1. Regulatory approval process
for In vitro Diagnostics in US
FACILITATED BY:
Dr M.P. VENKATESH
Assistant Professor
Dept. of Pharmaceutics
Regulatory Affairs Group
JSSCP
MYSURU
Presented by:
Vinod Raj.k
I.M.Pharm
Regulatory Affairs group
JSSCP
MYSURU
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2. Definition:
•In vitro diagnostic products are those reagents, instruments, and systems
intended for use in diagnosis of disease or other conditions, including a
determination of the state of health, in order to cure, mitigate, treat, or
prevent disease or its sequelae.
•Such products are intended for use in the collection, preparation, and
examination of specimens taken from the human body.
•In the US, IVDs are defined under 21 CFR 809 and are regulated under
guidelines similar to medical devices.
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3. How In Vitro Diagnostic’s are classified?
FDA classifies IVD products into Class I, II, or III according to the level of
regulatory control that is necessary to assure safety and effectiveness. The
classification of an IVD (or other medical device) determines the appropriate
premarket process.
It’s Classified As
•Class I
•Class II
•Class III
The Code of Federal Regulations lists the classification of existing IVDs in 21
CFR 862, 21 CFR 864, and 21 CFR 866.
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4. Classification Level of risk Controls Examples
Class 1 Low to moderate
risk
General controls Complement
reagent, phosphorus
(inorganic) test
systems
• E. coli serological
reagent
Class 2 Moderate to high
risk
General controls
and
special controls
• Immunological
test system
• Glucose test
system
• Coagulation
Instruments
Class 3 High risk General controls
and PMA
(premarket
approval)
• Automated PAP
smear readers
• Nucleic Acid
Amplification
devices for
Tuberculosis
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5. Regulatory Pathway:
Diverse paths for obtaining US FDA approval:
•For the Class I devices that are the subject of the guidance document, FDA
intends to propose an amendment to the classification regulations to exempt
these devices from 510(k) requirements that currently apply.
•While FDA proposes and finalizes these down classifications and
exemptions, it will exercise enforcement discretion with regard to 510(k)
submission requirements for the relevant devices.
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6. The devices subject to enforcement discretion includes the following:
• Clinical chemistry devices, such as iron (non-heme) test systems, breath-
alcohol test systems, and others;
• Hematology devices, such as platelet-adhesion tests, euglobulin lysis time
tests, and others;
• Immunology and microbiology devices, which include hemoglobin
immunological test systems.
Contd….
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7. •For US Market approval, there are several factors other than classification that
influence the process for regulatory approvals .
• If the new test can be shown to be substantially equivalent to an existing
device which is considered as predicate device, then the 510(k) is the
regulatory path for approval.
•If new diagnostic technology cannot be considered substantially equivalent to
an existing technology, and will be used to make a critical medical decision
concerning the diagnosis, treatment, or medical management, then the
premarket approval (PMA) is the regulatory path of choice.
Contd…
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8. • If no predicate device exists and the test is of low or moderate risk, it may
be eligible for a de novo reclassification.
• If the test is done “in house,” in the designated laboratory only, for a patient
sample that is sent to the laboratory from an outside physician’s office or
medical facility, then the test can be potentially marketed under “home brew”
guidelines (also known as laboratory developed tests) regulated under the
Clinical Laboratory Improvement Amendments (CLIA).
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Contd…

9. What is a Premarket Notification [510(k)]?
•A 510(k) is a premarketing submission made to FDA to demonstrate that the
device to be marketed is as safe and effective, that is, substantially equivalent
(SE), to a legally marketed device that is not subject to premarket approval
(PMA).
•Each person who wants to market Class I, II and some III devices intended for
human use in the U.S. must submit a 510(k) to FDA at least 90 days before
marketing unless the device is exempt from 510(k) requirements.
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10. •FDA reviews 510(k) submissions in a 90-day timeline. If there are
unaddressed scientific issues, the review scientists can ask for additional
information and put the submission temporarily on hold.
•If FDA finds the information provided by the sponsor meets the standard of
equivalency, the product is cleared for marketing in the United States. If FDA
finds that there is no predicate for the device, or that the new device does not
have equivalent performance to the identified predicate, then the device is
found not substantially equivalent.
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11. CLASS 1
CLASS 1
EXEMPT
CLASS 2
TRADITIONAL
510 K
CLASS 3
PREMARKET
APPLICATION
LOW RISK MODERATE RISK HIGH RISK
Device needs to show equivalence
to a legally marketed predicate
FDA
CLEARANCE
510(K) review
90 Days
Device need to
demonstrate
safety and effectiveness
FDA
APPRO
VAL
PMA review
180 days
De novo
510(K)
No
predicate
Device
need to
demonstrate
S &E
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A
P
P
R
O
V
A
L
P
R
O
C
E
S
S

