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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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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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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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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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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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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•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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• 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…

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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•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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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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