Replacement Reagent Policy Update

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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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Reason for Policy

• 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.

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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 manufacturers 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

• Method comparison, precision, reference range
  etc

• 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.

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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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Replacement Reagent Process

• 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.

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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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CLIA Categorization

• 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.

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Questions