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Replacement Reagent PolicyUpdate

DATA FOR COMMERCIALIZATION OF ORIGINAL EQUIPMENT MANUFACTURER, SECONDARY and

GENERIC REAGENTS FOR AUTOMATED ANALYZERS issued 6/10/96

Jim Callaghan

April 22, 2003

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Replacement Reagent Policy

• Well characterized clinical laboratory testing systems intended for use by clinical laboratory professionals.

• Previously cleared instruments and reagents, when a claim is made for a new reagent/instrument combination.

• Introduction of new instrument family members of a previously cleared instrument family.

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• Each reagent/instrument combination, or new instrument family member normally requires a 510(k).

• A different process was developed utilizing existing 510(k) notification procedures to handle the potential for numerous submissions.

Reason for Policy

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Rationale Behind The Policy

• There are sufficient controls for these types of claims and test system modifications when an acceptable test system validation protocol is in place.

• “Add-to-file” is an appropriate vehicle to convey device modification information to the FDA and comply with the 510(k) regulatory process.

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Replacement Reagent Policy

• Changes since the policy was first implemented, such as:

– Quality Systems Regulation (QSR)

– Special 510(k)

– FDAMA

– Clinical Laboratory Improvement Amendments (CLIA) to FDA.

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Replacement Reagent Policy

• The RR-policy did not and does not apply to:

– class III devices– devices intended for use in support of blood

banking practices – systems intended for over-the-counter (OTC)

use– exempt general purpose reagents.

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Replacement Reagent Policy

• Consult with the appropriate branch chief on eligibility for assays that could have serious health risks associated with their use.

• SPECIAL 510(k) – like the Special 510k the RR-Policy is intended for modifications to a previously cleared device.

• Use the Special 510(k), when the modified test system does not meet acceptance criteria of the validation protocol.

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REAGENTS

• REAGENTS - necessary substances that produce reactions allowing an analyte to be measured.– Includes calibrator and quality control material.

• GENERIC reagents - are intended to be used manually, or with any open system. – Laboratories assume responsibility for

performance validation.

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REAGENTS

• OEM reagents - analyzer manufacturer’s reagents specifically for their analyzers.

• REPLACEMENT reagents - Generic reagents produced for use with specified analyzers by suppliers other than an OEM supplier.– Replacement reagents may be marketed and

labeled for one specific analyzer or may claim multiple analyzers.

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ANALYZERS

• Closed Systems - analyzers and OEM reagents provided by the same manufacturer and are configured only to be used in combination with each other.

• Open Systems - analyzers manufactured with general-purpose features for use only with "replacement or generic reagents".

• Partially Closed System - is a combination of the above

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ANALYZERS

• Device Family - a group of one or more devices manufactured by or for the same manufacturer and having the same:– Basic design and performance characteristics

related to device safety and effectiveness, that share a common Design History File (DHF)

– Intended use and function– Device classification and product code.

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LABELING

• Operator Manual - labeling accompanying instrument for operating instructions.

• Package Insert - reagent labeling which may give instructions and also refer to an operator manual for detailed instruction.

• Application Sheet – typically contains analyzer settings, volumes, and parameters to assist laboratories in implementing use of secondary reagents with a specified open analyzer system.

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OTHER DEFINITIONS

• TEST SYSTEM – is comprised of all test components required to perform an in vitro diagnostic test, i.e. clinical laboratory analyzer, reagents, calibrators and controls.

• ADD-TO-FILE – notification to the original file of validation protocols and intent to introduce a reagent on a specific analyzer, or introduce an new instrument family member based on passing acceptance criteria in the protocol.

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Equivalent Specifications • The original policy required the analyzer

to be cleared for each analyte prior to a replacement reagent claim.

• Use on an analyzer requires the analyzer to have the capability to run the method the assay utilizes.

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Clarifications

• Class I instruments –Class I devices such as many of these analyzers, are exempt from 510(k).

