Analyte Specific Reagents (ASRs) Frequently Asked Questions

1. Analyte Specific Reagents (ASRs)Frequently Asked Questions AMDM Annual Meeting April 24, 2008 Bradley Merrill Thompson

2. Topics • What the Final Guidance Requires • Challenges the ASR Rule and Guidance Create • The Bigger Picture • Alternative Approaches and Points of View • Path Forward

3. ASR FAQ Guidance Background: • New guidance issued Sept. 17, 2007, to update/clarify FDA’s most current thinking on ASRs • Responds to AdvaMed FAQ proposal • One of the primary goals of the rule was to ensure the quality of the primary, active reagents of finished laboratory-developed tests (LDTs) 4-Part Guidance: • Part 1 – The ASR Rule • Part 2 – The ASR Definition • Part 3 – Manufacturer Marketing Practices • Part 4 – RUO/IUO ASRs

4. Part I: The ASR Rule The ASR Rule is made up of 3 parts: • Classification • Restrictions on sale, distribution, and use • Labeling ASRs may be in class I, II or III, with attendant premarket requirements • Class I are exempt from 510(k) ASRs are used by clinical laboratories in LDTs and are the “active ingredients” of tests. Subject to general controls, cGMPs, labeling, listing, MDR reporting, plus: • Special restrictions on the sale and promotion, such as only to high complexity labs and limited instructions for use; and • Disclosures to end users that analytical and performance characteristics are not established.

5. Roles: Manufacturers vs. Labs • FDA’s position = a laboratory cannot validate the way the individual ASRs and other components are combined by the manufacturer (identity, concentration, purity) as appropriate for meeting the intended use and specifications of their in-house test. • But laboratories themselves are not precluded by the ASR rule from selecting and combining individual ASRs and other components in the development of their own in-house tests.

6. Part II: What meets the ASR Definition? Basic definition -- An ASR must have the following three characteristics: • Used to detect a single ligand or target (e.g., protein, single nucleotide change, epitope); • Not labeled with instructions for use or performance claims; and • Not promoted for use on specific designated instruments or in specific tests.

7. Part II: What meets the ASR Definition? Examples of ASRs: • a single antibody (e.g., an anti-troponin I polyclonal or monoclonal antibody, whether untagged or tagged, e.g., conjugated to horseradish peroxidase) • a single forward/reverse oligonucleotide primer pair (e.g., a primer pair for amplification of a single amplicon, such as for amplification of the ΔF508 locus of the gene encoding the cystic fibrosis transmembrane regulator (CFTR)), or single forward or reverse primer individually • a nucleic acid probe (whether untagged or tagged, e.g., conjugated to biotin or Cy™3) intended to bind a single complementary amplified or unamplified nucleic acid sequence • a single purified protein or peptide (e.g., purified B-type natriuretic peptide)

8. Part II: What meets the ASR Definition? Examples of what are not ASRs: • Multiple individual ASRs (antibodies) bundled together in a single pre-configured or optimized mixture so that they must be used together in the resulting LDT • Products that include or require more than a single ASR • Reagents that are designed to require use in a specific assay or on a designated instrument (e.g., arrayed on beads). (The requirement for reagents and designated instruments to be used together constitutes a performance claim that they will work properly when used in combination, since those specific reagents are intended for use with that specific instrument.) • Control material or calibrators • Products that have specific performance claims, or procedural instructions, or interpretations for use • Reagents offered with software for interpretation of results • Software for interpretation of assay results • Microarrays

9. Part III: Manufacturer Marketing Practices Overview • Because ASRs are building blocks of LDTs, they cannot be promoted or sold together with other ASRs or general purpose reagents (GPRs). • Manufacturers must avoid marketing ASRs in a manner that suggests use of particular ASRs together for a specific purpose. • Manufacturers cannot provide instructions (or application sheets) for developing or performing an assay with an ASR. The IFU should include only information for proper storage, handling, chemical composition, concentration, cross-reactivities, stability, etc. ASR manufacturers should not make claims to laboratories regarding analytical or clinical performance for ASRs.

10. Part III: Manufacturer Marketing Practices Labeling and configuration • ASR labeling may indicate the affinity of the reagent, but cannot name the product in a way that it describes a specific clinical use. • The ASR manufacturer cannot provide software for specific use with an ASR (including templates or analysis algorithms). In FDA’s view, this becomes an IVD test. • Regarding instrumentation: • Cannot promote specific instruments for use with an ASR • However, can promote “open” instruments that have user-defined capabilities that allow the user to select, define, optimize, and validate the test performance characteristics and interpretation criteria.

11. Part III: Manufacturer Marketing Practices Communication/help • Labs are responsible for the design and performance of the test. The manufacturer cannot tell a lab which ASRs are useful for a particular application. • An ASR manufacturer should not assist with the development or validation of an LDT using its specific ASR. Under the CLIA regulations, the laboratory must conduct validation and verification of test performance specifications. This validation by the laboratory is the minimum requirement under CLIA for the laboratory to generate clinical results for tests of high complexity.

