MSACL April 4, 2019 Majda Haznadar, Kris Roth, Doug Jeffery majda.haznadar@fda.hhs

1. MSACL April 4, 2019 Majda Haznadar, Kris Roth, Doug Jeffery majda.haznadar@fda.hhs.gov kristian.roth@fda.hhs.gov doug.jeffery@fda.hhs.gov FDA Overview of the Process for Clearance and Approval of Mass Spectrometry-based In vitro Diagnostic Devices www.fda.gov

2. DISCLAIMER This presentation is intended for informational purposes only and does not constitute legal or regulatory advice. Please see the Federal Food, Drug, and Cosmetic Act and 21 CFR Subchapter H for a full list of requirements by FDA www.fda.gov

3. Our Path Today Majda: • Device Risk Classification • Pre-submissions (Pre-Subs) • 510(k) • De Novo Kris: • MALDI-TOF MS and Exemption Panel Discussion: Majda, Kris, Doug www.fda.gov

4. In Vitro Diagnostic (IVDs) Are Medical Devices [21 CFR 809.3]: • Reagents, instruments, and systems used in diagnosis of disease or other conditions… • In order to cure, mitigate, treat, or prevent disease… • Intended for use in the collection, preparation, and examination of specimens taken from the human body. www.fda.gov

5. How Are IVDs Classified? Low likelihoodof harm Class I – most 510(k)exempt • Regulatory path determined using a risk-basedapproach Class II -510(k) • Classification (I, II,or • III) depends onrisk High or unknown likelihood ofharm, or how toprevent harm isunknown Class III -PMA .

6. Risk • Depends on Intended Use ofdevice • Level of FDA review and type of studies required depend on intended use and anticipatedrisk • Level of risk may not be related tothe • technology • Controls give assurance that risk islow

7. Classification/Controls • Class I – Low Risk - GeneralControls • Registration andListing • Labeling • Good ManufacturingPractices • 510(k)Clearance • Class II –Moderate risk - SpecialControls • General controlsinsufficient • Performancestandards • Special labelingrequirements • Postmarketsurveillance • Class III – High risk – General Controls andPremarket • Approval 7

8. Submissions Are Reviewed by a Large Team of Experts Submission Sponsor (IVD Manufacturer) Administrative Processing Clearance or Approval Review Team Lead Reviewer Consultants: Technical, Analytical, Medical, Statistical Division Management Receipt of Electronic Documents Tracking of Deadlines Electronic Sign-in and Sign-out

9. Pre-Subs www.fda.gov

10. Q-Subs cover many different submitter requests Breakthrough Device Designation Requests** *Determines if Investigational Device Exemption (IDE) is needed **For certain medical devices and device-led combination products that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions www.fda.gov

11. Pre-Subs are one type of Q-Sub • Pre-submissions (Pre-Subs) • Questions related to a future submission • Can be • written feedback and a face to face meeting • written feedback and a teleconference (easier to schedule) • purely written feedback www.fda.gov

12. Pre-Subs have Broad Applicability • Future submission can be a PMA, 510(k), De Novo, CLIA Waiver, or IDE www.fda.gov

13. Pre-Subs have Broad Applicability • Future submission can be a PMA, 510(k), De Novo, CLIA Waiver, or IDE • Can address many types of questions, the more specific the better (more on this later) www.fda.gov

14. Pre-Subs have Broad Applicability • Future submission can be a PMA, 510(k), De Novo, CLIA Waiver, or IDE • Can address many types of questions, the more specific the better (more on this later) • Can be useful at different stages of product development www.fda.gov

15. Uncertainty is Best Addressed Early • Course corrections are less expensive when made early • More opportunity to work towards win-win approaches www.fda.gov

16. Describe Your Device in Detail • How does it work? • How is the device used in clinical practice? www.fda.gov

17. Critical Element of a Pre-Sub: Intended Use (IU) • The most important part of any pre-sub • Analytical and clinical validation studies should support the IU of the proposed device • Clinical study should be conducted in the IU population • May be amended/modified over time www.fda.gov

18. Assay name • Technology • Instrument name • Sample matrices (serum, plasma) • Quantitative or qualitative • Clinical use – disease /condition • The clinical purpose (diagnosis, prognosis, monitoring) • The target population for whom the test is intended • Setting (clinical laboratory, point-of-care, etc.) IU Elements www.fda.gov

