (device analog to drug NDA) process unless they
are reclassified
• New and not novel—enters the market as
“substantially equivalent”—inherits the classification
status of the device that it emulates-- “the 510k
process”
510(k) process: The new and not novel
• This is a notification process, not an approval
process
• A positive response to a 510k application is a
“clearance”—FDA makes no representation that
the device is “safe and effective for its intended
use(s).”
• 98% of all post-1976 devices have entered the
market through this mechanism
Substantial Equivalence
• Must have same intended use as a predicate
device.
• “Piggy backing” now codified—substantially
equivalent to a device that was substantially
equivalent to a pre-1976 device
Investigational Devices
• IDE similar to IND for drugs, except not all IDEs
require FDA approval
• If pose no significant risk, just require IRB
approval—IRB makes that determination
Significant Risk/NonSignificant Risk Determinations
What is Significant Risk?
• Is intended as an implant and presents a potential for
serious risk to the health, safety, or welfare of a subject;
• Is purported or represented to be for a use in supporting
or sustaining human life and presents a potential for
serious risk to the health, safety, or welfare of a subject;
• Is for a use of substantial importance in diagnosing,
curing, mitigating, or treating disease, or otherwise
preventing impairment of human health and presents a
potential for serious risk to the health, safety, or welfare
of a subject; or
• Otherwise presents a potential for serious risk to the
health, safety, or welfare of a subject. (21 CFR 812.3(m))
Likely Significant Risk (SR) devices
• Many devices that are obviously SR will be
submitted to FDA for IDE approval
▫ Most of those devices are submitted to IRB review
after FDA has made that determination
▫ An SR device must meet all FDA IDE regulations
and must have FDA approval before enrolling
• IRBs do not have to make the SR or NSR
determination if FDA has already made the risk
determination.
▫ IRB role is then to confirm the issuance of the IDE
Likely Non-Significant Risk (NSR)
Devices
• Here the sponsor does not need to submit to
FDA and FDA leaves the determination to the
IRB
▫ In most of these cases, FDA will have no role in
the risk determination—and will not even be
aware of the study
IDE Exempt
• If using an investigational device in research
must first determine if the device is exempt from
IDE regulations.
IDE Exempt Devices
• Consumer preference testing
• Testing of a device modification
• Testing of two or more devices in commercial
distribution if the testing does not collect safety or
effectiveness data, or put subjects at risk.
• Studies of an already cleared medical device in
which the device is used or investigated in
accordance with the indications in the cleared
labeling
▫ If the study is looking at a new use, it is not exempt
IDE Exempt Devices
• A diagnostic device if the testing:
 Is noninvasive
 Does not require an invasive sampling
procedure that presents significant risk
 Does not by design or intention introduce energy
into a subject AND
 Is not used as a diagnostic procedure without
confirmation by another medically established
diagnostic product or procedure.
Not Exempt?
• If a device is determined to NOT be exempt from
an IDE, the full IRB must determine if the device
meets the criteria of Significant Risk
• Exempt from IDE requirements does not mean
that the device study is exempt from other
IRB/FDA requirements for clinical research
study
IRB Considerations of NSR
Determination
• The sponsor’s description of why the study is not SR
• Whether the proposed NSR research study meets
the definition of “significant risk”
▫ The proposed use of the device as well as any protocol
related procedures and tests, not just the device (test
article) alone. (This process is different and separate
from the typical IRB review of risk)
▫ Whether the subject will undergo additional
procedures
• Additional information from the sponsor, if needed.
•
Significant Risk Criteria (Review)
▫ A device that presents a potential for serious
risk to the health, safety, or welfare of a subject
AND:
 Is intended as an implant or
 Is used in supporting or sustaining human life or
 Is for use of substantial importance in diagnosing,
curing, mitigating or treating disease, or otherwise
prevents impairment of human health: or
 Otherwise presents a potential for serious risk to the
health, safety, or welfare of a subject.