• These analyzers are not exempt, when an analytical claim is made for a class I reserved device, by virtue of the limitations to exemptions under 862.9, 864.9…, or a class II device.

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Clarifications

• These test systems are considered combination devices "Guidance on the CDRH Premarket Notification Review Program 6/30/86 – Blue Book Memo (K86-3)" http://www.fda.gov/cdrh/k863.html.

• When any of these analyzers are regulated as a combination device, the accessory is classified in the highest of the predicate device classifications of the system combination.

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Clarifications

• When a replacement reagent claims use on an open system, the analyzer needs to have a previous 510(k) clearance.

• We ask that the reagent manufacturer have the instrument manufacturer submit a 510(k) for the instrument with a non-exempt reagent.

• The analyzer manufacturer can use any cleared reagent or can jointly seek clearance for a new reagent along with the instrument.

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Validation Protocols

• All studies listed in the table need to be addressed in the protocol submitted to the FDA.

• If a study is not applicable, a justification needs to be provided on why the study is not necessary.

• Protocols are accepted based on one-on-one with the reviewer and may need to be modified.– Some higher risk assays may require some sort of data.

• Method comparison, precision, reference range; etc…

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Reagent / Instrument Validation Protocols

• Reagents protocols are assay specific.

• Instrument protocols are method specific.

• Protocols are based on studies performed in the original submission.

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Reagent / Instrument Validation Protocols

• Both replacement reagent and new family member protocols need predefined acceptance criteria.– Criteria for replacement reagents should be assay

specific, designed to challenge the performance characteristics.

– Criteria for the introduction of a new family member should be method specific, general enough to evaluate all analytes within each method, and designed to challenge the performance characteristics.

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Software Validation Protocol

• CDRH is concerned that software controlled medical devices introduced into the market are manufactured under well-developed software lifecycle processes.

• The software documentation in the original family clearance serves new family member software validation protocol and should be certified to.

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Software Validation Protocol

• In order to certify to this protocol you need to ensure your documentation on file is current

• “Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices “ (May 29, 1998): http://www.fda.gov/cdrh/ode/57.html

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Process

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Replacement Reagent Process

• Use the “Add-to-file” process and submit your protocol after you receive your primary clearance.

• After your protocol is accepted, notify FDA after each analyzer has been validated according to the accepted protocol.

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• This notification should include a statement that “abc” replacement reagent has been validated on the “XYZ” open system analyzer using the described protocol in K######/A### submitted on mm/dd/yyyy.

• The notification should also include any application sheets or specific labeling for the associated analyzer.

Replacement Reagent Process

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New Family Member Process

• Submit Protocol for all methods to allow the roll over of reagents to the new family member.

• Validate your new instrument family member.

• Notify FDA of your intent to market your new instrument family member you validated.

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New Family Member Process

• This notification should include a statement that “abc” instrument family member has been validated using the method and software protocols in K######/A### submitted mm/dd/yyyy.

• Include a list of all associated reagents and 510(k) numbers intended to be rolled over onto the analyzer.

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New Family Member Process

• Enough details on the analyzer so FDA can concur with your family member designation.

• These processes can be followed in one notification for the original 510(k), a Special 510(k) or an “Add‑to‑file”.

– issues may come up with protocols

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New Reagents For Family Members

• Traditional 510(k) on a representative Family member analyzer.

• Assay specific protocol for this new reagent on the family member instruments.

• Declare validation for all appropriate family members.

• Have all the processes complete at the time of submission in order to introduce the new reagent on all family members.

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CLIA Categorization

• All new test system combinations are usually based on historical information pertaining to the instrument on which the test system is dependent, or on past family member categorizations.

• However, it is important that all variables are considered in categorizing a new test system.

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• Notifications will need labeling in sufficient detail to determine categorization.

– Replacement reagents require a package insert.– New family member require instructions for use

such as an abbreviated operators manual.

CLIA Categorization

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