19. Analyte(s) IU Example (DEN170019) Matrix Instrument The Vitamin D 200M Assay for the Topaz System is intended for in vitro diagnostic use in the quantitative determination of total 25-hydroxyvitamin D (25-OH-D) through the measurement of 25-hydroxyvitamin D3 (25-OH-D3) and 25-hydroxyvitamin D2 (25-OH-D2) in human serum using LC-MS/MS technology by a trained laboratory professional in a clinical laboratory. The Assay is intended for use with the Topaz System. The Vitamin D 200M Assay for the Topaz System is intended to be used in conjunction with other clinical or laboratory data to assist the clinician in making individual patient management decisions in an adult population in the assessment of vitamin D sufficiency. Condition Intended Population www.fda.gov

20. Analytical Performance Characteristics • Precision • Linearity/assay reportable range • Limit of Detection • Cross reactivity/ Interfering substances • Method comparison (to the predicate or reference method) • Matrix comparison • Traceability, Stability • Controls and calibrators • Reference range www.fda.gov

21. Clinical Performance Characteristics • Examples of parameters in clinical studies: Sensitivity/Specificity, Negative Predictive Value (NPV)/Positive Predictive Value (PPV) based on comparison to a gold standard (i.e., American College of Rheumatology (ACR) classification criteria, biopsy, etc.) • Inclusion/Exclusion criteria should be well defined www.fda.gov

22. Clinical Study Specimens • Specimens: where possible, the set of subjects and specimens to be tested include: • Specimens across the entire range of disease state to reflect the target population for the device (e.g. stage, grade) • Differential diagnosis specimens (normal samples are not appropriate for determining specificity) www.fda.gov

23. Pre-Sub Meeting Milestones www.fda.gov

24. Do ask Specific Questions • Our goal is to meet your current need • If your question is specific, we can address it • If your question is vague or too broad, we’ll do our best, but may miss your real need www.fda.gov

25. Which Questions are a Good Fit for a Pre-Sub or Submission Issue Mtng? • Does FDA agree with the proposal for use of contrived samples in analytical studies described in Section X? • Is this sufficient for a 510(k)? • We have provided a response to FDA's question about clinical study sample size, along with a justification based on a power analysis. Is this plan acceptable? If not please provide further guidance. • Does FDA agree with all of our analytical performance studies? • … www.fda.gov

26. Which Questions are a Good Fit for a Pre-Sub or Submission Issue Mtng? • Does FDA agree with the proposal for use of contrived samples in analytical studies described in Section X? • Is this sufficient for a 510(k)? • We have provided a response to FDA's question about clinical study sample size, along with a justification based on a power analysis. Is this plan acceptable? If not please provide further guidance. • Does FDA agree with all of our analytical performance studies? • … www.fda.gov

27. Address our Answers • When you submit your next submission… • If you didn’t follow our advice, say why www.fda.gov

28. Write a Clear Cover Letter • What type of Q-Sub do you want? • If Pre-Sub • Do you want written feedback only or do you want a meeting? • If a meeting, propose three specific meeting dates • Ongoing Q-Sub? • Same device and intended use • With whom should we correspond? www.fda.gov

29. Successful Meetings take Planning and Focus • Focus the meeting on what you want to get out of it • Do not spend 10-15 minutes on a company history or its management • Allow 2/3 of the time for discussion • Limit background review to 1/3 • Dedicate someone to take minutes • Should not ask questions based on new information provided during the meeting – we may not be able to answer them www.fda.gov

30. Q-Submission Nomenclature – Amendments and Supplements • Amendments contain additional information about an existing request for feedback, for example: • Slides • Agenda updates • Meeting minutes • Meeting minutes disagreements • Change of Submitter/Correspondent • Supplements contain new requests for feedback on the same device/indication • Can be any kind of Q-Sub www.fda.gov

31. In Summary, submit a Pre-Sub when… • A new intended use • Contains new technology or analytes • Clinical Implications Unclear • Presents complex data/statistical questions • Presents a significantly new approach to analytical or clinical study designs or analyses • Uses a predicate or reference method that is unclear or uncertain www.fda.gov

32. 510(k)Pre-Market Submissions www.fda.gov

33. What is a 510(k)? • Demonstration of Substantial Equivalence (SE) to legally marketed device in U.S. also known as a predicate • For Class II and Class I (reserved) devices. www.fda.gov

34. A 510(k) Is Required When… • Introducing device to the market for the first time • Changing a device’s indications for use/intended use and/or labeling • Making modification(s) to device that could affect safety or effectiveness www.fda.gov