12. Part III: Manufacturer Marketing Practices Literature: • Manufacturers can provide labs with info/peer-reviewed/published literature on the characteristics of the ASR itself (single target). • However, may not send articles/info that describes the use of an ASR in a specific test or application, or information regarding an ASR’s clinical utility, clinical performance, or validation protocols.

13. Part IV: RUO/IUO ASRs • ASRs can be used for research applications. • RUO products defined as those in the laboratory research phase of development – that is, either basic research or initial search for potential clinical utility and not represented as an effective IVD. • IUO products are in the clinical investigation phase of development to determine the safety and effectiveness of the product and verify the clinical performance characteristics. Multi-analyte reagents can be IUO as they would be destined for the IVD marketplace after submission to FDA.

14. Topics • What the Final Guidance Requires • Challenges the ASR Rule and Guidance Create • The Bigger Picture • Alternative Approaches and Points of View • Path Forward

15. Concerns Expressed in Comments Policy Objections: • ASRs will have very limited applicability, because most tests—including the majority of molecular tests—require multiple analytes • The new guidance will disrupt health care because many ASRs will have to be pulled off the market. In turn, this will: • Drive up the cost of care • Compromise quality if labs are forced build the tests from basic building blocks • Sacrifice lab-to-lab consistency

16. Concerns Expressed in Comments Procedural and Legal Objections: • Guidance departs from the regulations • The regulation does not limit the scope to a single ligand or target • The regulation does not preclude software or microarrays • FDA should have used rulemaking • FDA should have provided a longer transition period • FDA infringes the First Amendment right to speech through undue restrictions on truthful communication

17. Open Questions • What role can manufacturers have with customers in troubleshooting their ASRs? • With respect to providing peer-reviewed literature on ASRs to customers, are the restrictions legal under the Washington Legal Foundation First Amendment case? • How do manufacturers do MDR reporting on a method the manufacturer doesn’t help develop or validate? • What if competitors continue without complying?

18. Topics • What the Final Guidance Requires • Challenges the ASR Rule and Guidance Create • The Bigger Picture • Alternative Approaches and Points of View • Path Forward

19. Who is the innovator? IVD Manufacturer Clinical Laboratory RUOs and IUOs IVDMIA Contract manufac-turing ASRs FDA Cleared/ Approved Kits Non-ASR LDTs IVD Manufacturer Innovation Constrained Within Building Block IVD Regulatory Paradigm ASRs

20. Remember ASR’s Close Cousin

21. Contracting Manufacturing Regulatory Requirements

22. Topics • What the Final Guidance Requires • Challenges the ASR Rule and Guidance Create • The Bigger Picture • Alternative Approaches and Points of View • Path Forward

23. Weaknesses in ASR-Based System • Leaves bifurcated system based on who does the innovation—manufacturer or lab • That system cannot represent the optimal balance between: • Regulatory protection of the public health and • Innovation, timely access, and advancement of the public health • Imposes yet another system built on artificial limits on communicating truthful information

24. Weaknesses in ASR-Based System • LDTs made with ASRs are disadvantaged in the marketplace relative to LDTs made without ASRs because of required warning • ASR regulation is very limited in scope—most needed products don’t fit the definition • Current system allows labs to act as generic competitors—making their own versions of FDA-cleared kits • Even with ASRs, there is too much variability lab-to-lab because of the lack of communication

25. Alternative Systems • One system that treats manufacturers and labs equally • FDA level of regulation • Lab level of regulation • Mixture of the two • AdvaMed Least Burdensome Proposal • Broader application of models proposed by ACLA or 21st Century Medicine groups • SACGT Recommendation • New category of FDA clearance based on review of analytical performance claims • Clarify the dividing line between legitimate LDTs and manufactured products, similar to IVDMIA, on the basis of factors similar to pharmacy compounding • Various legislative proposals

26. Alternative Points of View • WLF claims that FDA lacks statutory authority to regulate products manufactured by labs • Some labs say leave the system as it is

27. Topics • What the Final Guidance Requires • Challenges the ASR Rule and Guidance Create • The Bigger Picture • Alternative Approaches and Points of View • Path Forward Actual Trial Question How far apart were the vehicles at the time of collision?

28. Discussion Needs to Occur • FDA or Congress needs to put a stake in the ground, to the effect that the current bifurcated system is unacceptable from a public health standpoint • Right now the stakeholders are struggling to overcome positions widely apart • If the parties get sufficiently motivated, a convener needs to step in • In the meantime, manufacturers must adapt to the new ASR environment and pursue alternative business models to avoid becoming merely providers of commodities rather than centers of innovation

29. Questions or Comments?