Sometimes Examples provide the Most
Insight NSR:
•
http://www.fda.gov/downloads/regulatoryinformation/guida
nces/ucm126418.pdf
▫ Conventional Gastroenterology and Urology Endoscopes
and/or Accessories
▫ Conventional General Hospital Catheters (long-term
percutaneous, implanted, subcutaneous and intravascular)
▫ Conventional Implantable Vascular Access Devices (Ports)
▫ Digital Mammography
▫ Externally Worn Monitors for Insulin Reactions
▫ Urethral Occlusion Device for less than 14 days
Sometimes Examples provide the Most
Insight--SR
•
http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126418.pdf
▫ Catheters for General Hospital Use - except for conventional long-term
percutaneous, implanted, subcutaneous and intravascular
▫ Collagen Implant Material for use in ear, nose and throat, orthopedics, plastic
surgery, urological and dental applications
▫ Aortic and Mitral Valvuloplasty Catheters
▫ Organ Storage/Transport Units
▫ Cochlear Implants
▫ Biliary Stents
▫ Electrical Stimulation Devices for sperm collection
▫ Antepartum Home Monitors for Non-Stress Tests
▫ Cervical Caps
▫ Condoms (for men) made from new materials (e.g., polyurethane)
▫ Contraceptive In Vitro Diagnostics (IVDs)
▫ Computer Guided Robotic Surgery
Effect of Decision
• NSR
▫ If the device does not meet the criteria of
Significant Risk, then is by default a NonSignificant Risk Device
▫ Do not need IDE from FDA to enroll subjects
• SR
▫ Must have IDE from FDA prior to enrolling
subjects
Expanded Access
From FDA website:
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/H
owtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm05134
5.htm#treatmentuse
Ways to Access an
Investigational Device for
Clinical Care
•Compassionate Use
•Emergency Use
•Treatment Use
•Continued Access
•* Humanitarian Use
Device Summary Table- see handout
Background
Clinical Care:
Compassionate
Use
Clinical Care:
Emergency Use
Clinical Care:
Humanitarian
Use
Clinical Care:
Emergency or
Off Label Use
of an HUD
Clinical Care:
Treatment Use
Clinical Care:
Continued
Access
Research
Use for patient or
small group who do
not meet protocol
inclusion criteria.
Treating physician
feels device will help
patient(s).
Allowed before or
during a clinical trial
Subject does not meet
inclusion criteria,
clinical trial is not
open at the
institution, life
threatening situation
and no time to get
IRB approval
Allowed before or
after start of clinical
trial
May only use as
emergency use one
time at each
institution- then
must have a
compassionate use
protocol.
Within 5 days of use
submit notification to
IRB.
Sponsor cannot
submit data as part of
an FDA application.
No- but use must be
reviewed by full
board AFTER USE.
No
Device that would
be used in less than
4000 patients
/year in the US. (
Orphan Device)
If use meets
criteria for
emergency use
see Emergency
Use column.
Provides access to
investigational
devices early in
development
process.
Allowed during a
clinical trial
Allows patients
access to device
after clinical trials
are completedawaiting FDA
approval.
Use of an
investigational
device for research
purposes
For patients with
serious or life
threatening
condition- may
receive outside of a
clinical trial.
Sponsor must
obtain a Treatment
use IDE from FDA.
May use outside
IRB.
IRB must
determine if device
is exempt from
IDE regulations. If
not exempt, must
determine if device
is significant risk.
Yes
Yes
Yes
No, but for offlabel use, need
some type of plan
of methods to
protect patient.
Yes, may use
sponsors
template.
Yes- submit
sponsors protocol
only
Yes-submit
sponsors protocol
only
Yes- may submit
per local protocol
template or
sponsors protocol
YES- use local
research template
to develop consent
Yes-may use local
research template
or one approved
by outside IRB.
No
Initial – Full
Board
ContinuationsExpedited
IRB Assurance
Form
Yes
Full Board
Yes
Full Board
Yes-use local
research template
to develop consent
unless waiver
approved
Yes
Full Board
IRB Assurance
Form
IRB Assurance
Form
IRB Assurance
Form
Other Issues
Must first identify
patient, then sponsor
submits IDE
application to FDA,
then submit
application to IRB.