35. A 510(k) Is NOT Required For… • A Private Label Distributer • who does not modify device or labeling • only adds company name or language like “distributed by__” • Re-packager or Re-labeler who does not alter the labeling • Not selling device in US • Manufacturer of parts • Devices Exempt by Statute or Regulation – there are currently 1003 class II devices exempt from 510(k) regulations. Calibrators and controls, recently exempt. www.fda.gov

36. 510(k)’s Intent There are two outcomes to a 510(k) application: • Substantially equivalent (SE) to a predicate • Not Substantially equivalent, automatically into class III • PMA – approval of Class III devices • De Novo www.fda.gov

37. 510(k) Remains the Principle Pathway to Obtain Market Authorization for Most Devices • The 510(k) program was established more than 40 years ago • CDRH receives ~3000 510(k)s per year • ~90% are found SE and go to market • Premarket Notification (510(k)) procedures are found in 21 CFR Part 807, Subpart E • When a submission is required • Exemptions from notification • Format and content of the submission • Content and format of a 510(k) summary or statement • Confidentiality of information www.fda.gov

38. A Device Must Be Compared To… • A legally marketed device (a predicate) that does not require a PMA, i.e. • A pre-amendment device (a device used as an IVD prior to 1976) • A device found by FDA to be Substantially Equivalent (SE) • A reclassified device • A device classified by a De Novo petition • “Paper predicates” can be used www.fda.gov

39. A Paper Predicate • A paper predicate is a device that only satisfies the LEGAL REGULATORY requirement that you are classified based on the classification of a device you are substantially equivalent to. • You DO NOT have to compare performance of your device with the paper predicate. • It is your responsibility to establish the ACCURACY of your device, this is usually done through a method comparison with the predicate. • You measure “TRUTH” through a reference method or through clinical diagnosis/truth. • For example, drugs of abuse immunoassays use GC-MS as their comparator. Troponin assays used clinical diagnosis for acute myocardial infarction. www.fda.gov

40. What Does FDA Review in a Submission? • Intended Use/Indications for Use • Analytical performance testing • Clinical performance testing • Device labeling (package insert/instructions for use) www.fda.gov

41. Clinical and Laboratory Standards Institute (CLSI) CDRH Recognizes Guidelines for IVDs Analytical Sensitivity Precision Liquid Chromatography-Mass Spectrometry Methods AND MANY MORE! http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm Use of CDRH-recognized guidelines can make performance testing and submission review faster and more efficient www.fda.gov

42. General Recommendations for Analytical Performance Testing Use Recognized CLSI Guidelines Use Real Patient Samples from the Intended Use Population and Intended Matrix Test Samples that Cover the Analytical Measuring Range and at Medical Decision Points www.fda.gov

43. Use Finalized Device for All Performance Testing Sample Processing LC-MS Analysis Data Processing Final Output www.fda.gov

44. Tips to a Successful Submission (Do’s) • Stay informed with new guidances • Read the FDA Decision Summaries of predicates to help determine what may be requested • Be organized and include page numbers, headings, and table of contents • Proofread everything. Ensure consistency throughout submission. Tell the story of equivalence • Read the labeling for claims not consistent with the proposed IFU www.fda.gov

45. Tips to a Successful Submission (Don’ts) • Avoid data dump • Follow the 510(k) Format Guidance • Provided info should have a purpose • Expect a 510(k) review to be interactive. BE AVAILABLE to answer questions. A quick conversation between the reviewer and the sponsor can add clarity to a submission. This can speed up review. www.fda.gov

46. De Novo Classification Request www.fda.gov

47. What is a De Novo Classification Request? • Classification process for novel devices whose type has not been previously classified • Based on risk • Predicate cannot be identified • Device has a new intended use or technical characteristics that raise new questions of safety and effectiveness www.fda.gov

48. De Novo Classification Establishes… • New necessarycontrols • Newregulation • New ProductCode www.fda.gov

49. De Novo Pathway Established byFDA Modernization Act of 1997(FDAMA) FDAgrants denovo Sponsorsubmits denovo FDAdeclines denovo FDA returns a determinationof NSE Sponsorsubmits 510(k)

50. Direct De Novo Pathway Established byFDA Safety and Innovation Act –FDASIA of 2012 FDAgrants denovo FDAdeclines denovo Sponsorsubmits de novo application