Replacement Reagent Policy Update

1. 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

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. Reagent / Instrument Validation Protocols • Reagents protocols are assay specific. • Instrument protocols are method specific. • Protocols are based on studies performed in the original submission.

20. 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.

21. 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.

22. 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

23. Process

24. 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.

25. 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.

26. New Family MemberProcess • 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.

27. New Family MemberProcess • 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.

28. New Family MemberProcess • 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

29. 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.

30. 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.

31. 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.

33. Questions