Considered
Research?
No- however FDA
requires an IDE# and
IRB Concurrence
Yes-submit sponsors
protocol only
Protocol
Called:
Humanitarian Use
Device (HUD)
OR Humanitarian
Device Exemption
(HDE)
Sponsor must have
HDE designation
from FDA.
No, however IRB
review required.
No, but need to
submit
Investigators
Brochure
Consent
Yes-submit and use
sponsors consent
Yes-use sponsors
consent if patient able
to consent.
No- may provide
patient with
product
information
Training
Review Type
No
IRB Chair only
No
Full Board- AFTER
use
No
Initial – Full Board
ContinuationsExpedited
Response
Letter of Concurrence
from IRB Chair
Letter of Concurrence
from IRB
IRB Assurance
Form
Off label use:
Follow same
criteria as
Humanitarian
Use.
For Off Label Use
FDA recommends
patient sign a
consent form and
that the PI has a
plan to protect
the patient.
PI should submit
summary report
to IRB following
the use. Must
report AE's to
IRB.
No, however IRB
review required.
Clinical Care: Compassionate Use
Back
ground
Other
issues
Research?
Protocol
Consent
Training
Review
Type
Response
Use for
patient or
small group
who do not
meet protocol
inclusion
criteria.
Treating
physician
feels device
will help
patient(s).
Allowed
before or
during a
clinical trial.
Must first
identify
patient,
then
sponsor
submits
IDE
applicatio
n to FDA,
then
submit
applicatio
n to IRB.
No- however
FDA
requires an
IDE# and
IRB
Concurrence
Yessubmit
sponsors
protocol
only
Yessubmit
and use
sponsors
consent
No
IRB
Chair
only
Letter of
Concurren
ce from
IRB Chair
Clinical Care: Emergency Use
Back
Ground
Other Issues
Research?
Protocol
Consent
Training
Review
Type
Response
Subject does
not meet
inclusion
criteria,
clinical trial is
not open at
the
institution,
life
threatening
situation and
no time to get
IRB approval
Allowed
before or
after start of
clinical trial
May only use as
emergency use
one time at each
institutionthen must have
a
compassionate
use protocol.
Within 5 days of
use submit
notification to
IRB.
Sponsor cannot
submit data as
part of an FDA
application.
No- but
use must
be
reviewed
by full
board
AFTER
USE.
No
Yes-use
sponsor
s
consent
if
patient
able to
consent
No
Full
BoardAFTER
use
Letter of
Concurre
nce from
IRB
Clinical Care: Treatment Use
Background
Other Issues
Research?
Protocol
Consent
Training
Review
Type
Response
Provides
access to
investigation
al devices
early in
development
process.
Allowed
during a
clinical trial
For patients
with serious or
life threatening
condition- may
receive outside
of a clinical
trial.
Sponsor must
obtain a
Treatment use
IDE from FDA.
Different from
Compassionate
Use: do not
need to identify
patient before
IRB approval.
Yes
Yessubmit
sponsors
protocol
only
YES- use
local
research
template
to
develop
consent
Yes
Full
Board
IRB
Assurance
Form
Clinical Care: Continued Access
Background
Other
Issues
Research?
Protocol
Consent
Training
Review
Type
Response
Allows
patients
access to
device after
clinical trials
are
completedawaiting
FDA
approval.
May use
outside
IRB.
Yes
Yessubmit
sponsors
protocol
only
Yes-may
use local
research
template
or one
approved
by outside
IRB.
Yes
Full Board
IRB
Assurance
Form
Differenc
e between
Treatmen
t Use :
does not
have to be
life
threateni
ng or
serious
disease.
Clinical Care: Humanitarian Use
Background
Other
Issues
Research?
Protocol
Consent
Training
Review
Type
Response
Device that
would be
used in less
than 4000
patients
/year in the
US.
( Orphan
Device)
Called:
Humanitarian
Use Device
(HUD)
OR
Humanitarian
Device
Exemption
(HDE)
Sponsor must
have HDE
designation
from FDA.