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What are the Clinical Laboratory Improvement Amendments of 1988
(CLIA '88)?
•CLIA '88 establishes quality standards for laboratory testing and an
accreditation program for clinical laboratories.
•CLIA '88 requirements vary according to the technical complexity in the
testing process and risk of harm in reporting erroneous results. The regulations
established three categories of testing on the basis of the complexity of the
testing methodology: a) waived tests, b) tests of moderate complexity, and c)
tests of high complexity.
•Manufacturers apply for CLIA '88 categorization during the premarket
process.

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•Under CLIA, laboratories performing only waived tests are subject to
minimal regulation. Laboratories performing moderate or high complexity
tests are subject to specific laboratory standards governing certification,
personnel, proficiency testing, patient test management, quality assurance,
quality control, and inspections.
•De Novo Classification for IVD Devices
•Prior to the FDA Modernization Act of 1997 (FDAMA), all devices on the
market as of May 28, 1976 were classified according to their risk. Any device
that was not classified was automatically assigned to Class III, requiring a
premarket approval (PMA) application. A device could be moved out of
Class III only through a cumbersome reclassification process.

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•FDAMA amended Section 513(f) to provide a new mechanism for
classifying new Class III devices for which there is no predicate device. It
allows the recipient of an NSE (not substantially equivalent) letter to
request a risk-based classification determination to be made for the device.
•In some cases, this allows a manufacturer to use the De Novo process to
submit a 510(k) for a new IVD that would otherwise have to get to market
via the PMA process.

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What is a Premarket Approval (PMA)?
A PMA is an application submitted to FDA to request approval to market,
or continue marketing, a class III medical device.
PMA approval is based on scientific evidence providing a reasonable
assurance that the device is safe and effective for its intended use or uses. For
IVDs, there is a unique link between safety and effectiveness since the safety of
the device is not generally related to contact between the device and patient.
For IVD products, the safety of the device relates to the impact of the device's
performance, and in particular on the impact of false negative and false positive
results, on patient health.

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•FDA reviews PMA submissions in a 180-day timeline. If there are unaddressed
scientific issues, the review scientists can ask for additional information and put
the submission temporarily on hold. If a product is a first of a kind, or if it
presents unusual issues of safety and effectiveness, it is generally reviewed
before it is approved by an advisory panel of outside experts.
•If FDA finds that a product is safe and effective, it receives an official
approval order for marketing in the United States. If FDA finds that a product
is not safe and effective, it may be non-approved.

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Limitations to FDA Review
There are several limitations to FDA's review of PMA applications:
•Lack of a "gold standard" against which to judge performance;
•Bias may occur in the collection of data to establish safety and
effectiveness, through problems in the study design or conduct;
•It can be challenging to determine the minimum performance required for
approval.

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What are the Requirements for IVD Labeling?
In Vitro Diagnostic Products have special labeling requirements under 21
CFR 809, Subpart B, In Vitro Diagnostic Products for Human Use. Before a
manufacturer obtains clearance or approval for an IVD product, they must
label the product in accordance with labeling regulations.

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References:
•http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidanc
e/IVDRegulatoryAssistance/ucm123682.htm
•http://www.uleduneering.com/fileadmin/user/Resource_Center/M
DRS/White%20Papers/Regulatory%20Path%20For%20IVD.pdf
•http://www.fda.gov/MedicalDevices/DeviceRegulationandGui
dance/IVDRegulatoryAssistance/ucm123682.htm

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