# Presentation: 313816

## Replacement Reagent and Instrument Family Policy issued on: December 11, 2003 

*	*

- The Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)
- Presented by
- James V. Callaghan

## The Replacement Reagent and Instrument Family Policy (RR-Policy)

**supersedes**
- 	“Data for Commercialization of Original Equipment Manufacturers (OEM), Secondary and Generic Reagents for Automated Analyzers,” issued June 10, 1996.

## RR-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.

## Validating and documenting changes to cleared test systems that do not significantly affect the safety and effectiveness of the device.
This guidance document addresses only previously cleared reagents and instruments. 

- This guidance document addresses only previously cleared reagents and instruments.

- RR-Policy

## RR-Policy

- Adding either a cleared reagent to a previously cleared instrument, or a new instrument family member to a previously cleared instrument family.
- Alternative approach to meeting the 510(k) requirements for changes in an existing device.
- Proper validation to demonstrate these types of changes do not significantly affect the safety and effectiveness of cleared devices.

## RR-Policy

- By evaluating your modified device against predefined acceptance criteria using a proper validation protocol, you establish sufficient control for assuring the safety and effectiveness for minor device modifications.
- This guidance document updates terminology and provides direction based on current FDA policies that incorporate lessons learned and least burdensome principles.

## RR-Policy

- The policy relies on “Deciding When to Submit a 510(k) for a Change to an Existing Device”, and
- Provides recommendations on the types of documentation that should be kept on file at your facility.
- Eliminates add-to-files for a change to a device that falls within the scope of this guidance document.

## Replacement Reagent Policy

**The RR-policy did not and does not apply to:**
- systems intended for over-the-counter (OTC) use,
- systems intended for professional home use,
- devices intended for point of care (POC) use,
- class III devices,
- changes in the intended use of a cleared product, or
- devices intended for use in support of blood banking practices.

## Table and regulatory scenarios are designed to help you determine the appropriate regulatory pathway. 

| Test System Current Regulatory Status |  |  |
| --- | --- | --- |
|   | Cleared | New/not cleared |
| Reagent | A | B |
| Instrument | C | D |

_**Regulatory status:**_A + C = Replacement reagent policyB + C = new 510(k) B + D = new 510(k) A + D = new 510(k) unless the instrument belongs to a cleared family, in which case the replacement reagent policy applies.

- Table and regulatory scenarios are designed to help you determine the appropriate regulatory pathway.

## Replacement Reagent Policy

- Consult with the appropriate Division Director 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.

## REAGENTS 

**REAGENTS - **necessary substances that produce reactions allowing an analyte to be measured.
- Changes to calibrator or quality control material involving the addition of new analytes require 510(k)
**GENERIC reagents -** are intended to be used manually, or with any open system.
- Laboratories assume responsibility for performance validation.

## 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.

## ANALYZERS 

**Principle of Analysis** is based on the assay method (e.g., antibody antigenic reaction schemes), assay calibration (e.g., one point versus multiple point), and mode of detection (e.g., photometric or fluorimetric).
-     An instrument refers to the pre-analytic, analytic, and/or post-analytic components including: mechanisms for sampling, processing and measuring human specimens, hardware for detection, and associated controlling software.

## 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.

## ANALYZERS

**Instrument Family** - consists of similar analyzers made by one manufacturer that yield the same analytic result from samples of the same specimen within stated tolerance limits:
- 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.

## ANALYZERS

**New instrument family member **- is an instrument that has a modification to any instrument family member in either the hardware or software, but not a change in analytical technology.
- The instrument should fit within the above definition of instrument family.

## ANALYZERS

**Representative family member** - is an instrument family member that best represents the basic design of the family.
- The representative instrument should not be so far removed from the original so as to become a new instrument (i.e., significant design or software changes).

## 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.

## 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.
**High Risk Device** - IVDs can be high risk to the extent that information from the device generates a misdiagnosis that may result in significant morbidity or mortality.

## 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.

## 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.

## Clarifications

**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.

## 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.

## Validation Protocols

- Method comparison, precision, reference range; etc...

## Slide 25

## Validation Protocols

- All studies listed in the table need to be addressed in the protocol.
- If a study is not applicable, a justification needs to be provided on why the study is not necessary.
- Document that the instrument/reagent combination meets the predetermined acceptance criteria in your validation protocol.

## Validation Protocols

- You should collect these data prior to marketing each new combination, and
- Maintain appropriate records at the site performing the validation.
- 21CFR Part 820.180 (Subpart M-Records)

## Reagent / Instrument Validation Protocols

- Reagents protocols are assay specific.
- Instrument protocols are method specific.
- Protocols are based on studies performed in the original submission.

## 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 new family members should be method specific, general enough to evaluate all analytes within each method.

## Slide 30

## Slide 31

## Slide 32

## 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.

## 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.

## 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.

- Replacement reagents require a package insert.
- New family member require instructions for use such as an abbreviated operators manual.

***CLIA Categorization ***

## Jim Callaghan
	CDRH/OIVD
	301-594-1243 ext. 148
	jvc@cdrh.fda.gov
Division Contacts
DCTD
Jean Cooper, Alberto Gutierrez, Carol Benson, - 301-594-1243
DMVD
Sally Hojvat, Freddie Poole  - 301-594-2096
DIHD
Joseph Hackett, Josephine Bautista, Maria Chan - 301-595-1293

***	***CDRH/OIVD
- 	301-594-1243 ext. 148
- 	jvc@cdrh.fda.gov
***Division Contacts***
***DCTD***
- Jean Cooper, Alberto Gutierrez, Carol Benson, - **301-594-1243**
***DMVD***
- Sally Hojvat, Freddie Poole  - **301-594-2096**
***DIHD***
- Joseph Hackett, Josephine Bautista, Maria Chan - **301-595-1293**

**Contacts**