No,
however
IRB review
required.
No, but
need to
submit
Investiga
tors
Brochure
No- may
provide
patient
with
product
informatio
n
No
Initial –
Full
Board
Continuat
ionsExpedited
IRB
Assurance
Form
Clinical Care: Emergency Use or Off
Label Use of an HUD
Background
Other
Issues
Research
?
Protocol
Consent
Training
Review Type
Response
If use meets
criteria for
emergency
use- see
Emergency
Use column.
For Off
Label Use
FDA
recommends
patient sign
a consent
form and
that the PI
has a plan to
protect the
patient.
PI should
submit
summary
report to
IRB
following the
use. Must
report AE's
to IRB.
No,
however
IRB
review
required.
No, but
for offlabel use,
need
some type
of plan of
methods
to protect
patient.
Yes, may
use
sponsors
template.
No
Initial – Full
Board
Continuatio
nsExpedited
IRB
Assurance
Form
Off label use:
Follow same
criteria as
Humanitarian
Use.
Research
Background
Other
Issues
Research
?
Protocol
Consent
Training
Review
Type
Response
Use of an
investigational
device for
research
purposes
IRB must
determine
if device is
exempt
from IDE
regulations.
If not
exempt,
must
determine
if device is
significant
risk.
Yes
Yes- may
submit
per local
protocol
template
or
sponsors
protocol
Yes-use
local
research
template
to
develop
consent
unless
waiver
approved
Yes
Full Board
IRB
Assurance
Form
Device Review Decision Tree
Yes: FDA Regs apply
Does this study involve the clinical investigation to determine
the safety and effectiveness of a device?
( e.g. – Are you evaluating the device for safety and efficacy? )
No: FDA Regs
DO NOT apply
Is study exempt from IDE Regulations
?
Answer NO if an In-vitro diagnostic
device.
Is the device a Research Use
Only Device (RUO)?
No
Yes
NO
Yes
Does the device being used have
FDA approval for any indication?
Will results be
used to
diagnose or
treat subjects?
Yes
Do all other procedures fit
under an expedited criteria
NO
To Full Board for Review. As expedited
criteria # 4 not applicable. DO NOT use
Expedited Criteria # 1 as the device is not
being evaluated therefore FDA regulations
do not apply.
Is study minimal
risk?
NOTE: FB does NOT determine SR/NSR
status but may determine if protocol is
minimal risk, therefore allowing future
continuations to be expedited via category #
9.
Category # 9: Continuing review of
research, not conducted under an
investigational new drug application or
investigational device exemption where
categories (2) through (8) do not apply but
the IRB has determined and documented at
a convened full IRB meeting that the
research involves no greater than minimal
risk and no additional risks have been
identified.
Do all other procedures fit
under an expedited
criteria?
Yes
Expedite
under category
# 4 and any
other
applicable
categories.
(RUO devices
not considered
a medical
device.)
Will other procedures
require study to be
reviewed by full board?
(e.g all procedures do not
fit under expedited
criteria or study is not
minimal risk )
No
Yes
NO
No
No
Yes
NO
Yes
Is study minimal
risk?
No
Yes
YES
NO
Is the device an in-vitro diagnostic
device?
Yes
To Full Board
for Review
NOTE: FB
does NOT
determine
SR/NSR
status
Expedite
under
category # 1
Study Involves Device: Overall
Summary
Use only/No evaluation of device: FDA
regulations do NOT apply: expedited via
category # 4
Evaluation of Device- FDA regulations
DO apply- If device exempt from IDE
regulations or NSR and protocol may
otherwise be reviewed by expedited
review procedures expedite via category
# 1.
Send full
protocol to
IRB for
review.
Send study to full
board to make
SR/NSR
Determination.
NSR
Full Board
determines study is
NSR- Expedite
review of protocol
under cat# 1.
Send protocol to
full board for
review and
SR/NSR
Determination
SR
Full Board
determines study is
SR: Full Board to
review protocol .
DO NOT expedite
review of protocol.